Table of contents :

Disorders of nervous system Malformations  Central nervous system (CNS) disorders  meningitis encephalopathies encephalitis brain injuries myelitis myelopathies spinal cord injuries (SCI) infections of CSF shunts CNS tumors neurovascular diseases hemorrhages ischemias neurodegenerative diseases Parkinson disease (PD) Alzheimer's disease (AD) Huntington disease (HD) dyslexia motor neuron diseases (MND) epilepsy mental disorders Peripheral nervous system (PNS) disorders  radiculopathies neuropathies neuritis nerve entrapping syndromes PNS tumors paralysis cranial nerve palsies spinal nerve palsies

Levels of consciousness (LOC) Muscle disorders  skeletal muscle disorders dyskinesias myositis myasthenia myalgia sine myasthenia skeletal muscle cancers smooth muscle disorders smooth muscle cancers Sense organs disorders somatic senses pain special senses diseases of taste diseases of olfaction diseases of ear and hearing diseases of outer ear diseases of middle ear diseases of inner ear diseases of eye and vision diseases of lacrimal apparatus diseases of the conjunctiva diseases of cornea diseases of uvea diseases of lens diseases of the vitreous glaucoma diseases of the retina diseases of optic nerve diseases of optic ways hypovision

Malformations

• neurocristopathy : any disease arising from maldevelopment of the neural crest.
• hemicephalia : congenital absence of the cerebrum.
• hemiencephalus : a fetus that lacks one cerebral hemisphere.
• triocephalus / triencephalus : a fetus in which the structures of the mouth, nose, and eyes are absent and the head is a shapeless mass
• microcephaly : a condition of abnormal smallness of the head usually associated with mental retardation
• hydromicrocephaly : microcephaly with an abnormal amount of CSF (hydrocephalus)
• macrocephaly : a condition of abnormal largeness of the head
• colpocephaly : enlargement of the occipital horns of the lateral ventricles, often accompanied by mental retardation, seizures, and visual disturbances that result from hypoplasia of the optic nerve.
• diencephalic syndrome : failure to thrive, emaciation, and sometimes nevus unius lateralis
• holoprosencephaly (HPE) : failure of cleavage of the prosencephalon with a deficit in midline facial development.

Aetiology :
• trisomy 13 / Patau syndrome
• HPE1 / familial alobar holoprosencephaly / arhinencephaly : a form in which the chromosomes are normal but otherwise resembling that due to trisomy 13
• HPE2
• HPE3
• HPE4
• HPE5
• HPE6
• HPE7
• holoprosencephaly-agnathia complex
• holoprosencephaly-polydactyly syndrome / pseudotrisomy 13 syndrome
• semilobar holoprosencephaly with craniosynostosis
• holoprosencephaly with fetal akinesia/hypokinesia sequence
• Lambotte syndrome / microcephaly, holoprosencephaly, and intrauterine growth retardation
Symptoms & signs : cyclopia occurs in the severe form; absence of the superior labial frenulum^ref
• encephalodysplasia : any congenital anomaly of the brain.
• Alpers' disease / Christensen-Krabbe disease / poliodystrophia cerebri / progressive cerebral or progressive infantile poliodystrophy : a rare disease of young children, characterized by neuronal degeneration of the cerebral cortex and elsewhere, accompanied by progressive mental deterioration, motor disturbances, seizures, and early death
• malformations of the cerebral cortex (MCC) / cortical dysplasia are often associated with severe epilepsy and developmental delay. About 40% of drug-resistant epilepsies are caused by MCC. Classification of MCC is based on embryological brain development, recognising forms that result from faulty neuronal proliferation, neuronal migration and cortical organisation
• hemimegalencephaly

Microscopic anatomy : an enlarged dysplastic hemisphere, lissencephaly and ectopic gray matter areas within cerebral white matter
Symptoms  & signs : early onset severe epileptic encephalopathy or as partial epilepsy
Therapy : anatomic hemispherectomy (removal or disconnection of a whole hemisphere excepted basal nuclei, thalamus, and hypothalamus)
• focal cortical dysplasia (FCD), MRI shows focal cortical thickening and simplified gyration. Patients have drug-resistant, often early onset epilepsy. Complete surgical ablation of FCD is accompanied by remission in up to 90% of patients, but may be technically difficult
• tuberous sclerosis
• bilateral periventricular nodular heterotopia (BPNH) consists of confluent and symmetric nodules of grey matter along the lateral ventricles. X-linked BPNH presents with epilepsy in females and prenatal lethality in most males. Most patients have partial epilepsy. Filamin A mutations have been reported in families and sporadic patients
• porencephaly / cerebral porosis / perencephaly / porencephalia : the presence of one or more cavities in the brain, which may or may not communicate with the arachnoid space, most often occurring in fetal life or early infancy. The 2 types are ...
• encephaloclastic porencephaly : a type in which the cavities are residues of destructive lesions after birth.
• schizencephalic porencephaly / schizencephaly : a type in which the cavities are the result of maldevelopment of the brain (cleft brain). It has a wide anatomo-clinical spectrum, including partial epilepsy in most patients
• macrogyria / pachygyria : moderate reduction in the number of sulci of the cerebrum, sometimes with increase in the brain substance, resulting in excessive size of the gyri.
• polymicrogyria / microgyria / polygyria : a developmental anomaly of the brain characterized by development of numerous small and prominent convolutions (microgyri), causing a wide spectrum of clinical manifestations ranging from early onset epileptic encephalopathy to selective impairment of cognitive functions
• bilateral perisylvian polymicrogyria may be familial. Patients present with faciopharingo-glosso-masticatory diplegia and epilepsy, which is severe in about 65% of patients.
• agyria / lissencephaly (LIS smooth brain) is a severe MCC characterised by absent or decreased convolutions : a malformation in which the convolutions of the cerebral cortex are not fully formed, so that the brain surface is smooth. Classical LIS is quite rare and manifests with severe developmental delay, spastic quadriparesis and severe epilepsy. XLIS mutations cause classical lissencephaly in hemizygous males and subcortical band heterotopia in heterozygous females. Thickness of heterotopic band and degree of pachygyria correlate well with phenotype severity

Aetiology :
• Miller-Dieker syndrome / lissencephaly syndrome
• X-linked lissencephaly / double cortex syndrome : a : unaffected individual; b : the white matter shows a heterotopic band of neurons ("subcortical band heterotopia", marked by an arrow), which underlies the normal cortex; c : the cortex is abnormally thick and shows poor formation of gyri and sulci ("smooth brain")


• status verrucosus : a wartlike appearance of the cerebral cortex, produced by disorderly arrangement of the neuroblasts so that the formation of fissures and sulci is irregular and unpredictable.
• periventricular leukomalacia (PVL) : bilateral necrosis of the white matter of the brain adjacent to the lateral ventricles, seen in the neonatal period, especially in premature newborns, and manifested by chalky, yellowish-white plaques in the white matter, with proliferation of astrocytes and microglia; cyst formation may lead to multicystic encephalopathy.
• midline anomalies
• complete callosal agenesis
• hypoplastic corpus callosum
• cavum septi pellucidi (CSP) : more prevalent in schizophrenic patients in comparison to healthy subjects was reported previously without a significant age dependence. Although small cava septi pellucidi are commonly present in the perinatal period, large cava are not common^{ref1, ref2}. It has become increasingly apparent in recent studies that very large cava septi pellucidi and cava vergae should be considered potentially clinically significant brain anomalies that may be associated with a variety of outcomes such as developmental delay, schizophrenia, and various types of mental retardation^{ref1, ref2, ref3, ref4, ref5, ref6}. Some believe that the formation of the septum pellucidum and neuronal migration are nearly coincident, and that this may explain why a persistently wide cavum frequently accompanies disordered neuronal migration. Associated with fetal alcohol syndrome (FAS)^ref
• cavum vergae (CV) : a cavity posterior to the septum pellucidum whose clinical significance has previously been unclear. It  can be associated with neurologic abnormality (delayed development, macrocephaly, learning disabilities, abnormal electroencephalograms, Apert's syndrome^ref)
• neural tube defects (NTDs) : a developmental anomaly consisting of failure of closure of the neural tube

Epidemiology : 1 in 1000. Children with higher birth order are more likely to have spina bifida but not anencephaly. This same effect is also seen for all NTDs combined, which probably reflects the association with spina bifida.
Aetiology : mutations in Shroom
• anencephaly : congenital absence of all or a major part of the brain
• deranencephalia : anencephaly marked by defect of the brain and upper part of the spinal cord
• hemianencephaly : congenital absence of one side of the brain.
• hemicrania : incomplete anencephaly or meroanencephaly
• meroanencephaly : congenital absence of part of the brain, usually the forebrain and midbrain.
• hydranencephaly : complete or almost complete absence of the cerebral hemispheres, the space they normally occupy being filled with cerebrospinal fluid.
Pathogenesis : area cerebrovasculosa, a membrane-covered, reddish, spongy mass, consisting of thin-walled blood vessels and variable amounts of ependyma, choroid plexus, and glial tissue, that replaces the forebrain
Web resources : Anencephaly at CDC
• exencephaly : a developmental anomaly characterized by acrania with the brain exposed.
• meningocele : hernial protrusion of the meninges through a bony defect in the skull or spinal column
• hydromeningocele : a meningocele forming a sac containing CSF but no brain or spinal cord substance
• encephalocele
• myelomeningocele
Localizations :
• cranial meningocele / craniomeningocele : hernial protrusion of the meninges through a cranium bifidum, usually forming a fluid-filled sac
• spinal meningocele : hernial protrusion of the meninges through spina bifida, usually posteriorly, forming a fluid-filled sac; locations are almost always in the thoracic or lumbar region although cervical and sacral ones do occur
• lipomeningocele : meningocele associated with an overlying lipoma, in spina bifida
Side of protrusion :
• anterior meningocele : a rare type of meningocele that protrudes anteriorly from the vertebral column, usually in the sacral region; symptoms often are mild and go unnoticed.
• posterior meningocele
Localizations :
• sacral meningocele : a meningocele in the sacral region; symptoms may remain occult until adulthood and include neurologic deficits and abdominal masses with pressure. Both posterior and anterior types have been observed
• pseudomeningocele
• spurious or traumatic meningocele / Billroth's disease / cephalhydrocele traumatica : a condition resembling cranial meningocele, but caused by trauma; meninges herniate through a skull defect after tearing of the arachnoid
• encephalocele / cephalocele / craniocele / encephalomeningocele / meningoencephalocele : hernia of part of the brain and meninges through cranium bifidum; it may be congenital, traumatic, or postoperative in origin
• basal encephalocele : an encephalocele in the region of the base of the skull.
• frontal encephalocele : encephalocele in the region of the frontal bone; seen more commonly in Asia and Africa than in the Western Hemisphere.
• occipital encephalocele : an encephalocele in the occipital region, the most common kind seen in the Western Hemisphere.

Aetiology : type III Chiari's malformation
• encephalocystocele / hydroencephalocele / hydrocephalocele : encephalocele into a distended sac containing CSF
• status dysraphicus / arrhaphia : faulty closure of the embryonic neural tube resulting in faulty formation of midline adult structures, such as the vertebral column, sternum, breasts, and palate
• tethered cord syndrome : a congenital anomaly resulting from defective closure of the neural tube; the conus medullaris is abnormally low and is tethered by one or more forms of intradural abnormality such as a short, thickened filum terminale, fibrous bands or adhesions, or an intraspinal lipoma.
• split cord malformations (SCMs) / spinal dysraphism : uncommon congenital spinal anomalies seen mostly in females
• diastematomyelia : a congenital anomaly, often associated with spina bifida, in which the spinal cord is split into halves by a bony spicule or fibrous band, each half being surrounded by a dural sac
• diplomyelia : lengthwise fissure and seeming doubleness of the spinal cord
Pathogenesis : formation of adhesions between ecto- and endoderm => accessory neurenteric canal between yolk sac and amnion  => an endomesenchymal tract condenses around the canal and bisects the developing notochord and neural plate => formation of 2 hemineural plates. The altered state of the emerging split neural tube and the subsequent ontogenetic fates of the constituent components of the endomesenchymal tract ultimately determine the configuration and orientation of the hemicords, the nature of the median septum, the coexistence of various vascular, lipomatous, neural, and fibrous oddities within the median cleft, the high association with open myelodysplastic and cutaneous lesions, and the seemingly unlikely relationship with fore and midgut anomalies. Multiple accessory neurenteric canals may lead to 2 or more noncontiguous SCMs, also known as composite SCM
Pang's classification^ref:
• type I SCM : 2 hemicords, each contained within its own dural tube and separated by a dura-sheathed rigid osseocartilaginous median septum
• type II SCM : 2 hemicords housed in a single dural tube separated by a nonrigid, fibrous median septum
All other associated structures in SCM such as paramedian nerve roots, myelomeningoceles manque, and centromedian vascular structures frequently do overlap between types and are not reliable typing criteria
• occult spina bifida without overt myelomeningocele sac (pure SCM)
• complex spina bifida with myelomeningocele sac
• dorsal bony septum variant associated with a hypertrophied posterior arch. The ventral dura is totally intact, and there is no fibrous septum connecting the bony arch to the dura.
Symptoms & signs : hypertrichosis and pes cavus
• myelocele : spina bifida in which the neural tissue of the spinal cord is exposed
• high-level : cervicothoracic
• low-level : lumbosacral
• myelomeningocele (MMC) / myelocystocele : spina bifida in which neural tissue and the investing meninges protrude from the spinal column forming a sac under the skin
• hydromyelomeningocele / hydromyelocele : a myelomeningocele that contains both CSF and spinal cord tissue
• hemimyelomeningocele
• lipomyelomeningocele : myelomeningocele with an overlying lipoma
Therapy : simultaneous insertion of shunt and correction of a myelomeningocele do not pose an additional risk to the child and do have some advantages, facilitating healing of the back without CSF leakage and protecting the brain from the effects of progressive ventricular dilatation
Laboratory examinations : echography
Prevention : NTD risk is reduced in various models by different maternal nutrient supplements, including folic acid (Pax3, Cart1, Cd mutants : it is recommended that all women consume 0.4 mg of synthetic folic acid daily if there is any possibility of becoming pregnant. Women who have had a previous pregnancy affected by NTD should increase their folic acid intake to 4.0 mg daily periconceptually), inositol (ct) and methionine (Axd). Lack of de novo methylation in embryos (Dnmt3b -null) leads to NTD risk, and we suggest a potential link between methylation and the observed female excess among cranial NTDs in several models. Some surprising NTD mutants (Gadd45a, Terc, Trp53) suggest that genes with a basic mitotic function also have a function specific to neural fold elevation. The genes mutated in several mouse NTD models involve actin regulation (Abl/Arg, Macs, Mena/Profilin1, Mlp, Shrm, Vcl), support the postulated key role of actin in neural fold elevation, and may be a good candidate pathway to search for human NTD genes.

• heredodegenerative disease : any disease of the CNS characterized by specific loss of neural tissue due to hereditary influence
• cortical obliteration or achromia : a condition in which the cerebral cortex is marked by areas in which the ganglion cells have disappeared
• meningism / meningismus / pseudomeningitis : the symptoms and signs of meningeal irritation associated with acute febrile illness or dehydration without actual infection of the meninges

Aetiology : subarachnoid hemorrhages
• meningitis : inflammation of the meninges (1% are polymicrobic)
• meningitis carcinomatosa / carcinomatous meningitis : a misnomer for meningeal carcinoma, a condition that is not inflammatory.
• hydromeningitis : meningitis with serous effusion
• neoplastic meningitis : meningitis resulting from cancer metastasis to the leptomeninges or subarachnoid space
• occlusive meningitis : leptomeningitis of children which leads to the closure of the lateral and median apertures of the fourth ventricle
• meningitis ossificans : ossification of the cerebral meninges
• otitic meningitis : a form that sometimes complicates an attack of acute otitis media
• meningitis sympathica : a condition of the CSF caused by inflammation in the neighborhood of the meninges. It is marked by increase in the pressure of the fluid and increase in its albumin and cellular content. The fluid is sterile and there may be symptoms of meningitis
• cerebrospinal meningitis : any inflammation of the membranes of the brain and spinal cord
• cerebral meningitis : inflammation of the meninges of the brain.
• basilar meningitis : that which affects the meninges at the base of the brain.
• uveomeningitis : a disorder characterized by lesions of the uvea accompanied by meningeal inflammation.
• autoimmune uveomeningitis
• Vogt-Koyanagi syndrome : uveomeningitis characterized by exudative anterior uveitis / iridocyclitis and choroiditis associated with patchy depigmentation of the skin and hair; the lashes and eyebrows also become whitened, and there may also be retinal detachment and associated deafness and tinnitus
• choriomeningitis : cerebral meningitis with lymphocytic infiltration of the choroid plexuses.

Aetiology : lymphocytic choriomeningitis virus (LCMV) (lymphocytic choriomeningitis : in adults 20 to 40 years of age during the late winter months. Infection results from contact with infected rodents and is usually asymptomatic or mild, although severe meningoencephalitis may occur)
• spinal meningitis : inflammation of the meninges of the spinal cord.
Symptoms & signs :
• Lafora's sign : picking of the nose regarded as an early sign of cerebrospinal meningitis.
• Leichtenstern's sign : in cerebrospinal meningitis, tapping lightly any bone of the extremities causes the patient to wince suddenly.
• acute meningitis

Epidemiology : in the 20th century, the annual incidence of bacterial meningitis ranges from approximately 3 per 100,000 population in the USA^ref, to 45.8 per 100,000 in Brazil^ref, to 500 per 100,000 in the "meningitis belt" of Africa. In one county in Minnesota, there was an incidence rate of viral meningitis of 10.9 per 100,000 person-years from 1950 to 1981, with most cases occuring in the summer months^ref
Aetiology :
• neurotropic viruses (50-75%; => viral, aseptic, lymphocytic, serous or sterile meningitis : any of several mild types of meningitis characterized by malaise, fever, headache, nausea, CSF pleocytosis (principally lymphocytic), abdominal pain, stiffness of the neck and back, and a short uncomplicated course)
• seasonal
• Summer and first autumn
• Enterovirus spp. (+ cutaneous rash) (75-90% of viral meningitis : expecially in babies < age 1, no after age 40)
• CoxsackievirusesB5 (frequent), A9, B3, and B4 (common); B1 and B6 (rare); excellent cultural isolation from CSF
• echoviruses 7, 9, 11, 30 (frequent), 4, 6, 18 (common); 2, 3, 12, and 22 (rare); excellent cultural isolation from CSF
• enterovirus 70 and 71 (frequent)
• polioviruses 1-3 (rare); poor cultural isolation from CSF
• measles virus => subacute sclerotising panencephalitis (SSPE)
• autumn and winter : lymphocytic choriomeningitis virus (LCMV) (benign lymphocytic meningitis / lymphocytic choriomeningitis) (less common); excellent cultural isolation from CSF
• Winter and Spring
• mumps virus (mumps meningitis) (less common); excellent cultural isolation from CSF
• Influenzaviruses A and B (rare)
• arboviral encephalitis at CDC (common); moderate cultural isolation from CSF
• Western equine encephalomyelitis virus (WEEV) (Western and central USA, babies and adults > age 50, mortality = 5-15%, few sequels, reservoir = birds)
• Venezuelan equine encephalitis virus (VEEV) (Southern USA, adults, mortality = 1%, rare sequels, reservoir = horses and small mammals)
• Eastern equine encephalitis virus (EEEV) (Atlantic and Gulf USA, babies, mortality = 50-75%, sequels in 80%, reservoir = birds)
• La Crosse virus
• Saint Louis encephalitis virus (whole USA, adults > age 50, mortality = 2-20%, sequels in 20%, reservoir = birds)
• Japanese encephalitis virus (JEV)
• nonseasonal
• Adenovirus spp. (rare); moderate cultural isolation from CSF
• HHV-1 / HSV-1 (less common); poor cultural isolation from CSF
• HHV-2 / HSV-2 (common; Mollaret's meningitis : recurrent febrile attacks, malaise, headache, and meningeal signs accompanied by a marked PMN inflammatory reaction in the CSF); moderate cultural isolation from CSF
• HHV-3 / VZV (rare); moderate cultural isolation from CSF
• HHV-4 / EBV (rare); poor cultural isolation from CSF
• HHV-5 / CMV (rare); poor cultural isolation from CSF
• HHV-6
• HIV-1 (common); moderate cultural isolation from CSF
• Rhinoviruses
• rabies virus; moderate cultural isolation from CSF
• rubella virus (rare)
• parainfluenzaviruses (rare)
• Bacteria => bacterial, purulent or pyogenic meningitis
• Gram +ve Bacteria
• Streptococcus pneumoniae (pneumococcal meningitis represents 0÷5 % of all meningitides in newborns < 1 month age, 10÷20 % total meningitis in babies with 1 month < age < 15 years, 30÷50 % after age 15; + cutaneous rash. Up to 50% the cases are secondary to other infections, such as pneumonia, bacterial endocarditis, cranial wounds, otitis, mastoiditis or infectious (paranasal) sinusitis, and reinfection may occur. The incidence is increased in asplenic or immunocompromised patients, such as those with sickle cell anemia or lymphocytic leukemia. Mortality = 30%)
• Staphylococcus aureus (5% total meningitis in newborns < 1 month age, 1÷2 % total meningitis in babies with 1 month < age < 15 years, 5÷15 % in adults > 15 years and elderlies; + cutaneous rash, also under nails)
• Actinomyces spp.
• Actinomyces israelii
• Streptococcus agalactiae
• Tropheryma whipplei
• Staphylococcus epidermidis (in fistulae)
• Propionibacterium acnes
• Bacillus anthracis
• Gram -ve Bacteria
• Neisseria meningitidis (meningococcal meningitis / epidemic cerebrospinal meningitis / cerebrospinal fever represents 0÷1 % total meningitis in newborns < 1 month age, 40÷60 % total meningitis in babies with 1 month < age < 15 years (expecially in babies 6 months < age < 2.5 yrs.), 1÷3 % in adults > 15 years, elderlies and immunocompromised ; + cutaneous rash. Mortality = 7%)
• Listeria monocytogenes (2÷10 % total meningitis in newborns < 1 month age, 1÷2 % total meningitis in babies with 1 month < age < 15 years, 5 % in adults > 15 years, elderlies and immunocompromised)
• Brucella melitensis
• Escherichia coli (in newborns and elderlies, after surgical operations)
• Haemophilus influenzae (in babies 6 months < age < 5 yrs. and elderlis with diabetes mellitus, pneumonia, infectious (paranasal) sinusitis, mastoiditis or splenectomy ; + cutaneous rash)
• Neisseria gonorrhoeae
• Bordetella bronchiseptica
• Alcaligenes spp.
• Yersinia enterocolitica
• Yersinia pestis (plague meningitis / meningeal plague : meningitis occurring as a rare complication of bubonic plague as a result of hematogenous spread of the infection from a bubo to involve the meninges, or less often as a primary infection without antecedent bubo formation)
• Chryseobacterium meningosepticum
• Pseudomonas aeruginosa (in newborns)
• Rickettsia rickettsii (+ cutaneous rash)
• Serratia marcescens (in newborns)
• Klebsiella pneumoniae (after surgical operations)
• Fusobacterium necrophorum
• Prevotella melaninogenica
• Bacteroides fragilis
• Enterococcus spp.
• Proteus spp.
• Salmonella spp.
• Enterobacter spp.
• Francisella tularensis
• Leptospira interrogans
• Borrelia burgdorferi
• Leptospira interrogans
• Mycobacterium bovis
• Nocardia spp.
Symptoms & signs : the classic triad of fever, neck stiffness, and a change in mental status is present in only 44% of acute bacterial meningitis; however, 95% have at least 2 of the 4 symptoms of fever, headache, neck stiffness, and altered mental status. On admission, 14% of patients are comatose and 33% have focal neurologic abnormalities
Prognosis : the overall mortality rate is 21%. The outcome is unfavorable in 34% of episodes (risk factors are advanced age, presence of otitis or sinusitis, absence of rash, a low score on the GCS on admission, tachycardia, a positive blood culture, an elevated ESR, thrombocytopenia, and a low CSF WBC count)^ref
Complications : intracranial sinus thrombosis, stroke, cerebral ischemia, brain abscess.
• Fungi : Cryptococcus neoformans var. neoformans (cryptococcal meningitis : it has both a subacute chronic form and a more serious acute form and is increased in immunocompromised patients)
The brain is protected from infection by the skull; the pia, arachnoid, and dural meninges covering its surface; and the blood-brain barrier. When any of these defenses are broached by a pathogen, infection of the meninges and subarachnoid space can occur, resulting in meningitis (Lindsay KW, Bone I, Callander R. Neurology and Neurosurgery Illustrated. New York, NY: Churchill Livingstone; 1991). Predisposing factors for the development of community-acquired meningitis include preexisting diabetes mellitus, otitis media, pneumonia, sinusitis, and alcohol abuse^ref
Pathogenesis : systemic infection => once the blood-brain barrier is breached, an inflammatory response within the CSF occurs. The resultant meningeal inflammation and irritation elicit a protective reflex to prevent stretching of the inflamed and hypersensitive nerve roots, which is detectable clinically as neck stiffness or Kernig or Brudzinski signs. The inflammatory process may progress to cerebral vasculitis or causes cerebral edema and intracranial hypertension
Symptoms & signs (see below for meningoencephalitis) : the classic clinical presentation of acute meningitis is the triad of fever, neck stiffness, and an altered mental state. However, less than two thirds of patients present with all 3 clinical findings^ref
• nonspecific findings such as fever, myalgia, and rash
• intracranial meningitis (including basal meningitis) : headache with or without papilledema and optic atrophy, lethargy, photophobia, personality alterations (sleepiness, inattention, disorientation, mnesic deficiency, primitive reflexes, perseveration), peripheral facial (VII) nerve paralysis, oculomotor (III) nerve palsy, trochlear (IV) nerve palsy, abducens (VI) nerve palsy, ataxia, nausea and vomiting (Lindsay KW, Bone I, Callander R. Neurology and Neurosurgery Illustrated. New York, NY: Churchill Livingstone; 1991)
• spinal meningitis : myelopathy or radiculopathy => hyposthenia in upper or lower limbs, sphincterial dysfunctions
• meningeal irritation (mild in acute viral meningitis) : in clinostatic position ...
• nucal stifness (rigor nucalis) assessed by examining the neck for rigidity by gentle forward flexion with the patient in the supine position.

(instead in babies head is dangling !)
• Amoss or Hoyne sign / tripod position : a position assumed by the patient with abdominal weakness or severe meningeal irritation while sitting in bed, in which he supports himself with his hands in a plane posterior to his pelvis (with the knees and hips flexed, the back arched lordotically, the neck extended, and the arms brought back to support the thorax). Also a sitting position assumed by the patient with respiratory insufficiency, in which his hands are placed anterior to the frontal plane (Sapira JD. The Art and Science of Bedside Diagnosis. Baltimore, Md: Urban & Schwarzenberg Inc; 1990)
• Binde sign (in babies with tubercular meningitis from Mycobacterium tuberculosis) : passive head rotation evokes rising of controlateral shoulder.
• Brudzinski's neck reflex / nape of the neck^ref (O'Connell JEA. The clinical signs of meningeal irritation. Brain. 1946;69:9-21) : passive neck flexion in a supine patient results in flexion of the knees and hips. In 1909, Josef Brudzinski, a Polish physician, described many meningeal signs in children (Brudzinski J. Un signe nouveau sur les membres inferieurs dans les meningites chez les enfants (signe de la nuque). Arch Med Enfants. 1909;12:745-752). In Brudzinski's original description of 42 cases of meningitis (including 21 cases of tuberculous meningitis), Brudzinski nape of the neck sign had a sensitivity of 97% and the contralateral reflex sign had a sensitivity of 66%^ref. Brudzinski himself claimed to confirm the specificity of his nape of the neck sign by attempting (and failing) to elicit it in children with other neurological conditions^ref
• Brudzinski's contralateral reflex sign : when passive flexion of the lower limb on one side is made, a similar movement will be seen in the opposite limb. In Brudzinski's original description of 42 cases of meningitis (including 21 cases of tuberculous meningitis), Brudzinski contralateral reflex sign had a sensitivity of 66%^ref
• Brudzinski-de Lepinay phenomenon or reflex : passive flexion of trunk evokes movements in ankles, knees and hips.
• jolt accentuation of headache by by asking the patient to turn his or her head horizontally at a frequency of 2 to 3 rotations per second. Worsening of a baseline headache represents a positive sign^ref
• Kernig's sign : Vladimir Kernig, a Russian physician, first published the description of the sign that bears his name in 1884^ref (Kernig W. Ueber ein Wenig bemerktes Meningitis-Symptom. Berl Klin Wochenschr. 1884;21:829-832) although the sign had been previously described by Lazarevic in 1880 and by Forst in 1881 (Sapira JD. The Art and Science of Bedside Diagnosis. Baltimore, Md: Urban & Schwarzenberg Inc; 1990). In Kernig's original description, when patients sat on the edge of a bed with their legs dangling, an attempt to extend the knee joint > 135°, or in severe cases > 90°, elicited spasm of the extremity that disappeared when the patient lay supine or stood up. Today, the maneuver is most commonly performed with the patient lying supine and the hip flexed at 90°. A positive sign is present when extension of the knee from this position elicits resistance or pain in the lower back or posterior thigh. The patient can easily and completely extend the leg when in dorsal decubitus position but not when in the sitting posture or when lying with the thigh flexed upon the abdomen. In Brudzinski's original description of 42 cases of meningitis (including 21 cases of tuberculous meningitis), Kernig sign had a sensitivity of 57%^ref. Uchihara and Tsukagoshi's prospective study^ref of younger adult patients (mean age, 39 years) reported a sensitivity of 9% and a specificity of 100% for the Kernig sign, while neck stiffness had a sensitivity of 15% and a specificity of 100%. Because this study enrolled patients presenting with fever and headache, and excluded those with mental status abnormalities or focal neurologic findings, the low reported sensitivities may result from excluding those patients with the highest likelihood of having meningeal signs.
• Lesage sign in babies : when lifted taking under armpits, babies don'try to walking
• Magnus-De Klein sign : passive head rotation evokes extension of controlateral limbs and flexion of homolateral limbs
• cheek phenomenon : if pressure is exerted on both cheeks just under the zygomas there is reflex upward jerking of both arms with simultaneous bending of both elbows
• Simon's sign : absence of the usual correlation between the movements of the diaphragm and thorax; seen in beginning meningitis.
• tache cérébrale or méningale / Trousseau's sign or spot / meningitic streak or stria : a congested streak produced by drawing the nail across the skin, seen in various nervous or cerebral diseases
• a complete neurologic examination follows these more specific tests for meningitis, including examination of the cranial nerves, the motor and sensory systems, reflexes, and testing for Babinski reflex
• a general examination follows, with an emphasis on the ears, sinuses, and respiratory system

Neck pain was reported to have a sensitivity of 28% among patients with meningitis^ref. Data from the prospective trial suggest that the clinical history also lacks specificity for the diagnosis of meningitis, with reported specificities of 15% for a nonpulsatile headache, 50% for a generalized headache, and 60% for nausea and vomiting^ref. Thus, clinical history alone is not useful in establishing a diagnosis of meningitis. The inaccuracy of the clinical history may relate to the frequently impaired mental status of patients with meningitis (pooled sensitivity, 67%; IC₉₅ = 52-82%), who are relatively incapable of providing an accurate clinical history^{ref1, ref2}

The frequency with which patients presented with the classic clinical triad of fever, neck stiffness, and a change in mental status (or headache^ref) was assessed in 3 studies. Although the pooled sensitivity for the presence of all 3 symptoms was low, 95% of patients had 2 or more symptoms^ref, and 2 studies reported between 99% and 100% of patients had at least 1 of these clinical findings^{ref1, ref2}. Thus, the diagnosis of meningitis may be effectively eliminated in adult patients presenting without any of the symptoms of fever, neck stiffness, or a change in mental status. Fever has a low specificity of 45%^ref. Normal body temperature may significantly lower the likelihood that a patient has meningitis, although the presence of a fever does not definitively establish the disease. The relationship between body temperature and meningitis may be U-shaped because hypothermic patients with sepsis are more likely to be severely ill than normothermic patients^ref. Indirect evidence of poor specificity comes from a case series of^ref 74 acute-care and 287 geriatric patients (hospitalized patients in the acute-care or rehabilitation geriatric wards) aged 17 to 92 years. Puxty et al^ref found that 13% of the acute-care patients and 35% of the geriatric patients had nuchal rigidity despite the absence of meningitis. Kernig sign was present in 1.5% of the acute-care and 12% of the geriatric populations. The low specificity of the meningeal signs may be due to the frequent presence of cervical arthritis and spondylosis among older patients. Clearly, a well-designed prospective study in which patients suspected of having meningitis are observed prospectively is necessary to definitively establish the accuracy of meningeal signs. Alterations in mental status, ranging from confusion to coma, have a pooled sensitivity of 67% (IC₉₅ = 52-82%), indicating that normal mental status may be helpful in ruling out meningitis in low-risk patients. One study directly comparing aseptic with bacterial meningitis reported that moderate to severe mental status abnormalities were more common in patients with bacterial meningitis than with aseptic meningitis (44% vs 3%, respectively)^ref. Similarly, a second study reported that all patients with bacterial meningitis had a change in mental status, while none of the aseptic meningitis patients did^ref.  Rashes occurred most frequently in the presentation of meningitis due to Neisseria meningitidis, with prevalences of 63%^ref and 80%^ref. A petechial rash occurred in 73% of patients with meningococcemia, whereas purpura was described in only 20% of these patients^ref. Petechial, purpuric, and ecchymotic rashes also occurred, with lower frequency, in infections caused by Haemophilus influenzae, Streptococcus pneumoniae, and Listeria monocytogenes. Since the overall incidence of N meningitidis among patients with community-acquired bacterial meningitis was low (14% in 1 series^ref), the pooled sensitivity of a rash for the diagnosis of meningitis was poor^ref
Laboratory examinations : lumbar puncture (pleocytosis with or without hypoglycorrachy)
Prognosis : despite the availability of antimicrobial therapy, meningitis-related case fatality rates remain high, with a 17% all-cause mortality rate between 1980 and 1988 reported for community-acquired and nosocomial bacterial meningitis among patients aged 16 years and older^ref. Among previously healthy patients who survive pneumococcal meningitis, up to 18% may experience long-term sequelae including dizziness, excessive fatigue, and gait ataxia^ref. Clinical signs and symptoms at presentation may predict prognosis^ref
Therapy : according to isolated agent
• subacute or chronic meningitis : when fails to improve over a period of 4 weeks

Aetiology :
• noninfectious conditions
• malignant neoplasms
• chemicals (monocytes or PMN, hypoglycorrachy, hyperproteinorrachy, xantochromia due to SAH in the weeks preceding the onset of symptoms of meningitis)
• primary inflammations
• neurosarcoidosis
• Vogt-Koyanagi-Harada syndrome / autoimmune uveomeningitis
• primary CNS vasculitis
• systemic lupus erythematosus (SLE)
• neuroBehçet
• chronic benignant lymphocytic meningitis
• Mollaret recurrent meningitis
• drug hypersensitivity
• Wegener's granulomatosis
• other causes :
• multiple sclerosis
• Cogan syndrome
• infectious agents
• bacteria
• common
• partly treated acute bacterial meningitis (mononucleated +/- PMN)
• parameningeal infections (otitis media, pleuropulmonary infections, right-left shunt as cause of cerebral abscess) (mononucleated +/- PMN)
• Mycobacterium tuberculosis : tubercular or tuberculous meningitis, usually spreading from pulmonary tuberculosis (PTB), in immunocompromised individuals, subacute, gelly exudate (mononucleated cells; also PMN in early stages; WBCs < 500/mL, hypoglycorrachy, hyperproteinorrachy)
• tuberculoma en plaque : a flat plaque on the surface of the frontoparietal cortex in tuberculous meningitis, producing the symptoms of brain tumor
• Whytt's disease : tuberculous meningitis causing acute hydrocephalus
• Roger's symptom : a temperature below the normal in the third stage of tuberculous meningitis.
• Treponema pallidum subsp.pallidum (gummatous meningitis : meningitis during the tertiary stage of syphilis in which there are many small gummata in the membranes) (mononucleated cells, hyperproteinorrachy)
• Borrelia burgdorferi (the European term is Bannwarth's syndrome) (mononucleated cells, hyperproteinorrachy)
• uncommon
• Actinomyces spp.(PMNs)
• Nocardia spp. (PMNs and occasionally mononucleated cells, often hypoglycorrachy)
• Brucella melitensis (mononucleated cells (rarely PMNs), hyperproteinorrachy, often hypoglycorrachy)
• Tropheryma whipplei (mononucleated cells)
• rare : Leptospira spp. (if untreated it may occasionally persist 3-4 weeks)
• fungi
• Cryptococcus neoformans var. neoformans (cryptococcal meningitis : it has both a subacute chronic form and a more serious acute form and is increased in immunocompromised patients) (mononucleated cells; not elevated in some patients with AIDS)
• Coccidioides immitis (mononucleated cells, sometimes 10-20% eosinophils, often hypoglycorrachy)
• Candida spp. (PMNs or mononucleated cells)
• Ajellomyces capsulatus var. farciminosus (mononucleated cells, hypoglycorrachy)
• Ajellomyces dermatitidis (mononucleated cells)
• Aspergillus spp. (mononucleated cells or PMNs)
• Sporothrix schenckii (mononucleated cells)
• rare : Pseudallescheria boydii (PMNs), Mucorales spp., Cladophialophora bantiana (Cladosporium trichoides), Curvularia spp., Drechsleraspp.
• protozoa
• Toxoplasma gondii (mononucleated cells)
• Trypanosoma brucei gambiense (mononucleated cells, hyperproteinorrachy)
• Trypanosoma brucei rhodesiense (mononucleated cells, hyperproteinorrachy)
• rare : Acanthamoeba spp., Naegleria fowleri
• helminths
• Gnathostoma spinigerum
• eosinophilic meningitis or meningoencephalitis : meningitis characterized by an increase in lymphocytes and a high percentage of eosinophils in the CSF
• Angiostrongylus cantonensis (eosinophils and mononucleated cells)
• Schistosoma spp.
• Echinococcus spp.
• Taenia cellulosae
• Taenia multiceps
• Taenia solium (mononucleated cells, possible presence of eosinophils, possible hypoglycorrachy)
• Baylisascaris procionis(eosinophils and mononucleated cells)
• Toxocara canis
• Fasciola hepatica
• Paragonimus spp.
• Gnathostoma spinigerum (eosinophils and mononucleated cells)
• Trichinella spiralis (lymphocytary pleiocytosis)
• Ascaris lumbricoides (allergy)
• rare
• viruses :
• mumps virus (mumps meningitis) (mononucleated cells)
• lymphocytic choriomeningitis virus (LCMV) (benign lymphocytic meningitis / lymphocytic choriomeningitis) (mononucleated cells)
• echoviruses 7, 9, 11, 30 (frequent), 4, 6, 18 (common); 2, 3, 12, and 22 (rare); excellent cultural isolation from CSF (mononucleated cells, possible hypoglycorrachy)
• HHV-1 / HSV-1 (less common); poor cultural isolation from CSF (mononucleated cells)
• HHV-2 / HSV-2 (common; Mollaret's meningitis : recurrent febrile attacks, malaise, headache, and meningeal signs accompanied by a marked PMN inflammatory reaction in the CSF); moderate cultural isolation from CSF (mononucleated cells)
• HIV-1 (common; acute retroviral syndrome); moderate cultural isolation from CSF (mononucleated cells)
• pachymeningitis : inflammation of the dura mater; the symptoms of the disease resemble those of meningitis
• cerebral pachymeningitis : inflammation of the dura of the brain.
• spinal pachymeningitis : inflammation of the dura of the spinal column.
• circumscribed pachymeningitis : pachymeningitis limited to a definite area of the dura.
• external pachymeningitis : inflammation of the outer layers of the dura.
• internal pachymeningitis : that which affects the inner layer of the dura.
• hypertrophic spinal pachymeningitis : a diffuse fibrosing form of pachymeningitis in the spinal canal
• hypertrophic cervical pachymeningitis : hypertrophic spinal pachymeningitis in the cervical region.
Aetiology :
• Treponema pallidum subsp.pallidum (syphilitic pachymeningitis)
• Mycobacterium tuberculosis (tubercular pachymeningitis)
• duroarachnitis : inflammation of the dura mater and arachnoid.
• leptomeningitis : inflammation of the leptomeninges.
• sarcomatous leptomeningitis : diffuse sarcomatous infiltration of the pia mater.
• arachnoiditis / arachnitis : inflammation of the arachnoidea
• acute arachnoiditis

Aetiology :
• trauma
• lumbar puncture
• chronic adhesive arachnoiditis / meningitis serosa circumscripta : thickening and adhesions of the leptomeninges in the brain or spinal cord

Aetiology :
• previous meningitis
• neurocysticercosis
• other disease processes
• trauma
• secondary to prior myelomeningocele repair
• secondary to therapeutic or diagnostic injection of substances into the subarachnoid space : obstetrical epidural analgesia
The signs and symptoms vary with extent and location :
• spinal arachnoiditis : chronic adhesive arachnoiditis in the spinal arachnoid, with root and spinal cord symptoms similar to those caused by pressure from a tumor
Common symptoms & signs : fever, headache
• encephalopathy : any degenerative disease of the brain.
• cerebropathy : any disorder of the cerebrum
• syringoencephalia : the formation of abnormal cavities in the brain substance
• syringoencephalomyelia : syringoencephalia + syringomyelia
• leukoencephalomalacia : encephalomalacia affecting primarily the white matter
• cerebromalacia : abnormal softening of the substance of the cerebrum
• leukoencephalopathy : any of a group of diseases affecting the white matter of the brain, especially of the cerebral hemispheres, and occurring as a rule in infants and children
• Lichtheim plaques : areas of degeneration in the cerebral white matter that are seen in pernicious anemia.
• necrotizing leukoencephalopathy : a complication sometimes seen after injection of methotrexate intrathecally to treat childhood leukemia of the CNS; symptoms include necrosis of white matter of the brain, sometimes with stupor and quadriplegia, and frequently with permanent learning disabilities.
• reversible posterior leukoencephalopathy syndrome (RPLS) is a brain-capillary leak syndrome related to hypertension, fluid retention, and the cytotoxic effects of immunosuppressive agents on the vascular endothelium. At least 82 reports in the English literature associate this syndrome with various conditions^ref, including chemotherapeutic drugs, immunosuppressants (cyclosporine, tacrolimus), G-CSF, cisplatin, epoetin, and immune globulin therapy^{ref1, ref2}, and bevacizumab^ref. It was initially reported by Hinchey et al. in 1996^ref.
• progressive multifocal leukoencephalopathy (PML) / Richardson's disease : an opportunistic infection of the central nervous system by the JC virus. Seen in immunocompromised hosts (including 5.1% of patients with AIDS and 0.07% of patients with hematologic malignancies; HTLV-1^{ref1, ref2}, patients treated with anti-CD49d / a₄ integrin mAb, ICF syndrome^ref, hyperimmunoglobulin E recurrent infection syndrome (HIES)^ref, ICL^ref, Wiskott-Aldrich syndrome^ref, solid organ transplantation and HSCT) : the major target cell of JCV infection and lytic replication in the CNS is the oligodendrocyte : the initial interaction between JCV and glial cells involves virus binding to N-linked glycoproteins containing terminal a(2-6)-linked sialic acids and RME. PML mostly occurs in different conditions of impaired cellular immunity like AIDS and rarely when humoral immunity is impaired^{ref1, ref2} (e.g. hyper IgM syndrome^{ref1, ref2}). E.g. there is a high frequency of polyomavirus infection in lymphoid cell preparations after allogeneic HSCT^ref. EBV-transformed B lymphocytes would favour JCV penetration and/or intracerebral reactivation of previously latent JCV infection with further development of simultaneous PML and cerebral CLL infiltration in an immunosuppressed patient^ref

Pathogenesis : the demyelination is usually found in the white matter of the cerebral hemispheres but may rarely be seen in the brain stem and cerebellum
Symptoms & signs : difficulties in speaking, sight and learning => sensitive and motory deficits within 3-6 months, cortical blindness, death within some months. Patients with PML lesions immediately adjacent to the hemispheric cortex are at risk of seizures (overall prevalence = 18%), which usually respond well to treatment and do not affect survival^ref
Laboratory examinations :
• on biopsy :
• hematoxylin and eosin (H&E) staining : multiple lesions of demyelination, enlarged oligodendrocytes with hyperchromatic nuclei (many containing eosinophilic intranuclear inclusions), and enlarged astrocytes with bizarre hyperchromatic nuclei. Immunohistochemical analysis demonstrated the expression of the JCV capsid protein VP-1 in the nuclei of infected oligodendrocytes and astrocytes. In rare cases of progressive multifocal leukoencephalopathy (PML) the lesions are atypical in that the characteristic alteration of oligodendrocytic nuclei is infrequent or absent, and the demyelinated foci contain mononuclear inflammatory infiltrates including numerous plasma cells^ref.
• in situ hybridization (ISH) with JC Enzo probe
• in situ PCR
• electron microscopy
• the prevalence of JCV DNA by PCR in CSF samples from Brazilian AIDS patients with focal brain lesions, without mass effect was 48.2%^ref.
• in vitro :
• JCV major capsid protein, VP-1, is responsible for red blood cell (RBC) agglutination and traditionally, hemagglutination (HA) and HA inhibition (HAI) assays have been employed for quantitation of JCV^{ref1, ref2, ref3, ref4, ref5, ref6, ref7}. However, the HA assay is poorly sensitive and the in vitro quantitation of JC viral load by HA is often impossible. Moreover HA assay cannot be efficiently employed to study
• semi-quantitative polymerase chain reaction (PCR) and quantitative real-time PCR have been recently developed and employed for the detection and quantitation of JCV^{ref1, ref2, ref3, ref4, ref5}. In clinical specimens, real time-PCR has proven to be an important method for monitoring JCV viral load^{ref1, ref2}, and is a reliable marker for PML prognosis^ref. Comparison of real-time PCR and hemagglutination assay for quantitation of JCV^ref
• LightCycler^® real-time PCR assay based on SYBR Green I detection^ref
The mean viral load of viruria was much higher in the healthy controls than in the renal transplant recipients [104020 DNA copies/mL (DS+/-62284) vs 4136 DNA copies/mL (DS+/-77371)]. A new quantitative PCR assay offers in 2 h time a reliable true quantification of viral DNA by densitometric analysis of the amplification product. To check for the possible presence of potential Taq polymerase inhibitors an internal control (the homemade pJCV-C plasmid) is used. The relation between polyomavirus infections and their possible involvement in post-transplant pathologies need further investigation. It would be useful to monitor the JCV-DNA load in urine and serum from more renal transplant recipients, including patients with nephropathy or active graft rejection over a longer period of time^ref
• acute lesions of PML survivors showed 2-fold higher standard score of the ratio of myoinositol (a glial marker) to creatine compared with lesions in patients whose disease progressed. Concomitantly, JCV-specific CTLs were only detected in the blood of PML survivors^ref
• a major characteristic that distinguishes PML from other more common lesions, such as toxoplasmosis or NHL, is the lack of contrast enhancement : anyway PML lesions can enhance after the administration of gadolinium^ref
• inflammatory infiltrates in brain biopsy of HIV⁺ and HIV^- patients with PML predominantly contained CD8⁺ T lymphocytes. In most samples from either HIV⁺ and HIV^- patients, positive correlations were found between the parenchymal CD8⁺ T cells and JCV-infected glial cells and conversely, negative correlations between the perivascular CD8⁺ T cells and JCV-infected glial cells in the surrounding brain. Most of these correlations remained significant after accounting for the degree of demyelination and location of the cells relative to lesions. Moreover, high numbers of CD8⁺ T cells were found within and at the border of active PML lesions. CD8⁺ T cells are primarily associated with JCV-infected glial cells in most PML cases and that an active ongoing recruitment of CD8⁺ T cells and possibly viral antigen-specific retention could occur. These observations are discussed in the context of the recent evidence of PML in multiple sclerosis and Crohn's patients treated with natalizumab, underscoring the role of CD8⁺ T lymphocytes in continued immunosurveillance of the CNS^ref
Prognosis : a rapid clinical course ensues with focal neurological deficits and a median time to death of 3.5 months without treatment. Prognosis correlated with CCL-2 / MCP-1 CSF levels^ref. PML-associated JCV frequently undergoes amino acid substitutions (designated VP1 loop mutations) in the outer loops of the major capsid protein, VP1^ref, restricted to 3 positions (55, 60, and 66) within the BC loop, 1 (123) within the DE loop, and 3 (265, 267, and 269) within the HI loop^ref. JCV-specific CTLs, when present in the blood and CSF of PML patients, confer better prognosis^ref. CTL responses to the JCV VP1p100 epitope have been associated with prolonged survival in PML patients^{ref1, ref2} : the same VP1 epitope is recognized in HLA-A*02 persons in response to either BKV or JCV infection^ref. Soluble 30-100 kDa factors secreted by activated T lymphocytes suppress replication of JCV in glial cells^ref
• central pontine myelinolysis : a form of widespread demyelination of the pons occurring in alcoholics (ethanol-addicted).
• subacute sclerosing leukoencephalopathy / subacute sclerosing panencephalitis
• leukodystrophy : disturbance of the white substance of the brain due to defect in the formation and maintenance of myelin in infants and children.
• spongiform leukodystrophy : spongy degeneration of CNS
• Hallervorden-Spatz disease / status dysmyelinatus / status dysmyelinisatus
• Alexander's disease
• sudanophilic leukodystrophy
• adrenoleukodystrophy
• hereditary cerebral leukodystrophy / Pelizaeus-Merzbacher disease or sclerosis / familial centrolobar sclerosis
• globoid cell leukodystrophy (GLD) / Krabbe's disease
• spongy degeneration of central nervous system / spongy degeneration of white matter / Canavan-van Bogaert-Bertrand disease
• hereditary adult-onset leukodystrophy
• metachromatic leukodystrophy (MLD) or leukoencephalopathy / sulfatide lipidosis
• leukoencephalopathy with vanishing white matter (VWM) / childhood ataxia with central nervous system hypomyelinization (CACH) / vanishing white matter leukodystrophy / Cree leukoencephalopathy (CLE) / ovarioleukodystrophy
Therapy : cell therapy
• status cribalis or cribrosus : a sievelike condition of the brain due to dilatation of the perivascular lymph spaces.
• diffuse sclerosis : sclerosis that affects large areas of the brain and spinal cord.
• encephalosclerosis : hardening of the brain.
• traumatic encephalopathy
• concussion, postconcussional or postconcussion syndrome / traumatic encephalopathy /  Friedmann's vasomotor syndrome / Homén's syndrome / post-traumatic brain syndrome : physical and personality changes that sometimes occur after concussion of the brain; they include amnesia, headache, dizziness, tinnitus, irritability, fatigability, sweating, palpitations of the heart, disordered sleep, and difficulty in concentrating
• boxer's traumatic encephalopathy : a syndrome due to cumulative head blows absorbed in the boxing ring, characterized by general slowing of mental function, occasional bouts of confusion, and scattered memory loss. It may progress to the more serious punch-drunk encephalopathy / boxer's dementia
• pneumocephalus / intracranial pneumatocele / pneumatocephalus / pneumocrania / pneumoencephalocele : the presence of air in the intracranial cavity
• intracranial aerocele : pneumocephalus resulting from trauma.
• pneumocephalus associated with pneumosinus dilatans of the frontal sinus^ref
• toxic encephalopathy
• progressive dialysis encephalopathy / dialysis dementia : a degenerative disease of the brain first described by Alfrey et al. in 1976^ref, associated with long-term use of hemodialysis, marked by speech disorders and constant myoclonic jerks, progressing to global dementia, with associated psychological changes; it is often accompanied by osteomalacia and is due to high levels of aluminum in the water used in the dialysis fluid or to aluminum-containing compounds given to control phosphorus levels
• lead encephalopathy or encephalitis / saturnine encephalitis : a condition caused by excessive ingestion of lead compounds, seen especially in young children. Pathological characteristics are edema and central demyelination; symptoms include nausea and vomiting and apathy followed by stupor, seizures, coma, and death
• Marchiafava-Bignami disease

Epidemiology : a very rare disorder affecting chiefly middle-aged male alcoholics
Aetiology : ethanol; also seen in patients with nutritional deficiency states.
Symptoms & signs : progressive degeneration of the corpus callosum characterized by progressive intellectual deterioration, emotional disturbances, confusion, hallucinations, tremor, rigidity, and convulsions
• bismuth subgallate : paranoid ideation, memory impairment, and defective gustatory and olfactory function while on bismuth subgallate therapy for use as a colostomy deodorant.
• hereditary encephalopathies
• mitochondrial encephalopathy : any of numerous familial encephalopathies of maternal (mitochondrial) inheritance associated with mitochondrial abnormalities, such as cytochrome-c oxidase deficiency.
• MELAS syndrome : mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes

Aetiology : A=>G SNP in position 3243 of the mitochondrial gene for tRNA^Leu(UUR)
• MERRF syndrome / Fukuhara syndrome : myoclonus with epilepsy and with ragged red fibers
• mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disease with mitochondrial DNA (mtDNA) alterations

Aetiology : mutations in the nuclear gene encoding thymidine phosphorylase (TP), which cause a loss-of-function of the cytosolic enzyme, TP. As a direct consequence of the TP defect, thymidine metabolism is altered
Symptoms & signs : ptosis, ophthalmoparesis, gastrointestinal dysmotility, cachexia, peripheral neuropathy, and leukoencephalopathy.
Laboratory examinations : skeletal muscle shows mitochondrial abnormalities, including ragged-red fibers and cytochrome c oxidase deficiency, together with mtDNA depletion, multiple deletions or both. High blood levels of this nucleoside are likely to lead to mtDNA defects even in cells that do not express TP, such as skeletal muscle. High concentrations of thymidine affect dNTP (deoxyribonucleoside triphosphate) metabolism in mitochondria more than in cytosol or nuclei, because mitochondrial dNTPs depend mainly on the thymidine salvage pathway, whereas nuclear dNTPs depend mostly on de novo pathway. The imbalance in the mitochondrial dNTP homeostasis affects mtDNA replication, leading to mitochondrial dysfunction^ref
Symptoms & signs :
• muscle : external ophthalmoplegia, exercise intolerance,
• brain : ataxia, retinal degeneration, sensorineural deafness, mental retardation or deterioration, optic atrophy, seizures, stroke, headache, neuropathy, parkinsonism
• Fanconi's syndrome
• diabetes mellitus, dysthyroidism, multiple lipomatosis, hepatic failure, hypoparathyroidism
• heart : block, arrhythmias, cardiomyopathies
Laboratory examinations : genealogic tree, EMG, [lactate, PCr/P_i]_{plasma, effort}, ¹H-MRS, muscular biopsy (HC, IHC, EM), molecular biology (Southern blot, PCR, Western blot)
• myoclonic encephalopathy of childhood / Kinsbourne syndrome : a neurologic disorder of unknown etiology with onset between ages 1 and 3, characterized by myoclonus of trunk and limbs and by opsoclonus, with ataxia of gait and intention tremor; some cases have been associated with occult neuroblastoma
• infantile neuroaxonal dystrophy / Seitelberger's disease : progressive hereditary degenerative encephalopathy transmitted as an autosomal recessive trait, beginning in infancy with muscular hypotonia and arrest of development in late infancy, followed by dementia, blindness, spasticity, and ataxia. Pathologically it is characterized by widespread focal swellings and degeneration of the axons with scattered spheroids in the brain. In some, but not all, cases it is caused by a deficiency of a-N-acetylgalactosaminidase
• infectious encephalopathies
• AIDS or HIV-related encephalopathy / AIDS dementia complex

Aetiology : HIV-1 infection
Pathogenesis : HIV-infected macrophages secrete the zymogen MMP-2 / gelatinase A, which is activated by exposure to MT1-MMP on neurons. Active MMP-2 processes CXCL12 / SDF-1—a chemokine overexpressed by astrocytes during HIV infection— into a highly neurotoxic cleaved SDF-1(5–67) peptide => neuronal death and inflammation principally in the subcortical white matter and deep gray nuclei
Symptoms & signs : a variety of cognitive, motor, and behavioral abnormalities Hypotrophy due to microglial cells infection, lateral ventricles ectasia, accentuation of cerebral clefts, behavioural changes (0 => 3 levels) : it is the main cause (24÷47%) of convulsive crises in AIDS patients
• subacute spongiform encephalopathy / prion disease / transmissible spongiform encephalopathy (TSE)
• kuru
• familial fatal insomnia (FFI)
• Neumann familial progressive subcortical gliosis
• Huntington disease-like 1 (HDL1)
• Gerstmann-Sträussler-Scheinker (GSS) syndrome
• prion disease with protracted course
• Creutzfeld-Jakob disease (CJD)
• metabolic encephalopathy : neuropsychiatric disturbances due to metabolic brain disease.
• primary
• Reye-Johnson syndrome

Epidemiology : encountered exclusively in children <15 years
Aetiology :
• mitochondrial dysfunction with reduced activity of liver mitochondrial enzymes : hypoketotic hypoglycemia with deficiency of hepatic carnitine palmitoyltransferase (CPT) type IA
• 1-4 days after infection from :
• Influenzaviruses B >> Influenzaviruses A
• HHV-3 / VZV
• rotaviruses
• coxsackievirus
... treated with acetylsalicylic acid => increased salicylate plasma levels (replace it with paracetamol in treatment of childhood fever!)
Pathogenesis : microvesicular steatosis of liver and renal tubules and cerebral neuronal degeneration. In fatal cases, the liver is enlarged and yellow with striking diffuse fatty microvacuolization of cells. Peripheral zonal hepatic necrosis has also been present in some cases. Fatty changes of the renal tubular cells, cerebral edema, and neuronal degeneration of the brain are the major extrahepatic changes. Electron-microscopic studies show structural alterations of mitochondria in liver, brain, and muscle.
Symptoms & signs : => persistent nausea and vomiting, hepatomegaly, but jaundice is characteristically absent or minimal; an encephalopathic phase may follow with acute cerebral edema (without flogosis), disturbances of consciousness, irritability, generalized seizures, stupor => metabolic coma, tachypnea, hyperventilation
Laboratory examinations :  elevations in serum aminotransferases and prothrombin time, hypoglycemia, metabolic acidosis, and hyperammonemia
Therapy : i.v. glucose 20%, fresh-frozen plasma, i.v. mannitol to reduce the cerebral edema
Prognosis : mortality = 50%; no chronic hepatopathy in survivors
• hypoglycemic encephalopathy

Aetiology : severe hypoglycemia, as in glycogen storage disease, oversecretion or overdose of insulin, etc.
• anoxic or hypoxic encephalopathy

Aetiology : hypoxia from either decreased rate of blood flow or hypoxemia; symptoms in mild cases include intellectual, visual, and motor disturbances. Severe cases, such as with cardiac arrest or blocking of the airways, can cause permanent damage within 5 minutes
• hypoxic-ischemic encephalopathy (HIE)

Aetiology : asphyxia
Symptoms & signs :
• in infants presumed to have suffered perinatal asphyxia, common symptoms are lethargy, feeding difficulties, and convulsions; serious cases may involve necrosis of neurons in the brain (selective, watershed infarction, periventricular leukomalacia) with psychomotor retardation and spastic motor deficits such as cerebral palsy
• in adults, syndromes range from cortical blindness to irreversible coma.
• Wernicke's disease, encephalopathy (WE) or syndrome

Aetiology : thiamine deficiency, usually from chronic alcohol abuse (first described by Wernicke in 1881) or soy-based milk substitute Remedia^® lacking thiamine
Symptoms & signs : a neurological disorder characterized by confusion, apathy, drowsiness, ataxia of gait, nystagmus, and ophthalmoplegia. It is almost invariably accompanied by or followed by Korsakoff's syndrome (organic amnesia) and frequently accompanied by other nutritional polyneuropathies
Therapy : i.m. or i.v. thiamine50 mg
• secondary to disease of other organs
• hypernatremic encephalopathy : a severe hemorrhagic encephalopathy

Aetiology : hyperosmolarity accompanying hypernatremia and dehydration.
• hypercalcemia
• Addison's disease
• uremic encephalopathy

Aetiology : uremia
Pathogenesis : hyperammonemia => increased Gln => increased Glu for Krebs' cycle => decreased neuronal respiration => decreased ATP
Symptoms & signs : lethargy, fatigue, inattentiveness, irritability, confusion, sensory disturbances, and sometimes seizures.
• hepatic, portal-systemic or portasystemic encephalopathy (HE)

Aetiology : advanced disease of the liver but also seen in the course of any severe disease or in patients with portacaval shunts.
Pathogenesis : hyperammonemia & hyperbilirubinemia (> 30 mg/dL : precipitated by excessive diet proteins, constipation, renal failure, stress or intestinal hemorrhages) => permeabilization of blood-brain barrier => decrease in activity of Glu-ergic synapses and increased captation of GABA synthetized by intestinal Bacteria => hyperactivity of GABA_A-ergic synapses (=> precipitated by agonists such as benzodiazepines or barbiturates (further their liver catabolism is decreased), prevented by antagonists like flumazenil) ; decrease in [branched amino acids : Val, Ile and Leu]_plasma / [aromatic amino acids : Tyr, Phe and Trp]_plasma => increase synthesis of inactive neurotransmitters (tyramine, octopamine, b-phenylethanolamine)
The mean+/-SEM values of circulating levels of TNF and ammonia at presentation in patients with grade 0 of HE (n = 30) were 3.89+/-0.2 pg/mL and 49.8+/-2.8 microg/mL respectively, in patients with grade 1 of HE (n = 26) were 8.56+/-0.34 pg/mL and 101.6+/-6.5 microg/mL respectively, in patients with grade 2 of HE (n = 22) were 11.59+/-0.48 pg/mL and 160.3+/-10.7 microg/mL respectively, in patients with grade 3 of HE (n = 20) were 19.98+/-0.94 pg/mL and 228.8+/-16.1 microg/mL respectively, and in patients with grade 4 of HE (n = 10) were 51.53+/-8.59 pg/mL and 284.2+/-20.3 microg/mL respectively. A significant positive correlation was found between circulating levels of TNF and those of ammonia (r = 0.62, P< 0.0001), and also between circulating levels of both substances and severity of HE in these patients (r = 0.95, P<0.0001, and r = 0.9, P<0.0001 respectively). TNF and ammonia were both significant independent predictors of severity of HE (P<0.0001 for both variables). The results of this study demonstrate a significant relationship between TNF and ammonia in patients with chronic liver failure and HE, and so strengthen the suggestion that TNF could be strongly involved in the pathogenesis of HE in these patients. Hence, we suggest a new theory in the pathogenesis of HE, the "TNF theory"^{ref1, ref2}
Symptoms & signs : fetor hepaticus, endocranial hypertension => cerebral or cerebellar herniations. Staging :
• I :  hyperexcitability
• II :  inversion of circadian rhythms, flapping tremor evoked by hyperextension of fingers
• III : hypersomnia, psychiatric changes of varying degree (temporal disorientation, stupor), spontaneous flapping tremor
• IV : hepatic coma (potentially reversible)
• pancreatic encephalopathy (PE)

Aetiology : acute pancreatitis, a part of multiple organ failure which results from acute systemic inflammatory reaction
Symptoms & signs : focal neurological signs and acute onset of dementia. This picture can fluctuate over time: cyclic progression with remission and relapses has been described. Patients who have been in fasting for a long time (more than 10 days) should be given thiamine intramuscularly in case Wernicke encephalopathy (WE) occurs. As soon as WE is diagnosed, a large doses of thiamine should be given immediately, is the key to reduce the mortality of encephalopathy complicating AP.
• biliary encephalopathy / kernicterus / bilirubin encephalopathy :

Aetiology : high levels of bilirubin in the blood usually seen in infants as a sequela of icterus gravis neonatorum
Pathogenesis : deep yellow staining of the basal nuclei, globus pallidus, putamen, caudate nucleus, cerebellar nuclei, bulbar nuclei, and gray substance of the cerebrum, accompanied by widespread destructive changes.
Symptoms & signs : severe neural symptoms
Therapy : phenobarbital and phethabarbital induce hepatic glucuronyl transferase and the bilirubin-binding Y protein
Web resources : Kernicterus at CDC
• hyperperfusion encephalopathies (HPE)
• cerebrovascular hypertension => hypertensive encephalopathy

Aetiology : malignant systemic arterial hypertension
Pathogenesis : overwhelmed autoregulation ability => edema, diffuse ischemia and hemorrhages in small vessels (100 mm in diameter)
Symptoms & signs : headache, seizures, diffuse impairment of LOC without focal neurologic signs
Laboratory examinations : edema in the subcortical white matter is seen on imaging studies and is usually reversible, although infarction or hemorrhage may supervene
Complications : intracranial hypertension => activation of orthosympathetic system (Cushing effect) => worsening of systemic arterial hypertension
Therapy : blood pressure should be reduced within 1-3 hours to save life
• after treatment of high-grade carotid stenoses or large intracranial arteriovenous malformations
• in high altitude mountain sickness
• posterior reversible encephalopathy (PRE) syndrome (PRES) / posterior reversible leukoencephalopathy syndrome (PRLS) : a clinicoradiological syndrome first reported in 1996

Aetiology :
• acute hypertensive encephalopathy
• immunosuppressants (cyclosporine A or tacrolimus)
• severe hypercalcemia
Symptoms & signs : acute or subacute partial or generalized seizures, headache, nausea and vomiting, confusion and visual abnormalities
Laboratory examinations : radiological features are reversible bilateral white matter abnormalities predominantly located in the posterior regions of the cerebral hemispheres (occipital lobe), demonstrated by hypodensities in CT or, better, by MRI (hyperintensities in T2wi and hypointensities in T1wi) : cortical and parieto occipital cortico subcortical regions asymmetrically. Frontal, temporal and cerebellous involvement is also observed in some cases. It rarely presents with predominant involvement of the brainstem and relative sparing of the supratentorial regions.
Therapy : reversible after 3 to 12 days of antihypertensive therapy or withheld of immunosuppressants. However, ischemic injury with irreversible damage may occur
• multicystic encephalopathy : the formation of large, multilocular cavities throughout the cerebral hemispheres, occurring in the perinatal period

Aetiology :
• anoxia
• necrotizing viral encephalitis (especially herpes simplex)
• neonatal meningitis
• periventricular leukomalacia
• Bing-Neel syndrome : the CNS manifestations of Waldenström's macroglobulinemia

Symptoms & signs : encephalopathy, hemorrhage, stroke, convulsions, delirium, and coma.
• subcortical arteriosclerotic encephalopathy / Binswanger's disease or dementia
• cerebrosclerosis : morbid hardening of the substance of the cerebrum.
• encephalitis : inflammation of the brain (see also encephalomyelitis)
• polyoencephalitis : inflammatory disease of the gray substance of the brain
• leukoencephalitis : inflammation of the white substance of the brain
• acute hemorrhagic leukoencephalitis of Weston Hurst / acute necrotizing hemorrhagic encephalomyelitis
• brainstem encephalitis
• HHV-4 / EBV
• Listeria monocytogenes (listeria rhombencephalitis)
• Bickerstaff's brainstem encephalitis (BBE)
• ventriculitis : inflammation of a ventricle, especially of a ventricle of the brain.
• ventriculoencephalitis : ventriculitis accompanied by encephalitis.
• panencephalitis : encephalitis, probably of viral origin, which produces intranuclear or intracytoplasmic Cowdry's type A inclusion bodies, which result in parenchymatous lesions affecting the gray and white matter of the brain simultaneously.
• Pette-Döring panencephalitis : a form of subacute encephalitis characterized by involvement of both the gray and white matter of the brain, and with a predilection for the basal ganglia.
• subacute sclerosing panencephalitis (SSPE) or leukoencephalopathy / Dawson's encephalitis / subacute inclusion body encephalitis / van Bogaert's sclerosing leukoencephalitis

Epidemiology: a rare and devastating form of leukoencephalitis usually affecting children and adolescents. 2-7 cases out of 1,000,000 cases of acute measles virus infection, 2-3 times more frequent among males, 85% between age 5 and 15. The debut of this disease in adults is rare, with a small number of cases in the medical literature and unfavorable influence of pregnancy on the course of the disease
Aetiology : high titers of measles virus RNA and antibodies in the serum and CSF, marking persistent infection 4-17 years after acute infection .
Pathogenesis :  in addition to the lesions of the white matter, there are demyelination, intranuclear inclusion bodies in nerve cells and oligodendroglia, and formation of neurofibrillary tangles, which would relate SSPE with other tauopathies.apoptosis and oxidative stress to DNA can contribute to the early neuronal damage, whereas lipid peroxidation and disturbed glutamate transport may be related to the subsequent neurodegeneration.
Symptoms & signs : insidious in onset, it characteristically produces progressive cerebral dysfunction over a course of several weeks or months and death within 6-36 months. Some patients show a very prolonged biphasal clinical course, with a period of disease-free remission that last several years. Chorioretinitis => blindness.
Therapy : oral isoprinosine, intraparenchymal IFN-a and intraventricular ribavirin
• acute encephalitis
• acute necrotizing encephalitis : encephalitis characterized by a particularly destructive reaction in the brain
• hemorrhagic encephalitis / Strümpell-Leichtenstern encephalitis : encephalitis in which there is inflammation of the brain with hemorrhagic foci and perivascular exudate
• acute hemorrhagic leukoencephalitis of Weston Hurst / acute necrotizing hemorrhagic encephalomyelitis
• herpes simplex encephalitis / herpetic encephalitis
• limbic encephalitis : encephalitis of the limbic system of the rhinencephalon
• non-herpetic acute limbic encephalitis (NHALE) : autoantibodies to GluRe2 and VGKC^{ref1, ref2}
• paraneoplastic limbic encephalitis. There is sometimes an association with tumors elsewhere in the body, although some authorities speculate a link to chemotherapy or other tumor treatments.
• herpes simplex encephalitis / herpetic encephalitis
Pathogenesis : degenerative changes of the hippocampus and amygdaloid nuclei
Symptoms & signs : memory loss, confusion, seizures, and progressive dementia
• Brown-Symmers disease : fatal acute serous encephalitis in children
• neurotropic viruses : often site-specific localizations. Babès' nodules, nodes or tubercles : collections of microglial cells around neurons in the CNS, seen in rabies and other types of viral encephalitis
• mastadenovirus spp.
• HHV-1 / HSV-1 (herpes simplex encephalitis / herpetic encephalitis / acute inclusion body encephalitis : the most common form of acute encephalitis (affects persons of any age : 90% all acute viral meningitis in babies and adults), characterized by severe hemorrhagic necrosis of inferomedial portions of the temporal lobe and the orbital portions of the frontal lobes along with, in the acute stages, intranuclear eosinophilic inclusion bodies in the neurons and glial cells. Onset is over several days and involves fever, headache, seizures, stupor, and often coma, frequently with a fatal outcome (70%))
• HHV-2 / HSV-2 : 75% all acute viral meningitis in newborns due to contamination during birth. Lethality : 60% if untreated, 25% if treated.
• HHV-3 / VZV
• HHV-4 / EBV
• HHV-5 / CMV
• HHV-6
• cercopithecine herpes virus 1
• louping ill virus
• Negishi virus
• Powassan virus (Powassan encephalitis)
• West Nile virus (WNV) (West Nile encephalitis)
• yellow fever virus (YFV)
• lymphocytic choriomeningitis virus (LCMV)
• encephalomyocarditis virus
• polioviruses
• rabies virus
• measles virus
• mumps virus
• rubella virus
• HIV-1
• epidemic encephalitis / encephalitis epidemica : any viral encephalitis that occurs in epidemics; common types are
• Influenzavirus A H₁N₁ (influenzal encephalitis)
• lethargic encephalitis / encephalitis lethargica (EL) / encephalitis A / von Economo's encephalitis or disease / Vienna encephalitis : a form of epidemic encephalitis, the original type described by von Economo

Epidemiology : observed in various parts of the world between 1915 and 1927. Since then, only sporadic cases have been described. An EL-like syndrome secondary to autoimmunity against deep grey matter neurons is still prevalent : anti-streptolysin-O titres are elevated in 65% of patients, 95% of EL patients have autoantibodies reactive against human basal ganglia antigens and histopathology in one case demonstrated striatal encephalitis with perivenous B- and T-lymphocytic infiltration^ref
Aetiology : despite temporally associated with the 1918 Spanish Influenzavirus A H₁N₁ pandemic, the etiologic association of influenza with EL is controversial and von Economo and other contemporary scientists thought that it was not the cause of EL : RT-PCR for influenza matrix and nucleoprotein genes was negative in all cases studied^ref
Pathogenesis : encephalitis of the midbrain and basal ganglia, with lymphocyte (predominantly plasma cell) infiltration.
Symptoms & signs : pharyngitis, headache, diplopia, fever, sleep disorder (somnolence, sleep inversion or insomnia), oculogyric crisis, dyskinesias, catatonia, increasing languor, apathy, drowsiness, and psychiatric symptoms (delirium), passing into lethargy and long-lasting coma
Prognosis : many patients who initially recovered subsequently developed profound, chronic postencephalitic parkinsonism
• California encephalitis virus (California encephalitis) (Eastern and North-central USA, babies, mortality < 1%, rare sequels, reservoir = rodents)
• La Crosse virus (La Crosse encephalitis)
• Ilheus virus (Ilheus encephalitis)
• Semliki forest virus (Semliki Forest encephalitis)
• Murray Valley encephalitis virus (Murray Valley encephalitis / Australian X encephalitis)
• Japanese encephalitis virus (JEV) (epidemic encephalitis B / Japanese encephalitis / Russian autumnal encephalitis / summer encephalitis)
• Saint Louis encephalitis virus (epidemic encephalitis C / St. Louis encephalitis) (whole USA, adults > age 50, mortality = 2-20%, sequels in 20%, reservoir = birds)
• Western equine encephalomyelitis virus (WEEV)
• Venezuelan equine encephalitis virus (VEEV)
• Eastern equine encephalitis virus (EEEV)
• tick-borne encephalitis viruses (tick-borne encephalitis / Russian endemic, Russian forest-spring, Russian tick-borne, or Russian vernal or vernoestival encephalitis / woodcutter's encephalitis)
• Russian Spring-Summer encephalitis virus : the more common, severe form of tick-borne encephalitis, occurring mainly in the far eastern part of Russia
• Central European encephalitis : the milder form of tick-borne encephalitis, first noted in Central Europe.
• in immunocompromised hosts
• JC virus
• HTLV-1
• HHV-5 / CMV (cytomegalovirus encephalitis : variable symptoms include seizures, clouding of consciousness, and other symptoms similar to those of the AIDS dementia complex)
• microglial nodular encephalitis : a manifestation of CMV encephalitis that appears earlier than cytomegalovirus ventriculoencephalitis and is characterized by acute onset with confusion and delirium.
• cytomegalovirus ventriculoencephalitis : a late-appearing type of CMV encephalitis seen in immunocompromised patients, characterized by high protein levels and pleocytosis of the CSF, encephalitis, cranial nerve deficits, ventriculomegaly with necrotizing ventriculitis, and sometimes ascending muscle weakness with nystagmus.
• echovirus
• coxsackievirus
• Bacteria
• Mycoplasma pneumoniae
• Bartonella bacilliformis
• Bartonella elizabethae
• Bartonella henselae
• Bartonella quintana
• Bartonella vinsonii
• Orientia tsutsugamushi
• Rickettsia prowazekii
• Rickettsia rickettsii
• Protozoa
• Toxoplasma gondii (in immunocompromised hosts)
• Naegleria fowleri
• vaccines
• anti-Orthopoxvirus vaccine
• anti-rabies virus vaccine
• anti-Bordetella pertussis vaccine
• anti-measles virus vaccine
• anti-Corynebacterium diphteriae vaccine
• chronic encephalitis
• chronic subcortical encephalitis / Binswanger's dementia, disease or encephalitis / subcortical arteriosclerotic encephalopathy: a degenerative dementia of presenile onset caused by thinning of the subcortical white matter of the brain; some have attributed it to sclerotic changes in the blood vessels

Laboratory examinations : fibromyelinic plaques (areas of overgrowth of medullated fibers and sheaths in areas of incomplete arteriosclerotic necrosis in the cerebral cortex)
• neurotropic viruses
• measles virus
• rubella virus
• HIV-1
• Bacteria
• Treponema pallidum subsp.pallidum
• Borrelia burgdorferi
• Protozoa
• Trypanosoma brucei (Dürck's nodes : granulomatous perivascular infiltrations in the cerebral cortex)
• Acanthamoeba spp.
• Balamuthia mandrillaris
• granulomatous amebic encephalitis (GAE) : a chronic type of encephalitis, usually seen in debilitated or immunocompromised persons, caused by infection with species of Acanthamoeba spp. and Naegleria fowleri; characteristics include focal granulomas, often with headache, seizures, nausea and vomiting.
• Ontario encephalitis : nausea and vomiting and wasting disease.
• purulent, pyogenic or suppurative encephalitis : encephalitis accompanied by suppuration and abscess formation
• Rasmussen's encephalitis
• meningoencephalitis / cerebromeningitis / encephalomeningitis / meningocerebritis : cerebral meningitis + encephalitis

Aetiology :
• eosinophilic meningoencephalitis / eosinophilic meningitis
• mumps meningoencephalitis : a usually benign form seen in children, caused by the mumps virus, and characterized by fever, nausea and vomiting, nuchal rigidity, lethargy, parotitis, headache, seizures, abdominal pain, diarrhea, and delirium.
• primary amebic meningoencephalitis (PAM) : a rare and often fatal acute, febrile, purulent meningoencephalitis caused by usually free-living soil and water amebas of the genera
• Naegleria fowleri
• Acanthamoeba spp.
• Hartmannellavermiformis
• Balamuthia mandrillaris
• toxoplasmic meningoencephalitis / toxoplasmic encephalitis or encephalomyelitis : the meningoencephalitis that sometimes occurs in toxoplasmosis (Toxoplasma gondii), characterized by seizures and mental confusion followed by coma. Pathologically, the brain may contain cysts and necrotic areas, with occasional hydrocephalus caused by blockage of aqueducts by sloughed material. It is often fatal if untreated. A sharply increased rate of infections, which may be recurrent, is seen in immunocompromised patients
• general paresis / paretic neurosyphilis / Bayle's disease / dementia paralytica / paralytic dementia / paretic neurosyphilis / syphilitic meningoencephalitis :  parenchymatous neurosyphilis (Treponema pallidum subsp.pallidum) in which chronic meningoencephalitis causes gradual loss of cortical function, resulting in progressive dementia and generalized paralysis, which generally occurs 10 to 20 years after the initial infection of syphilis
Pathogenesis : acquisition from nasopharynx => colonization of mucosal surfaces => entry in CSF => inflammation of subarachnoid space => increase in blood-brain barrier permeability => interstitial oedema => intracranial hypertension : if occlusion of fourth ventricles foramina occurs => hydrocephalus
Symptoms & signs :
• other suppurative foci (caused from the same microorganism)
• meningeal irritation (mild in acute viral meningitis)
• cyanosis
• myalgia
• anorexia
• nausea and vomiting
• headache
• fever
• paraesthesiae
• loss of consciousness => lethargy
• apnoea in babies
• intracranial hypertension
• photophobia
• seizures (from fever, hyponatremia or cerebral abscess)
• unresponsive mydriasis
• abducens (VI) nerve palsy
• decerebrate rigidity (excessive contraction of extensor muscles)
• "gun cock" position
• rash
Laboratory examinations :
• CT (shows focal injuries)
• MRI
• rachiculture, protidorrachia, glycorrachia, [Cl^-], cells
• hemoculture
Chemotherapy : intratecal with application of Ommaya's or Rickham's intraventricular reservoir.
• gliosis / astrocytosis : proliferation of astrocytes (on the contrary of fibroblasts they don't secrete collagens but increase branching)
• diffuse gliosis : gliosis affecting the whole of the cerebral tissue, or widely scattered through it.
• hemispheric or unilateral gliosis : gliosis affecting one of the cerebral hemispheres.
• hypertrophic nodular gliosis : a form of gliosis in which the brain is symmetrically enlarged because of hyperplasia of the neuroglial tissue.
• isomorphic gliosis : gliosis in which there is a regular and parallel arrangement of glial fibers.
• perivascular gliosis : a form of arteriosclerosis of the cerebral vessels, marked by an increase of neuroglia.
• mesial temporal or hippocampal sclerosis : loss of neurons in the hippocampal region with gliosis, sometimes seen with uncinate epilepsy
• skull and rachid tumors
• CNS tumours : they never give extraencephalic metastases (sometimes local metastases by endoliquoral route), but have local malignancy as early infiltrations render surgical ablation useless. Relapses lead to endocranial hypertension, which is the actual cause of death. CNS tumor are rarer than epithelial tumors due to lesser proliferative activity : as proliferation is higher in babies, they are usualy pediatric cancers and usually affect glial cells as they have greater proliferative activity than neurons
• encephaloma : any swelling or tumor of the brain
Epidemiology : 2,000 children are diagnosed with brain cancer annually in the USA
Areas of the tumor :
• central area : 90% of neoplasm mass, low GF, low CBF, gross BBB alterations, high Glc metabolism, high extracellular fluid concentration, low P_O2
• peripheral area :
• brain adjacent to the tumor (BAT) : 5-10% of neoplasm mass, high GF, mild blood-brain barrier (BBB) alterations (lack of perivascular glial sheaths, basal membrane alterations, no zonulae occludens, irregular fenestrae), low Glc metabolism, high extracellular fluid, normal P_O2 : it can be surgically resected without major side effects only in right frontal or temporal lobes of right-handed patients
Aetiology :
• occupational lead exposure^ref
• sibship size and number of younger siblings : the rate ratios (RR) for having >= 4 siblings vs none were significantly increased for hemangioblastoma (RR = 1.68), childhood neuroblastoma (RR = 2.01), and ependymoma (RR = 1.83, p trend < 0.01). For age at diagnosis 15 years, the RRs for individuals with >= 3 younger siblings compared to none were 1.34 for astrocytoma, 2.30 for medulloblastoma, 2.61 for ependymoma, 3.71 for meningioma, and 2.13 for neuroblastoma, with significant trends in risk. Non-significant decreased risks were found between the number of older siblings and nervous system tumors^ref
Histological types :
• primary tumors : human brain tumours grow from a type of "cancer stem cell"^ref that gives rise to other cancerous cells. Cancer stem cells appear to have some of the properties of stem cells, such as the potential to give rise to a larger population of cells, although they are not necessarily the same thing. For example, they may be differentiated cells that undergo a backwards step to take on some of these properties, although the pathway remains unclear. When 100 CD133⁺ cells, which has been found on the surface of other stem cells in the body are injected into the brains of 19 mice, 16 of them sprouted brain tumours similarly to those in the patients from which they came, resembling glioblastomas and medulloblastomas, for example^ref. This suggests that mice tumours will be a good way to study the human disease.
• glioma / neurogliocytoma / neuroglioma / neurospongioma : originally, a tumor composed of tissue representing neuroglia in any of its stages of development; the term has been extended to include all the primary intrinsic neoplasms of the brain and spinal cord.. Malignancy directly relates with the number of intratumoral bleedings, cysts and necrosis.

Aetiology : Turcot's syndrome / glioma-polyposis syndrome
• astrocytic glioma / astrocytoma (10-15%): a tumor composed of astrocytes; it is the most common type of primary brain tumor and is also found throughout the CNS.

Histologic appearance :
• gemistocytic astrocytoma : an astrocytoma whose cells resemble gemistocytes / gemistocytic astrocyte; their cytoplasm is swollen, homogeneously hyaline, and acidophilic in appearance, the nucleus assumes an eccentric position. Their tendency to undergo malignant transformation is variable.
• astrocytoma fibrillare / fibrillary astrocytoma : an astrocytoma whose cells resemble fibrous astrocytes, usually a Grade I or Grade II astrocytoma found in the cerebrum of an adult, but occasionally occurring in the brain stem or cerebellum. A minority are malignant and undergo anaplastic changes.
• pilocytic astrocytoma / piloid astrocytoma : an astrocytoma resembling the fibrillary type but with its fibrils arranged in parallel rows; its grade of malignancy is low. The most common kind is the cerebellar juvenile pilocyticastrocytoma. In adults the pilocytic type is usually found in the cerebrum, optic chiasm and brainstem.
• polar spongioblastoma / spongioblastoma polare / piloid astrocytoma / unipolar spongioblastoma : a rare malignant brain tumor seen from childhood to young adulthood, characterized by palisades of unipolar spongioblasts; sites may be either cerebral or cerebellar
Laboratory examinations : CT detects hypodensity or mixed density area, calcifications and cysts
• protoplasmic astrocytoma / astrocytoma protoplasmaticum : a tumor composed of protoplasmic astrocytes. The distinction between this type and fibrillary astrocytoma has been questioned.
• anaplastic astrocytoma : a malignant to highly malignant form of astrocytoma that often degenerates into a glioblastoma multiforme; variously classified as a Grade II or a Grade III astrocytoma, usually found in cerebellum.

Laboratory examinations : CT detects mixed density, necrosis, cysts, edema, enhancement, and ring sign
• astroblastomas : an astrocytoma of Grade II; its cells resemble astroblasts, with abundant cytoplasm and 2-3 nuclei.
Malignancy : Kernohan grading proposed a 4 grade system according to labeling index (LI), growth fraction (GF), time of cycle (Tc), time of doubling (TD), and cell loss fraction (CLF) that was patterned after the histological grading system for epithelial neoplasms as used at the Mayo Clinics, Rochester, MN. Many new grading systems were proposed afterwards, but this is still in use in many laboratories (Kernohan JW, Mabon Re, Svien HJ & al. A simplified classification of gliomas. Proc. Staff Meet. Mayo Clin. 24:71-75 (1949))
• grade I astrocytomas : a group of generally slow-growing astrocytomas
• most fibrillary astrocytoma
• most pilocytic astrocytomas
• grade II astrocytomas : astrocytomas with slightly more malignant potential than those of grade I, including
• astroblastomas
• some fibrillary astrocytoma
• some pilocytic astrocytomas
• some anaplastic astrocytomas
Laboratory examinations : CT detects hypodensity, most commonly in hemisphere or thalamus or brainstem
Prognosis : 5-year OS = 50%
• malignant astrocytoma / glioblastoma
• grade III astrocytomas : moderately malignant astrocytomas, including
• most anaplastic astrocytomas
• the less malignant of the glioblastoma multiforme group.
Prognosis : 5-year OS = 20%
• grade IV astrocytomas : astrocytomas that are highly malignant; this group includes only the glioblastoma multiforme type, although some less malignant glioblastomas are sometimes classified as Grade III.
• glioblastoma multiforme / spongioblastoma multiforme : the most malignant type of astrocytoma, usually classified as Grade IV, one of the most common primary tumors of the brain (including corepus callosum and basal nuclei); it also occurs in the brain stem in children and occasionally in the spinal cord of an adult or child. It is a rapidly growing tumor, usually found in the cerebral hemispheres and composed of a mixture of spongioblasts, astroblasts, and astrocytes. LI = 5-10%, Tc = 48-72 hrs; GF = 30-40%; TD = 7 days; CLF = 85-90%.
• cerebral gliomatosis / neurogliosis cerebri : a rare variant of glioblastoma multiforme in which one hemisphere or the entire brain is infiltrated diffusely with anaplastic astrocytes
Aetiology : coexpression of EGFR deletion mutant variant III (EGFRvIII) and the tumor-suppressor protein PTEN was identified as a molecular signature in pretreatment glioblastoma tissue that predicts sensitivity to EGFR inhibitors. However, several tumors that were responsive to erlotinib in the validation data set exhibited PTEN loss, and one of these did not express EGFRvIII, suggesting that alternative mechanisms of action exist^ref.
Laboratory examinations : CT detects mixed density area, hemorrhages, necrosis, cysts, and edema
Prognosis : 5-year OS < 1%
Therapy :
• surgery + adjuvant radiotherapy
• VEGFR2 inhibitors
• EGFR inhibitors : coexpression of EGFRvIII and PTEN by glioblastoma cells is associated with responsiveness^ref
• GHRH and its mRNA are also found in human cancers of the breast, ovary, prostate, lung, and other tumors, suggesting that GHRH is also a tumor growth factor. Various studies show that GHRH antagonists have antiproliferative effects in many tumor models; however, glioblastomas were examined only recently. Previous studies have demonstrated that s.c. administration of GRP39 antagonist (JV-1-36) inhibited growth of s.c. U-87MG human glioblastomas and increased survival of nude mice with orthotopic implants of glioblastomas. Although treatment with JV-1-36 reduced tumorigenicity, it is not known whether peripherally administered GHRH antagonists can cross the blood-brain barrier. Brain endothelial cells joined by tight junctions form the blood-brain barrier, a "barrier" between the general circulation and the CNS. After i.v. injection, iodinated JV-1-42 (¹³¹I-JV-1-42) enters the brain intact at a rate of 0.8514 µl/g per min with a serum half-life of 12.2 min. A one-site binding hyperbolic model indicated that the maximal percent of i.v. dose taken up per gram of brain was 0.41%. Coinjection of unlabeled JV-1-42 indicated that the transport from blood to brain is not saturable; however, transport from brain to blood is saturable and involves P-glycoprotein. Taken together, these results demonstrate that i.v.-administered ¹³¹I-JV-1-42 readily crosses the blood-brain barrier and accumulates in the brain. This finding indicates that GHRH antagonists could provide a potential treatment for malignant glioblastomas^ref
Localization :
• cerebellar astrocytoma : an astrocytoma in the cerebellum
• juvenile pilocytic astrocytoma : a pilocytic astrocytoma found in the cerebellum in children, one of the most common juvenile brain tumors; it grows slowly and has a low grade of malignancy
• diffuse cerebellar astrocytoma : a cerebellar astrocytoma that is solid, dense, and infiltrative and resembles a fibrillary astrocytoma; it occurs more frequently in adults and has a higher grade of malignant potential than a pilocytic astrocytoma.
• subependymal giant cell astrocytoma : a rare, usually slow-growing astrocytoma found in the wall of the lateral ventricle; it is sometimes associated with tuberous sclerosis.
• neuroastrocytoma : a glioma composed mainly of astrocytes, closely resembling an astrocytoma and most commonly found in the floor of the third ventricle and the temporal lobes, although it may arise in almost any part of the CNS
• nasal glioma : a tumor-like mass composed of ectopic neural tissue in the nasal cavity.
• optic glioma
• glioma retinae / retinoblastoma
• oligodendroglioma / oligodendroblastoma (2-5%) : a usually benign neoplasm derived from and composed of oligodendrocytes in varying stages of differentiation; the majority are seen in adults in the white matter of the cerebral hemispheres
• anaplastic oligodendroglioma
Laboratory examinations : CT detects isodensity or hypodensity area, calcifications and enhancement
Prognosis : 5-year OS = 60%
• mixed glioma : a glioma in which the cytological components are of more than one cell type
• oligoastrocytoma : the most common form of mixed glioma consisting of elements derived from astrocytes and elements derived from oligodendrogliocytes.
• ganglionic glioma / ganglioglioma / ganglioglioneuroma / neuroglioma ganglionare : a ganglioneuroma / gangliocytoma / ganglioma / neurocytoma / ganglionar, ganglionated, or ganglionic neuroma (benign neoplasm composed of nerve fibers and mature ganglion cells; regarded by many as a fully differentiated neuroblastoma) in the CNS
• papillary glioneuronal tumor (PGNT) may be regarded as a variant of ganglioglioma or as a complex variant of extraventricular neurocytoma and belongs to a wide group of benign, dysembryoplastic or even hamartomatous neuroepithelial tumors, which may differentiate into both, glial or neuronal direction
• pleomorphic astrocytoma may posses neurocytic differentiation
• desmoplastic infantile gangliogliomas (DIGs) are extremely rare cerebral mixed glial and neuronal (glioneural) tumors that may be regarded as complex superficial dural astrocytoma usually occurring in the first 4 years of age but exceptional cases have been reported in young adults. They are exclusively supratentorial (generally localised in parietal or temporal lobes), generally have a voluminous size, and are partially cystic with peripheral contrast enhancement. Histologically they are characterized by a divergent astrocytic and ganglionic differentiation and a prominent desmoplastic stroma; more primitive cells may be observed, which present a higher number of mitoses and these areas can mimic the features of malignant astrocytomas. At histological examination, this tumor exhibited extensive desmoplasia and comprised 2 types of tumoral cells: small cells with round nuclei, positive for NSE, neurofilaments and synaptophysin and sometimes presenting typical morphological features of neuronal differentiation, and large cells with abundant eosinophilic strongly staining for GFAP. DIGs are a distinct form of developmental neuroepithelial tumour, probably arising from neural progenitor cells in subcortical zone along with mature subpial astrocytes : the absence of p53 protein expression suggests that DIG probably has different molecular genetic pathways from other supratentorial astrocytomas. Total resection, if possible, is the treatment of choice, without further adjuvant therapy. After incomplete resection, adjuvant chemo-and/or radiotherapy is generally applied, despite the potential negative side effects in such young patients. A review of the literature suggest that in most DIGs adjuvant therapy is not justified even after incomplete resection. After tumor recurrence a second surgical intervention should be considered instead of adjuvant therapy. An exception may be made for rare, deep-seated DIGs, which are more aggressive and have a poorer outcome.

Prognosis : DIGs have generally a good prognosis: recurrence-free intervals of up to 14 years have been reported and spontaneous disappearance of tumor residuals has also been described, possibly attributable to the induction of apoptosis.
• DNT may present gliomatous areas (complex DNT)
• desmoplastic cerebral astrocytoma of infancy / desmoplastic infantile astrocytoma
• DNT-like neoplasm of septum pellucidum
• glioneurocytic tumor with neuropil rosettes / rosetted glioneuronal tumor
• papillary ganglioneuroma or glioneuronal tumor
• sympathicoblastoma / sympathicogonioma / sympathoblastoma / sympathogonioma : a neuroblastoma arising in one of the ganglia of the sympathetic nervous system
• dysembryoplastic neuroepithelial tumor (DNT / DNET) are an important cause of refractory partial epilepsies. They usually occur within dysplastic cortex and tend to affect the temporal lobes. DNT of the posterior fossa is a very rare entity. The EEG of these patients is characterised by slowing and/or epileptiform abnormalities with a multifocal distribution. Children with DNT and epilepsy may benefit from surgical management; however, seizure outcome is not always favorable. Although the majority of children remain seizure free after surgical excision of DNT, a considerable number have recurrent seizures. Short-term outcome is influenced by older age at surgery and longer duration of epilepsy. Residual tumor is a significant risk factor for poor seizure outcome. Recurrent tumor can occur.
• mixed glioblastoma-cerebral neuroblastoma (supratentorial primitive neuroectodermal tumors (PNET)).
• medulloblastoma (4%; 20% of childhood brain cancers) : a malignant, highly radiosensitive cerebellar tumor composed of undifferentiated neuroglial cells and usually considered a type of neuroepithelial tumor. Most medulloblastomas occur in children and arise in or adjacent to the roof of the fourth ventricle

Pathogenesis :
• Notch2 is amplified in 15% of  medulloblastoma and promotes cancer cell growth by 27%. Inhibitors like DFK-167 reduce growth of cancerous cells in culture by 80%, although unwanted side effects and dosing problems may make it a poor choice for treating human brain cancer^ref. In 80% of the medulloblastomas there are lower levels of Notch1 gene products compared to Notch2^ref. Notch1 proteins normally provide a brake on growth of medulloblastoma cells and blocking their activation would cancel out some of the drug’s effects. They are, in some cases, associated with inappropriate activation of the Hedgehog (Hh) signalling pathway. overexpression of the polycomb group gene B lymphoma Mo-MLV insertion region (mouse) (Bmi1) promotes cell proliferation and induces leukaemia through repression of Cdkn2a (also known as ink4a/Arf) tumour suppressors. Conversely, loss of Bmi1 leads to haematological defects and severe progressive neurological abnormalities in which de-repression of the ink4a/Arf locus is critically implicated. Bmi1 is strongly expressed in proliferating cerebellar precursor cells in mice and humans, where it is essential for cerebellar development and is overexpressed in human medulloblastomas.
• there is a striking amplification of genetic coding representing a 28-fold increase in base pairs of DNA in that specific region of chromosome 14 in 60-70% of medulloblastoma cells : multiple extra copies of OTX2 gene, had been switched back on among tumor cells removed from patients with medulloblastoma brain tumors^ref. All trans-retinoic acid or ATRA, suppressed growth and induced cell death among the OTX2-laden tumor cells. More than half of medulloblastomas grown in the laboratory responded to ATRA treatment. RNAi knocked down OTX2 expression and killed the tumors cells which expressed OTX2. In contrast, the RNAi did not do any damage to the cells which did not express OTX2^ref
Microscopic anatomy : Homer Wright rosette
Therapy : surgery + adjuvant radiotherapy, VEGFR2 inhibitors. Standard surgery and radiation for medulloblastoma cures approximately 60% of children, but often results in many neurological and learning disabilities
Prognosis : 5-year OS = 60-85%
• medulloepithelioma / neurocytoma / neuroepithelioma : a rare type of neuroepithelial tumor, usually found in the brain or retina, composed of primitive neuroepithelial cells lining the tubular spaces
• diktyoma / dictyoma
• central neurocytoma : most neurocytomas are well differentiated, being associated with better long-term survival than the more aggressive atypical lesions. Neurocytomas are rare neuronal tumours, and are defined as tumours comprising cells with neuronal differentiation; they commonly arise in the ventricles derived from precursor cells of subventricular matrix. However some patients with neoplasms with histologic atypia and elevated proliferation potential may have a poor outcome. Treatment of choice is complete surgical excision. Adjuvant therapy is reserved for patients with residual or recurrent lesions including reoperation, radiotherapy or chemotherapy. Atypical extraventricular neurocytomas are characterized by an MIB-1 labeling index >3% or atypical histologic features.
• cerebellar liponeurocytoma is characterized by areas of lipomatous differentiation and apparently by a favorable prognosis
Pathogenesis :
• PIK3CA mutations are known to occur in as much as 30% of colorectal and gastric cancers and glioblastomas and they are also present, to a lesser extent, in breast and lung cancer. A cluster of 13 mutations on 2 particular areas of the PIK3CA gene, exons 9 and 20, have been identified in 14% of anaplastic oligodendrogliomas, 5% of medulloblastomas, 5% of glioblastomas and 3% of anaplastic astrocytomas. No PIK3CA mutation variants are found in samples of ependymomas or low-grade astrocytomas. 9 of the 11 PIK3CA mutations are consistent with alterations observed in the colorectal cancers. 2 additional, new mutations are also observed.
• 1p deletion^ref :
• complete hemizygous losses of 1p, which are tightly associated with 19q loss and oligodendroglial phenotype : longer overall and progression-free survival (p < 0.0001)
• partial 1p deletions mainly observed in astrocytic tumors and not associated with 19q loss : pejorative prognostic value
• gliosarcoma : a glioma, usually a glioblastoma multiforme, that has sarcomatous components.
• central primitive neuroectodermal tumors (PNET)
• pituitary adenomas (5-10%)
• craniopharyngioma (1-2%)
• acoustic neurinoma (2-5%)
• intrasellar glioneuronal hamartoma with GH-cell pituitary adenoma.
• meningioma : a benign (15-20%) or malignant (sarcomatous/angioblastic : < 1%), slow-growing tumor of the meninges, usually next to the dura mater, probably arising from cells associated with arachnoid villi. It may erode the skull or cause hyperostosis, and intracranial hypertension is common.
• intracranial meningioma (IM)
• leptomeningioma : a tumor of the leptomeninges
Risk factors :
• hormonal disorders
• roentgen irradiation
• hereditary-genetic factors
• cranio-cerebral trauma
Anatomic location :
• meningioma of the olfactory groove : a meningioma located in the ethmoid fossa (olfactory groove); symptoms include anosmia, visual defects including Kennedy's syndrome, and psychic disturbances due to upward compression of frontal lobes and downward displacement of anterior cerebral artery (moria : an abnormal tendency to joke, particularly inappropriately)
• convexity meningiomas : a diverse group of meningiomas located within the sulci of the brain, usually anterior to the rolandic fissure; they may be silent for long periods. Symptoms include seizures, weakness of the arm and face, and personality changes.
• parasagittal meningioma : a meningioma located next to the superior sagittal sinus, often growing into the sinus and obliterating it; symptoms are variable according to location and may include seizures, leg weakness or paresthesias, and visual field defects
• falcine meningioma / falx meningioma : a meningioma in or near the falx cerebri; symptoms are similar to those of a parasagittal meningioma.
• posterior fossa meningioma : a meningioma in the posterior cranial fossa
• cerebellopontine angle meningioma : located in the cerebellopontine angle; it may cause cerebellopontine angle syndrome
• clival meningioma : located over the middle or rostral part of the clivus, compressing pons and bulb, and dislocating basilar artery; symptoms include trigeminal (V) nerve paralysis, seventh, or eighth cranial nerve and gait ataxia

Therapy : transoral surgical ablation
• tentorial meningioma : located on the tentorium cerebelli; it may cause seizures, visual hallucinations, and visual field deficits.
Symptoms and signs : Ménière-like syndromes
• meningioma of the sphenoid ridge : a meningioma located along the sphenoid ridge

Symptoms & signs :
• trigeminal neuralgia / tic douloureux
• unilateral exophthalmos progressing to blindness
• Kennedy's syndrome
• superior orbital fissure syndrome
• suprasellar meningioma / meningioma of the tuberculum sellae : a meningioma located above the sella turcica near its tuberculum; because of its proximity to the optic chiasm, it pushes against the optic nerve and causes bitemporal hemianopia and other visual deficits
Histologic features (have not been shown to influence clinical behavior) :
• angioblastic meningioma / angioblastoma : a meningioma with many blood vessels, which may vary in size from capillary to cavernous
• cystic meningioma : a meningioma containing or adjacent to cysts.
• fibroblastic meningioma / fibrous meningioma / meningofibroblastoma : a meningioma characterized by fibrous tissue with bundles of spindle cells
• transitional meningioma : a meningioma histologically intermediate between the meningotheliomatous and fibroblastic types; calcification of whorls of cells often causes psammoma bodies (psammomatous meningioma / psammoma)
• meningotheliomatous meningioma / syncytial meningioma / meningothelioma : a meningioma characterized by plump cells with poorly defined boundaries, sometimes in whorls or lobules
Therapy :
• neoadjuvant embolization of meningeal vessels
• partial intraneoplastic surgical ablation to prevent damage to vital parenchyma
• adjuvant stereotaxic radiosurgery(conventional radiotherapy is useless due to very low mitotic index)
• many express estrogen receptor and progesterone receptor => hormonal therapies
• leptomeningeal mucosal melanoma (LMM) / meningeal melanocytoma (< 1%)
• cranial LMM
• cerebellopontine angle
• spinal LMM
• lumbar meninges
Epidemiology : < 1% of all pediatric malignancies; first described as an entity different from pigmented meningiomas and schwannomas in 1972
Aetiology : neurocutaneous melanosis (NCM)
Pathogenesis : usually tend to locate on leptomeninges and to extend into the adjacent neural compartment rather than the outside (atypical varieties also accompanied by identical lesions in both surrenal glands and renal capsule - structures containing neural-crest-derived cells outside the CNS - have entire dural origin and extradural growing pattern with destruction of the adjacent bone)
Symptoms & signs : intracranial hypertension resulting from hydrocephalus secondary to tumoral obliteration of basal cisterns, but the passage of time from the initial symptomatology to diagnosis is frequently delayed
• neuroblastoma : supratentorial (see neuroblastoma in PNS)
• Hutchison syndrome : neuroblastoma with metastases to the skull
• ependymal tumors
• ependymoblastoma / malignant ependymoma : a rare malignant tumor composed of primitive ependymal cells. Some neuropathologists classify such tumors as malignant forms of ependymoma but some consider them a type of neuroepithelial tumor

Therapy : VEGFR2 inhibitors
• ependymal glioma / ependymoma / ependymocytoma (2-5%) : a neoplasm composed of differentiated ependymal cells; most ependymomas are slow growing and benign, but malignant varieties occur; usually in peritrigonal ventricular area
• subependymoma : an ependymoma in which there is a diffuse proliferation of subependymal fibrillary astrocytes among the ependymal tumor cells. A few are malignant and others cause obstructive hydrocephalus, but many are clinically silent and are discovered only at autopsy.
Laboratory examinations :
• CT detects mixed density area, enhancement, and ring sign
• ependymal rosette : glandlike structures consisting of tumor cells with epithelial features and having long, slender processes extending into a lumen
Therapy : surgery + adjuvant radiotherapy
• choroid plexus papilloma (< 1%) : a slow-growing benign tumor of the choroid plexus that often invades the leptomeninges. In children it is usually in a lateral ventricle but in adults it is more often in the fourth ventricle. Hydrocephalus is common, either from obstruction or from tumor secretion of CSF. If it undergoes malignant transformation it is called a choroid plexus carcinoma.
• primary central nervous system lymphoma (PCNSL) (1-2%; usually in cerebral hemispheres and basal nuclei)
• germ cell tumors (GCT) (< 1%)
• chordoma / chordocarcinoma / chordoblastoma / chordosarcoma  / chordoepithelioma : a malignant tumor arising from the embryonic remains of the notochord, usually along the sella or in the sacrococcygeal region
• teratoid/rhabdoid tumor (ATRT) is a rare aggressive cancer that arises either in the cerebellum or cerebral cortex and often spreads through the CNS. While children with ATRT under 3 years of age have a dismal prognosis, children > 3 years can be treated with radiotherapy followed by chemotherapy using alkylating agents (cyclophosphamide, cisplatin, vincristine and etoposide). Older children who experienced relapse of ATRT could be saved using ICE chemotherapy (ifosfamide, carboplatin- and etoposide).
• epidermoid cyst / epidermoid / epidermoidoma / epidermoid tumor : a benign tumor formed by inclusion of epidermal elements, especially at the time of closure of the neural groove and located in the skull, meninges, or brain; it may grow gradually because of accumulations of desquamated debris and may become calcified
• congenital cholesteatoma (< 1%) : a benign tumor resulting from inclusion of epidermal elements at the time of closure of the neural groove; it may be in or near the ear but more often is in the form of an intracranial cholesteatoma
• intracranial cholesteatoma : a congenital cholesteatoma that is a type of epidermoid cyst of the skull, meninges, or brain; it grows slowly, often in the cisterns. Symptoms vary depending on what part of the brain is under pressure, but may become life-threatening.
• CNS metastases :
• leptomeningeal metastases

Aetiology :
• lung cancer (24%)
• breast cancer (41%)
• melanoma (12%)
• gastrointestinal cancers (13%)
• other cancers (10%)
• brain metastases :

Aetiology :
• lung cancer (40%)
• breast cancer (19%)
• melanoma (10%)
• gastrointestinal cancers (7%)
• genitourinary cancers (7%)
• other cancers (17%)
Pathogenesis : intracranial hypertension
Symptoms & signs : focal neurological disturbances (e.g. seizures) unless in "mute" areas (eg. frontal or temporal lobes), headache (related to diameter and grade of cerebral edema)
Laboratory examinations :
• if CT detects 1 metastasis => practice MRI (more sensitive)
• if CT detects > 1 metastases => radiotherapy + chemotherapy
Therapy :
• neurosurgical metastasectomy
• radiotherapy + GR agonists + diuretics + anticonvulsivants
• if < 3 metastases : stereotaxic radiotherapy (SRT) (maximum bundle diameter = 0.25 cm) 30 Gy
• if > 3 metastases : hypofractionated whole-brain radiotherapy (WBRT) / whole-brain irradiation (WBI) (3 Gy per fraction (1.5 Gy from right and 1.5 from left) for 10 days in 2 weeks
• spinal metastases :

Aetiology :
• hematogenous metastases from extra-CNS tumors (80%) : 5-10% of all solid tumors cause spinal metastases
• endoliquoral metastases from primary CNS tumors (20%), expecially primary central nervous system lymphoma (PCNSL)
Localization :
• extradural (50%)
• lung cancer (11-18%)
• breast carcinoma (9-24%)
• melanoma (4%)
• gastroenteric cancers (6%)
• CRC, cervical adenocarcinoma, ovarian cancers, sarcomas (< 5%)
• genitourinary cancers (18%)
• other cancers (30%)
• lymphomas (6%)
• prostate adenocarcinoma and renal cell carcinoma (5%)
• subarachnoid
• intradural
• medulloblastoma
• germinomas
• pinealocytoma
• breast cancer
• lung cancer
• vertebral body => osteolysis => vertebral compression
• radicular
• lumboaortic lymphadenitis
• testicular cancer
Anatomical localization :
• thoracolumbar (47%)
• proximal thoracic region (38%)
• cauda equina (13%)
• cervical segment (2%)
Pathogenesis : demyelinization, ischemia, venous block => vasogenic edema
Symptoms & signs : lumbalgia (90% at onset), sensory, autonomic and motor deficiencies (reversible only if rapidly treated)
Therapy :
• radiotherapy with direct posterior irradiation field or opposite lateral irradiation fields (for cervical rachid; E = 4-6 MeV; length = 6-12 cm)+ GR agonists
• if < 3 metastases : stereotaxic radiotherapy (SRT) (maximum bundle diameter = 0.25 cm) 30 Gy
• if > 3 metastases : hypofractionated radiotherapy (3 Gy per fraction (1.5 Gy from right and 1.5 from left) for 10 days in 2 weeks
• 76% experience pain reduction vs. 36% in decompressive laminectomy; improvement of motor (48.6%) and visceral (40%) deficiencies lasting for 8 months; 80% of people still able to walk at diagnosis maintain ability, while 20-30% of people unable to walk at diagnosis reacquire ability.
• neurosurgery (spondylodesis with titanium bars : esential to treat pathologic fractures, histological diagnosis if the primary tumor is unknown, and radioresistant tumors) + adjuvant radiotherapy
• meningeal or leptomeningeal carcinoma or carcinomatosis : carcinomatous infiltration of the meninges, particularly the pia and arachnoid; it may be primary or secondary, especially metastatic from small-cell lung carcinoma (SCLC) or breast carcinoma
Summary of possible histological tumor types according to localization :
• supratentorial tumors :
• extraaaxial supratentorial tumors
• meningioma
• epidermoid
• chordoma
• neurinoma
• craniopharyngioma
• intraaxial supratentorial tumors
• gliomas
• ganglioglioma
• neuroblastoma
• pinealocytoma
• pinealoblastoma
• germinomas
• teratoma
• dermoid
• lipoma
• primary central nervous system lymphoma (PCNSL)
• brain metastases
T staging :
• T1 : unilateral tumor < 5 cm
• T2 : unilateral tumor > 5 cm
• T3 : tumor infiltrating or invading ventricular system
• T4 : tumor passing the midline and invading the contralateral cerebral hemisphere or diffusing subtentorially
• subtentorial tumors
• extraaxial subtentorial tumors
• neurinoma
• meningioma
• epidermoid
• dermoid
• lipoma
• chordoma
• choroid plexus papilloma
• glomus jugulare tumor
• brain metastases
• intraaxial subtentorial tumors
• astrocytoma (babies and elderlies)
• medulloblastoma (babies)
• ependymoma
• hemangioblastoma
• brain metastases (elderlies)
• intradural spinal tumors :
• extramedullary tumors (menisci at imaging) :
• primary tumors :
• neurinoma and neurofibroma (cervical > lumbar > dorsal)
• meningioma (dorsal > cervical > lumbar)
•  spinal metastases
• intramedullary tumors :
• gliomas (90%)
• astrocytomas (cervical > dorsal > lumbar; eccentric fusiform dilatation with cysts)
• ependymoma (lumbar > dorsal > cervical; centromedullary fusiform dilatation, with pseudocapsule and cysts with hemosiderin depots at upper pole)
• spinal hemangioblastoma : a hemangioblastoma of the spinal cord, usually small and encapsulated and in an intramedullary location; an high-flow vascular structure.
• vertebral hemangioendothelioma : a benign vascular tumor of the spine, seen primarily in middle-aged adults; usually asymptomatic, but in time it may expand or hemorrhage and compress the spinal canal and cord.
T stage :
• T1 : unilateral tumor < 3 cm
• T2 : unilateral tumor > 2 cm
• T3 : tumor infiltrating or invading the ventricular system
• T4 : tumor passing the midline and invading the contralateral hemisphere or spreading supratentorially
No lymphatics => no N stage ! Endoventricular metastases.
AJCC stage groupings :
• stage IA : T1, M0, G1
• stage IB :
• T2, M0, G1
• T3, M0, G1
• stage IIA : T1, M0, G2
• stage IIB :
• T2, M0, G2
• T3, M0, G2
• stage IIIA : T1, M0, G3
• stage IIIB :
• T2, M0, G3
• T3, M0, G3
• stage IV :
• any T, M0, G4
• T4, M0, any G
• any T, any G, M1
Summary of most common infant CNS tumors :
• medulloblastoma
• neuroblastoma
• pilocytic astrocytomas
• craniopharyngioma
• pinealocytoma / pinealoblastoma
• brainstem astrocytoma
Pathogenesis : vasogenic and cytotoxic edema => endocranial hypertension
Symptoms & signs (in addition to those due to endocranial hypertension):
• superficial tumors :
• rolandic cortex : contralateral hemiparesis
• frontal cortex : psychic disorders, motor aphasia
• parietal cortex : stereoagnosia
• temporo-occipital carrefour (Meyer bundle) : reduced contralateral visual field
• temporal cortex : receptive aphasia
• occipital cortex
• deep tumors
• nuclei of base : parkinonism (hemiparesis, tremor, bradykinesia)
• midline :
• chiasma or chiasmatic syndrome : a syndrome indicative of lesion affecting the optic chiasma: impairment of vision, limitations of the field of vision (bitemporal heteronymous hemianopia), central scotoma, headache,vertigo, and syncope.
• infundibulum : dysendocriniae
• isthmus encephali : butterfly glioblastomas arising in one hemisphere and extending in the other) : stupor
• Bruns' sign or syndrome : intermittent headache, vertigo, nausea and vomiting, and visual disturbances on sudden movement of the head, characteristic of cysticercus infection of the fourth ventricle, lesion of the fourth ventricle, or tumors of the midline of the cerebellum and third or lateral ventricles
• sylvian aqueduct syndrome / Koerber-Salus-Elschnig syndrome : impairment of vertical gaze, retraction nystagmus, convergence nystagmus, convergence spasms, and poor or absent reaction of the pupils (which are usually of normal size) to light or near vision. It is caused by a neoplasm, inflammation, or vascular lesion adjacent to the periductal gray matter of the aqueduct of Sylvius
• Bristowe's syndrome : a series of symptoms caused by a tumor of the corpus callosum, including hemiplegia and apraxia.
• cavernous sinus syndrome / Foix syndrome / Jefferson's syndrome
• cerebellopontine angle syndrome
• Garcin's half base syndrome : unilateral paralysis of all or most of the cranial nerves due to a tumor at the base of the skull or in the nasopharynx
• Negri-Jacod syndrome or triad / petrosphenoid syndrome : unilateral blindness and ophthalmoplegia with facial hemiplegia or trigeminal neuralgia as a result of damage to the second, third, fourth, trigeminal (V) nerve paralysis, and sixth cranial nerves, often from a tumor or other lesion just behind the sphenoid bone
• Foster-Kennedy's syndrome
Laboratory examinations : diagnosis of type of space-occupying lesion, intracranial hypertension, focal signs, localization (supratentorial/subtentorial, intradural/extradural), cerebral edema, mass effect, and histological type according to age and location)
• CT in emergencies (they are not accidentaliomas) looks for density, necrosis, cysts, edema, enhancement, ring sign, and hermorrhages.
• MRI in diagnostics (better assessment of posterior fossa and skull base)
• presurgical cerebral angiography to assess infiltration or dislocation of blood vessels
• stereotactic biopsy (side effect : brain hemorrhages in 1-2%)
Differential diagnosis with skull and rachid tumors according to direction where cerebral cortex is pulled.
Therapy :
• partial surgical ablation (cytoreduction) eventually followed by adjuvant radiotherapy for radiosensitive tumors (i.e. medulloblastoma, germinomas, pinealoblastoma, choroid plexus papilloma, anaplastic ependymoma, and primary central nervous system lymphoma (PCNSL), and partially glioblastomas, anaplastic astrocytomas, malignant oligodendrogliomas, and grade I-II oligoastrocytomas)
• operatory microscope to remove tumor tissue from the inner part to the outer part
• microsurgery
• US aspirator (vaporize tumor tissue but not blood vessels)
• laser photocoagulation or photoevaporation
• neuronavigator
• radical radiotherapy or stereotaxic radiosurgery for unresectable patients with radiosensitive tumors
• chemotherapy for patient who relapse after adjuvant radiotherapy : lipophilic nitrosoureas (BCNU and CCNU)
• palliation :
• high-dose steroids (dexamethasone up to 16-20 mg/die)
• antiepileptic drugs (phenytoin, phenobarbital)
Web resources :
• Brain tumor
• Brain tumor trials and treatments
• American Brain Tumor Association Home Page
• American Brain Tumor Association Literature
• The Brain Tumor Society
• infections of CSF shunts

Aetiology :
• Staphylococcus epidermidis (36-80%)
• Staphylococcus aureus (25%)
• Enterobacteriaceae (5-10%)
• Propionibacterium spp. (2-35%)
• traumatic brain injury (TBI) : a nondegenerative, noncongenital insult to the brain from an external echanical force, possibly leading to permanent or temporary impairments of cognitive, physical and psychosocial functions with an associated diminished or altered state of consciousness

Epidemiology : annually in the US 1.5 million Americans sustain a TBI,  80,000 people experience the onset of long-term disability following TBI, and 50,000 die as a result of TBI. Incidence of TBI outnumber breast cancer (175,000), spinal cord injury (11,000), HIV/AIDS (16,273), and multiple sclerosis (10,400). 5.3 million Americans live with TBI-related disabilities. Survivor typically faces 5-10 years of intensive services - estimated cost US$ 4 million/year. Economic cost of TBI in US estimated US$ 48 billion / year
Aetiology :
• motor vehicle accidents, expecially among whites in the USA (50%)
• falls (20-30%, the most common cause in individuals aged > 75 yrs)
• firearm injuries (12%, leading cause among individuals aged 25-34 yrs)
Pathogenesis :
• primary or direct injuries result from what has occurrred to brain at the time of the injury
• skull injuries
• linear fractures of roof or base
• comminute fracture with deepening of bone fragments or foreign bodies
• dural laceration => cerebrospinal fluid fistula : a fistula between the subarachnoid space and a body cavity, with leakage of CSF
• rhinoliquorrhea / CSF rhinorrhea
• reservoir sign : the ability of a patient to produce CSF rhinorrhea at will by moving the head, indicating presence of a fistula with pooling in a paranasal sinus.
• cerebrospinal fluid otorrhea
• craniosinus fistula : a fistula between the intracranial space and one of the paranasal sinuses, permitting the escape of CSF into the nose
Other causes include bone erosion caused by a mass or other pathologic process
Complications : infectious meningitis and intracranial hypotension
• cerebral laceration
• brain contusion
• hematoma
• infection
Therapy : removal of fragments and dural plastic surgery
• intraosseous components
• laceration of dural arteries or veins, often by fractured bones (often middle meningeal artery and its branches, sometimes by diploic veins in the skull's marrow) => frontotemporal extradural hematoma => transtentorial herniation
• venous sinuses of dura mater : not an emergency
• bridging veins joining cortical veins to venous sinuses of dura mater : that space increases in cerebral atrophy (more common in elderlies due to cerebral arteriosclerosis) and veins are put into traction, so that some may break during dislocation of the encephalon => subdural hemorrhage
• cerebral parenchyma
• concussion of the brain (functional damage : syncope and amnesia)
• brain contusion
• diffuse axonal injury to the white matter of the brain can be caused by ischemia or strains during high-speed acceleration/deceleration produced in lateral motions of the head
• intracerebral hematoma
• secondary brain injuries are due to altered cerebral autoregulation (linear instead of sigmoid responsiveness of CBF between 50-100 ml/100 g/min to variation in MAP) => hyperemia =>
• vasogenic cerebral edema
• intracranial hypertension
• localized => cerebral hernias
• diffuse => decreased cerebral blood flow => cerebral hypoxia => hypoxic encephalopathy => cytotoxic cerebral edema
It may be revented by good patient care. Hyperventilation decreases perfusion of the brain tissue. Protect airway, give oxygen, maintain blood pressure, control temperature, glycemia, volemia and ICP
Types :
• closed head injury
• acceleration/deceleration :
• if a moving object hits a movable head (e.g. head gets hit with a bat)
• if a moving head hits something stationary (e.g. if you have a car wreck and your head hits the dashboard)
• shaken type of movement (e.g. shaken baby syndrome when head rocks back and forth in skull)
2 types are :
• linear : brain moves straight along a linear opath
• angular : brain rotates at an angle, twists, or rolls
• non-acceleration : much more rare, referred to as a crushing injury; if a moving object hits a head that is fixed (e.g. if a car falls on head while you're working under it)
• penetrating/closed head injury : skull is no longer intact, part of skull or debris gets into the brain
• low velocity : an example is if you get hit so hard with a baseball that it breaks skull and causes part of it to lay on the brain
• high velocity : an example is if during a gunshot wound the bullet penetrates the skull and goes into the brain matter
Systemic symptoms & signs : traumatic encephalopathy
• brain contusion : contusion with loss of consciousness as a result of direct trauma to the head, usually associated with fracture of the skull. It is due to ex vacuo repercussion : laceration against asperities of anterior and posterior cranial fossas (coup or proximal contusion) and hot-spots located opposite to the site of direct injury (contrecoup or remote contusion). The amount of energy dissipated at the site of direct impact determiens whether the ensuing contusion if of the coup or contrecoup type. Most of the energy of impact from a small hard object tends to dissipate at the impact site, leading to a coup contusion. On the contrary, impact from a larger object causes less injury at the impact site since energy is dissipated at the  beginning or end of the head motion, leading to a contrecoup contusion
• concussion of the brain / commotio cerebris : loss of consciousness as the result of a blow to the head or sudden movement of the brain within the head as from violent shaking of the head. In mild concussion (mild diffuse axonal injury) there is transient loss of consciousness with possible impairment of higher mental functions, such as retrograde amnesia and emotional lability. In severe concussion there is prolonged unconsciousness with impairment of the functions of the brain stem, such as transient loss of respiratory reflex, vasomotor activity, and dilatation of the pupils (see postconcussional syndrome)
• closed head syndrome (the complex of symptoms characteristic of cerebral injury without cranial penetration)
• head or chest trauma-induced apnea or bronchoinhalation => hypoxia and hypercapnia worsening vasogenic cerebral edema
• internal or external hemorrhage (spleen, femoral, pelvic fracture with vascular lesions) => systemic arterial hypotension
=> cerebral hypoxia => hypoxic encephalopathy => cause of death in 25% of trauma patients and 50% of  motor vehicle accidents; significant long-term disability. Patients with TBI have been described as the "walking wounded"^ref owing to their lingering neuropsychological problems. Lishman studied 670 cases of head injuries from the Second World War and reported that "simple measures of the amount of brain damage... were indeed related to the amount of psychiatric disability encountered one to five years later."^ref As many as 77% of patients with TBI have been given a diagnosis of depression^ref. Mood disorders may result in the restriction of social contact as well as increased loneliness and are major barriers to functional and social rehabilitation^ref. Technological improvements and better emergency medical care have reduced the incidence of severe TBI while increasing the numbers of patients with mild or moderate TBI. Such patients are more adversely affected by their emotional problems than by their residual physical disabilities^ref. It is important to screen these patients for depression and to conduct neuropsychological testing soon after head injury in order to facilitate treatment and reentry into the community, as well as to optimize the long-term outcome. The boundary between mild and moderate TBI is 1 hour of loss of consciousness and the cutoff between moderate and severe TBI is 1 day of loss of consciousness. However, there is variation in the classification of mild TBI. Some authors (American Congress of Rehabilitation Medicine. Definition of mild traumatic brain injury. J Head Trauma Rehabil 1993;8:86-87) use 30 minutes of loss of consciousness as the criterion, and others 20 minutes^ref, and still others (International classification of diseases, hospital edition, 9th rev., clinical modification: ICD-9-CM. 6th ed. Vol. 1, 2 & 3. Los Angeles: Practice Management Information Corporation, 2002) define "brief" loss of consciousness as lasting < 1 hour. In practice, we more often use the duration of post-traumatic amnesia to determine the level of severity, since that information is available to us more often than are data on loss of consciousness.
Laboratory examinations :
• GCS
• Glasgow Outcome Scale : a scale used to describe outcome after serious head injury, based on the general level of social functioning regained. Patients are assigned to one of 5 categories :
• good recovery
• moderately disabled
• severely disabled
• vegetative
• dead
• rapid trauma survey
• note level of consciousness (alert, verbal, and pain unresponsiveness (AVPU), secure airway and prtect cervical spine
• assess breathing (do not allow the patient to become hypoxic)
• assess circulation : control major bleeding and prevent hypotension
• transport decision and interventions
• do brief neurological examination and GCS if altered LOC
• detailed exam :
• vital signs
• sample history
• head-to-toe exam, including neuroogical and GCS, fluid leak, battle sign
• further bandaging and splinting
• continuous observation
• serial neurologic examinations :
• circulation/respiration
• intracranial pressure (ICP) (if GCS <= 8) : intraventricular >> intraparenchymal >> intradural; eventually therapeutic liquorocentesis
• radiologic studies
• laboratory studies (fibrinogen and platelets are significantly decreased in TBI patients)
• monitoring brain metabolism :
• jugular venous catheter^{ref1, ref2} : possible better outcome in adults
• jugular bulb venous oxygen saturation (SjvO₂)
• arteriojugular venous oxygen difference (AJVO₂)
• cerebral metabolic rate for oxygen (CMRO₂)
• brain sensors : brain tissue pH, PaO₂ (ti-pO2), PCO₂, lactate
Complications : post-traumatic epilepsy worsens the clinical conditions via dyspnea and cerebrovascular hypertension
Necroptic findings : plaques jaunes [Fr. “yellow plaques”] : old traumatic injuries on the surface of the brain, appearing as depressed, yellowish-brown patches on the crests of the gyri.
Therapy : prompt recognition and treatment may improve outcome; all patients with head or facial trauma have cervical spine injury until proven otherwise
• respiratory support : maximize oxygenation with PEEP = 4-5 cmH₂O. Hypoxemia is predictive of morbidity^ref. Neurogenic pulmonary edema and concurrent lung injury => PEEP > 10 cmH₂O increases ICP and may impair cerebral venous return^{ref1, ref2}
• circulatory support : management aimed at maintaining CPP = MAP- ICP > 70 mmHg ^ref: the number of hypotensive episodes is related to outcome^ref. Children (particularly < 24 months old) are at increased risk of cerebral hypoperfusion after TBI. Low CBF is predictive of mortality^ref. MAP should be increased up to 120 mmHg
• management of pain and agitation with opiates and benzodiazepines => difficult to assess neurological examination, monitor for hypotension, short-acting agents (e.g. remifentanyl has t_1/2 = 10 minutes) beneficial, neuromuscular blockade if ARDS. Do opiods increase CBF ? Increased ICP with concurrent decreased MAP and CPP has been documented. Elevation of ICP is transient and there is no resulting ischemia from decreased MAP/CPP^ref.
• lowering intracranial hypertension : ICP is usually low (< 15 mmHg). If the ICP goes up (> 20-25 mmHg) the BP must go up (between 80-90 mmHg) to maintain the CPP
• reduce edema
• diuretic therapy :
• osmotic diuretic (hyperosmolar therapy) : mannitol 18% (0.25-1 g/kg or 100 mL every 4 hrs) increases osmolarity, induces vasoconstriction (adenosine) / less effect if autoregulation is impaired and if CPP < 70. Initial increase in blood volume, BP and ICP followed by a decrease. Questionable mechanisms of lowering ICP^ref . Contraindications : hyperosmolarity > 320 mOsm; renal failure
• loop diuretics : furosemide decreases CSF formation, decreases systemic and cerebral blood volume (impairs sodium and water movement across BBB), may have best effect in conjunction with mannitol^{ref1, ref2}
• hypertonic fluid administration : reduction in mean ICP in children 2 hours after bolus administration of 3% saline^ref. ICP is lowered by resuscitation with hypertonic saline vs.lactated ringers solution in an animal model^ref. Reduction in mean ICP within 12 hours of continuous infusion of 3% saline acetate solution. Little continued benefit after 72 hrs of treatment : goal is natremia = 145-155 mEq/L^ref.
• GR agonists have been used to treat head injuries for > 30 years but are noit recommended. In 1997, findings of a systematic review suggested that these drugs reduce risk of death by 1-2%. The CRASH trial showed there is no reduction in mortality with methylprednisolone in the 2 weeks after head injury. The cause of the rise in risk of death within 2 weeks is unclear^ref.
• promote venous return by keeping neck midline and elevating head of bed by 20°^{ref1, ref2, ref3}
• reduce nursing activity associated with elevated ICP (turning, suctioning, bathing, awakening, cough during bronchoaspiration)^ref
• assisted mechanical hyperventilation to lower P_CO2 down to 25 mmHg => reflex vasocostriction. Hyperventilation is no longer recommended for treatment of head injury except in the case of herniation syndrome as a lot of evidences support normoventilation^{ref1, ref2, ref3, ref4, ref5, ref6, ref7}. Hyperventilation should be moderate and transient in the management ofvery acute elevation of ICP and preemptive for activities known to increase ICP, but no lower than 30-35 cmH₂O. Moderate hyperventilation (PaCO₂ < 30 mmHg) may be associated with worse outcome. Avoid even prophylactic hyperventilation in first 24 h post TBI to prevent ischemia
• presence, touch and voice of family/significant others does not significantly increase ICP and has been demonstrated to decrease ICP^{ref1, ref2, ref3}
• decrease cerebral metabolic rate => reduction in cerebral oxygen requirements
• chemoprophylaxis of post-traumatic epilepsy with barbituratesand phenytoin (15 mg/kg in bolus + 5 mg/kg for maintenance; therapeutic range of phenytoinemia = 11-20 mg/dL) is not recommended for the prevention of PTS. Options may be used to trat early PTS in high risk patients
• pentobarbital coma : adverse effects include hypotension and bone marrow dysfunction => used only after unsuccessful attempts to control ICP and maximize CPP with other therapies. Improved outcome not fully supported by research^{ref1, ref2}
• hypothermia for treatment of severe brain injuries (put patients on a cooling blanket at 32-33°C for > 48 hrs). Prevention and aggressive treatment of fever. Significant beneficial effect on neurologic outcome with transient, mild hypothermia (32-34°C for 24-48 hrs). Seizure incidence and ICP reduced. Hyperthermia produces deleterious effects on neuronal recovery and BBB integrity.
• evacuate hematoma
• drain CSF with ventriculostomy when possible (intraventricular catheters use is limited by degreee of edema and ventricular effacement)
• craniotomy (permanence, risk of infection, questionable benefit)
• surgical ablation of lacerated centre
Web resources :
• Traumatic brain injury at CDC
• Brain injury at CDC
• Bicycle-related head injuries at CDC
• neurovascular diseases
• Harting bodies : deposits of calcium (calcospherites) in the cerebral capillaries.
• cerebral amyloid angiopathy (CAA) / congophilic angiopathy : vascular amyloidosis affecting small and medium-sized arteries of the leptomeninges and cerebral cortex, resulting in microinfarcts or in parenchymatous hemorrhage


Aetiology :
• most cases are sporadic and occur most often in the elderly
• hereditary form with autosomal dominant inheritance due to E693Q mutation in the b-amyloid precursor protein (APP) / protease nexin-II. In contrast to Alzheimer's disease (AD), the brains of those affected by hereditary cerebral hemorrhage with amyloidosis–Dutch type (HCHWA-D) show few parenchymal amyloid plaques. In APP_Dutch mice and HCHWA-D human brain, the ratio of the amyloid-b₄₀ peptide (Ab₄₀) to Ab₄₂ is significantly higher than that seen in APPwt mice or AD human brain. Genetically shifting the ratio of Ab_Dutch40/Ab_Dutch42 toward Ab_Dutch42 by crossing APP_Dutch mice with transgenic mice producing mutated presenilin-1 redistributes the amyloid pathology from the vasculature to the parenchyma, emphasizing the differing roles of Ab₄₀ and Ab₄₂ in vascular and parenchymal amyloid pathology^ref
Symptoms & signs : asymptomatic or may result in recurrent cerebral hemorrhagic stroke or dementia.
• cerebellar hemangioblastoma: hemangioblastoma of the cerebellum, often cystic

Aetiology : an autosomal dominant form is associated with von Hippel-Lindau (VHL) syndrome
Symptoms & signs : secondary polycythemia due to ectopic EPO incretion
• intracranial aneurysm : any aneurysm situated within the cranium

Epidemioogy :  prevalence : 6%
Aetiology :
• brain, congenital cerebral or berry aneurysm (> 90%) : a saccular aneurysm of a cerebral artery, usually at the junction of vessels in the circle of Willis; its narrow neck of origin and larger dome resemble those of a berry. It is due to lack of inner elastic coat or hypoplasia of muscular coat
• Wyburn-Mason's syndrome
• degenerative aneurysm :
• arteriosclerotic aneurysm (7%) : a fusiform aneurysm
• septic or mycotic aneurysm (0.5%) : a peripheral aneurysm
• trauma (0.5%)
• neoplastic aneurysm from myxomas
Pathogenesis :
• degeneration of inner elastic coat
• Ehlers-Danlos disease
• fibromuscular dysplasia
• PKD
• hypoplasia of common carotid artery
• cerebrovascular hypertension
The aneurysm consists of a fundus and a neck, whose diameter may be
• < 3 mm
• 3-10 mm
• > 20 mm (large aneurysm)
• > 25 mm (giant aneurysm). Complications : cerebral ischemia or thrombosis => thrombembolism => cerebral ischemia
The muscular coat arrests at the neck while inner elastic coat continues into the neck, so that the wall consists of fibrous, intimal and adventitial coats
Localizations : arterial bifurcation
• 90% : anterior circle of Willis
• 30% : inferior cerebral artery (ICA)
• 30% : middle cerebral artery (MCA)
• origin of posterior communicating artery
• 30% : anterior comunicating artery (ACoA)
• suprasellar aneurysm : aneurysm of the internal carotid artery above the sella turcica.
• 10% : posterior circle of Willis
• 20% : multiple
Symptoms & signs : pulsating monolateral exophthalmos
Laboratory examinations : DSA and DSA> angio-CT
Therapy :
• surgical craniotomy and clipping : MRI-compatible Ti clips close the neck and the sac coagulates and undergo fibrosis
• endovascular treatment with platinum detachable coils (inserted via femoral artery) that induce thrombosis of aneurysm. It is recommended for aneurysms with
• Hunt-Hess grade > IIIA
• elderlies
• compromised general conditions
• critical location
• carotid-ophthalmic bifurcation and paraclinoid aneurysms
• apical or basilar (risk of closure of perforating arteries nourishing the brainstem)
• vertebrobasilar junction and posterior cranial fossa
23.5% of patients allocated to endovascular treatment are dead or dependent at 1 year, compared with 30.9% of patients allocated to neurosurgery, an absolute risk reduction of 7.4%. The early survival advantage was maintained for up to 7 years and was significant. The risk of epilepsy was substantially lower in patients allocated to endovascular treatment, but the risk of late rebleeding was higher^ref.
• early surgery
• advantages :
• decreased bleeding
• decreased late neurological deficiencies
• therapy within 3 hours
• disadvantages
• cerebral edema
• ischemic complications due to intraoperatory temporal-frontal divarication
• intraoperatory rupture
• limitations :
• advanced age
• giant aneurysm
• unfavorable site
• compromised general conditions
• incipient vasospasm
Guidelines :
• Hunt-Hess grade 1-3
• good general conditions => early surgery
• compromised genral conditions => endovascular treatment
• Hunt-Hess grade 4-5 :
• without hematoma => endovascular treatment +/- surgical clipping
• with hematoma => early surgery
Prognosis :
• innocent aneurysm : risk < + 2% / yr
• previously bleeded aneurysm :

risk of ... after ...	24 hrs	72 hrs	8 days	30 days	6 months	12 months
rebleeding	4.8%	7.8%	15%	35%	50%	55%
death due to rebleeding		26%		50%	70%

Complications : increasing volume =>
• asymptomatic (1-5%)
• pseudotumor and/or cerebral ischemia

‡
• rupture of sac (90%) when Ø_neck = 5-7 mm (incidence = 10-12 cases every 100,000 inhabitants; males > females) =>
• subarachnoid hemorrhage (SAH) (from aneurysm of circle of Willis)
• intraparenchymal hemorrhage (from middle cerebral artery (MCA) perforating arteries; severe if perimesencephalic)
• intraventricular hemorrhage (from anterior communicating artery (ACoA) aneurysm)
• subdural hemorrhage (rare; usually posttraumatic)
Prognosis : 50% dies before first aid. Of those who receive aid :
• 50% dies anyway or remains severely invalid after recovery (Karnofsky performance status (KPS) score < 40)
• 20% worsen despite admittance : 8% recovers fully, while 9% survives with severe deficiencies
• 30% survives without important disabilities
Web resources :
• Brain Aneurysm Foundation (BAF)
• 3-D Visualization of Brain Aneurysms
• agenesis of one or more communicating arteries
• hypoplasia of cerebral artery and enlargement of communicating artery(ies)
• sinus phlebitis : inflammation of a cerebral sinus
• cerebral angiomas : McCormick-Jellingh classification
• capillary teleangiectasis : ventral pons > cerebellum > basal nuclei > cerebral white matter

Aetiology : Rendu-Osler-Weber syndrome
• cerebral cavernous malformation (CCM) / cavernous hemangioma / angioma cavernosum / strawberry mark or nevus / cavernoma : cerebral cortex or brainstem
• solitary CCM : up to 40% of solitary cavernous angiomas may develop in the vicinity of a venous angioma
• multiple CCM
Epidemiology : prevalence 0.5-1%
Histology : no interposed parenchyma, sizes range from mm to cm
Symptoms & signs : 50-70% develop focal signs, seizures, stroke symptoms, massive cerebral hemorrhages, and headache in their 20’s or 30’s.
Laboratory examinations : angio-CT and MRI
Therapy :
• surgery : indications
• absolute : well reachable, arterial afference and venous efference involving noncritical areas
• relative : afferences from deep choroidal arteries involving periventricular areas
• no embolization as small
• no radiotherapy as radioresistant
• venous angioma or malformation : spinal cord >  encephalon. Surrounded by glia. This is a normal compensatory variant with no need for therapy.
• cerebral arteriovenous malformation (AVM) / arteriovenous angioma of brain : a congenital anomaly of the brain vasculature composed of arterial and venous channels with many interconnecting shunts without an intermediate capillary bed

Epidemiology : prevalence = 0.1-0.9%
Histology : they develop from fourth week somite; sizes range from mm to whole hemisphere (from cortex to lateral ventricles). It occurs in middle cerebral artery (MCA) > posterior cranial fossa (6-25%). As within angioma blood flows at 400 cm/s (normally in sylvian artery blood flows at 40-60 cm/s) => cerebral aneurysm (10%) : it doesn't break and regress once the angioma is removed.
Symptoms & signs vary with location :
• cerebral hemorrhages (1-5% of cerebral hematomas)
• on the venous side (50%; 32% have previous hemorrhage detected at surgery) => symptoms & signs less severe than in aneurysmaal hemorrhages
• intraparenchymal hemorrhage (63%; 10-40% of all causes)
• subarachnoid hemorrhage (32%)
• intraventricular hemorrhage (5%)
Source of hemorrhage :
• small AVM (86%; due to higher flow rate)
• intermediate AVM (75%)
• giant AVM (46%)
• within nidus => little damage
• rare vasospasm on the contrary of subarachnoid hemorrhage thanks to smaller blood volume within cisternae
Prognosis : likelihood of rebleeding :
• first rebleeding : +25% every 15 years
• second rebleeding : +25% every 4 yers
• third rebleeding : +25% every year
• focal epileptic seizures (first symptom in 48-67%)
• relapsing diffuse, unilateral (sometimes contralateral) headache
• comitated headache: paresthesias at extremities due to vasoconstriction in angioma, with aura lasting > 30'
• heart failure (due to blood stealing)
• hydrocephalus
• transient or permanent neurological deficiencies (paresis, dysphagia, dementia, visual disturbances)
• large malformations may have cranial bruits
Therapy :
• stereotactic radiosurgery (SRS) may obliterate 90% of angiomas leading to intimal hyperplasia within 2 years
• devascularization : circumscribed incision (retracting and cauterizing the arteries at the pial level and the draining vein, except the major draining vein)
• multiple endovascular glue embolization via femoral artery or fragment embolization 2-6 weeks after surgery. Complication : embolic stroke.
• CNS hemorrhages
• intracranial hemorrhage : bleeding within the cranium
• meningorrhagia / meningorrhea : hemorrhage from the cerebral or spinal membranes
• epidural or extradural hemorrhage : intracranial hemorrhage into the epidural or extradural space
• Aetiology : closed severe brain injury with rupture of squamous process of  temporal bone => damage to and leakage of blood from the middle meningeal artery, producing compression of the dura mater and thus compression of the brain (intracranial hypertension)
• acute form
• subacute form
• chronic form
 => meningohematoma / epidural hematoma : accumulation of blood in the epidural space (whose width varies according to the degree of adherence of dura mater to outer table of skull)
Symptoms & signs : severe localized headache, ipsilateral fixed mydriasis , brief loss of consiousness followed by a lucid period and finally by rapid decrease in level of consciousness
Laboratory examinations : concave displacement at CT scan
Therapy : drainage of hematoma
Prevention : use of helmets
Prognosis : unless evacuated, it may result in transtentorial herniation, and death
• subdural hemorrhage : cerebral hemorrhage into the subdural space of the roof due to rupture of cortical veins or pial arteries in subarachnoid space=> subdural hematoma : accumulation of blood in the subdural space =liquefaction=> subdural hygroma
• severe acute form : both blood and CSF enter the space as a result of laceration of the brain, rupture of the bridging veins joining cortical veins to venous sinuses of dura mater, and a tear in the arachnoid, adding subdural compression to the direct injury to the brain => immediate intracranial hypertension

Aetiology :
• closed brain injury with acceleration in elderlies
• rupture of aneurysm of circle of Willis (very rarely !)
Prevention : use of safety belts + air bags
• subacute form
• chronic form : only blood effuses into the subdural space as a result of rupture of the bridging veins joining cortical veins to venous sinuses of dura mater. The effusion is a gradual process and cortical atrophy may prevent onset of intracranial hypertension (once improperly named hemorrhagic pachymeningitis)

Aetiology :
• usually due to repetitive closed minimal brain injuries with acceleration (e.g. falls in alcoholists)
• meningiomas in youngs (focal neurological signs revert with surgical ablation)
Pathogenesis : the coagulated mass enlarges thanks to osmotic gradient and compresses surrounding parenchyma => intracranial hypertension
Symptoms & signs : there is a lucid interval between the first loss of consciousness (secondary to the trauma) and the secondary loss of consciousness; weeks after the injury, in post-traumatic headache and progressive focal neurological signs (hemiparesis, ...) that reflect the location of the mass. In babies (shaken baby syndrome) acceleration is facilitated by the poor muscle tone and onset of symptoms is slower as the skull is extensible => whiplash shake syndrome : a constellation of injuries to the brain and eye that may occur when a child < 3 years old, usually < 1 year old, is shaken vigorously while being held by the trunk or limbs with the head unsupported. This causes stretching and tearing of the cerebral vessels and brain substance, commonly leading to subdural hematomas and retinal hemorrhages, and sometimes associated with cerebral contusion. It may result in paralysis, blindness and other visual disturbances, convulsions, and death
Laboratory examinations : concave displacement at CT scansickle
Therapy : drainage of hematoma
Prognosis : mortality rate = 60-80%
• subarachnoid hemorrhage (SAH) : intracranial hemorrhage into the subarachnoid space

Aetiology :
• spontaneous rupture of
• aneurysm of
• circle of Willis (75% : not protected by autoregulation)

Complications : fibrotic organization => acute communicating hydrocephalus
• middle cerebral artery within Silvius's scissure
• cerebral arteriovenous malformation (AVM)
• head trauma
• thrombosis of sinus of dura mater
• coagulopathies
• SAH sine materia
• < 2 mm
• perimesencephalic
Symptoms & signs (differential diagnosis with meningitis thanks to lack of fever) :
• violent occipital headache
• photophobia
• menigismus
• Lasègue sign
• intracranial hypertension => nausea and vomiting
• hypothalamic–pituitary axis is common after SAH, with ACTH deficiencies occurring in 2.5 to 40% and GH deficiency occurring in 20-25% of subjects tested 3 to 66 months after SAH^{ref1, ref2, ref3}. Untreated ACTH and GH deficiency have important implications that may hinder recovery from SAH^ref. Central diabetes insipidus has been reported in patients after the clipping of an anterior communicating aneurysm with or without previous hemorrhage^{ref1, ref2}. Such patients frequently have hypodipsia or adipsia as a result of damage to the hypothalamic osmoreceptors and are at risk for life-threatening hypernatremia, since increasing their fluid intake does not compensate for the polyuria caused by diabetes insipidus. Timely recognition of this complication is critical and should lead to therapy with desmopressin, a prescription for scheduled fluid intake, and close monitoring of the volume and electrolyte status to maintain euvolemia.
• impaired consciousness :
• confusion
• syncope
• coma
Laboratory examinations :
• CT : hyperdense blood eventualy lining insular cortex (differential diagnosis with globular parenchymatous hemorrhage) and within cisterae. Hyperdensity attenuates within 1 week (differential diagnosis with hyperdensity due to parenchymatous hemorrhage which attenuates within 1 month). Ventriculomegaly may be the only sign. The sensitivity of new-generation CT (NGCT) scans for SAH was 93.1% for the patients with symptom duration < 24 hours and 83.8% for those with symptom duration > 24 hours. The overall sensitivity was 91.2%. All the patients who had SAH not detected by NGCT scans were diagnosed by LP. There was no significant relationship between NGCT scanner resolution and sensitivity for SAH^ref. 2% of cases will be missed by relying on a CT scan only^ref. SAH when performed at or before 12 hours of symptom duration was 100% (80/80), and 81.7% (49/60) after 12 hours of symptom duration. 11 of the 140 patients had a negative CT and positive spinal fluid analysis, yielding an overall sensitivity of 92.1%^ref. Anyway in the presence of a history suggestive of typical or atypical subarachnoid hemorrhage, all patients with a normal head CT scan should undergo a ...
• lumbar puncture : the 4-tube method for the red-cell count to differentiate between a traumatic tap and a subarachnoid hemorrhage has proved to be obsolete^ref, but can still be useful within the first few hours after subarachnoid hemorrhage, when xanthochromia has not yet developed
Complications :
• rebleeding
• blood mixes up with CSF in subrachnoid space => liberation of oxyHb => contraction of media coat => necrosis and endothelial proliferation => flogosis => diffuse and persistent vasospasm (> 60%) => ischemia
• embolism from aneurysmatic sac
• intraventricular hemorrhage : cerebral hemorrhage into the ventricles, usually fatal.
• brain, cerebral, intracerebral or parenchymatous hemorrhage / encephalorrhagia : a hemorrhage into the cerebrum => intraparenchymal or parenchymatous hematoma : a mass of blood within the brain tissue itself, usually from rupture of an artery or vein within the brain

Epidemiology : males (higher preavalence of systemic arterial hypertension) > females, onset at age 50-70 (higher frequency before age 40) when perforating arteries stemming from sylvian and anterior cerebral arteries are usurated
Aetiology :
• cerebrovascular hypertension
• cerebral arteriovenous malformation (AVM)
• cerebral cavernous malformation (CCM) / cavernoma
• cerebral aneurysm
• rupture of aneurysm of middle cerebral artery within Silvius's scissure
• brain injury
• capillary teleangiectasias (brainstem location)
• dural arterovenous fistula (lobar localization)
• spinal manipulation therapy (SMT) (neck manipulation may cause cervical artery dissection)
• cerebral amyloid angiopathy / congophilic angiopathy (lobar localization)
• neoplasms
• brain metastasis (lobar localization)
• choriocarcinoma
• malignant melanoma
• renal cell carcinoma
• bronchogenic carcinoma
• glioblastoma multiforme
• medulloblastoma
• space-occupying lesions (vascular wall erosions, malformated vessels)
• transformation of previous ischemic stroke (in 1-6% of ischemic strokes, expecially large hemispheric ones) (basal ganglia, subcortical regions and lobar location)
• coagulopathies (located everywhere)
• hemophilias
• Rendu-Osler-Weber syndrome
• idiopathic thrombocytopenic purpura
• anticoagulants : the incidence of anticoagulant-associated intracerebral hemorrhage (AAICH) quintupled during the 1990s. The majority of this change can be explained by increasing warfarin use. Anticoagulant-associated intracerebral hemorrhage now occurs at a frequency comparable to subarachnoid hemorrhage^ref
• leukemia
• Marfan syndrome
• vasculitides
• panarteritis nodosa
• drug abuse (lobar localization)
• amphetamines
• cocaine
• ethanol
• venous thrombosis
• cerebral pericapillary hemorrhage / brain purpura / pericapillary encephalorrhagia : a hemorrhagic encephalopathy resembling acute hemorrhagic leukoencephalitis of Weston Hurst / acute necrotizing hemorrhagic encephalomyelitis but without the inflammatory or necrotic changes of that disorder. It is marked by small pericapillary hemorrhages in the white matter of the brain, with adjacent demyelination and destruction of the axons; clinical manifestations include stupor and coma. The etiology is uncertain, but it is sometimes secondary to viral pneumonia or arsenical intoxication
Pathogenesis : they represent 10% of hemispheric strokes and 80% of cerebellar and brainstem strokes. Extravasated blood flows along white matter => increased intracerebral blood volume and cytotoxic cerebral edema => intracranial hypertension. If patient doesn't die (i.e small-sized hemorrhage or hemorrhage involving an area not critical) microglia infiltrates the hemorrhagic area => gliosis with no collagen deposition (uneffective repair) => cavity => pseudocyst filled with trasudate
Locations :
• typical location (i.e. lobar hemorrhage from rupture of Charcot-Bouchard microaneurysms in perforating arteries in patients with systemic arterial hypertension)
• atypical locations
• basal ganglia
• caudate nucleus (9%)
• putamen (32.5%)
• capsuloganglionic hemorrhage : hemorrhage into the basal ganglia and internal and external capsule of the brain.
• thalamus (22%)
• lobes (19.5%)
• posterior lobe => lateral or homonymous hemianopia
• cerebellum (7%)
• pons (10%)
Symptoms & signs : silent, occurring during hypertensive episodes, prodromes (headache, syncope, alterations of memory, spatial and temporal disorientation, focal signs)
Laboratory examinations :
• CT
• acute phase : hyperdensity due to increased absorption coefficient of hemoglobin (790 HU), mass effect and perilesional edema
• subacute phase (7-15 days) : decreased hyperdensity (after 1 month the area is isodense with surrounding parenchyma)
• chronic phase : ring impregnation around hypodense area, but hemorrhage doesn't overlap vascular nourishment areas
• angio-CT detects hematoma which increases in volume
• MRI
• hyperacute phase :
• 0-12 hours : oxyhemoglobin
• 12-72 hours : deoxyhemoglobin
• early subacute phase (3-7 days) : intracellular methemoglobin
• late subacute phase (7-15 days) : extracellular methemoglobin
• chronic phase (> 15 days) : hemosiderin
• DSA in arterial phase if an atypical location is suspected
Therapy :
• decrease vascular pressure (not too much as neurons around hematoma are already poorly perfused due to compression of arteries) with hypotensive drugs
• antiepileptic drugs
• mannitol
• GR agonists
• surgical drainage of hematoma if V > 30 mL or ICP > 25 mmHg or hematoma is located in posterior cranial fossa
• superficial hematoma => craniectomy
• deep hematoma => stereotaxic drainage with Archimede's screw-like device
• intraventricular hematoma or hydrocephalus => external derivation
• assisted ventilation in patients in coma
Prognosis :
• circulatory arrest if V > 50 mL
• death when
• putamenal hematoma : V > 140 mm³
• thalamic hematoma : Ø > 3.3 cm
• cerebellar hematoma : Ø > 3 cm
• Duret's hemorrhages : small, linear hemorrhages in the midline of the brainstem and upper pons caused by traumatic downward displacement of the brainstem.
Therapy : activated coagulation factor VII
• intramedullary hemorrhage / hematomyelia : hemorrhage into the spinal cord, usually confined to the gray substance

Aetiology :
• trauma
• arteriovenous malformation (AVM)
Symptoms & signs : acute flaccid paralysis with sensory disturbances.
• intracranial hematoma
• CNS ischemias : cerebral blood flow (CBF) = cerebral perfusion pressure (CPP) / cerebrovascular resistance (CVR) = [mean arterial pressure (MAP) - intracranial pressure (ICP)] / [L ^. n / (pr⁴)]
• vascular syndrome : any syndrome due to occlusion or stenosis of vessels supplying the nervous system.
• syncope
• cerebrovascular accident (CVA) / stroke syndrome / apoplexy / ictus sanguinis / ictus cerebri : a condition with sudden onset caused by acute vascular lesions of the brain

Guidelines : suspected stroke => transport to ER => cardiovascular stabilization => neurological evaluation => CT scan => transport in stroke unit (therapy, monitoring of vital paramaters, diuresis, feeding, hydration, and general conditions)
Epidemiology : 75% occur after age 65 years; despite the relative risk is higher in men, the absolute number of strokes is higher in women due to longer life duration (55% of all strokes and 50% of stroke mortality in USA)
• incidence : 6.5 millions per year in USA (> 50 million survived patients living in USA), 194,000 new cases per year in Italy (80% are new cases, 20% are relapses; 207,000 new cases are projected in 2008)
Risk factors :
• not modifiable : older age (prevalence doubles every 10 years after age 55), male sex (higher life expectancy => prevalence greater in males but incidence higher in females (61% are fatal), OCs, HRT), nonwhite race (African-American or Hispanic-American, China; +30% hemorrhagic stroke in Japan), family history of stroke, TIA (1-yr stroke incidence = 12%, +5%/yr), SNPs in PDE4D
• modifiable :
• major : tobacco smoking (RR = 2-4; risk disappears after 2-5 years of cessation; OR = 1.2-1.8 for passive smoking), carotid stenosis, systemic arterial hypertension (events in 25-30%; in elderlies hypertension causes stroke in 3.8% vs.AMI in 2.7%), IGT (RR = 2) and diabetes mellitus (RR = 2-8 for ischemic stroke), but reduction of ABP is more important than control of glycemia
• minor : drug abuse, atrial fibrillation (3-5% per year; occurs in 50% of thromboembolic stroke, of which 66% are cardioembolic), hyperhomocysteinemia, thrombophilic diathesis, HRT/OCs, excessive alcohol, left ventricular hypertrophy, hypercholesterolemia (+30% only for ischemic stroke : statins reduce AMI and stroke in both primary and secondary prevention), PFO, ASA, cardiomyopathy, mitral annular calcification, VP, aortic arc atherosclerosis, migraine with aura, infections
• predisposing factors : obesity, physical inactivity
Aetiology :
• ischemic stroke (70-85% in Westernized countries; 60% in Asian countries) : stroke syndrome caused by ischemia of an area of the brain

Risk factors : older age, tobacco smoking, diabetes mellitus, systemic arterial hypertension, hypercholesterolemia
Aetiology :
• endolumenal stenosis (occlusion)
• cerebral embolism (75%) : embolism of a cerebral artery due to cardiac embolism (20%), paradoxical embolism (30%) or artero-arterial embolism (15%)in ascending orta, aortic arc before right carotid artery or carotid bifurcation => embolic stroke; onset of symptoms is usually sudden, reflecting abrupt loss of blood flow to the region of the occluded artery
• thrombembolism (99%)
• dilated cardiomyopathy
• MVP : relevant only in presence of thickening, click+mesodiastolic murmur
• endocarditis
• mechanical valve prostheses
• cryptogenic stroke : compared with those with stroke of determined origin, patients with cryptogenic stroke (n=46) were significantly younger, have
• a higher prevalence of ASD, PFO (61% versus 19%; OR = 3.10), ASA (OR = 6.14), PFO+ASA (OR = 15-59), but no association after age 55 years^ref)
• less atherosclerosis risk factors.
• more MRI venogram (MRV) scans with a high probability for pelvic DVT(20%) than patients with stroke of determined origin (4%, P<0.03), with most having an appearance of a chronic DVT^ref
• ASD, PFO (OR = 3.10), ASA (OR = 6.14), PFO+ASA (OR = 15-59), but no association after age 55 years^ref
• pelvic deep venous thrombosis (DVT).
• IHD (AMI acting (0.8%) or pregress (8% in females, 11% in males within 6 years) => prophylaxis with antiplatelet drugs and LMWH
• asymptomatic carotid stenosis (> 50%) : RR +1-2%/yr, greater if stenosis > 75% 45% of strokes are lacunar infarctions due to microembolisms
• atheroembolism
• fat embolism
• cancer embolism
• gas embolism (cerebral air-gas embolism (CAGE))
Microembolism may arise from :
• carotid artery : monolateral embolism during systole
• cardiac chambers : bilateral embolism during diastole
Laboratory examinations : TCD with multifrequency detector to assess quality of embolus. Artifacts are discerned as they transit simultaneously rather than serially in all locations; microembolic survey (MES) in prosthetic valve recipients
Localizations :
• sylvian artery
• basilar artery
• cerebral thrombosis (25%) : thrombosis of a cerebral vessel
• thrombotic microangiopathy (TMA) due to HHV-6 reactivation in immunosuppressed transplant recipients^ref
• cerebral arterial thrombosis
• large vessel thrombosis (1-5%)
• lacunar infarct / lacune / cerebral lacunae (20-25%; 7% at age 60, 35% at age 90 years) : small (< 1 cm³) areas of cerebral ischemic infarction resulting from occlusion of deep, small end-arterial branches of the middle cerebral, posterior cerebral, and basilar arteries; occurring in the basal ganglia, internal capsule, pons, and white matter of the brain, usually in older patients with systemic arterial hypertension, arteriosclerosis and diabetes mellitus causing lipohyalinosis of small vessels; depending on their location, lacunes may be asymptomatic (e.g. in frontal lobes) or cause significant focal impairment (e.g. in sensory or motor areas)
• pure motor or sensory stroke
• ataxic hemiparesis
• dysarthria with dysdiadochokinesia of hand
• pure dysarthria
• ocular muscle impairment
• focal dystonia
• parkinsonism
• combined sensory-motor stroke
They regress spontaneously. The presence of multiple lacunes is known as status lacunaris
Aetiology :
• superimposed on a plaque of atherosclerosis
• systemic hypercoagulability
• cerebral venous thrombosis (CVT) (rare)

Aetiology :
• infectious
• local infections :
• acute otitis media
• infectious rhinitis
• infectious (paranasal) sinusitis
• orbital cellulitis
• systemic infections :
• bacteria
• Streptococcus spp.
• Staphylococcus aureus
• Staphylococcus epidermidis
• viruses
• parasites : Plasmodium spp., Trichinella spp.
• fungi : Aspergillus spp.
• noninfectious :
• local  causes :
• brain injury
• meningioma
• brain metastases
• jugular vein catheterism
• general causes :
• systemic hypercoagulability
• pregnancy and puerperium
• androgens
• CHF
• CNS tumors
• CTDs
Localizations :
• intracranial sinus thrombosis : thrombosis of a sinus of the dura mater

Aetiology :
• brain injury
• systemic hypercoagulability
• intracranial suppurative thrombophlebitis
• Streptococcus spp.
• Staphylococcus aureus
• Staphylococcus epidermidis
Localizations :
• sagittal sinus thrombosis
• atrophic, marantic or marasmic thrombosis : thrombosis, usually of one of the sagittal sinuses, occurring in the wasting diseases of infancy and of old age
• transverse sinus thrombosis

Symptoms & signs : Griesinger's sign : edematous swelling behind the mastoid process
• cavernous sinus thrombosis : thrombosis affecting the cavernous sinus.
• infectious thrombophlebitis of cavernous sinus
• from hematogenous spread
• from contiguous infections
• infectious rhinitis
• infectious (paranasal) sinusitis
• orbital cellulitis
Symptoms & signs : exophthalmos, pain, papilledema, extraocular muscles palsy
Symptoms & signs :
• cavernous sinus syndrome / Foix syndrome / Jefferson's syndrome
• Tolosa-Hunt syndrome : unilateral ophthalmoplegia associated with pain behind the orbit and in the area supplied by the first division of the trigeminal nerve; it is thought to be due to nonspecific inflammation and granulation tissue in the superior orbital fissure or cavernous sinus
Laboratory examinations : Tobey-Ayer test : the jugular vein on the side of the suspected thrombosis is compressed. A rise in spinal fluid pressure should occur; its absence indicates presence of thrombosis
Prognosis : mortality rate during peri-hospitalization period is 5.6% (range, 0%-15.2%) and 9.4% (range, 0%-39%) at the end of follow-up period. 88% of surviving patients recover completely or have only a mild functional or cognitive deficit. 66% of patients with CVT recanalized within the first few months after presentation, and 2.8% (range, 0%-11.7%) had objectively confirmed recurrence.^ref
=> thrombotic stroke : onset of symptoms ranges from minutes to days after the obstruction. Fragmentation of a subcritical cerebral thrombus may lead to thromboembolic obstruction downstream
• parietal stenosis : critical stenosis may be worsened by systemic arterial hypotension
• cerebral atherosclerosis
• cerebral arteriolosclerosis
• fibromuscular dysplasia
• cerebral vasculitides
• cerebral arteritis
• polyarteritis nodosa (PAN)
• Wegener's granulomatosis
• Takayasu arteritis
• giant cell arteritis (GCA)
• primary CNS vasculitis
• meningitis
• moyamoya disease or syndrome [Jap. moyamoya foggy or smoky, from the angiographic appearance] : cerebral ischemia due to occlusion of large arteries at the circle of Willis, with secondary proliferation of an abnormal network of vessels at the base of the brain, causing progressive neurologic disability; hemorrhage may occur from the dilated vessels.
• cerebral phlebitis
• vasospasm
• following subarachnoid hemorrhage (SAH)
• migraine (reversible diffuse segmental vasocontriction)
• giant aneurysm
• watershed infarction : cerebral infarction in a watershed area during a time of prolonged systemic arterial hypotension
• carotidopathies
• carotid artery stenosis
• dissection of extracranial carotid artery
• vertebrobasilar insufficiency, ischemia or syndrome / basilar artery insufficiency or syndrome
• subclavian steal syndrome
• heat stroke or apoplexy / thermoplegia : a condition caused by exposure to excessive heat, natural or artificial, and marked by dry skin, vertigo, headache, thirst, nausea, and muscular cramps; body temperature may be dangerously elevated, contrasting with heat exhaustion in which the body temperature may be subnormal
• exertional heat stroke : resulting from the production of heat by skeletal muscle during exercise faster than it can be dissipated by thermoregulatory mechanisms; it is usually accompanied by lactic acidosis.
• insolation / sunstroke / ictus solis / thermic fever : a condition produced by exposure to the sun, and marked by convulsions, coma, a high temperature of the skin (fever > 40°C), headache, mydriasis.
• lightning stroke : loss of consciousness and shock with burns, frequently fatal, caused by lightning
• eclampsia
• drugs (drug-induced vasculitis and acute systemic arterial hypertension)
• amphetamines
• cocaine
• Binswanger's disease / chronic progressive subcortical encephalopathy
• cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL)

Aetiology : missense mutations in NOTCH-3
Pathogenesis : strokes of small vessels, progressive dementia, and diffuse symmetrical white matter alterations
Symptoms & signs : migraine with aura (40%)
Laboratory examinations : osmophilic inclusion bodies in smooth muscle cells of blood vessels in brain or skin biopsy; PCR
• undeterminated aetiology (30%)
• at least 2 different aetiologies identified
• no aetiology identified
• incomplete evaluation
Differential diagnosis between ischemia in :

	carotid area	vertebrobasilar area
aphasia	very frequent	never
dysarthria	only with paresis of VII-XIII cranial nerves	frequent
drop attack : sudden loss of balance without loss of consciousness, usually seen in elderly women; various causes are hypothesized.	never	possible
nystagmus	never	frequent
diplopia	never	frequent
alternate paresis	rare	more frequent
upper limb paralysis	more severe distally	more severe proximally
headache	not frequent	frequent
persistent vomiting	rare	frequent
hemianopia	possible	frequent
monolateral amaurosis fugax	frequent	never
bilateral amaurosis fugax	very rare	frequent
dissociate sensibility	never	sometimes (Wallenberg's syndrome)
perioral paresthesias	not rare	usually facial
nucal rigidity and pain	very rare	not rare, often lateralized

Pathogenesis : neurons die within 3-4' of anoxia, followed by death of glial cells. Both male and female brain cells are killed by oxygen starvation (suffocation, heart attack or severe bleeding), but in different ways : male cells, for example, suffer a crash in levels of the antioxidant glutathione, while female cells do not (one possible treatment is N-acetylcysteine). Microscopic findings include : red neurons (intensely eosinophilic cytoplasm and peripheral pyknotic nuclei) => neoangiogenesis => extravasation of neutrophils that infiltrate the infarcted area and lyse neurons => coagulative necrosis
• red infarction
• white infarction
• 6-12 hours : pale, opaque area, mild reduction of consistence
• 12-48 hours : soft, granular, edematous area
• 48-72 hours : net demarcation, grossly granular, gray-yellow collor
• => gradual colliquation => resorption by macrophages => pseudocyst
Consequences relate to :
• kind of thrombus : it may dissolve or move causing TIA
• size of occluded vessel => vascularized area (last field law : the field which ischemize for first is the more distant)
• side circulations
• Willis' circle : predisposing conditions are
• agenesis of anterior communicating arteries => no communication between left and right carotid artery
• agenesis of posterior communicating artery => no communication between vertebrobasilar and carotid circles
• hypertrophy of posterior communicating artery and hypotrophy of first tract of posterior cerebral artery causes the latter to depend entirely on carotid blood input.
• watershed area : any of several areas over the convexities of the cerebral or cerebellar hemispheres, distant from the circle of Willis, where the vascular beds of two cerebral arteries meet and form anastomoses. At times of prolonged systemic hypotension, these are particularly susceptible to infarction, with those fed by the largest arterial branches being the first affected.
• extracranial anastomoses between
• left and right carotid circles
• intracranial and extracranial carotid circles
• atrophy of Huebner artery
• none for perforating arteries => lacunar infarctions
Laboratory examinations :
• CT : 50% have no signs in first 24 hours
• within 6 hours :
• hypodensity of gray matter (insular cortex, lenticular nucleus, convex cortex) (50%) if > 33% of hemisphere is involved
• hyperdensity of thromboembolized vessel (40%). False positives from high hematocrit or vascular parietal calcifications or thickening
• day 2-3 : cerebral edema, mass effect
• week 2-3 : fog effect
• since day 2 to month 3 : gyriform contrastographic impregnation due to broken BBB
• MRI
• diffusion weighted imaging (DWI) detects cytotoxic edema earlier than any other imaging technique (it may be practiced even during acute phase but only after exclusion of cerebral hemorrhage with CT)
• first signs after just 8 hours (sensitivity = 80% within 24 hours), but less specific in differential diagnosis with cerebral hemorrhage in hyperacute phase. Better spatial resolution and direct vascular visualization
• in acute, subacute and chronic phases MRI detects blood
• acute phase : cortical hyperintensity in DP and T2wi
• subacute phase : cortical hyperintensity in DP and T2wi, hypointensity in T1wi, poromalacia (CSF replaces parenchyma), perilesional gliosis, and wallerian degeneration
• echocolordoppler (ECD)
• carotid artery ECD
• vertebral artery ECD
• echoencephalography / transcranial echocolordoppler (TCD)
• CBC
Primary prevention :
• anticoagulant drugs (not in patients with systemic arterial hypertension unless hypercreatininemia, mild-to-moderate renal failure or high.-risk patient. Not in any case if there is hemorrhagic diathesis)
• carotid revascularization
Secondary prevention :
• antiplalet drugs reduce by 22% incidence of major cardiovascular events and by 23% the incidence of ischemic stroke. Indications:
• previous ischemic stroke : acetylsalicylic acid (75-150 mg/day) =relapse=> ticlopidine (250 mg/day) > clopidogrel (75 mg/day)
• thrombosis : acetylsalicylic acid 100-325 mg/day or 50 mg/day + dipyridamole 400 mg/day, or ticlopidine 500 mg/die or clopidogrel 75 mg/day (less side effects). Aspirin should be used in preference to warfarin for patients with intracranial arterial stenosis^ref
• thrombembolism : warfarin (INR = 2-3), acetylsalicylic acid 325 mg/die, indobufen. Absolute indications for anticoagulant therapy in patients with AF include :
• TIA or ischemic cerebral stroke
• atrial thrombosis
• CHF
• DM
• age > 75 years
• systemic arterial hypertension
• patent foramen ovale (PFO) : acetylsalicylic acid 325 mg/die
• + atrial septal aneurysm (ASA) or deep vein thrombosis (DVT) : warfarin (INR = 2-3)
• relapse : surgery
• high risk of cardiovascular events (staable angina or ACS (including pregress AMI), PTCA/CABG, lower limb obliterating arteriopathy, hemodialysis)
• atrial fibrilation : if cardioversion is not indicated => INR = 2-3 (RR = 68% for warfarin, 21% for acetylsalicylic acid)
• asymptomatic carotid artery stenosis : acetylsalicylic acid
• surgery : revascularization of asymptomatic carotid artery stenosis if the morbidity/mortality of the hospital is < 80%
• extracranial/intracranial (EC/IC) bypass
• carotid endarterectomy
• vertebral artery transposition
• carotid-sylvian bypass
• axillary-axillary bypass
• cholesterol-lowering drugs on the basis of the overall cardiovascular risk (see NCEP/ATPIII guidelines) : symptomatic carotid stenosis is a CHD risk equivalent. In very high risk patients cholesterolemia should be reduced to < 70 mg/dl
• a reduction of SBP by 12 mmHg and DBP by 5 mmHg (independently from the baseline values) reduces stroke and AMI incidence by 35%.
Therapy : up to 30% of stroke patients recover spontaneously, without any treatment at all
• glycerol
• selection for fibrinolysis / thrombolysis (side effect : cerebral hemorrhages)
• systemic r-tPA within 3 hours (only 3-5% of stroke patients reach hospital in time to receive it; contraindications : systemic arterial pressure > 185/110; platelets < 100,000, hematocrit < 25%, glycemia < 50 or > 400 mg/dL; use of heparin within 48 hours and prolonged PTT or raised INR; rapid symptom improvement; stroke or head trauma in previous 3 months; previous intracranial hemorrhage; major surgery in previous 14 days; mild symptoms; gastrointestinal bleeding in previous 21 days, recent AMI; coma or stupor) : 2 peripheral endovenous routes 0.9 mg/kg (max 90 mg), 10% as a bolus, the remaining within 1 hour, ABPM (if uncontrolled suspend infusion, administer cryopreciptated and practiced cerebral neuroimaging urgently), avoid urethral catheterism for > 2 hours. Ttohe blood clot dissolves in only 13% of patients.
• locoregional r-UK within 6 hours for middle cerebral artery strokes, or 12 hours for vertebrobasilar artery strokes
• i.v. heparin for cerebral venous thrombosis (even with red infarction)
• neuroprotective agents in acute ischemic stroke : focal cerebral ischaemia (FCI) causes release of excitatory amino acid (EAA) neurotransmitters, principally glutamate, with resultant over-stimulation of EAA receptors and downstream pathways. Excess glutamate release is a pivotal event in the evolution of irreversible ischaemic damage in animal models of ischaemia, and drugs that modulate glutamate action either by inhibiting its release, or blocking post-synaptic receptors, are potent neuroprotective agents
• hypothermia
• calcium channel blockers (CCBs) have mild effectiveness when administered within 3 hours
• NMDA receptor antagonists (side effect : severe psychotic crises)
• free radical scavenger tirilazad and ebselen / edselen
• anti-ICAM-1 antibody enlimomab
• GABA_A agonist clomethiazole
• sodium channel antagonist fosphenytoin
• magnesium
• glycine site antagonist GV150526
• piracetam
• MDL 28170
• FGF-2 / bFGF
• superoxide dismutase (SOD)
• lubeluzole
• CDP-choline
• GM₁ ganglioside
• NXY-059 : the administration within 6 hours after the onset of acute ischemic stroke significantly improved the primary outcome (reduced disability at 90 days), but it did not significantly improve other outcome measures, including neurologic functioning as measured by the NIHSS score^ref
• the theory has been that AT₁-blockers or their association with ACE inhibitors (ACEI) would be superior to ACEI alone in decreasing total and cardiovascular morbidity and mortality. However, these trials have had unsuccessful results and angiotensin II seems to be cerebroprotective. Activation of both AT₂ and AT₄ receptors may account for the superiority of AT₁-blockers over ACEI in protecting against brain ischaemia, especially in patients with higher risk of stoke than of cardiac complications^ref
• surgery
• carotid thrombectomy (in post-endoarteriectomy occlusions)
• sylvian embolectomy (within 6 hours)
• a tiny corkscrew made from a springy mixture of nickel and titanium can be pulled straight and stored inside a cylindrical casing, but springs back into shape when pushed free of its shell. It is inserted via femoral artery within 8 hours from stroke, driven to the clot, twisted into it and pull it out
Prognosis : 80% experience relapse (30% within 1 year; +7% per year, expecially when due to atherothrombosis > lacunar)
• cerebral hemorrhage (hemorrhagic stroke; 15-20% in Westernized countries; 40% in Asian countries)
• subarachnoid hemorrhage (SAH) (1-2%)
• intraparenchymal hemorrhage (10%)
• subdural hemorrhage (<1%)
• epidural hemorrhage (<1%)
Risk factors : rheumatic heart disease, CHF, age > 65 years, systemic arterial hypertension, previous cerebral TIA or stroke, DM, positive transesophageal echocardiography (auricular blood velocity < 20 mm/s, complex aortic atheroma)
Prognosis : 75% experience a relapse
Primary prevention :
• withdrawal of drug absuse, thrombolysis in AMI, no anticoagulants
• cessation of smoking, reduction of ABP (> 140/85 without DM, < 135-130/85-80 if DM + nephropathy) reduces by 38% incidence in adults and elderlies. Drugs recommended are AT1 antagonist or CCBs + diuretics or b-blockers
Pathogenesis : cytotoxic cerebral edema => intracranial hypertension
• unstable patients
• stroke in evolution
• crescendo TIA
• stroke in evolution / developing stroke : a preliminary, unstable stage of stroke syndrome in which the blockage is present but the syndrome has not progressed to the stage of completed stroke
• transient ischemic attack (TIA) : a brief attack (< 24 hours, usually 5-15 minutes) of cerebral dysfunction of vascular origin, with no persistent neurological deficit due to vascular occlusion > 80%. They may be prodromes of strokes.
• carotid circle (more common) :
• anterior cerebral artery
• middle cerebral artery
• vertebrobasilar circle :
• posterior cerebral artery : impaired vision and vertiginous syndrome (differential diagnosis with labyrinthine and psychiatric vertigo)
• reversible ischemic neurologic deficit (RIND) / minor stroke : a type of cerebral infarction whose clinical course lasts 24 < x < 72 hours (or 3 weeks); brain imaging usually reveals a lacunar infarction
• completed stroke : stroke syndrome reflecting the infarction of the vascular territory that is put at risk by a stenosis or occlusion of a feeding vessel. In most severe cases almost the whole hemisphere may be affected (if the entire hemisphere appears affected, this is the result of compression of blood vessels in the healthy area (therapeutic area) by cerebral edema, creating an ischemic penumbra)
• progressing stroke
• spectacular shrinking deficit (SSD) : sudden major hemispheric stroke syndrome followed by rapid improvement within a few hours after stroke, leaving mild or no deficits. Experimentally,^{ref1, ref2} brief MCA occlusion (MCAO) causes selective neuronal necrosis and apoptosis with intact glial cells and microvessels in the caudoputamen and cerebral cortex. In these ischemic lesions, the brain tissue framework is preserved and no cavitation develops. This ischemic lesion with selective neuronal death and gliosis has been termed "incomplete infarction"^{ref1, ref2, ref3}. Nakano et al^ref reported that selective neuronal damage slowly progressed in the dorsolateral striatum of rats for 4 weeks after 15 minutes' MCAO and that microvacuolation never occurred in the ischemic area. However, very few reports are available on the serial changes in the human brain after transient hemispheric ischemia leading to SSD, which represent the clinical equivalent of the experimental conditions described above.

Aetiology : transient internal carotid artery (ICA)-middle cerebral artery (MCA) occlusion caused by cardiogenic embolus^ref
• ischemia reperfusion injury (IRI)
Symptoms & signs :
• reflecting the focus, including contralateral hemianesthesia (which impairs motor neurorehabilitation) and central hemiparesis (paralytic stroke / ictus paralyticus : hypotonia and hyporeflexia) =15-30 days=> contralateral hypoaesthesia, hypertonia (flexed arm and hyperextended leg used to support the whole body during gait => sickling gait; if the legs remains flaccid death may occur due to complications from prolonged lying in bed, e.g. aspiration pneumonia and decubitus ulcers) and hyperreflexia =long-term=> muscle atrophy), vertigo, numbness, aphasia (if involving the left lobe in right-handed people or the right lobe in left-handed people), and dysarthria; it is often followed by permanent neurologic damage
• ischemic reflex : the elevation of arterial pressure in response to cerebral ischemia
• character changes, depending on where the damage hits. Some may become more impulsive, others depressed. Now researchers have shown that damage to a small but very specific brain area can wipe out an addiction to smoking. 14 patients all stopped smoking immediately after having a stroke that damaged their insular cortex. This seems to be not because they were concerned about their health, but because they had lost all interest in cigarettes. 1-2 had even forgotten that they used to smoke. The insular cortex is a relatively primitive part of the brain whose functions include providing an emotional context for experiences, such as drug taking, along with some higher-level, decision-making functions involved, for example, in forming memories. The seemingly huge impact of switching off this area could have implications for addiction research in general. Throwing off an addiction for good is tough because cues in the environment — a whiff of tobacco smoke, or the room where you used to shoot up — automatically invokes the emotion associated with the last fix. But such triggers don't seem to trouble the patients with a damaged insula. Addiction is caused by an imbalance between 2 neuronal systems — the impulsive system controlled by a brain area (the amygdala) that helps to process emotions and a reflective system controlled by the forebrain. The reflective system anticipates and assesses the consequences, good or bad, that any action will have for the future. Most addiction research focuses on the impulsive system. Some drug addicts behave similarly to stroke patients with forebrain damage when it comes to decision making. In tests designed to assess financial risk-taking behaviour, they impulsively chose to take as much cash as possible up front, even when that option is linked to a major loss of cash in the longer term. This implies that their impulsive system is winning out over the more logical, risk-assessing system. But other addicts will make the clever decision — to take less cash up front and benefit long-term. These kinds of addicts tend to have more functional lives. They have not broken up their families, and they hold down their jobs, because their reflective system is not damaged and they make sensible decisions. I think these kinds of addicts will find it easier to stay off drugs if they go clean. Selective damage to the insula cortex seems to filter out some of the information from the impulsive system when it comes to making a decision. As a result, smokers whose reflective capacities are functional seem to be able to make the rational decision to give up, without experiencing withdrawal pain. Just how this information could be used to help addicts in general is not yet clear. But first of all it is important to pinpoint exactly where the systems can become damaged. It may be possible in the future to suppress neuronal activity in the insula, for example, to see if that helps addicts to kick their habits.
Laboratory examinations :
• CT
• MRI
• echocolordoppler (ECD) : the inversion of arterial blood flow in frontal branch of ophthalmic artery suggests occlusion of internal carotid artery
• carotid artery ECD
• vertebral artery ECD
• echoencephalography / transcranial echocolordoppler (TCD)
• specific stroke scales :
• prehospital stroke assessment tools :
• Cincinnati Stroke Scale
• Los Angeles Prehospital Stroke Screen (LAPSS)
• acute assessment scales :
• Canadian Neurological Scale (CNS)
• Glasgow Coma Scale (GCS)
• Hemispheric Stroke Scale
• Hunt & Hess Scale
• Mathew Stroke Scale
• Mini-Mental State Examination (MMSE)
• National Institutes of Health Stroke Scale (NIHSS)
• Orgogozo Stroke Scale
• Oxfordshire Community Stroke Project Classification (Bamford)
• Scandinavian Stroke Scale
• functional assessment :
• Berg Balance Scale
• Rankin scale^ref was developed in 1957 :
• perceived disability :
• 0 : none
• 1 : slight
• 2 : moderate
• 3 : severe
• physical independence :
• 0 : no problems
• 1 : a few problems but can walk with assistance
• 2 : unable to walk without assistance
• 3 : bedridden
• ability to work and pursue activities
• 0 : able to do everything done before
• 1 : can't do everything but able to look after self
• 2 : needs some help with tasks
• 3 : needs help with bodily needs
• 4 : requires constant care and attention
Patient status grades :
• I : no significant disability; able to carry out usual duties
• II : slight disability, unable to carry out some activities done previously, able to look after own affairs without assistance
• III : moderate disability, able to walk without assistance, requires some help
• IV : moderately severe disability, unable to walk without assistance, unable to to attend to own bodily needs without assistance
• V : severe disability, bedridden, incontinent, requires constant nursing care and attention
Limitation :
• some physical laborers may be identified as Grade II if unable to return to a previous level of demanding activities even though otherwise quite fit.
• a patient may recover function more slowly so that disability may be less after several months than when discharged after the acute event.
• modified Rankin scale (MRS)^{ref1, ref2} measures independence :
• 0 : no symptoms at all
• 1 : no significant disability despite symptoms; able to carry out all usual duties and activities
• 2 : slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance
• 3 : moderate disability; requiring some help, but able to walk without assistance
• 4 : moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance
• 5 : severe disability; bedridden, incontinent and requiring constant nursing care and attention
• 6 : dead
• Stroke Impact Scale (SIS)
• Stroke Specific Quality of Life Measure (SS-QOL)
• outcome assessment :
• American Heart Association Stroke Outcome Classification (AHA SOC)
• Barthel index (BI) was developed in 1965^ref and later modified by Granger and coworkers^ref as a scoring technique that measures the patient's performance in 10 activities of daily life. The BI is considered a reliable disability scale for stroke patients^{ref1, ref2}. The maximal score is 100 if 5-point increments are used, indicating that the patient is fully independent in physical functioning. The lowest score is 0, representing a totally dependent bedridden state.
• self-care
• feeding :
• 0 = unable
• 5 = needs help cutting, spreading butter, etc., or requires modified diet
• 10 = independent
• bathing :
• 0 = dependent
• 5 = independent (or in shower)
• grooming :
• 0 = needs to help with personal care
• 5 = independent face/hair/teeth/shaving (implements provided)
• dressing :
• 0 = dependent
• 5 = needs help but can do about half unaided
• 10 = independent (including buttons, zips, laces, etc.)
• bowels :
• 0 = incontinent (or needs to be given enemas)
• 5 = occasional accident
• 10 = continent
• bladder :
• 0 = incontinent, or catheterized and unable to manage alone
• 5 = occasional accident
• 10 = continent
• toilet use :
• 0 = dependent
• 5 = needs some help, but can do something alone
• 10 = independent (on and off, dressing, wiping)
• mobility
• transfers (bed to chair, and back) :
• 0 = unable, no sitting balance
• 5 = major help (one or two people, physical), can sit
• 10 = minor help (verbal or physical)
• 15 = independent
• mobility (on level surfaces) :
• 0 = immobile or < 50 yards
• 5 = wheelchair independent, including corners, > 50 yards
• 10 = walks with help of one person (verbal or physical) > 50 yards
• 15 = independent (but may use any aid; for example, stick) > 50 yards
• stairs :
• 0 = unable
• 5 = needs help (verbal, physical, carrying aid)
• 10 = independent
Guidelines :
• the index should be used as a record of what a patient does, not as a record of what a patient could do.
• the main aim is to establish degree of independence from any help, physical or verbal, however minor and for whatever reason.
• the need for supervision renders the patient not independent.
• a patient's performance should be established using the best available evidence. Asking the patient, friends/relatives and nurses are the usual sources, but direct observation and common sense are also important. However direct testing is not needed.
• usually the patient's performance over the preceding 24-48 hours is important, but occasionally longer periods will be relevant.
• middle categories imply that the patient supplies over 50% of the effort.
• use of aids to be independent is allowed
• Functional Independence Measurement (FIM™)
• Glasgow Outcome Scale (GOS)
• Health Survey SF-36™ & SF-12™
• other diagnostic & screening tests :
• Action Research Arm Test
• Blessed-Dementia Scale
• Blessed-Dementia Information-Memory-Concentration Test
• DSM-IV criteria for the diagnosis of vascular dementia
• Hachinkski Ischaemia Score
• Hamilton Rating Scale for Depression
• NINDS - AIREN criteria for the diagnosis of vascular dementia
• Orpington Prognostic Score
• Short Orientation-Memory-Concentration Test
Therapy :
• reduction of arterial blood pressure (increased in 80% of ischemic strokes and 90% of hemorrhagic strokes) : autoregulation of CBF is lost => ABP decreases spontaneously in 1-4 days, but systolic values reached predict mortality; unfortunately no antihypertensive drug exists that doesn't cause cerebovascular steal or have very short half-life. The ideal drug should act rapidly within minute, have a dose-dependent effect, parenteral administration, lack of intracerebral effect and regression of lesions, vasodilating effect and/or maintenance of autoregulation. ABP should be < 180/110 if the patient undergoes thrombolysis.
• cytidine 5'-diphosphocholine (CDP-choline) / citicholine, produced endogenously, citicoline serves as a choline donor in the metabolic pathways for biosynthesis of acetylcholine and neuronal membrane phospholipids, chiefly phosphatidylcholine. The principal components of citicoline, choline and cytidine, are readily absorbed in the GI tract and easily cross the blood-brain barrier. It might increase the phosphatidylcholine (PC) levels by attenuating PLA₂ stimulation and loss of CTP-phosphocholine cytidylyltransferase activity. TNF-a also stimulates proteolysis of CCT. TNF-a and IL-1b are induced in brain ischemia and may disrupt PC homeostasis by increasing its hydrolysis (increase PLA₂ and PC-PLC activities) and inhibiting its synthesis (decrease CCT activity). The beneficial effects of CDP-choline may result by counteracting TNF-a and/or IL-1 mediated events, integrating cytokine biology and lipid metabolism^{ref1, ref2, ref3}
• oral protein supplements have no effect on the risk of death or poor outcome, compared with usual hospital meals^ref. There are no important benefits from early tube feeding for patients who can't swallow, although there is a non-significant reduction in deaths over 6 months; patients who need tube feeding do worse if they are fed through a percutaneous endoscopic gastrostomy (PEG) tube rather than a nasogastric tube (absolute increase in risk of death or poor outcome 7.8%, 95% CI 0% to 15.5%)^ref. For now, routine oral supplements are cautioned against for patients who can eat, and routine PEG tube feeding is cautioned against for patients who can't.
• Notch can boost the survival of 3 different types of stem cell^ref. Notch sits on cell surfaces and is vital for the correct growth of embryos. Rats afflicted with a stroke-like brain injury that normally dulls their movement and infused i.t. for 1 week with a molecule that stimulates Notch, improved movements. The rats also sprouted a collection of new cells in the brain. The researchers do not yet know whether this could be used to treat humans after a stroke, because stimulating Notch could have many other, perhaps unwanted, effects in the brain. But it does suggest that drugs that provoke Notch or a related protein might one day be used to persuade stem cells in the brain or other tissues to do what doctors want. Harnessing the body's own stem cells could offer an enticing alternative to attempts to harvest them from other sources, such as embryos. This is where stem-cell biology needs to be. Many researchers are seeking chemicals or proteins that can coax stem cells into multiplying or generating particular cell types. But even when they are successful, the details are often unclear: exactly how does a particular protein, sprinkled on to the outside of a cell, end up causing changes inside? Rousing Notch stops stem cells from dying within minutes. This rapid effect suggests that Notch has knock-on effects on signals being transmitted within the cell. Indeed, the team uncovered two chains of molecules triggered by Notch that have opposing effects on the cell and are fundamental in controlling growth of cancer cells. One promotes cell survival and division. A second seems to nudge stem cells into becoming other cell types instead. You can think of stem cells as being in a balance between these 2 pathways. The team showed that triggering the survival pathway helps both human ESCs and cells from the developing mouse pancreas survive in a dish. This same mechanism could be common in many, or even most, stem cells. The results also support the idea that cancer, in which cells divide uncontrollably, hijacks mechanisms normally used to schedule the orderly division of stem cells. Tinkering with Notch could run the risk of triggering cancer. But tweaking other parts of the cellular machinery might have effects only in the brain
Prognosis : 20% experience a relapse within 5 years. 50% has permanent invalidity. It is the 6th/7th cause of morbidity (the 4th projected in 2010) worldwide.
• mortality : the 2nd/3rd cause of mortality, 5 million deaths per year in USA (> 1.5 million per year are nonfatal). Mortality has been reduced by 60% since 1972 to 2000 in USA thanks to the increased control of hypertension (from 10% in 1970-80s to 34% in 1999-00) and better therapies
Web resources :
• Internet stroke center at Washington University in St.Louis : cerebrovascular diseases
• Stroke or Cerebrovascular Disease at CDC
• Associations :
• American Stroke Association
• UK Stroke Association
• spinal embolism : embolism of an artery in the spinal cord.
• intracranial hypertension (ICH): intracranial pressure (ICP) > 200 mmH₂O; if symmetrically distributed it may have few neurologic symptoms but if it is asymmetrical, as with hydrocephalus, neurologic symptoms are often severe.
• posterior cranial fossa (90%)
• intermediate cranial fossa (50-60%)
• anterior cranial fossa (30-35%)
Aetiology : encephalothlipsis / compression of the brain / cerebral compression : any condition in which the brain is compressed, such as by a tumor or other mass, blood clot, or abscess
• new mass
• hematoma after brain hemorrhage
• space-occupying neurological syndromes
• brain or cerebral abscess / pyencephalus / pyocephalus : one affecting the brain as a result of extension of an infection (e.g., otitis media) from an adjacent area or through bloodborne infection
• frontal abscess : one in the frontal lobe of the brain
• encephalopyosis : suppuration or abscess of the brain.
• encephalosepsis : gangrene of brain tissue.
Aetiology :
• Bacteria
• Bacteroides fragilis
• Enterobacteriaceae
• Streptococcus spp.
• Staphylococcus aureus
• Haemophilus spp.
• Fusobacterium spp.
• Clostridium spp.
• Actinomyces spp.
• Nocardia asteroides
• Protozoa
• Toxoplasma gondii
• Metazoa
• neurocysticercosis
• Taenia cellulosae
• Taenia saginata
• Taenia solium
• cenurosis
• Taenia brauni
• Taenia glomerulatus
• Taenia multiceps
• Taenia serialis
Symptoms & signs : Macewen's sign / cranial cracked-pot sound : on percussion of the skull behind the junction of the frontal, temporal, and parietal bones, there is a more resonant note than normal in internal hydrocephalus and cerebral abscess
Empiric therapy based on infection source :
• paranasal sinusitis => penicillin or third generation cephalosporin (cefotaxime or ceftriaxone) + metronidazole
• otitis media => penicillin + metronidazole + ceftazidime
• dental infection => penicillin + metronidazole
• bacterial endocarditis => nafcillin or vancomycin + metronidazole +third generation cephalosporin
• lung abscess, urinary sepsis, intraabdominal infection => ceftazidime + metronidazole + penicillin
• head trauma => nafcillin or vancomycin + third generation cephalosporin
• neurosurgery => vancomycin + ceftazidime
• congenital cyanotic cardiopathies => penicillin or third generation cephalosporin + metronidazole
• purulent pachymeningitis : abscess on the dura mater
• extradural or epidural abscess : an abscess of the brain, between the dura mater and the internal table of skull
• intradural abscess / pachymeningitis intralamellaris: one within the layers of the dura mater
• subdural abscessor empyema : pus collection between dura mater and arachnoid

Aetiology :
• Haemophilus influenzae
• Streptococcus pneumoniae
• increased mass of a normal brain component
• blood : cerebrovascular hypertension with loss of autoregulation
• CSF : hydrocephalus / hydrocephaly / hydrencephaly / hydrencephalus : a condition marked by dilatation of the cerebral ventricles and accompanied by an accumulation of CSF within the skull; the fluid is usually under increased pressure, but occasionally may be normal or nearly so. Differential diagnosis with
• hydrocephalus ex vacuo (a paraphysiologic compensatory replacement by CSF of the volume of tissue lost in atrophy of the brain, as in senile dementia) and cerebral edema.
• hydrocephaloid disease : a condition similar to hydrocephalus, but marked by depression of the fontanels, due to diarrhea or some other wasting disease with dehydration.
• pseudohydrocephalus : abnormally large appearance of a normal-sized head, due to smallness of the face and body, as in Silver's syndrome
Aetiology :
• CSF hypersecretion

Aetiology : congenital choroid plexus papilloma
• impaired venous reabsorption

Aetiology : fibrosis of arachnoidal villi after subarachnoid flogosis
• obstruction of the CSF pathways (most often) : obstruction is located with imaging or by injecting a colouring substance into ventricles
• communicating hydrocephalus : tetraventricular hydrocephalus in which there is no obstruction in the ventricular system, and CSF passes readily out of the brain into the spinal canal and subarachnoid space, but is not absorbed
• congenital or primary hydrocephalus : hydrocephalus resulting from a developmental obstruction of the CSF pathways

Aetiology :
• encephalocele
• lack of pacchionian granulations
• acquired or secondary hydrocephalus : hydrocephalus resulting from a disease process

Aetiology :
• cerebral hemorrhages
• obstruction of ventricular shunt
• acute exudative meningitis
• subarachnoid flogosis => fibrosis of basal system
• otitic hydrocephalus : acute hydrocephalus caused by spread of the inflammation of otitis media to the cranial cavity.
• tumor and non-neoplastic masses
• occult normal-pressure hydrocephalus

Epidemiology : middle-aged and older persons
Aetiology : inadequacy of the subarachnoid spaces of the convexity (diseases that irritate basal meningeal arteries or block upflow of CSF, e.g. meningitis, SAH or acute trauma)
Pathogenesis : no cortical atrophy except hippocampal atrophy
Symptoms & signs : mild to moderate dementia, early-onset gait disorder (ataxia or apraxia), and urinary incontinence with hydrocephalus, i.e., with enlarged ventricles, bifrontal or bioccipital headache, mnesic disorders, apthy, distractability
Laboratory examinations : the CSF pressures are at the upper end of normal, but with the excess spinal fluid volume, that pressure is actually abnormally high; radionuclide cisternography and continuous CSF pressure monitoring.
Therapy : therapeutic lumbar puncture (30-50 mL) or ventriculoperitoneal shunt
• platybasia / basilar impression : bulging upwards of the floor of the posterior cranial fossa adjacent to the foramen magnum due to softening of skull bones or a developmental anomaly

Laboratory examinations : angulus sphenoidalis ossis parietalis / sphenoid angle of parietal bone / anterior inferior angle of parietal bone / Welcker's angle : the anteroinferior angle of the parietal bone, which articulates with the greater wing of the sphenoid bone and the frontal bone
• dynamic or spinal subarachnoid block : a condition in which the flow of CSF is interfered with by an obstruction in the spinal canal

Symptoms & signs : Queckenstedt's phenomenon, sign or test : when the veins in the neck are compressed on one or both sides for 10", in healthy persons there is a rapid rise in the pressure of the CSF, which returns quickly to normal when pressure is taken off the neck. When there is a block in the vertebral canal the pressure of the CSF is affected little or not at all by this maneuver
Laboratory examinations : Ayer's test (with a spinal manometer, the pressure in lumbar puncture and that in a cisternal puncture should be identical in the normal subject)
• noncommunicating, obstructive or tension hydrocephalus : hydrocephalus due to ventricular block that prevents communication with subarachnoidal space
• congenital or primary hydrocephalus : hydrocephalus resulting from a developmental obstruction of the CSF pathways

Aetiology :
• obstructive malformative hydrocephalus (70% of all congenital hydrocephalus)
• Chiari's malformation or deformity (40% of all congenital hydrocephalus)
• aqueduct of Silvius
• bifurcation
• branching
• true stenosis (X-linked recessive trait) (20% of all congenital hydrocephalus)
• segmentation
• atresia of foramina
• Dandy-Walker malformation (DWM), deformity, or syndrome : a congenital anomaly caused by failure of the roof of the fourth ventricle to develop during embryogenesis, characterized by cystic dilatation of the fourth ventricle filled with spinal fluid (Dandy-Walker cyst; up to separate cerebral and cerebellar hemispheres with a deep cleft), absence or hypoplasia or increased indentation of the vermis, and enlargement of the posterior fossa; hydrocephalus is usually present

Epidemiology : an incidence of one out of 25,000 to 35,000 cases, and are present in approximately 4% of cases with hydrocephalus. Others have reported that in pediatric cases hydrocephalus is associated with DWM in 13% of the cases.
Aetiology : heterozygous deletion of the linked genes ZIC1 and ZIC4^ref
• post-flogistic gliosis (30% of all congenital hydrocephalus)
• expansions
• intracranial cysts
• vascular malformations
• tumors
• ependymoma
• posthemorrhagic hydrocephalus : hydrocephalus in an infant following intracranial hemorrhage that has distended the ventricles and obstructed normal pathways for CSF; in some infants it resolves spontaneously, but in others it leads to permanent neurodevelopmental deficits.
• acquired or secondary hydrocephalus : hydrocephalus resulting from a disease process
• ventriculitis => gliosis => closure of aqueduct or foramina
• space-occupying lesions => closure of foramina or ventricles
• tumors
• acoustic neurinoma
• posterior cranial fossa tumors
• nonneoplastic masses
• acromegaly
• trauma
Pathogenesis : cortical atrophy (basal nuclei neurons are the last to atrophize as they are more resistant),
Symptoms & signs :
• infant hydrocephalus (prior to closure of the skull sutures) : compensatory skull dilatation (turbant look : enlargement of the head, prominence of the forehead, verticalized orbit roof, dilated and nonpulsating fontanellae, diastasis of the skull sutures), mental deterioration, Parinaud's syndrome (setting-sun or sunrise sign : dilatation of sovrapineal recess of third ventricle => compression of colliculus superior, including nuclei of oculomotor nerve => downward deviation of the eyes, so that each iris appears to “set” beneath the lower lid, with white sclera exposed between it and the upper lid; indicative of intracranial pressure (hemorrhage or meningoependymitis), hydrocephalus, or pineal tumor) convulsions, monolateral or bilateral abducens nerve palsy. In stenosis of aqueduct of Silvius => roof expansion and small posterior cranial fossa; in stenosis of communicating vessels => symmetrical dilatation of whole skull; congenital atresia of foramina => selective enlargement of posterior cranial fossa. Nowadays it represents an indication for therapeutic abortion.
• adult hydrocephalus (unextendible skull) : headache, blood vessel compression => hypoperfusion => psychic retardation => confusion and dementia, incontinence, imbalance, Parinaud's syndrome, amaurosis (compression of posterior cerebral artery against free border of tentorium), papilledema. It may be of sudden onset (acutehydrocephalus) or be slowly progressive (chronic hydrocephalus)
Laboratory examinations : ventriculomegaly: gross enlargement of a ventricle of the brain
Therapy :
• ventriculostomy
• ventriculoatrial shunt
• ventriculocisternal shunt
• ventriculoperitoneal shunt
• ventriculopleural shunt
• ventriculovenous shunt
• brain tissue :
• brain cells :
• brain neoplasms
• thoracic or lumbar spinal cord neoplasms
• focal or diffuse brain or cerebral edema / wet brain : excessive accumulation of fluid in the brain substance
• intracellular or cytotoxic edema

Aetiology : neuronal necrosis
• trauma
• increased permeability of capillaries : CNS ischemia
• anoxia
• high-altitude cerebral edema (HACE) is the end-stage of acute mountain sickness (AMS)
• exposure to toxic substances
• therapy of ketoacidotic coma
• meningitis
Pathogenesis : cytotoxic metabolites
Therapy : GR agonists
• interstitial or vasogenic edema

Aetiology :
• brain neoplasms
• trauma
• CNS ischemia
• brain abscess
• pseudotumor cerebri
Pathogenesis : rupture of tright junctions and astrocytes in blood-brain barrier (BBB)
Therapy : IV osmotic diuretics
• hyperostosis cranii
• pseudotumor cerebri / benign intracranial hypetension : a condition caused by venous sinus occlusion and cerebral edema, marked by intracranial hypertension with normal CSF, headache, nausea and vomiting, and papilledema without retinal hemorrhage or exudates => reduction or loss of sight, but without neurological signs except occasional abducens paralysis

Epidemiology : obese young females
Aetiology :
• idiopathic
• dysmenorrhoea
• pregnancy
• menarche
• Turner syndrome
• systemic arterial hypertension
• sideropenic anemia
• respiratory failure
• drugs
• GR agonists
• vitamin A
• oral contraceptives
• tranquilizers
• L-T₄ (in babies)
• defect in cerebral venous drainage
• empty sella syndrome
Pathogenesis : focal mass increase => increased pressure gradient => compensation by low-pressure systems (Monroe-Kellie principle : veins and arteries cannot compensate much pressure due to functional brain impairment => the ventricular system is the main compensatory system), decreased cerebral perfusion pressure (CPP) => Cushing's phenomenon (compensatory increase in MAP and relative bradycardia (70÷80 bpm)) and compensatory vasodilatation (Bayliss effect) further increases ICP and decreases CPP => once compensation is exhausted => cerebral compression / compression of the brain : => dislocation of medial structures of encephalus through endocranial compartments => complications (see below)
Symptoms & signs : headache, nausea and vomiting, slow ideation, torpor, abducens nerve palsy, monolateral or bilateral  papilledema (arachnoid and pia mater accompany cranial nerves) => compression of central retinal vein
Complications :
• stenosis of aqueduct of Silvius
• thrombosis or rupture of stretched perforating arteries
• cerebral hernia / hernia cerebri : protrusion of the brain substance through the skull, through either a cranium bifidum, the foramen magnum, or the tentorial notch
• encephalocele
• subfalcial or transfalcial hernia => compression of anterior cerebral artery
• transoccipital hernia / tonsillar hernia or herniation : protrusion of the cerebellar tonsils through the foramen magnum (as in Chiari's malformation or deformity), exerting pressure on the medulla oblongata => cardiorespiratory arrest
• caudal transtentorial, tentorial or uncal herniation (the commonest) : downward displacement of the most medially-placed cerebral structures (uncus and gyrus hippocampi) through the tentorial notch, caused by a supratentorial mass. Pressure is exerted on underlying structures, including oculomotor (III) nerve palsy (=> anisocoria), gyrus cinguli, midbrain coma (=> sufference of activating reticular substance => mesencephalic coma (reversible : central neurogenous hyperventilation, decerebrate rigidity, doll's head phenomenon) => pontine coma (irreversible) => bulbar coma), and posterior cerebral artery. In some cases lateral displacement causes compression of the opposite cerebral peduncle, causing the onset of contralateral (with respect to the original hemiparesis) Babinski's sign and hemiparesis  (Kernohan-Woltman sign)
• Kernohan's notch : a groove in the cerebral peduncle caused by displacement of the brain stem against the tentorium in some cases of transtentorial herniation
Location :
• diencephalic hernia : Cheyne-Stokes breathing, reactive miotic pupils
• mesencephalic hernia : tachypnea, median, unreactive and unconjugted pupils, decorticated posture
• bulbar hernia : loss of all brainstem reflexes
=> herniation syndrome
Therapy : if ICP > 20-25 mmHg for t > 5'
• CSF drainage through ventriculostomy (if practiced)
• bed raising from the side of the head
• osmotic therapy : mannitol 25-100 g 4 times/4 hours according to needs (maintain serum osmolarity < 320 mOsm/L)
• GR agonists : dexamethasone 4 mg 4 times/6 hours for vasogenic edema due to tumors or abscess (avoid GR agonists inn patients with head trauma or ischemic or hemorrhagic stroke)
• decrease cerebral metabolic rate with sedation (e.g., morphine, propofol, midazolam); if necessary induce neuromuscular paralysis after endotracheal intubation and mechanical ventilation
• hyperventilation up to P_aCO2 = 30-35 mmHg (which induces vasodilatation)
• vasopressors : phenylephrine, dopamine, noradrenaline to maintain mean arterial pressure (MAP) high enough to ensure CPP > 70 mmHg (maintain an euvolemia to minimize deleterious systemic effects of pressure agents)
• evaluate second-choice solutions for refractory elevated ICP
• pentobarbital coma
• aggressive hyperventilation up to P_aCO2 < 30 mmHg
• hemicraniectomy
• intracranial hypotension : ICP < 50 mmH₂O

Aetiology :
• rhinoliquorrhea / CSF rhinorrhea
• tumor shrinkage after therapy
• cervical spine manipulation^ref
• post–lumbar puncture syndrome

Aetiology : several hours after lumbar puncture
Pathogenesis : lowering of intracranial pressure by leakage of CSF through the needle tract => transoccipital tonsillar hernia
Symptoms & signs : lumbar puncture headache in the erect posture, sometimes with nuchal pain, nausea and vomiting, diaphoresis, and malaise
Therapy : relieved by recumbency
Prognosis : lasting a few days
• respirator brain : the congested, swollen brain of a patient who has been on a respirator longer than one day after suffering cerebral anoxia and ischemia; necrotic and autolytic changes begin to occur and the patient is comatose or brain dead.
• split brain : a brain in which connections between the hemispheres, mainly the corpus callosum, have been severed or otherwise disrupted; done surgically (corpuscallosotomy) on experimental laboratory animals and in humans to provide access to the third ventricle or to control epilepsy
• split-brain syndrome : an association of symptoms produced by disruption of or interference with the connection between the hemispheres of the brain
• neurodegenerative disorders : progressive and irreversible loss of neurons from specific regions of the brain
• transneuronal degeneration : atrophy of certain neurons after interruption of afferent axons or death of other neurons to which they send their efferent output.
• Türck's degeneration : secondary parenchymatous degeneration of nerve tracts of the cord.
• granulovascular degeneration : a condition in which the ganglion cells become filled with vacuoles containing condensed granules of protoplasm.
• gray degeneration : degeneration of the white substance of the spinal cord, in which it loses myelin and assumes a gray color
• rim degeneration : degeneration of the spinal cord affecting the periphery only
• Wilson's disease / hepatolenticular degeneration
• comma degeneration : progressive degeneration of the nervous matter of the comma tract (interfascicular fasciculus).
• cerebellar diseases
• cerebellitis : inflammation of the cerebellum
• hemicerebellitis
• acute cerebellitis

Aetiology :
• idiopathic lymphocytic cerebellitis
• viruses
• HHV-1 / HSV-1
• HHV-3 / VZV (anti-centrosome antibodies)^ref
• HHV-4 / EBV^{ref1, ref2, ref3, ref4}
• HHV-6A
• influenzavirus^ref
• mumps virus^{ref1, ref2}
• respiratory syncitial virus (RSV)^ref
• VEEV^ref
• bacteria
• Mycoplasma pneumoniae^{ref1, ref2, ref3, ref4} (antiganglioside GM₁, GM₂, and GT_1b antibodies)
• Salmonella typhi (typhoid cerebellitis)^{ref1, ref2, ref3, ref4}
• Coxiella burnettii^ref
• Leptospira spp. (cerebellitis leptospirosa)^ref
• Rickettsia conorii^ref
• Streptococcus pneumoniae (rare complication of pneumococcal meningitis)^ref
• Listeria monocytogenes^ref
Laboratory examinations : presence of succinate, acetate, lactate, and amino acids on in vivo ¹H magnetic resonance spectroscopy from a large area of restricted diffusion in the vermis on diffusion-weighted imaging, a finding specific for bacteria-induced infection^ref
• subacute cerebellitis
• Borrelia burgdorferi^{ref1, ref2}
• chronic cerebellitis
• anti-glutamate receptor d2 antibody^ref
• paraneoplastic neurologic syndrome (PNS)
Complications : often complicated by acute obstructive hydrocephalus or tonsillar herniation.
Therapy : high doses of i.v. GR agonists
• cerebellar degeneration
• chronic alcoholism (ethanol)
• paraneoplastic subacute cerebellar degeneration : the most common paraneoplastic syndrome affecting the brain, occurring most commonly with ovarian carcinoma, breast carcinomaand Hodgkin's disease, characterized pathologically by severe loss of Purkinje cells and clinically by insidious and progressive truncal and appendicular ataxia, dysarthria, nystagmus, and occasionally dementia. In some women with gynecologic or breast carcinoma, it is associated with autoantibodies (anti-Yo, anti-Ri, and anti-PCD) causing degeeneration of median line and vermis
• primary progressive cerebellar degeneration / Holmes' degeneration : a familial disease marked by motor disorders and due to cerebellar degeneration, occurring in adults between the ages of 30 and 40 and progressing slowly to a fatal termination
• cerebellar melanotic neuroectodermal tumor of infancy (MNTI)
Symptoms & signs :
• Hahn's sign : persistent rotation of the head from side to side in cerebellar disease of childhood.
• Wartenberg's sign : reduction or absence of the pendulum movements of the arm in walking; seen in patients with cerebellar disease.
• triad of Luciani : asthenia, atonia, and astasia, the 3 major symptoms of cerebellar disease.
• extrapyramidal disease : any of a group of disorders involving lesions of the extrapyramidal tract and marked by abnormal involuntary movements, dystonia, dyskinesia, postural disturbances, and psychic disorders (poor attention, ideation, and emotional and instinctual control) (extrapyramidal syndrome)
• striatal or hyperkinetic-dystonic syndromes

Symptoms & signs : muscular dystonia, hyperkinesia, Souques' sign (when the patient seated in a chair is suddenly thrown back, the lower extremities do not extend normally or otherwise attempt to counteract the loss of balance; it indicates advanced striatal disease)
Aetiology :
• athetosis / mobile spasm : a form of dyskinesia marked by ceaseless occurrence of slow, sinuous, writhing movements, especially severe in the face and upper limbs (worsened by fatigue and emotions, disappearing in sleep), and performed involuntarily, due to asynchronous contraction of agonist and antagonist muscles
• hemiathetosis : athetosis affecting one side of the body only
• monathetosis : athetosis of one limb
• pupillary athetosis / hippus
Aetiology :
• double congenital athetosis : congenital bilateral athetosis due to birth trauma, which may occur in association with spastic paraplegia, as in ...
• Vogt's syndrome / syndrome of corpus striatum : a syndrome associated with birth trauma, characterized by bilateral athetosis, walking difficulties, spasmodic outbursts of laughing or crying, speech disorders, excessive myelination of the nerve fibers of the corpus striatum, giving it a marbled appearance (status marmoratus / état marbré), and sometimes mental deficiency
• spastic diplegia or paraplegia / Little's disease
• kernicterus
• vascular disorders in basal nuclei
• ballismus / ballism : violent flinging dyskinesia caused by contractions of the proximal limb muscles as a result of destruction of the subthalamic nucleus (Luys' body) or its fiber connections
• hemiballismus / body of Luys syndrome : a violent form of dyskinesia involving only one side of the body and being most marked in the upper extremity (violent throwing, flexion, and rotation)
• chorea : the ceaseless occurrence of a wide variety of rapid, highly complex (not repetitive as in tics), jerky, dyskinetic movements that appear to be well coordinated and afinalistic but are performed involuntarily (not dominated by will as in tics).

Aetiology :
• posthemiplegic chorea : a form that affects the partially paralyzed muscles after hemiplegia
• Dubini's chorea or disease / electric chorea : an acute, fatal form due to acute infection of the CNS
• hyoscine chorea : chorea-like movements occurring in acute hyoscine (scopolamine)intoxication.
• hysterical chorea : conversion disorder in which the symptoms are choreiform movements.
• mimetic chorea : that which is caused by imitation.
• Sydenham's chorea
• chorea gravidarum
• striatal vasculitis due to systemic lupus erythematosus (SLE)
• senile chorea / chronic progressive nonhereditary chorea : a benign, usually mild disorder of the elderly, marked by choreiform movements unassociated with mental disturbance
• Huntington's chorea or disease (HD) / chronic progressive hereditary chorea / degenerative chorea / St Vitus' dance (mal de San Vito)

Epidemiology : affects 1 in 10,000 people ; onset at age 25-45
Aetiology :
• inherited autosomal dominant mutations in interesting transcript 15 (IT15) / huntingtin, expressed throughout the body (brain, pancreas, intestine, muscle, liver, adrenals, and testes). Normal huntingtin has 34 glutamine (polyQ) repeats, is cleaved, stays in the cytoplasm and is likely antiapoptotic with a role in axonal transportation. Mutant proteins with > 40 repeats invade the nucleus through pores, where their effects are both a gain of function through the generation of polyglutamine fragments, and a loss of antiapoptotic function. Abnormally extended huntingtin may disable transcription factors like CREB binding protein (CBP), which includes an 18-glutamine stretch, as well as clog proteasomes. Polyglutamine is more likely to aggregate than other amino acids, and neurons are more likely to feel the effects than other cells. Huntingtin forms toxic NH₂-terminal fragment complexes that are promoted by the age-dependent decrease in proteasome activity. One suggestion for why polyglutamine tract expansion proteins are toxic to cells was that they caused aggregates to form in the cytoplasm and the nucleus, which then recruit transcription factors containing normal-length polyQ sequences—such as TATA box binding protein (tbp)—thereby removing them from their normal functional location. But transcription dysregulation can also be observed in the absence of aggregates of the polyQ-expanded proteins : once aggregates have formed, they are no longer competent to effectively recruit tbp, so apparently the toxic interaction that leads to a dysfunction of the transcription factor is exerted by soluble forms of the polyQ expanded protein. PolyQ-expanded proteins are produced throughout life and are normally dealt with quite ably by cellular defence mechanisms against misfolded proteins—perhaps for decades. Nothing happens until presumably an imbalance occurs between the chaperone capacity and the production of such potentially toxic forms, and this may perhaps be a result of an aging process of cells. Probably the most surprising result is that it had been generally assumed that the mechanism by which these polyglutamine proteins might inactivate transcription is by sequestering or recruiting the transcription factors into large inclusion bodies. Tbp does not require frank sequestration, and it seems to be due to an interaction with a small oligermeric form of the protein, not a large aggregate. When you speak about the conformational transition that seems to be the crucial step for toxicity, it is a different thing if the monomer has already interacted with another monomer or is involved in a small aggregate^ref
• Huntington-like neurodegenerative disorder 2
• junctophilin 3 (JPH3)
Proteins involved in pathogenesis :
• BDNF (reduced expression)
• calbindin 1 (depletion)
• huntingtin interacting protein 1
• huntingtin-associated protein interacting protein (HAPIP) / duo
• L-kynurenine/a-aminoadipate aminotransferase (dysfunction => decreased levels of endogenous kynurentic acid)
• quinolinate phosphoribosyltransferase (nicotinate-nucleotide pyrophosphorylase (carboxylating)) => elevation of quinolinate levels in the brain
Pathogenesis : degeneration in the neostriatum (striatopallidal tract) and cerebral cortex. Asymptomatic disease can be made irreversibly manifest by administering L-DOPA
• chorea corpuscles : a name given peculiar round hyaline bodies, concentrically laminated and strongly refractile, found in the perivascular sheaths of the vessels of the corpora striata and internal capsule in chorea.
Symptoms : hypotonia, chronic progressive chorea (involuntary movements : grinasse,  flexorotation of whistles and fingers, head rotations, shoulders lifting, absymmetry of facial movements, irregular breathing) and mental deterioration (amnesia, neurosis or depression => depressive psychosis or dementia); the age of onset is variable but usually in the fourth decade of life, with death within 15 years.
Treatment :
• chemotherapy
• oral administration of the disaccharide trehalose decreases by 40% polyglutamine aggregates in cerebrum and liver, decreases weight loss by 25%, improves motor dysfunction (they walk more normally and are less likely to fall off a rotating rod) and extends lifespan by 10% in a transgenic mouse model of HD. These beneficial effects are the result of trehalose binding to expanded polyglutamines and stabilizing the partially unfolded polyglutamine-containing protein^ref
• gene therapy
• cell therapy
Prognosis : average duration = 17 years (max : 30 years)
Web resources : Huntington’s Disease Society of America (HDSA)
Features : grotesque gait (discharges of agonist muscles while the antagonists are relaxed)
• chorea cordis : chorea with great irregularity of the heart's action.
• fibrillary chorea / paramyoclonus : myoclonus in several unrelated muscles.
• paramyoclonus multiplex / Friedreich's disease / myoclonus multiplex : a term coined by Friedreich to describe a form of myoclonus of unknown etiology starting in the muscles of the upper arms and shoulders and spreading to other parts of the upper body
• hemilateral or one-sided chorea / chorea dimidiata / hemichorea : chorea which affects only one side
• methodic chorea : a variety in which the movements take place at regular intervals.
• chorea nocturna : chorea in which the movements continue during sleep.
• chorea nutans : nodding spasm, or chorea with nodding head movements.
• paralytic chorea : chorea in which immobility replaces movement
• dancing or saltatory chorea: any chorea that involves involuntary jumping or dancing movements
• status choreicus : a severe and persistent form of chorea.
• Bonhoeffer's symptom : loss of normal muscle tonus in chorea
• choreoathetosis : a condition marked by choreic and athetoid movements
• Mount-Reback syndrome / familial paroxysmal choreoathetosis : a rare autosomal dominant disorder characterized by paroxysmal attacks of choreoathetosis and dystonic movements with Kayser-Fleischer rings on the corneas. It appears in childhood or young adulthood and does not involve a change in consciousness
• paroxysmal kinesigenic choreoathetosis : the most common form of Mount-Reback syndrome, with the choreoathetotic movements provoked by sudden movements or startling
• pallidal or hypertonic-hypokinetic syndromes

Symptoms & signs : muscular hypertonia, bradykinesia, tremor
Aetiology :
• parkinsonism
• hemiparkinsonism : parkinsonism affecting only one side of the body.
• akinetic-rigid syndrome : muscular rigidity with varying degrees of slowness of movement; seen in parkinsonism and disorders of the basal ganglia.
Epidemiology : prevalence 1-3% of individuals over the age of 65 (onset at age 30-40 in juvenile-onset  PD), 4 million people worldwide. Onset is rare before age 40, and its incidence increases with increasing age, with 68 years the average age of onset. 60,000 new cases of PD are diagnosed each year, adding to the estimated one to 1.5 million Americans who currently have the disease. The latest epidemiology studies indicate that worldwide numbers will increase from an estimated 4.1 million in 2005 to 8.7 million people with PD by 2030. There were nearly 18,000 PD-related deaths in the United States in 2004.
Aetiology :
• primary parkinsonism :
• idiopathic Parkinson disease (PD) / paralysis agitans / shaking paralysis (20%)

Loci :
• Parkinson disease (autosomal recessive, juvenile) 2, parkin (PARK2)
• Parkinson disease (autosomal dominant, Lewy body) 3 (PARK3)
• Parkinson disease (autosomal dominant, Lewy body) 4 (PARK4)
• Parkinson disease (autosomal recessive) 6 (PARK6) : due to mutations in PTEN-induced kinase 1 (PINK1) on chromosome 1p36^ref
• Parkinson disease (autosomal recessive, early onset) 7 (PARK7) / DJ-1 : DJ-1, localized in mitochondria, may sense oxidative signals via oxidation at cysteine 106. DJ-1 might influence stress response gene expression at transcriptional and post-transcriptional levels by interacting with PIAS and other nuclear cofactors and with cytosolic RNA-binding protein complexes. Such complexes may also be associated with GAPDH, which has functional links to apoptosis and Parkinson disease^{ref1, ref2, ref3, ref4, ref5}
• Parkinson disease (autosomal dominant) 8 (PARK8)^ref
• Parkinson disease (autosomal recessive early-onset) 9 with pyramidal degeneration and dementia (Kufor-Rakeb syndrome) (PARK9)

Aetiology : autosomal recessive loss-of-function mutations in a predominantly neuronal P-type ATPase gene, ATP13A2. Whereas the wild-type protein was located in the lysosome of transiently transfected cells, the unstable truncated mutants were retained in the endoplasmic reticulum and degraded by the proteasome^ref
• Parkinson disease 10 (PARK10)
• a₁-antichymotrypsin, precursor
• glutathione S-transferase M1
• 5-HT₆
• IL-1b
• microtubule-associated protein tau
• NADH dehydrogenase 1
• NADH dehydrogenase 2
• NADH dehydrogenase (ubiquinone) flavoprotein 2, 24kDa
• NAD(P)H dehydrogenase, quinone 1
• NAD(P)H dehydrogenase, quinone 2
• NR4A2
• a-synuclein (non A4 component of amyloid precursor) (in women)
• ubiquitin carboxyl-terminal esterase L1 (UCHL1) (ubiquitin thiolesterase) (in women)
• FGF20 : SNPs and haplotypes are both positively (one intronic , rs1989754 (P=.0006), and 2 SNPs, rs1721100 (P=.02) and ss20399075 (P=.0008), located in the 3' regulatory region; also the haplotype (A-G-C-C-T) (P=.0003)) and negatively (haplotype (A-G-G-G-C) (P=.0009)) associated with risk of PD^ref
• Steele-Richardson-Olszewski syndrome / progressive supranuclear palsy (PSP) (10%)
• atypical PSP / Parkinson-dementia syndrome
Epidemiology : onset during the sixth decade
Aetiology : mutation in the microtubule-associated protein (MAP) tau
Symptoms & signs : loss of voluntary vertical eye movement (supranuclear ophthalmoplegia, especially paralysis of the downward gaze), pseudobulbar paralysis or syndrome (spastic laughing and crying due to bilateral lesions of geniculate ways), dysarthria, dystonicrigidity of the neck and trunk, bradykinesia, and dementia.
• multiple system atrophy (MSA) : a name grouping 4 cerebral degenerative diseases considering them different forms of the same disease process
• olivopontocerebellar atrophy or degeneration / Dejerine-Thomas syndrome : any of a group of progressive hereditary disorders involving degeneration of the cerebellar cortex, middle peduncles, ventral pontine surface, and olivary nuclei. They occur in the young to middle-aged and are characterized by ataxia, dysarthria, and tremors similar to those of parkinsonism. Both autosomal dominant and autosomal recessive types have been distinguished
• Shy-Drager syndrome / chronic idiopathic orthostatic hypotension : a progressive disorder of unknown etiology that begins with symptoms of autonomic insufficiency including orthostatic systemic arterial hypotension, impotence in males, constipation, urinary urgency or retention, and anhidrosis; these are followed by signs of generalized neurologic dysfunction such as parkinsonism-like disturbances, cerebellar incoordination, muscle wasting and fasciculations, and coarse tremors of the legs
• striatonigral degeneration : a form of MSA in which nerve cell degeneration occurs mainly in the region of the substantia nigra and the neostriatum. Symptoms are similar to those of parkinsonism, with rigidity, slowing of movements, poor balance, and mumbling speech, but parkinsonian tremor is absent.
• one form of parkinsonism
Pathogenesis : neuronal multisystem degeneration, including degeneration of striatopallidal and nigrostriatal tracts
Symptoms & signs : autonomic/urogenital failure which may be associated with either L-DOPA-unresponsive parkinsonism (80% : MSA-P subtype) or with cerebellar ataxia (20% : MSA-C subtype).
Laboratory examinations : glial cytoplasmic inclusions (GCI), neuronal cytoplasmic inclusions (NCI)
Therapy : pharmacological treatment of motor features is disappointing except for a transient L-DOPA response in a minority of MSA-P patients.
• rapid-onset dystonia-parkinsonism (RDP)

Epidemiology : onset from age 4 to 58
Aetiology : 6 different mutations in ATP1A3, which regulate the transit of sodium and potassium, which are necessary for proper nerve signaling throughout the body
Symptoms & signs : rapid onset within days or hours
• corticobasal degeneration (CBD) : degeneration of corticostriatal tract

Symptoms & signs : limb apraxia (usually ideomotor), constructional and visuospatial difficulties, acalculia, frontal dysfunction, and nonfluent aphasia. The limb apraxia is associated with deficits in drawing, copying, and handwriting, but there is emerging evidence that the problems with handwriting are not due exclusively to the apraxia. The findings with respect to episodic memory are more variable, but when there is impairment in this area, it tends to be milder than that seen in Alzheimer's disease (AD). Semantic memory functioning appears relatively preserved but has been poorly studied. Problems with speech are common, and may be due to dysarthria or buccofacial apraxia
Therapy : it doesn't respond to dopaminergic treatment
• secondary parkinsonism (associated with other peculiar symptoms) :
• occult normal-pressure hydrocephalus
• intraaxial supratentorial tumors
• extrinsic aetiology (80%), usually refractory to all forms of treatment
• cerebrovascular atherosclerosis
• trauma (e.g. boxeurs)
• parkinsonian syndrome / postencephalitic parkinsonism : a form of parkinsonism due to idiopathic degeneration of the corpus striatum or substantia nigra, frequently occurring as a sequel of lethargic encephalitis / von Economo's encephalitis, associated with other extrapyramidal disturbances (myoclonus, torsion spasms, and oculogyric crisis (a crisis occurring in epidemic encephalitis, postencephalitic parkinsonism, or secondary to use of antipsychotic agents; the eyeballs and head become fixed in one position (typically upwardly rotated in postencephalitic parkinsonism, laterally rotated in neurodysleptic crises), for minutes or hours
• toxin-induced PD models :
• cocaine abuse is a significant problem in the USA, including its use by approximately 1% of pregnant women. Cocaine acts as an indirect agonist of dopamine at the dopamine transporter, resulting in the presence of excess dopamine in the synapse. Since synaptic dopamine can rapidly oxidize to form free radicals, exposure to this drug might produce damage in dopaminergic systems such as the substantia nigra pars compacta, damage to which is a hallmark of Parkinson's disease. In mice exposure to cocaine both in utero or as adults did not affect substantia nigra cell number, but did make these neurons more susceptible to the parkinsonian toxin MPTP. Long-lasting changes in D₂ receptor mRNA levels as well as changes in the monoamine transport system and several growth factors. Use of cocaine might be a predisposing factor for development of Parkinson's disease in both adults exposed chronically as well as in individuals exposed prenatally^ref
• D₁antagonists
• D₂ antagonists (antipsychotics and hydrophobic prokinetics)
• reserpine
• rotenone^ref
• paraquat (PQ)^{ref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8}
• carbon monoxide poisoning
• 6-hydroxy-dopamine (6-OHDA) model
• N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model. Both neurotoxins selectively and rapidly destroy catecholaminergic neurons, whereas in humans the PD pathogenesis follows a progressive course over decades. This discrepancy reflects one important and principal point of weakness related to most animal models
• high iron and manganese (manganism) intakes double the risk
• maneb (MB) remains in farmed soil for 20-75 days following application and can be found on produce for > 3 weeks, even after washing^{ref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8ref9, ref10}, and has specifically been implicated to have adverse effects on dopamine (DA) systems, but the role MB plays in modulating the oxidative state of DAergic cells has not previously been described. Since glutathione (GSH) is a major cellular antioxidant, it was hypothesized that exposure to MB would disrupt this system. The current study primarily utilized the PC12 cell line, which displays a catecholaminergic phenotype. Low concentrations of MB (50–1000 ng/ml) had little effect on cell viability, as measured by LDH release. These same concentrations, however, led to increases in GSH and its oxidized form, GSSG. Effects on viability and GSH were correlated to a primary mesencephalic culture system. Furthermore, these effects were markedly different from those observed with paraquat. To determine how MB would affect cells in which antioxidant systems were compromised, PC12 cells were treated with L-buthionine-(S,R)-sulfoximine (BSO) to deplete cellular GSH, followed by treatment with MB. Results suggest that following an insult to the GSH antioxidant system, MB can act as an additional insult to the system and prevent the normal recovery of those defenses. Altered protein levels of heme oxygenase-1 (HO-1) further indicated an oxidative stress response elicited by MB in PC12 cells. DAergic neurons, as a population, are inherently vulnerable to oxidative stress, and the disruption of antioxidant systems by the fungicide MB may contribute to the neurodegeneration of these cells, especially with concurrent exposures to other environmentally relevant oxidative stressors, such as PQ^ref.
• polychlorinated biphenyls (PCBs) have been shown to adversely impact dopaminergic (DAergic) pathways, but the role ROS play in neurotoxicity remains unclear. To test the hypothesis that PCB exposure compromises dopamine neurons by stimulating ROS production, the direct toxicity and oxidative stress response following PCB Mixture Aroclor 1254 exposure was examined both in MN9D dopamine cells and primary mesencephalic cultures. PCBs induced a time- and concentration-dependent increase in ROS production, which preceded cytotoxicity. Whereas intracellular GSH depletion exacerbated PCB effects, antioxidant pretreatment attenuated ROS production and cell death. Coincident alterations in antioxidant defense enzymes also accompanied ROS production, including decreased MnSOD and increased CuZnSOD protein levels. The robust elevation in heme oxygenase-1 levels further support the activation of oxidative stress mechanisms following PCB exposure. Furthermore, PCBs produced concentration-dependent reductions in intracellular dopamine levels and elevated dopamine turnover. Although the intracellular source of ROS remains unknown, these results suggest that sublethal PCB concentrations activate an oxidative stress-related pathway, which potentially disrupts dopamine neuron function^ref
Web resources :
• Neurotoxicology.com
• International Neurotoxicology Association
• Neurotoxicology at eMedicine
• Journals :
• NeuroToxicology
• Neurotoxicology and Teratology
Protective factors :
• mitochondrial complex 1 J haplogroup (found in about 26% of Caucasians, versus 66% of Asians and > 90% of sub-Saharan Africans)
• obese individuals who have never smoked may face an increased risk of developing PD, and the most recent BMI was inversely related to PD risk. Men who gained 45 of more pounds from early adulthood to baseline faced a nonsignificantly higher risk compared with men who gained less than 5 pounds, but the association was reversed in women. Only among never smokers was greater waist circumference or waist-to-hip ratio associated with a higher PD risk in both men and women, the researchers note, even after adjusting for BMI. Among ever smokers, waist circumference and waist-to-hip ratio were not associated with the risk of PD^ref
Proteins involved in pathogenesis :
• a-synuclein-interacting protein / synphilin
• b-synuclein
• ubiquilin 1
Pathogenesis : dopamine can be degraded by the sequential actions of MAO and COMT to yield 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxy-4-hydroxyphenylacetic acid (HVA) : in human beings HVA is the primary product but the first step generates H₂O₂, which, in the presence of ferrous ion (relatively abundant in the basal ganglia) generates hysroxyl free radicals => reduction in the function of complex I of the mitochondrial electron transport chain => impaired metabolic capacity => impaired membrane potential => relieved Mg²⁺ blockade on NMDA ionotropic receptors => excitotoxicity (influx of Ca²⁺ => activation of calpains, ...) => a-synuclein aggregation => Ub-proteasomal failure (Lewy bodies). Dysfunction of parkin (a ubiquitin E3 ligase) and DJ-1 could contribute to these deficits => degeneration of > 70% of dopaminergic neurons of the substantia nigra pars compacta (SNpc) projecting to the striatum (nigrostriate tract). As striatum inhibits the substrantia nigra pars reticulata (SNpr) and medial globus pallidus (MGP) via direct and indirect (lateral globus pallidus (LGP) and subthalamic nucleus (STN)) pathways, the net effect of the reduced dopaminergic input is to increase markedly the inhibitory outflow from the SNpr/MGP to the ventroanterior and ventrolateral nuclei of the thalamus and hence reduce excitation of the motor cerebral cortex => atrophy of frontal and temporal cortex is more severe than in AD (knife-blade gyri)
Symptoms & signs :
• bradykinesia/akinesia : upper limb (hemiinattention, apendolarism) => both upper limbs => even lower limbs; bradylalia
• facial hypomimia/amimia
• sialorrhea
• hyperhidrosis
• rigidity with cogwheel or trochlea phenomenon
• parkinsonian tremor
• impairment of postural balance leading to disturbances of gait => compensatory camptocormia / camptospasm / camptocormy (a static deformity consisting of forward flexion of the trunk) and falling
• push test : when the patient is pushed backward or forward he continues to move until he hurts against an object
• parkinsonian crisis : a condition sometimes observed in parkinsonism, superficially resembling akinetic mutism or coma vigil, the patient lying stiff and motionless, and making no spontaneous communication
• depression (40%)
• parkinsonian dementia (eventually due to therapies)
• Myerson's sign : ready induction of blepharospasm when the frontalis muscle is tapped
• the luminance pattern electroretinogram (PERG) is reported to be abnormal, indicating dysfunction of retinal ganglion cells (RGCs).
Prognosis : without treatment PD progresses over 5 to 10 years to rigid, akinetic state in which patients are incapable of caring for themselves (Lewy body dementia (LBD)). The rate of progression varies among individuals, with death occurring within 5 years in 25% and within 10 years in 60% of the cases. Death frequently results from complications of immobility, including aspiration pneumonia or pulmonary embolism.
Therapy :
• chemotherapy
• cell therapy
• gene therapy
• in situ ASCs recruitment and homing : TGF-a, EGF, FGFs, GDNF and BDNF
• deep brain stimulation (DBS)
• computer-brain interface (CBI)
• thalamotomy
• therapeutic vaccine
Experimental animal models : unilateral nigral lesion with 6-hydroxydopamine (6-OHDA) in rats
Web resources :
• Parkinson's Disease Society
• Awakenings : the internet focus on Parkinson's disease
• Michael J. Fox Foundation for Parkinson's Research
• The Parkinson's Institute
• Parkinson's Disease Foundation (PDF)
Bibliography : Parkinson's Disease: Diagnosis and Clinical Management. Factor, Stewart A.; Weiner, William J.New York: Demos Medical Publishing, Inc.; ©2002. [Free at NCBI Bookshelf ! ]
• juvenile paralysis agitans (of Hunt) / paleostriatal syndrome / pallidal atrophy or syndrome / Ramsay Hunt syndrome : a condition developing in early life, usually familial but occasionally occurring sporadically, marked by increased muscle tonus with the characteristic attitude and facies of paralysis agitans, due to progressive degeneration of the globus pallidus; involvement of the substantia nigra and pyramidal tracts may occur
• acquired hepatocerebral degeneration
• kernicterus
• hypoparathyroidism
• Alzheimer's disease (AD)
• motor neuron diseases (MND)

Epidemiology : 1,000 deaths in Britain every year
Aetiology : 8% of patients inherit their disease and therefore presumably have some other genetic predisposition
• primary MNDs
• chronic MNDs
• involving mainly the upper motor neuron => pyramidal signs
• pseudobulbar paralysis or syndrome

Aetiology : bilateral (not necessarily symmetric) lesions of pyramidal corticonuclear tract (geniculate fasciculus) in the lower part of the ascending frontal gyrus, in the knee of internal capsule (vascularized by the posterior cerebral artery), or in the brainstem, usually due to arteriosclerosis in PCA, AICA, or PICA (associated with multi-infarct dementia), brain tumors, multiple sclerosis, or amyotrophic lateral sclerosis.
Symptoms & signs : bilateral central glossopharyngeal (IX) nerve paralysis, vagus (X) nerve paralysis and accessory (XI) nerve palsy), and hypoglossal (XII) nerve palsy (sometimes also trigeminal (V) nerve paralysis and facial (VII) nerve paralysis); spastic laughing and crying due to liberation of subcortical mimic-emotional centers from cortical control; other pyramidal signs or other cranial nerve paralysis
• Erb-Charcot heredofamilial spastic spinal paralysis / primary lateral sclerosis (PLS) : a form of MND in which the degenerative process is limited to the corticospinal pathways
• familial or hereditary spastic paraplegia (FSP / HSP) / hereditary cerebrospinal paralysis : any of a group of hereditary disorders consisting of gradually developing paralysis in 1, 2, or all 4 limbs, with spasticity. There is degeneration of corticospinal tracts but sensory abnormalities are not present

Aetiology :
• autosomal dominant : mutations in
• SPG3 / FSP1 / Strümpell's disease : a hereditary form of lateral sclerosis in which the spasticity is principally limited to the legs : 14q : atlastin
• SPG3A
• SPG3B
• SPG4 / FSP2 : 2p : SPG4 / spastin (a protein which destabilizes microtubules) are responsible for > 40% of all cases of HSP (autosomal dominant)^ref
• SPG6 / FSP3 : mutations in SPG6 / NIPA1
• SPG8 : SPG8
• SPG9
• SPG10 : mutation in the SPG10 / kinesin family member 5A (KIF5A)
• SPG12 : SPG12
• SPG13 : SPG13
• SPG17 (Silver syndrome)
• SPG18
• SPG19
• autosomal recessive : mutations in
• SPG5A : 8p12
• SPG5B
• SPG7 : 16q : SPG7 / paraplegin (pure and complicated autosomal recessive)
• SPG11 : 15q : SPG11
• SPG14 : 3q
• SPG15 : 14q
• SPG20
• SPG21 (Mast syndrome)
• SPG23
• SPG24
• SPG25 (with disc herniation)
• X-linked
• Xq21 : SPG2 / PLP1 (Pelizaeus-Merzbacher disease; uncomplicated)
• Xq28 : SPG1 / L1CAM1
• SPG16 (complicated, X-linked recessive)
• adrenomyeloneuropathy : mutations in Xq21 (adrenoleukodystrophy protein)
Symptoms & signs : Huntington's sign : the patient is recumbent, with his legs hanging over the edge of a table, and is told to cough. If the coughing produces flexion of the thigh and extension of the leg in the paralyzed limb, it indicates that the paralysis is due to an upper motor neuron lesion.
• involving mainly the lower motor neuron => lower motor neuron syndromes (LMNS) / anterior cornual syndrome / anterior horn cell disease (AHCD) or syndrome (AHCS) : muscular atrophy due to lesions of the anterior horns of the spinal cord.
• motor neuropathy (MN)
• progressive lower motor neuron disease (LMND)
• progressive bulbar palsy / inferior polioencephalitis / bulbar, glossolabial, glossopharyngolabial, labial, labioglossolaryngeal, labioglossopharyngeal, or progressive bulbar paralysis / Duchenne's paralysis or syndrome : progressive labioglossopharyngeal paralysis due to degeneration of the lower motoneuron first (atrophy of the muscles of the lips, tongue, mouth, pharynx, and larynx due to lesions of the motor nuclei of the lower brain stem) and of the upper motoneuron then (=> aspiration pneumonia and malnutrition + pseudobulbar paralysis or syndrome) => secondary damage to upper limb muscles => trunk => lower limbs. It is a chronic, generally fatal disease with onset usually in late adulthood but also earlier in patients with amyotrophic lateral sclerosis, syringobulbia, or multiple sclerosis
• Brown-Vialetto-van Laere syndrome : an autosomal recessive syndrome consisting of progressive bulbar palsy with any of several cranial nerve disorders, including nerve deafness, facial weakness, dysarthria, and dysphagia.
• progressive bulbar palsy of childhood / Fazio-Londe atrophy or disease / progressive infantile bulbar palsy : a rare type of progressive bulbar palsy that occurs in young children
• progressive spinal amyotrophy (PSA) / spinal muscular atrophy (SMA) / hereditary motor neuronopathy / Aran-Duchenne disease or muscular atrophy / Cruveilhier's atrophy or paralysis / wasting paralysis : a progressive degenerative disease of the motor cells of the spinal cord

Aetiology : disruption of the telomeric copy of a duplicated gene survival motor neuron 1 (SMN1)
Symptoms & signs : pseudomyopathic myasthenia beginning usually in the small muscles of the hands, but in some cases (scapulohumeral type) in those of the upper arm and shoulder, the atrophy progresses slowly to the muscles of the lower extremity. Depending on the age of onset, the maximum muscular activity achieved, and survivorship, 3 types of recessive SMA are recognized:
• Eichhorst's atrophy : the femorotibial form of progressive muscular atrophy with contraction of the toes.
• leaping atrophy : progressive muscular atrophy beginning in the hand and extending to the shoulder without affecting the muscles of the arm.
• type I (SMA1) / infantile acute SMA / Werdnig-Hoffmann disease : onset before month 3; babies never seat and die before age 2 due to respiratory failure
• SMA1 with congenital bone fractures : mutations in
• type II (SMA2) : intermediate form SMA with onset between 3 and 18 months; babies can seat but neither walk nor stay upright and die after age 2
• type III (SMA3) / Wohlfart-Kugelberg-Welander syndrome (KWS) / juvenile or proximal SMA : a hereditary form of SMA, usually transmitted as an autosomal recessive trait, due to lesions of the anterior horns of the spinal cord. Onset between 2 and 17 years, with atrophy and weakness of the proximal muscles of the lower extremities and pelvic girdle, followed by involvement of the distal muscles and muscular twitchings
• congenital nonprogressive SMA of lower limbs with contractures : mutations in 12q23-q24
• X-linked lethal infantile SMA : mutations in
• adult SMA : mutations in  12q24, 5q12.2-q13.3, beginning between the end of the fourth and the sixth decade and showing rapid progression without evidence of cortical spinal tract dysfunction.
• SMA with respiratory distress 1 (SMARD1) : mutations in IGHMBP2
• X-linked spinobulbar muscular atrophy (SBMA) / Kennedy's disease (KD)

Aetiology : (CAG) amplification in AR
Epidemiology : onset at age 20-40
Symptoms & signs : proximal myasthenia and cramps, peribuccal fasciculations and hand tremor; often associated with endocrine disorders (gynecomastia, diabetes mellitus, testicular atrophy); long course
• scapulo-humeral spinal amyotrophy
• type I / Start-Kaeser disease (autosomal dominant)

Epidemiology : onset at age 30-50
Symptoms & signs : amyotrophy of foot dosal flexor muscles => scapular girdle => faciale and pharyngeal muscles
• type II (autosomal recessive)

Epidemiology : onset before age 5
Symptoms & signs : X-linked cardiomyopathy (differential diagnosis with Emery-Dreifuss muscular dystrophy / scapuloperoneal muscular dystrophy)
Prognosis : severe
• progressive facioscapulohumeral and scapulohumeral spinal amyotrophy
Differential diagnosis : facioscapulohumeral muscular dystrophy (FSHMD)
• distal progressive spinal amyotrophies
• Hiramaya disease : oblique amyotrophy from cubital border of forearm to interosseous muscles and ipotenar eminence
• GM₂ gangliosidosis
• both upper and lower motor neuron
• amyotrophic lateral sclerosis (ALS) / Lou Gehrig's disease : a MND marked by progressive degeneration of the upper neurons that give rise to the corticospinal tract and/or of the lower motor neurons of the brain stem and anterolateral columns of spinal cord. Gehrig was the New York Yankees first baseman who succumbed in 1941^ref

Epidemiology : incidence = 1-3 cases every 100,000 inhabitants / year (5-9 cases among people aged 55-65)
Aetiology :
• sporadic ALS / Charcot's disease (90%)
• ALS1 / familial ALS (FALS) (5-10% : probably an underestimate, primarily due to inadequate recording of family history in the patients' charts, and to the not infrequent occurrence of reduced disease penetrance in pedigrees with familial ALS. The true familial ALS frequency may be at least double this) : mutations in^{ref1, ref2}
• autosomal dominant
• 21q : CuZn-SOD / SOD1 (20% of all familial ALS cases and a few % of apparent sporadic ALS ; 2% of all MNDs)
• 22q : heavy neurofilament subunit
• X_cent : unknown
• senataxin
• mitochondrial : cytochrome c oxidase
FALS is neuropathologically classified into 2 subtypes:
• classical FALS in which degeneration is restricted to only motor neurons
• FALS which is characterized by the degeneration of the posterior column in addition to the lesion of the motor neuron system
Childhood- and adolescent-onset forms of familial ALS carry the designation 'juvenile ALS" and are usually autosomal recessive
• ALS2: mutations in alsin
• ALS3: mutations in 18q21
• ALS4 / distal hereditary motor neuropathy with pyramidal features : mutations in 9q34
• ALS5: mutations in 15q15.1-q21.1
• ALS6: mutations in
• ALS7: mutations in
• juvenile ALS with dementia / ALS-dementia complex :
• progressive muscular atrophy with ALS : mutations in SOD1
• ALS-plus syndromes
• ALS with frontotemporal dementia : mutations in 9q
• amyotrophia with behavioural disorders and parkinsonian characteristics : mutations in 17q (tau protein)
Pathogenesis : mechanisms of neurodegeneration include oxidative stress, glutaminergic excitotoxicity, damage to vital organelles, and aberrant protein aggregation. SOD1 scavenges superoxide radicals in the cytoplasm. The effect of the mutation varies greatly, from little or no loss to complete loss of scavenging activity. Even though the mutant protein is expressed in every tissue and cell type in the body, it seems to damage motor neurons alone. In transgenic mouse models of the disease, for example, expression of the mutant protein in all tissues may be elevated by a factor of 10, but degeneration is confined to the spinal motor neurons. To examine the role of individual types of cells in SOD1-mediated ALS, Boillee et al. manipulated the expression of mutant SOD1 in motor neurons or microglia^ref The investigators generated mice that expressed a mutant version of SOD1 in a manner that allowed them to "turn down" the level of the mutant protein in specific types of cells. First, they generated mice in which the mutant gene was flanked by short sequences of DNA that are recognized by a bacterial enzyme (called Cre recombinase) that catalyzes the excision of the short sequences together with all intervening DNA (in this case, the mutated SOD1 gene) from the genome. The researchers established several lines of such mice with multiple copies of the gene inserted in tandem into germ-line DNA. They then determined the age of the onset of disease and the timing of progression in the mice, establishing a baseline for comparison. Previous work had shown that the more mutated SOD1 genes a mouse carried, the greater the level of mutant SOD1 protein and the shorter its life. Boillee et al. replicated this finding. The mice were then mated to mice that express Cre recombinase in a particular type of cell (that is, the motor neuron or the microglia), which resulted in progeny with repressed levels of mutant SOD1 in that cell type. (The mutant SOD1 is expressed in all cells, but the expression of Cre recombinase in, say, the microglia excises the mutated gene and hence diminishes synthesis of mutant SOD1.) The investigators observed that in mice carrying even a modestly diminished load of mutant SOD1 in their motor neurons, the onset and progression of the disease were substantially delayed. This finding is consistent with a delayed onset of disease in SOD1-mutant mice treated with small interfering RNAs that specifically target the expression of mutant SOD1. The investigators noted that the selective diminution of the mutant protein in microglia greatly delayed the progression of late-stage disease — a period characterized by axonal degeneration and a loss of motor neurons. This finding implies that an activity of mutant SOD1 in microglia initiates events that hasten the demise of motor neurons. Activation of microglia is accompanied by increased expression of surface-membrane proteins that form gap junctions between cells. Moreover, infiltrating macrophages, which replenish microglial populations, may become fusogenic when activated. Close apposition of microglia with motor neurons has been observed in neurodegenerative conditions, but whether actual connections are made, allowing for the passage of molecules through a cytoplasmic bridge, is uncertain. If Cre recombinase could be transferred to motor neurons, any resultant decrease in the level of expression of mutant SOD1 could delay the progression of ALS. The fact that only the late stage of disease was affected in these mice fits with this scenario, since activation of microglia tends to occur during the later stages of disease. Another possibility — and one that is much more interesting with regard to the disease mechanism — is that activated microglia supply toxins to the motor neurons or otherwise induce neuronal degeneration. Or perhaps toxins (or some other property of the mutant SOD1) damage microglia, which lose their protective function. The question is whether microglia expressing mutant SOD1 directly injure motor neurons or whether a protective function of microglia is diminished. Activated microglia, which are present in the murine models of ALS and are typically found in patients with the disease, have been shown to have both neurotoxic and neuroprotective properties in other disease settings.  Although the study by Boillee et al. suggests a role of microglia in the modification of disease progression, it is not certain that mutant SOD1 in microglia is critical to disease pathogenesis. Recent studies show that a fatal ALS-like disease develops in mice expressing particularly unstable mutants of SOD1; the unstable protein is rapidly degraded and does not accumulate to appreciable levels in cells other than degenerating motor neurons^{ref1, ref2, ref3}.2,3,4 Questions remain about the mechanism by which mutant SOD1 in microglia contributes to the degeneration of motor neurons, but the study by Boillee et al. provides compelling evidence that even a modest reduction in the level of expression of mutant SOD1 in motor neurons, and perhaps in other non-neuronal cells, could substantially alter the course of disease. The therapeutic implications for an approach that lowers the level of expression of mutant protein might extend to other autosomal dominant neurodegenerative diseases, such as Huntington's disease.
Grading : reduced motor units
• A : mild, nonspecific reduction
• B : moderate reduction
• C : severe reduction
Symptoms & signs : onset at limbs (65-80%) or bulbar paralysis (20-25%)
• due to disease of upper motoneurons (pyramidal syndrome) :
• hypotonia
• spastic paraplegia
• hyperreflexia
• Babinski's sign
• emotional lability (ALS-dementia and ALS-related frontal lobe dementia)
• due to disease of lower motoneurons (peripheral neurogenic or amyotrophic syndrome) :
• muscle atrophy (initially in interosseous hand spaces, tenar and ipotenar eminences => ape hand)
• the bulbar symptoms of ALS include :
  
• dysphagia
• dysarthria (due to bulbar nuclei involvement for IX, X, and XI cranial nerves)
• hypophonia
• sialorrhea
• tongue atrophy and fasciculations (even of tongue)^ref
• respiratory failure
• hyporeflexia
• lack of objective sensory disorders
• cramp
Clinical forms :
• progressive bulbar paralysis (PBP) (25%; the most severe)
• cervical or common form (41%) : unilateral => bilateral brachial onset
• pseudopolyneuritic form (30%; the least severe) : asymmetric distal deficits in lower limbs + achillean areflexia + lack of objective sensory disorders, fasciculations and spastic hypertone
Laboratory examinations :
• EMG
• cervical rachid MRI and/or CT for differential diagnosis with cervical spinal cord tumors
• cerebrospinal fluid (CSF) examination
• nerve and/or muscle biopsy
• genetic testing should only be performed after thorough clinical examination and in cases with a proven or uncertain family history of ALS. It is not warranted in cases with no proven family history for three generations, unless the patient shows the characteristic phenotype associated with recessive inheritance of the D90A CuZn-SOD mutation.
Prognosis : it kills most of its victims within 2 to 5 years after symptoms appear; 3-year survival = 50%; 5-year survival = 18.7%; 10-year survival = 7.6%.
Therapy :
• chemotherapy
• pharmacological activation of the heat shock response with arimoclomol, a coinducer of heat shock proteins (HSPs), may be a successful therapeutic approach to treating ALS, and possibly other neurodegenerative diseases^ref
• tracheostomy
• assisted ventilation
• parenteral nutrition
• intrathecal baclofen (ITB) pump for ALS patients with intractable spasm-related pain
Experimental models : transection of the facial nerve in mice
Web resources :
• ALS Association
• World Federation of Neurology (WFN) ALS
• Usenet sci.med.diseases.als
• NIH: ALS Fact Sheet
• ventrolateral or anterolateral sclerosis : sclerosis of the ventral and lateral columns of the spinal cord, leading to spastic paraplegia
• lateral sclerosis : a motor neuron disease consisting of degeneration of the lateral columns of the spinal cord, leading to spastic paraplegia
• vitamin B₁₂ deficiency (Rieser-Russel syndrome)
• posterolateral sclerosis / subacute combined degeneration of spinal cord / combined system disease or sclerosis / Lichtheim's disease or syndrome / Putnam-Dana syndrome / funicular myelosis

Epidemiology : most often affecting persons over 40 years of age
Aetiology : vitamin B₁₂ deficiency
Pathogenesis : the cervical and thoracic medullary white matter, especially the posterior and lateral columns (funiculi), are primarily affected. The white matter tracts involved show demylination with degeneration of myelin sheaths and axonal loss.
Symptoms & signs : involvement of the posterior columns (70-90%) leads to paresthesia (80-85%), impaired proprioception (70%-90%), and loss of vibration sense, whereas involvement of the lateral column leads to paresis (55-80%), ataxia, unsteadiness of gait, and sometimes emotional disorders; usually associated with pernicious anemia^{ref1, ref2}
Laboratory examinations : the described medullary changes can be visualised on MRI^{ref1, ref2, ref3, ref4, ref5, ref6}  The age of these patients (one woman and five men) ranged from 10 to 69 years (mean 46.3 years). All showed an intramedullary hyperintensity on the T2 weighted images, which is thought to be mainly due to demyelination. By contrast, axonal loss is thought to occur later and to a lesser degree^ref. This demyelination was located in the cervical spinal cord in 2 patients^{ref1, ref2}, in the cervical and thoracic spinal cord in three patients including the one we report on^{ref1, ref2}, and only in the thoracic spinal cord in the remaining patient^ref. In all but one patient^ref, multiple levels were affected. The posterior columns were the site of maximal signal intensity change in our patient and 3 others^{ref1, ref2, ref3}. These MRI findings are compatible with histopathological findings, mainly demyelination. Gd-DTPA was administered twice; one patient showed mild enhancement^ref. It is important to recognise these changes on spinal MRI. As MRI becomes more accessible, the MRI examination can be performed before the results of laboratory tests are available. As the clinical picture of vitamin B12 deficiency or CVID can be puzzling, changes on MRI can help to establish the diagnosis. Although extensive changes within the spinal cord have also been reported in multiple sclerosis, they are unusual^ref. Follow up studies performed at 10 weeks^ref, 4 months^ref, 5 and 10 months^ref, 6 months^ref, and at 3 years (Berger and Quencer^ref and our patient) always disclosed a reduction or resolution of the intramedullary hyperintensity after treatment with vitamin B₁₂. Thus the effect of treatment can be successfully monitored with MRI. As the therapy leads to a remyelination of the affected white matter tracts, their signal intensity on the T2 weighted sequence returns to normal in parallel with improvement of the clinical picture. If improvement begins as early as 10 weeks after therapy, the main reason for the clinical picture and the MRI changes cannot be ascribed to axonal loss
Therapy : vitamin B₁₂
• acute MND
• HHV-3 / VZV
• paralytic poliomyelitis
• coxsackievirus
• secondary MNDs
• structural injuries :
• parasagittal or foramen magnum tumors
• cervical spondylitis
• Chiari's malformation or deformity or syringomyelia
• spinal cord arteriovenous malformation (AVM)
• infections :
• bacterial infections :
• Borrelia burgdorferi
• Clostridium tetani
• viral infections
• paralytic poliomyelitis
• HHV-3 / VZV
• tropical spastic paraparesis (TSP) / chronic progressive myelopathy / HTLV-1–associated myelopathy (HAM)
• intoxications, physical agents
• amyotrophic lateral sclerosis-Parkinsonian dementia complex (ALS-PDC) / Guamanian amyotrophic lateral sclerosis (ALS-G) and parkinsonism dementia (PD-G)

Epidemiology : Guam's Chamorro people – up to 33% per village
Aetiology : biomagnification (the increasing accumulation of bioactive, often deleterious molecules through higher trophic levels of a food chain) of the neurotoxic nonprotein amino acid b-methylamino L-alanine (BMAA). Free-living Cyanobacteria produce 0.3 µg/g BMAA, but produce 2-37 µg/g as symbionts in the coralloid roots of cycad trees. BMAA is concentrated in the developing reproductive tissues of the cycad Cycas micronesica, averaging 9 µg/g in the fleshy seed sarcotesta and a mean of 1,161 µg/g BMAA in the outermost seed layer. Local flying foxes (Pteropus mariannus), which forage on the seeds, accumulate a mean of 3,556 µg/g BMAA (when rats ingest BMAA, 90% of it stays in their bodies rather than being excreted). Flying foxes are a prized food item of the indigenous Chamorro people who boil them in coconut cream and eat them whole (wings, brains, fur and all) at weddings, village fiestas and religious events. Chamorros who die of ALS-PDC have an average of 6.6 µg/g BMAA in their brain tissues. The biomagnification of BMAA through the Guam ecosystem fits a classic triangle of increasing concentrations of toxic compounds up the food chain. Biomagnification of cyanobacterial BMAA may not be unique to Guam; our discovery of BMAA in the brain tissue from Alzheimer's patients from Canada suggests alternative ecological pathways for the bioaccumulation of BMAA in aquatic or terrestrial ecosystems^ref. They have been epidemiologically linked to an environment severely deficient in calcium (Ca²⁺) and magnesium (Mg²⁺). Transient receptor potential melastatin 7 (TRPM7) is a bifunctional protein containing both channel and kinase domains that has been proposed to be involved in the homeostatic regulation of intracellular Ca2+, Mg2+, and trace metal ion concentration. There is evidence that TRPM7 is constitutively active and that the number of available channels is dependent on intracellular free Mg²⁺ levels. A TRPM7 variant was found in a subset of ALS-G and PD-G patients that produces a protein with a missense mutation, T1482I. Recombinant T1482I TRPM7 exhibits the same kinase catalytic activity as WT TRPM7. However, heterologously expressed T1482I TRPM7 produces functional channels that show an increased sensitivity to inhibition by intracellular Mg²⁺. Because the incidence of ALS-G and PD-G has been associated with prolonged exposure to an environment severely deficient in Ca²⁺ and Mg²⁺, this variant TRPM7 allele confers a susceptibility genotype in such an environment^ref
Symptoms & signs : similar to amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease (AD)
Therapy :
• lathyrism : a morbid condition seen in humans and other animals after excessive ingestion of seeds of the genus Lathyrus, which contain b-aminopropionitrile, an inhibitor of the enzyme lysyl oxidase. The disease is characterized by spastic paraplegia, pain, hyperesthesia, and paresthesias. It has been recognized since the time of Hippocrates, and was common in Britain, Spain, France, Italy, Russia, India and northern Africa, but is now only of historical interest except during famines when people are forced to eat the seed. Symptoms in man include partial or total paralysis, usually of the lower extremities, but in severe cases the arms as well. The disease may progress if ingestion of the seeds continues. Prodromata include pains, prickly sensations, hypoesthesia, cramps, muscular tremors, muscular wasting (in chronic cases), loss of bladder control. It can be fatal. Livestock are variably susceptible -- mostly the horse. Symptoms may develop over months.
• epidemic spastic paraparesis / konzo / tropical ataxic neuropathy

Aetiology : linamarin
Symptoms & signs : spastic paraparesis, painful peripheral neuropathy
• lead
• aluminum
• other metals
• drugs : strychnine, phenytoin
• electroshock, X-rays
• mainly involvement of lower motor neuron
• autoimmune
• plasma cell dyscrasia
• autoimmune polyradiculopathy
• multifocal motor neuropathy with conduction block
• mainly motor peripheral neuropathy
• paraneoplastic
• paracarcinomatous/lymphoma
• metabolic alterations
• hypoglycemia
• hyperparathyroidism
• hyperthyroidism
• folic acid, vitamin B₁₂, and vitamin E deficiency
• malabsorption syndromes
• mitochondrial dysfunction
• hyperlipidemia
• hyperglycinuria
• methylcrotonylglycinuria
Web resources : Motor Neurone Disease Association
• organic mental disorder
• dyspraxia : partial loss of ability to perform coordinated acts.
• disconnection syndrome : any neurologic disorder caused by an interruption in impulse transmission along cerebral fiber pathways; one result may be an inability to carry out a desired movement in response to a given sensory input, as in the apraxias.
• Liepmann's apraxia
• neglect : disregard of or failure to perform some task or function.
• hemispatial neglect : failure to respond to stimuli on one side, usually opposite the side of a lesion in a cerebral hemisphere
• psychomotor retardation : generalized slowing of mental and physical activity, as is common in depression and in catatonic schizophrenia

Laboratory examinations :
• intelligence test : a set of problems or tasks posed to assess an individual's innate ability to judge, comprehend, and reason
• Bender Gestalt test / Bender Visual-Motor Gestalt test : a psychological test used for evaluating perceptual-motor coordination, for assessing personality dynamics, as a test of organic brain impairment, and for measuring neurological maturation. The subject is asked to make free-hand copies of 9 simple geometric designs presented separately on cards or sometimes to reproduce the design from memory
• Binet's test : a method of testing the mental capacity of children and youth by asking a series of questions adapted to, and standardized on, the capacity of normal children at various ages. According to the answers given, the mental age of the subject is ascertained
• Goodenough draw-a-man test / Goodenough draw-a-person test : a method of testing the general intelligence of children by asking the subject to draw a picture of a man to the best of his or her ability.
• Goodenough-Harris drawing test : a revision of the Goodenough draw-a-man test, in which scoring emphasizes the presence or absence of body and clothing detail rather than artistic skill
• hypertrophic olivary degeneration

Aetiology : trauma, infection, demyelination, neoplasm, or vascular injury in the components of the dentatorubroolivary pathway, results in olivary hypertrophy rather than atrophy. Myoclonic contractions of the soft palate and nystagmus represent the effects of transsynaptic degeneration of the inferior olivary nuclei. After treatment with trihexyphenidyl, there
was some improvement in the patient’s visual symptoms^ref
• post-malaria neurological syndrome (PMNS) : development of transient neurological (generalised convulsions or fine tremor) or psychiatric (acute confusional state or psychosis) symptoms within 2 months after the acute severe infections (parasites cleared from blood (and in cases of cerebral malaria full recovery of consciousness) in Vietnam and Thailand. Overall incidence of PMNS after falciparum malaria is 1.2 per 1000. Oral use of mefloquine is not the only risk factor for PMNS but it is a strong one (RR = 9.2)^ref. Where an effective alternative drug is available, mefloquine should not be used after treatment of severe malaria.
• epilepsy

Epidemiology : prevalence = 4-10 cases every 1,000 inhabitants (higher in newborns > infants > elderlies > adults); incidence = 24-53 cases every 1,000 inhabitants (0.03-0.05%) per year; 5-10% of population has 1 seizure during lifetime (prevalence is higher in babies and elderlies)
A single episode is called a seizure / convulsion / fit / ictus epilepticus, often named for the kind of epilepsy it represents: the International League Against Epilepsy (ILAE) classification, 1981, is based on clinics and EEG :
• focal, localized, or partial epilepsy epilepsy due to a localized, limited structural brain lesion in a specific, known area of the cerebral cortex and consisting focal or partial seizure (symptoms vary with different lesion locations) :
• simple partial seizure : the most localized type of partial seizure, with a discharge that is predominantly one-sided or that presents localized features, and without loss of consciousness. If it progresses to another kind of seizure it is called an epileptic aura : a subjective sensation or motor phenomenon that sometimes gives warning of an approaching generalized or complex partial seizure. Formerly considered part of the prodrome of a seizure, it is now known to be itself a type of simple partial seizure and may occur without progression to a more serious attack.
• signal symptom : a sensation, aura, or other subjective experience that gives warning of the approach of an epileptic or other seizure.
• Séguin's signal symptom : the involuntary contraction of the muscles just before an epileptic attack.
• intellectual or reminiscent aura : a simple partial seizure with psychic manifestations, causing a dreamy mental condition
Symptoms & signs are varied :
• focal motor seizure : a simple partial seizure consisting of clonus or spasm of a muscle or muscle group
• single
• crispation : slight convulsive or spasmodic muscular contractions producing a creeping sensation.
• in a continuous and repetitive series
• adversive seizure : a type of focal motor seizure in which there is forceful, sustained turning to one side by the head, eyes, or entire body.
• widespread gliomatosis cerebri
• benign epilepsy with centrotemporal or rolandic spikes / benign rolandic epilepsy : a self-limited, autosomal dominant disorder of childhood consisting of partial seizures manifested by facial movements and grimaces, often followed by tonic-clonic seizures. The EEG from the primary somatomotor area (rolandic area) shows characteristic repetitive high-voltage spikes
• Bravais-jacksonian epilepsy : epilepsy characterized by focal motor seizures with unilateral clonic movements that start in one group of muscles and spread systematically to adjacent groups, reflecting the cortical, epileptic and jacksonian march of the abnormal electrical epileptic activity through the motor cortex. The seizures are due to a discharging focus in the contralateral motor cortex. It may be followed by Todd paralysis, lasting from a few minutes to many hours or sometimes days
• hemiepilepsy : epilepsy affecting one side of the body only.
• sensory epilepsy : seizures manifested by paresthesias or hallucinations of sight, smell, or taste
• somatosensory epilepsy : sensory epilepsy with paresthesias such as tingling, numbness, or burning.
• visual epilepsy : sensory epilepsy in which there are visual hallucinations such as flashes of light or colors
• sensory seizure : a simple partial seizure manifested by paresthesias or other hallucinations (teichopsia), vertigo, instability, including several types of aura or a reflex seizure in response to a sensory stimulus.
• psychic seizure : perception of strange flavours or sounds, sensations flowing from stomach to head, anxiety, depersonalization, deja vu, deja veçu, micropsia, macropsia
• autonomic seizure : piloerection, sweating, hot flushes
• abdominal epilepsy / Moore's syndrome : paroxysmal abdominal pain, the expression of an abnormal neuronal discharge from the brain
• epigastric aura : a simple partial seizure with autonomic manifestations, causing an uncomfortable sensation in the epigastrium.
Chemotherapy : antiseizure drugs (carbamazepine)
• complex partial epilepsy: with impairment of consciousness lasting 30"-2' (the patient does not react to visual stimuli or verbal commands and can't remember the crisis). An attack is often preceded by a hallucinatory aura, most often visual or auditory but sometimes involving the other senses. Sometimes anterograde amnesia and, when the dominant hemisphere is involved, postictal aphasia.
• psychic, psychomotor or mesial temporal lobe epilepsy (TLE) (MTLE) : associated with disease of the temporal lobe (mesial temporal or hippocampal sclerosis or small-sized temporal lobe) and characterized by frequent aura, cessation of every activity, fixed gaze, unilateral involvement, deficiency of memory after administration of amobarbital (Wada's test), varying degrees of impairment of consciousness; the patient performs complex partial seizure (automatisms = quasipurposive acts; automatic seizure); usually refractory to AEDs, requires surgery.
• mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS)
• uncinate epilepsy : temporal lobe epilepsy caused by a lesion in the uncinate region (e.g. mesial temporal or hippocampal sclerosis) and therefore associated with hallucinations of smell and taste.
• gelastic epilepsy : uncontrollable mirthless laughter
• masticatory
• procursive epilepsy : aimless running or wandering (epileptic fugue)
• rotatory epilepsy : rotating body movements
• uncinate epilepsy
Therapy : antiseizure drugs (phenytoin, carbamazepine, valproate, gabapentin, lamotrigine, levetiracetam, tiagabine, topiramate, zonisamide), gene therapy
• partial epilepsy with secondarily generalized epilepsy : usually preceded by epileptic aura, with tonic-clonic seizures (grand mal epilepsy), expecially from simple partial epilepsy originating in frontal lobe (arising with adversive lateral head rotations); lasting 1-2'. Chemotherapy : antiseizure drugs (carbamazepine, phenytoin, valproate, primidone, phenobarbital, gabapentin, lamotrigine, levetiracetam, tiagabine, topiramate, zonisamide)
• primarily generalized epilepsy : epilepsy in which the seizures are generalized and arise simultaneously from symmetrical areas of both hemispheres, due to widespread structural brain lesions or cellular or biochemical alterations; focal onset cannot be identified
• absence (epilepsy) / petit mal (epilepsy) / minor epilepsy : epilepsy characterized by absence (seizure), consisting of a sudden momentary break in consciousness of thought or activity (suspension of working memory due to functional inactivation of prefrontal network), often accompanied by automatisms or clonic movements, especially closure of the eyelids, chewing or hand clonus, but with no impairment of postural tone; consciousness is recovered immediately. On the EEG it is characterized by a specific symmetrical spike and wave type occurring at 3 Hz and provoked by hyperventilation. Usually onset is at age 4-8 and represent 15-20% of childhood epilepsies : 60-70% have spontaneous remission during adolescence. They may occur hundreds of times during the day and are often associated with generalized tonic-clonic seizures responsive to therapy.
• atypical absence : more prolonged loss of consciousness, more gradual opnset and end, more severe motor signs and sometimes also focal neurological signs, EEG shows generalized slow spike and wave complexes occuring at < 2.5 Hz
• Lennox-Gastaut syndrome / petit mal variant : an atypical form of absence epilepsy characterized by diffuse slow spike waves (< 3 Hz), often with atonic, tonic, or clonic seizures and mental retardation; there may also be other neurological abnormalities or multiple seizure types. Unlike typical absence epilepsy, it may persist into adulthood. It seems to be due to an aspecific response of the nervous sytem to a difuse injury as a developmental anomaly, perinatal hypoxia or ischemia, trauma, infection or other acquired disease
• astatic or atonic seizure : an absence seizure characterized by sudden loss of muscle tone lasting 1-2" => head or whole body falls, usually having its onset in childhood or adolescence in the set of another epileptic syndrome. EEG shows generalized spike-wave discharges followed by diffuse slow waves corresponding to the phase of muscular atonia.
• petit mal status : any of a variety of clinical disorders with symptoms ranging from momentary interruption of consciousness to longer-lasting spells of loss of motor control lasting 6 < t < 30".
Chemotherapy : antiseizure drugs (ethosuximide, valproate, lamotrigine)
• grand mal (epilepsy) / major epilepsy / haut mal epilepsy (10%) : a symptomatic form of epilepsy lasting about 1', usually associated with metabolic disorders

Symptoms & signs : often preceded by prodromic symptoms that need to be differentiated by the epileptic aura of the partial epilepsy with secondarily generalized epilepsy; characterized by loss of consciousness, with generalized tonic-clonic or centrencephalic seizures
• generalized hypertonia lasting 10-20" =>
• generalized hyperextension => fall down
• tonic contraction of masseter and temporal muscles => self-biting of tongue (absent in syncopal seizures, where the hypertonic crisis is delayed after the loss of consciousness) => hemorrhage with impaired blood swallowing
• forced expiration through hypertonic vocal chords (=> scream; absent in syncopal seizures) => respiratory arrest => hypercapnia and hypoxemia => cyanosis(differential diagnosis with pallor of syncope)
• urinary incontinence (and rarely fecal incontinence)
• increased orthosympathetic acitivity causes tachycardia, systemic arterial hypertension, and mydriasis
• clonic convulsions lasting < 1' (differential diagnosis with syncopal seizures which are only tonic)
• alternated flexions and extensions, expecially at limbs due to sudden arrests of hypertonia
• hemophtoe
• loss of control of smooth sphincters => urinary incontinence
• total decontraction lasting about 30' => sleepiness, unresponsiveness to stimuli, muscular hypotonia, and excessive salivation that may cause dyspnea, partial obstruction of the airways, urinary incontinence and fecal incontinence (postcritical or subcritical coma)
• vertiginous epilepsy : focal seizures giving rise to a sensation of vertigo; occasionally these are auras of more general seizures
Chemotherapy : antiseizure drugs (valproate (works in 70% of patients) : second choice drugs (carbamazepine, phenytoin, primidone, phenobarbital, lamotrigine, topiramate) work only in 10% of patients)
• tonic seizure : a seizure characterized by tonic but not clonic contractions lasting a few seconds, usually occurring in
• Lennox-Gastaut syndrome / petit mal variant
• multiple sclerosis
• clonic seizure : a rare kind of seizure in which there are generalized clonic contractions without a preceding tonic phase.
• myoclonic or myoclonus epilepsy : any form of epilepsy accompanied by myoclonus(lasting 1"). EEG is characterized by bilateral synchronous spike and wave complexes
• severe myoclonic epilepsy in infancy (SMEI)
• juvenile myoclonic epilepsy / Janz syndrome : a syndrome of sudden myoclonic jerks, occurring particularly in the morning or under conditions of stress or fatigue (sleep deprivation), with no loss of consciousness; seen primarily in children and adolescents. Occasionally the jerks may progress to absence seizures (33%) and generalized tonic-clonic seizures. Poor response to AEDs.
• jackknife or salaam convulsions, seizures, or spasms / West's syndrome / infantile massive spasms : a syndrome of severe myoclonus appearing in the first 18 months of life and associated with general cerebral deterioration; it is marked by severe flexion spasms of the head, neck, and trunk and extension of the arms and legs; EEG shows hypsarrhythmia.

Therapy : ACTH
• progressive familial myoclonic epilepsy : myoclonic epilepsy that is hereditary
• Baltic myoclonic epilepsy / Unverricht's or Unverricht-Lundborg disease : a progressive, autosomal recessive form of myoclonic epilepsy seen in Finland. Onset is between the ages of 6 and 13 and there are degenerative changes in the brain without presence of Lafora bodies. Mental deterioration is milder and survival is longer than in Lafora's myoclonic epilepsy
• Lafora's disease or myoclonic epilepsy : a slowly progressive autosomal recessive form of epilepsy beginning in childhood and characterized by attacks of intermittent or continuous clonus of muscle groups, resulting in difficulties in voluntary movement; there is mental deterioration, sometimes progressing to complete dementia, and the presence of Lafora bodies in various cells, including those of the nervous system, retina, heart, muscle, and liver.
• progressive encephalopathy with edema, hypsarrhythmia, and optic nerve atrophy (PEHO) syndrome was first described in 1991 by Salonen et al in the Finnish population^ref. It is an apparently autosomal recessive condition characterized by the association of progressive encephalopathy, subcutaneous edema, hypsarrhythmia, and optic atrophy; it manifests between the second week and third month of life as hypotonia, absence or early loss of visual fixation, seizures with hypsarrhythmia^{ref1, ref2}, early arrest of motor and mental development, and optic atrophy. Those affected show characteristic dysmorphic features: narrow forehead, epicanthic folds, short nose with upturned nares, open mouth, gingival hypertrophy, prominent auricles and receding chin (general hypoplasia of the face), and tapering fingers^ref. Transitory or permanent subcutaneous edema, evident in the limbs and face, is also typically present. Radiologic examination reveals marked cerebellar and brainstem atrophy at the earliest stage, whereas cerebral atrophy appears later^{ref1, ref2}. Myelination can be conspicuously delayed. The diagnostic clnical criteria according to Somer^ref are :
• necessary criteria :
• infantile, usually neonatal hypotonia
• convulsive disorders manifesting with myoclonic jerking and infantile spasms
• profound psychomotor retardation with severe hypotonia; absence of motor milestones and speech
• absence or early loss of visual fixation with atrophy of optic disk by 2 years of age; normal electroretinogram, extinguished visual evoked potentials
• progressive brain atrophy in neuroimaging studies, particularly in the cerebellum and brain stem; milder supratentorial atrophy
• supportive criteria :
• subtle dysmorphic features with narrow forehead, epicanthic folds, short nose, open mouth, receding chin, and tapering fingers
• edema of the face and limbs, especially in early childhood
• brisk tendon reflexes in early childhood
• abnormal brainstem auditory evoked potentials
• absent cortical responses of somatosensory evoked potentials
• slow nerve conduction velocities in late childhood
• dysmyelination in magnetic resonance imaging
The clinical presentation of PEHO-like syndrome is similar to that of PEHO syndrome, except that neuro-ophthalmologic or neuroradiologic signs are absent^ref. In addition to Finnish patients, cases of PEHO and PEHO-like syndrome have been identified occasionally in Australia^ref and some countries in Europe^{ref1, ref3} but never in Italy. The clinical characteristics and pattern of family occurrence suggest that it is an autosomal recessive metabolic condition^ref; however, no biochemical or genetic markers have yet been identified. To rule out an underlying degenerative metabolic condition potentially associated with cerebellar hypoplasia or hypotrophy, plasma and urinary amino acids, urinary organic acids, and plasma 7-dehydrocholesterol should be determined and isoelectric focusing of serum transferrin should be performed. Riikonen et al reported significantly low levels of IGF-1 in the cerebrospinal fluid of children with PEHO syndrome but not in those with PEHO-like syndrome^ref, whereas Vanhatalo and Riikonen found markedly increased levels of nitric oxide and metabolites in the cerebrospinal fluid of PEHO patients but modestly increased levels of these substances in patients with PEHO-like syndrome^ref. The latter authors suggested that nitric oxide was involved in the pathologic phenomena of these conditions, but, so far, this has not proved useful in diagnosing the conditions or interpreting the differences between them. The diagnosis of both conditions remains exclusively clinical^ref. A careful clinical and instrumental follow-up is necessary in patients with a PEHO-like phenotype. This can detect later onset of signs and symptoms, such as optic atrophy, which allows us to confirm the diagnosis of PEHO syndrome or points to different conditions with different etiology but similar clinical features.
Symptoms & signs : bilateral blepharoclonus (orbicularis oculi muscle contracts 3 times per second)
Chemotherapy : antiseizure drugs (valproate, lamotrigine, topiramate)
• unclassified crises
• neonatal seizures
• infant spasm
Timing :
• nocturnal epilepsy : epileptic attacks occurring at night or while the patient is asleep
• matutinal epilepsy : epileptic seizures occurring in the morning on awakening
• diurnal epilepsy : epileptic attacks occurring in the daytime or when the patient is awake.
Onset :
• late or tardy epilepsy : epilepsy beginning in middle age or later.
• larval or latent epilepsy : unerupted epileptic seizures, represented only by characteristic waves in the EEG
• serial seizures : seizures occurring in series, with return of consciousness between individual attacks
• status epilepticus : any prolonged series of similar seizures without return to full consciousness between them, which may lead to encephalopathy; the 2 major types are
• (convulsive) status epilepticus / tonic-clonic status epilepticus : a continuous series of generalized tonic-clonic seizures without return to consciousness, a life-threatening emergency
• nonconvulsive status epilepticus : status epilepticus that does not include generalized tonic-clonic seizures. It is serious but not usually life-threatening.
• complex partial seizures
• petit mal seizures
• simple partial status / epilepsia partialis continua / Koshevnikoff's (Koschewnikow's, Kozhevnikov's) epilepsy : a form of status epilepticus with focal motor seizures, marked by continuous clonic movements of a limited part of the body (preservation of consciousness, lasting 20-60"). Chemotherapy : antiseizure drugs(carbamazepine, phenytoin, valproate, gabapentin, lamotrigine, levetiracetam, tiagabine, topiramate, zonisamide)
Chemotherapy :
• diazepam or lorazepam (0.1 mg/kg i.v. at 2 mg/min)
• when still persisting after 5-25' : phenytoin (20 mg/kg at 50 mg/min)
• when still persisting after 25-35' : phenytoin (other 5-10 mg/kg)
• when still persisting after 35-55' : phenobarbital (20 mg/kg i.v. at 50-75 mg/min) (barbiturate coma => artificial respiration)
• when still persisting after 55-65' : phenobarbital (other 5-10 mg/kg)
• if severe systemic alterations (e.g. severe hyperthermy) occur or seizures lasting for > 60-90' : induction of anesthesia with midazolam / propofol
Aetiology :
• idiopathic, cryptogenic or essential epilepsy : epilepsy of unknown origin, possibly associated with some inherited predisposition for seizures
• idiopathic generalized epilepsy (IGE) : the prevalence of T1DM is increased by a factor of 4 in young adults with IGE^ref
• physiologic epilepsy : biologic or electrobiologic seizures based on physiologic and not on organic or structural abnormalities of the brain
• acquired, symptomatic or organic epilepsy : acquired epileptic seizures caused by
• in newborns (< 1 month)
• perinatal hypoxia and ischemia
• intracranial hemorrhage and brain injury (post-traumatic epilepsy)
• acute CNS infections
• metabolic disorders (hypoglycemia, hypocalcemia, hypomagnesemia, pyridoxine deficiency) : pipecolic acid is a diagnostic marker in pyridoxine-dependent seizures^ref
• drug withdrawal
• developmental disorders
• genetic diseases
• first and second childhood (> 1 month and < 12 years)
• febrile seizures
• genetic diseases (metabolic, degenerative, and primary epileptic syndromes)
• CNS infections
• developmental disorders
• brain injury
• idiopathic crisis
• adolescents (12-18 years)
• brain injury
• genetic diseases
• infections
• cerebral tumors
• substance abuse
• idiopathic crisis
• catamenial or menstrual epilepsy : epileptic seizures associated with menstruations, affecting up to 70% of women with epilepsy. Catamenial seizures are common among women with focal or generalized epilepsy, which affects an estimated 1 million women in the United States. Presently, there is no specific, FDA-approved drug treatment for catamenial epilepsy. Despite the increased use of wide-ranging antiepileptic and hormonal drugs, catamenial seizures are often refractory to many treatments. Cyclical changes of ovarian hormones estrogens and progesterone are now widely believed to be essential for the genesis of catamenial seizures. Generally, progesterone has antiseizure effects, while estrogens facilitate seizure susceptibility. The progesterone metabolite allopregnanolone has been identified as a key endogenous neurosteroid with powerful antiseizure activity. Allopregnanolone is a potent, positive allosteric modulator of GABA_A receptors. Progesterone and allopregnanolone exposure and withdrawal affects GABA_A receptor plasticity. In animal models, withdrawal from chronic progesterone and, consequently, of allopregnanolone levels in brain, has been shown to increase seizure susceptibility. Natural progesterone therapy is proven to be effective in women with epilepsy. Consequently, synthetic neurosteroids that are devoid of hormonal side effects represent a novel class of antiepileptic drugs for women with catamenial epilepsy. Ganaxolone, a GABA_A receptor-modulating synthetic neuroactive steroid, is a particularly promising treatment for catamenial epilepsy. Future studies are clearly warranted to determine the molecular pathophysiology and an effective treatment of catamenial epilepsy^ref.
• young adults (18-35 years)
• traumas
• ethanol abstinence
• substance abuse
• cerebral tumors (epileptogenic cavernous hemangioma may undergo continuous microhemorhage or abrupt massive hemorrhage)
• idiopathic crisis
• electroshock
• adults (> 35 years)
• cerebrovascular diseases
• cerebral tumors
• ethanol abstinence
• metabolic disorders (uremia, liver failure, alterations of hydroelectrolyte equilibrium, hypoglycemia)
• Alzheimer's disease (AD) and other CNS neurodegenerative disorders
• idiopathic crisis
• drugs
• antimicrobials :
• isoniazid
• b-lactams and derivatives
• quinolones
• acyclovir
• ganciclovir
• anaesthetics and analgesics
• meperidine
• tramadol
• local anaesthetics
• class 1B antiarrhythmic drugs
• immunomodulators
• cyclosporine
• OKT3
• tacrolimus
• IFNs
• psychotropic drugs
• antidepressants
• antipsychotics
• lithium
• radiographic contrast agents
• teophylline
• suspension of hypnotic sedative substances
• ethanol
• barbiturates
• benzodiazepines
• drug abuse
• amphetamines
• cocaine
• phencyclidine
• methylphenidate
• flumazenil (in patients dependent on benzodiazepines)
• lead
• pentylenetetrazol
• activated epilepsy : epileptic seizures induced by electrical or drug stimulation for the purpose of observing the pattern of clinical and EEG response.
• reflex or sensory epilepsy : epileptic seizures (reflex seizure) occurring in response to sensory stimuli
• auditory stimuli (audiogenic epilepsy)
• musical stimulus (musicogenic epilepsy)
• flickering light (photic or photogenic epilepsy) seen in uremic encephalopathy
• reading (reading epilepsy)
Pathogenesis : any of a group of syndromes characterized by at least 2 paroxysmal episodes of abnormally synchronous nervous impulse discharges within a given cerebral neuronal population (cortical epilepsy); such a discharge may successively spread to other brain areas by contiguity (e.g. in jacksonian epilepsy) or through the normal nervous ways
• epileptogenic focus : the area of the cerebral cortex responsible for causing epileptic seizures.
• secondary epileptogenic focus : a second focus that develops in a different part of the brain because of a spread of the pathologic process outward from the original epileptogenic focus; it may develop into a new, independent focus that continues to operate after the original one has been treated.
• mirror focus : a type of secondary epileptogenic focus that develops in the opposite hemisphere as an approximate mirror image of the original focus
Hypersynchronous neuronal firing is a hallmark of epilepsy, but the mechanisms underlying simultaneous activation of multiple neurons remains unknown. Epileptic discharges are in part initiated by a local depolarization shift that drives groups of neurons into synchronous bursting. In an attempt to define the cellular basis for hypersynchronous bursting activity, we studied the occurrence of paroxysmal depolarization shifts after suppressing synaptic activity using tetrodotoxin (TTX) and voltage-gated Ca²⁺ channel blockers. Paroxysmal depolarization shifts can be initiated by release of glutamate from extrasynaptic sources or by photolysis of caged Ca²⁺ in astrocytes. 2-photon imaging of live exposed cortex showed that several antiepileptic agents, including valproate, gabapentin and phenytoin, reduced the ability of astrocytes to transmit Ca²⁺ signaling. As such, these findings identify astrocytes as a proximal target for the treatment of epileptic disorders^ref.
Symptoms & signs : the crisis may be asymptomatic (when affecting mute areas) or manifested as episodic impairment or loss of consciousness, abnormal motor phenomena, psychic or sensory disturbances, or perturbation of the autonomic nervous system.
Differential diagnosis with other kinds of crises :
• syncope
• psychologic disorders (psychogenic crises, hyperventilation, panic attack) : in hysteria the patient doesn't hurt during fall, doesn't bite his tongue, has neither cyanosis nor urinary incontinence, and crisis lasts up to 90"
• metabolic crises (alcoholic absence, delirium tremens, hypoglycemia, hypoxia, psychoactive substances (e.g. hallucinogens))
• migraine (confusional migraine, status migrainosus, basilar migraine)
• TIA (basilar artery TIA)
• toxic crises
• sleep disorders (narcolepsy, benign myoclonus, somnambulism, terror sleep, REM sleep disorder, restless leg syndrome)
• dyskinesias (tic, nonepileptic myoclonus, paroxysmal choreoathetosis)
• in babies :
• migraine with recurrent abdominal pain and vomiting
• benign paroxysmal vertigo
• apnea
• pavor nocturnus
• somnambulism
• undeterminated crises
... is made with :
• no trigger factor or prodromic symptom other than aura
• sudden onset of unconsciousness
• tonic-clonic movements lasting 30-60" (in syncope < 15"))
• tongue biting, facial cyanosis (pallor in syncope) and sialorrhea
• conservation of corneal reflex
• resistance to passive eye opening, i.e. preservation of consciousness
• movement from uncomfortable position
• headache (rarely in syncope)
• postcritical disorientation and sleepiness lasting from a few minutes to hours (< 5' in syncope)
• postcritical myalgia (sometimes even after syncope)
• incontinence (infrequent in syncope)
• remembering of crisis (except in mesial temporal lobe epilepsy (MTLE))
• seizures can be induced by suggestion
• shorter course but longer duration of unconsciousness (minutes instead of seconds)
• symptoms are constant in different crises
• video-EEG (intracranial electrodes are required for epilepsy originating from deep structures, e.g. in mesial temporal lobe epilepsy (MTLE)) : performed to study the association between the epileptic seizure's clinical manifestation and the electroencephalographic record, and is very valuable to locate seizure onset areas.
• fMRI enables the assessment of hippocampal structures, indicating if there is mesial temporal sclerosis.
Therapy :
• never after first crisis
• for second crisis occurring > 24 hrs after the former : therapy is practiced only in adults and cases with definite diagnosis
• also in babies after third or fourth crisis
• neurosurgery is based on
• ablation of epileptogenous neuronal population (when functionally almost "mute")
• lesionectomy
• hemispherectomy (only in babies, where nerve plasticity is higher; in patients already hemiplegic with progressing contralateral compensation, at removal of the damaged hemisphere symptoms improve)
• topectomy, lobectomy (e.g. temporal lobectomy inn adults with mesial temporal sclerosis causing uncinate epilepsy) or lobotomy
• multiple subpial resection
• interference with spreading of discharge)
• corpuscallosotomy (for multifocal or secondarily generalized epilepsies with drop attacks, or in functionally "eloquent" areas; first practiced in anterior 2/3, then eventually extended to posterior 1/3)
• upregulation of modulating areas (e.g. lobus anterius of cerebellum)
• vagus nerve stimulation (VNS)
It is used only when drugs cannot control symptoms (accordingly to what is required by patient's job) (15%) or when side effects are untolerable (on average, it takes > 10 years to try all combinations of the main 8 different drugs, but this is a period too long to wait for in babies), with reachable hot-spots. Presurgery examinations include :
• phase I  (noninvasive examinations)
• intercritical EEG
• critical EEG
• neuropsychological tests
• MRI
• PET
• SPECT
• phase II (invasive examinations)
• Wada test / intracarotid sodium amobarbital test (ISAT) for preoperative lateralization of hemispheric dominance in patients with clinically refractory epilepsy candidates to epilepsy surgery for mesial temporal lobe epilepsy (MTLE). Technically, the exam is performed by placing a catheter into the internal carotid arteries through a puncture in the femoral artery. The catheter is positioned in the internal carotid artery and amobarbital is injected. The hemisphere ipsilateral to the side of proposed surgery is anesthetized first. Since amobarbital is a fast acting barbiturate, the time the patient remains anesthetized (and consequently the testing time) is limited to a few minutes. Anesthetic efficacy can be determined by the time it takes for full return of motor function, and the presence of memory and language can only be interpreted while the opposite hemisphere is paralyzed, which is clinically measured by the motor strength of the contralateral upper limb. Its goal is to promote selective and temporary interruption of hemispheric functioning, seeking to define language lateralization and risk for memory compromise following surgery. Although most multidisciplinary teams who specialize in epilepsy surgery use the WT for evaluation of both memory and language, the way results are interpreted, as weel as the amount of amobarbital used tend to vary considerably. There are significant variations among the criteria used to consider positive or negative results. Some protocols base the final result on the correct answer rate (correctly memorized stimuli), while others base the results on the asymmetry between the correct answer rate obtained in both hemispheres^ref. Some protocols have been proposed^{ref1, ref2}. Behavioral modification is expected during the procedure. Even though it may last several minutes, in most cases it is subtle and easily manageable, while is bizarre in 5% of people^ref. As motor inactivation usually is thought to be the most robust feature of the Wada test, this case demonstrates that fMRI may reveal residual functional cortex in cases of inconclusive Wada results^ref.
• intraoperatory EChoG
• "cranial" EChoG
• electrocorticography
• psychological support
Prognosis : it is a progresive disease as in time the downstream area becomes epileptogenous itself (as seen in experimental animals with implanted electrical stimulator, once the latter is removed)
• 70% is relapse-free after 5 years of therapy
• 20% experience relapse within 2-5 years
Experimental animal models :
• electrically-induced seizures (amygdala-kindling, maximal electroshock)
• chemically-induced seizures (pentylenetetrazole, picrotoxin, NMDA)
Web resources :
• International League Against Epilepsy (ILAE)
• Epilepsy at CDC
• Seizures in Children
• The Epilepsy Foundation
Bibliography : Imitators of Epilepsy. 2nd ed. Kaplan, Peter W.; Fisher, Robert S., editors New York: Demos Medical Publishing; ©2005  [Free at NCBI Bookshelf ! ]
• central sleep apnea / central apnea : sleep apnea resulting from failure of stimulation by the respiratory centers in the medulla; both hereditary varieties and varieties accompanying other brain stem disorders have been observed.
• brain cooling system : thermoregulated equipment for sensing and controlling brain temperature in neurophysiological and neuropsychological applications
• myelopathy : any of various functional disturbances or pathological changes in the spinal cord, often referring to nonspecific lesions in contrast to the inflammatory lesions of myelitis.
• ascending myelopathy : myelopathy that progresses cephalad along the spinal cord.
• descending myelopathy : myelopathy that progresses caudad along the spinal cord.
• leukomyelopathy / funicular myelopathy : any disease of the white substance of the spinal cord.
• poliomyelopathy : any disease primarily affecting the gray matter of the spinal cord.
• hemorrhagic myelopathy : myelopathy associated with hemorrhage
• necrotizing myelopathy : myelopathy marked by necrosis of the spinal cord.
• focal myelopathy : myelopathy affecting a small area only, or several small areas
• systemic myelopathy : myelopathy which affects distinct tracts in the spinal cord.
Aetiology :
• acute myelopathies
• viruses (see below)
• bacteria
• Mycobacterium tuberculosis
• Treponema pallidum subsp.pallidum
• Borrelia burgdorferi
• Brucella melitensis
• Mycoplasma pneumoniae
• parasites
• Toxoplasma gondii
• Schistosoma spp.
• vaccines
• autoimmune diseases
• systemic lupus erythematosus (SLE)
• Sjogren syndrome
• multiple sclerosis
• heroin, general anesthetics
• epidural anesthesia
• electrocution
• diver's palsy / decompression syndrome
• vascular :
• medullary infarction of Adamkiewicz artery : thanks to peripheral compensatory circles, damage is mainly periependymal
• medullary hemorrhage due to arteriovenous malformation (AVM)
• venous congestive myelopathy is a progressive disorder frequently associated with arteriovenous fistulas, usually dural. By causing diffuse spinal cord enlargement and enhancement on imaging, it may simulate a neoplasm and prompt a biopsy.  Recognition of this entity by surgical pathologists is important, leading to the correct identification of a non-neoplastic lesion as well as of a surgically treatable disease^ref
Experimental animal models : Stensen's experiment : the experiment of cutting off the blood supply from the lumbar region of the spinal cord of an animal by compressing the abdominal aorta; it produces paralysis of the posterior parts of the body
• contusion of spinal cord : organic injury to the cord due to a blow to the vertebral column, with resultant transient or prolonged dysfunction below the level of the lesion
• concussion of spinal cord / commotio spinalis : transient spinal cord dysfunction due to mechanical injury
• traumatic myelopathy : myelopathy which follows spinal cord injury (SCI)
• spinal cord compression : a condition in which pressure is exerted on the spinal cord => compression myelopathy
• cervical spinal cord compression => cervical myelopathy

Aetiology :
• osteoarthritis
• rheumatoid arthritis
• cervical spondylosis (spondylotic cervical myelopathy / cervical spondylotic myelopathy), often in those with a congenitally small spinal canal

Epidemiology : 100% within age 70, 80% within age 50
Pathogenesis :
• direct medullary compression (diameter < 12 mm) due to
• osteophytes (also radicular compression syndrome)
• diskal protrusion
• hypertrophy of articular surfaces (also radicular compression syndrome)
• fibrotic thickening of yellow ligaments
• flexo-extension intermittence
Laboratory examinations : CT, no X-rays
• medullary ischemia due to anterior spinal artery and radicular artery compression

Symptoms & signs :
• anterior cord syndrome / anterior myelopathy / anterior spinal artery syndrome : injury to the ventral spinal cord caused by blockage of the anterior spinal artery and infarction of the areas it supplies. Below the level of the lesion complete paralysis, hypalgesia, and hypesthesia occur but there is relative preservation of the posterior sensations of touch, position, and vibration.
• posterior cord or column syndrome : sensory deficits and ataxic phenomena derived from a lesion of the posterior columns of the spinal cord.
• transverse myelopathy : myelopathy which extends across the spinal cord.
• Brown-Séquard's syndrome, paralysis or sign : a syndrome due to damage of one half of the spinal cord, resulting in ipsilateral paralysis and loss of discriminatory and joint sensation, and contralateral loss of pain and temperature sensation
• motor syndrome : alterations of second motoneuron in upper limbs and first motoneuron in lower limbs
• brachyalgia and medullary syndrome
Laboratory examinations : MRI
Therapy : anterior cervical discectomy, corpectomy followed by fusion (ACDCF), cervical posterior laminectomy => transformation of vertebral canal in a vertebral splint
• epidural, intradural, or intramedullary neoplasms (5%)

Therapy : radiotherapy
• spinal arachnoiditis
• epidural abscess
• discal hernia
• posttraumatic compression due to vertebral fracture, vertebral dislocation or hemorrhage
• epidural aerocele : a collection of air between the dura mater and the wall of the spinal column.
• concussion myelopathy : myelopathy due to concussion of the spinal cord
Common symptoms & signs :
• mild : cervicalgia, mild hand impairment, hyperreflexia in lower limbs, normal plantar reflex, mild hyposthenia in lower limbs
• severe : hyposthenia in upper limbs, hypotrophy of interosseous muscles, hyperreflexia of upper limbs, exhaustible/non-exhaustible patellar clonus and foot clonus, Babinski's sign, spastic paraparesis
• lumbar caudal compression (spinal cord ends at the intervertebral space between L1 and L2 !)

Aetiology :
• lumbar spondylosis (diameter < 14 mm)
• caudal dysplasia syndrome / caudal regression syndrome / sacral agenesis
• spinal arachnoiditis
Pathogenesis : compression of the spinal nerve roots
Symptoms & signs :
• lumbosacral radiculopathy
• cauda equina syndrome : dull aching pain of the lumbosacral area, perineum, and bladder, generally radiating in a sciatic fashion, with associated anesthesia of genitals, perineum, buttocks and lower limbs (excepted the upper third of the inner anterior side of thigh), flaccid areflexic paralysis of lower limbs, sphincterial disorders with retention first and incontinence then, sexual impotence, achillean and plantar cutaneous areflexia (also patellar areflexia if the lesion involves L2 root)
Symptoms & signs (vary with location and degree of pressure) :
• diparesis, paraparesis, tetraparesis or hemiparesis (death when above C5 due to phrenic nerve palsy)
• sensibility level
• spinal shock (the loss of spinal reflexes after injury of the spinal cord, which affects the muscles innervated by the cord segments situated below the site of the lesion) => osteotendinous hyperreflexia
• sphincterial disorders
• pathologic reflexes (including Babinski's sign)
Pathogenesis : zone of partial preservation (a region where there may be only partial damage to nerves, including 1-3 spinal segments below the level of the injury)
Symptoms & signs : metameric or segmentary syndrome (a syndrome produced by a lesion of the gray matter of the spinal cord, and marked by weakness and wasting in the affected segment), priapism, retrograde ejaculation, male sterility, Riddoch's mass reflex, André Thomas sign (pinching of the trapezius muscle causes gooseflesh above the level of a spinal cord lesion)
Frankel classification / American Spinal Injury Association (ASIA) rating scale : a classification dividing spinal cord injuries into 5 groups according to severity of deficit below the level of injury :
• group A, complete interruption of all sensation and motor function
• group B, incomplete interruption, with some sensation but no motor function
• group C, incomplete interruption, with demonstrable voluntary motor function but at a minimal, nonuseful level
• group D, incomplete interruption, with some voluntary motor function that is useful to the patient
• group E, recovery to normal functioning attained.
Therapy :
• exercise may speed spinal cord repair. Injured rats that run have 3 times more BDNF (which promotes cell survival) than inactive rodents and higher levels of synapsin 1 (which helps neurons release neurotransmitters)
• recombinant cethrin (source : Alseres Pharmaceuticals, Inc.)
• P2X₇ inhibitors improve recovery after acute SCI^ref
• EphA4^-/- (an activator of astrocytes) mice produce very little scar tissue around damaged spinal nerves and regain all of their stride length within 3 weeks after cut of the spinal cord paralysing the left hind limb, and after 1 month they had recovered ankle and toe movement. In contrast, the control group recovers only 70% of their stride length, and no ankle or toe movement. A large percentage of the spinal cord nerves had regrown across the damaged section in the mice that lacked EphA4, compared with hardly any in the control group
• the clinical outcome of SCI depends in part on the extent of secondary damage, to which apoptosis contributes : neutralization of CD95L promoted axonal regeneration and functional improvement in injured adult animals^ref
• build bridges across gaps, so that nerves can grow :
• solid bridges (collagen) require invasive surgery that can cause extra trauma to the injury
• liquid bridges : when the solution is injected into a damaged rodent spinal cord, it turns into a gel-like solid whose scaffold is designed to disintegrate after 4-6 weeks, hopefully leaving healthy spinal cord behind. The liquid is made up of negatively charged molecules laced with a tiny protein fragment that nerve cells can recognize and latch on to. Normally, they repel one another and keep the substance in liquid form, but when the fluid encounters positively charged molecules (such as the Ca²⁺ or Na⁺ ions found in living tissue) they clump together almost instantly in a particular way, forming a mass of tiny, hollow tubes each about 5 nm wide and several hundreds of nm long which allow nerve cells to grow through and around them. Anyway after a spinal-cord injury, the surrounding cells multiply to form a dense scar : this barrier is impenetrable to nerve cells, so enzymes that can break it down may also need to be added. When stem cells are added to the scaffolding solution, they turn into neurons and begin to grow within the solidified bridge
• hybrid brain-machine interface (HBMI)
Web resources :
• Spinal cord injury at CDC
• Spinal Injuries Association
• Spinal cord injury resource center
• subacute myelopathy
• carcinomatous, paraneoplastic or paracarcinomatous myelopathy : a rapidly progressive, paraneoplastic myelopathy, most often associated with carcinoma of the lung, but also seen with other carcinomas. It is characterized by a rapidly developing myelopathic syndrome due to necrosis of both the gray and white matter of the spinal cord.
• chronic myelopathies
• viruses
• vacuolar myelopathy : loss of myelin and spongy degeneration of the spinal cord with microscopic vacuolization, similar to that of subacute combined degeneration of the spinal cord, caused by infection with HIV-1. Symptoms include spastic paraparesis, sensory ataxia in the lower limbs, and unsteadiness of gait.
• chronic progressive myelopathy / HTLV-1–associated myelopathy (HAM) / tropical spastic paraparesis (TSP)

Epidemiology : in the mid 1980s a French group in Martinique discovered^ref an association between HTLV-1 seropositivity and chronic progressive myelopathy of previously unknown aetiology, known as Jamaican neuropathy or tropical spastic paraparesis (Cruickshank EK, 147–58). An association with a similar disease was described in Japan by Osame and his colleagues^ref, who called the disease HTLV-1 associated myelopathy; subsequently it was established that these are the same condition (Report from the scientific group on HTLV-1 infection and its associated diseases, convened by the regional office for the Western Pacific of the World Health Organisation in Kagoshima, Japan, 10–15 December 1988. Wkly Epidemiol Rec 1989;49:382–3) and it is now generally referred to as HAM/TSP. HAM/TSP typically develops^ref in a woman in her forties as a progressive spastic weakness of the legs, usually associated with low back pain, urinary frequency or incontinence, and paraesthesiae in the legs. The course is variable: most patients progress over 6 months to 2 years, but in some the disease activity appears to continue indefinitely. The final state also varies between the ability to walk with one stick and being bed bound with painful spasms and contractures. The lifetime risk of HAM/TSP is about 1–2%^ref; estimates of the prevalence vary between 0.1% and 2% of infected individuals, rising sharply with age. The mean age at onset of HAM/TSP is about 40 years, and women are affected twice or three times more often than men. There are well documented cases in which HAM/TSP develops within months of infection by contaminated blood products^ref; this contrasts strongly with ATL, which usually develops after an incubation period of decades^ref. ATL and HAM/TSP can occur together^{ref (Tamiya S, 768–70),} but no more frequently than would be expected as a result of chance.
Aetiology : HTLV-1
Pathogenesis : the recent results, summarised above, cast light on the reasons for individual variation in disease risk in HTLV-1 infection. However, the mechanism of pathogenesis of HAM/TSP and the other inflammatory diseases remains a matter for speculation. By exclusion of other possibilities, we and others have suggested^{ref1, (Bangham CRM, 41-8), ref3, ref4}, that the tissue damage in the CNS is caused by lymphocytes, chronically activated by the HTLV-1 Tax protein acting as an antigen and/or a mitogen, which migrate into the CNS as a result of the Tax induced upregulation of adhesion molecules on their surface. HTLV-1 infected or activated lymphocytes have indeed been shown to secrete large amounts of certain cytokines and metalloproteinases^ref, which might be toxic in high local concentrations in the CNS. However, it must be emphasised that this is a speculative scheme at present. It is to be hoped that the results of further genetic studies on the risk of HAM/TSP will suggest pathways of pathogenesis that can be subjected to experimental testing.
Symptoms & signs : muscle weakness, hyperreflexia, and clonus in the lower limbs, and extensive plantar responsive and a spastic gait;  gradually progressivespastic paraparesis, characterized by progressive difficulty in walking and weakness of the lower extremity, sensory disturbances, and urinary incontinence, with no evidence of spinal compression or motor neuron involvement
Laboratory examinations : the cerebrospinal fluid shows a mild pleocytosis, HTLV-1 antibodies, and a mild to moderate increase in protein concentration^ref. The main neuropathological features of HAM/TSP^{ref1, ref2} are scattered lesions of diffuse demyelination in the cerebrum and (particularly) the lower cervical and upper thoracic spinal cord, and a widespread mononuclear cell infiltrate with perivascular cuffing and parenchymal invasion associated with these demyelinated areas.
Therapy : there is no treatment of proved value in HAM/TSP. Drugs used in informal therapeutic trials have included corticosteroids, anabolic steroids, zidovudine (AZT), and vitamin C^{ref1, ref2, ref3}, but none gave lasting benefit. Recently, Taylor and colleagues^ref have obtained evidence that lamivudine (3TC) (150 mg twice daily) can reduce the provirus load of HTLV-1. Again, the effects—symptomatic improvement and reduction in provirus load—were temporary, but it is possible that drug regimens that produce a more sustained reduction in proviral load will provide some benefit, particularly if started early in the course of clinical disease. These exciting preliminary findings are shortly to be tested in a randomised, placebo controlled trial.
Prognosis : unlike ATL, HAM/TSP is not usually a fatal condition, although a precise estimate has not been made of the effect of HAM/TSP on life expectancy. The mean duration of disease at death is about 10 years^{ref1, ref2, ref3}; death is usually attributed to infections or tumours.
• HTLV-2
• HHV-6
• bacteria
• Mycobacterium tuberculosis
• Treponema pallidum subsp.pallidum : tabes dorsalis or spinalis / tabetic neurosyphilis / Duchenne's disease / locomotor ataxia / posterior spinal sclerosis : parenchymatous neurosyphilis in which there is slowly progressive degeneration of the posterior columns and posterior roots and ganglia of the spinal cord, occurring 15 to 20 years after the initial infection of syphilis

Symptoms & signs : lancinating lightning pains, normal cold and heat senses, while position and vibratory senses are impaired (dissociated anesthesia) => ataxia (tabetic gait), Hutchinson's mask : a sensation as if the skin of the face were compressed by a mask), optic nerve atrophy, urinary incontinence, hypotonia, hyperreflexia, and trophic joint degeneration (Charcot's joints)
• tabetic crisis : a painful paroxysm with functional disturbance occurring in the course of tabes dorsalis.
• bronchial crisis : a paroxysm of dyspnea in the course of a case of tabes dorsalis.
• clitoris crisis : an attack of sexual excitement
• laryngeal crisis : paroxysmal spasm of the larynx in the earlier course
• pharyngeal crisis : a sudden attack marked by peculiar sensations in the pharynx and involuntary swallowing movements.
• thoracic crisis : an attack of pain resembling angina pectoris, but with spasmodic contracture of the muscles of the chest and arms
• visceral crisis : a paroxysm of shooting pain in any viscus
• cardiac crisis : a severe paroxysm of palpitation of the heart
• gastric or intestinal crisis : a paroxysm of intense abdominal pain
• rectal crisis : a severe seizure of rectal pain
• nephralgic crisis : a paroxysm of pain in the ureter
• renal crisis : an attack of pain resembling renal colic
• vesical crisis : a severe seizure of pain in the bladder
• status criticus : a severe and persistent form of tabetic crises.
• Abadie's sign : insensibility of the Achilles tendon to pressure
• Berger's sign : an irregularly shaped or elliptical pupil in the early stages of tabes dorsalis, paralytic dementia, and certain paralyses.
• Biernacki's sign : analgesia of the ulnar nerve in general paresis and tabes dorsalis.
• Fränkel's sign : excessive range of passive movement of the hip joint, indicating diminished tone of the surrounding musculature
• Gowers' sign : abrupt intermittent oscillation of the iris under the influence of light; seen in certain stages
• Pitres' sign : hypoesthesia of the scrotum and testes
• Saenger's sign : a light reflex of the pupil that has ceased returns after a short stay in the dark; observed in cerebral syphilis but not in tabes dorsalis.
• stairs sign : difficulty in descending a stairway
• Westphal's sign : loss of the knee jerk
• Haenel symptom : in tabes there is a lack of sensation on pressure over the eyeballs.
• Remak's symptom : either polyesthesia or a prolongation of the lapse of time before a painful impression is perceived, seen in tabes dorsalis.
• Borrelia burgdorferi
• Brucella melitensis
• parasites
• Toxoplasma gondii
• Schistosoma spp.
• autoimmune diseases
• systemic lupus erythematosus (SLE)
• neuroBehçet
• multiple sclerosis
• vasculitides
• sarcoidosis
• radiation myelopathy : a slowly progressive myelopathy occurring > 6 months after excessive exposure of the spinal cord to radiation, usually in the form of radiation therapy.
• toxic, nutritional, and metabolic myelopathies
• lathyrism
• epidemic spastic paraparesis / konzo / tropical ataxic neuropathy
• vitamin B₁₂ deficiency
• adrenoleukodystrophy
• malformations
• Chiari's malformation or deformity : a congenital anomaly in which the cerebellum and medulla oblongata, which is elongated and flattened, protrude into the spinal canal through the foramen magnum (transoccipital hernia); it is classified into 3 types according to severity
• type I Chiari's malformation : prolapse of the cerebellar tonsils into the spinal canal without elongation of the brainstem (tonsillar ectopia)
• type II Chiari's malformation / Arnold-Chiari malformation : herniation of the cerebellar tonsils and vermis through the foramen magnum into the spinal canal. It is always associated with lumbosacral myelomeningocele, and hydrocephalus and mental defects are common

Symptoms & signs :
• banana sign : a flattened and curved, bananalike shape of the cerebellar hemispheres seen in axial section in sonography of the fetal skull
• lemon sign :  scalloping of the frontal bones giving the skull a lemon-shaped configuration in axial section in sonography of the fetal skull during the second trimester of pregnancy
• type III Chiari's malformation : complete herniation of the cerebellum to form an occipital encephalocele
It may be accompanied by hydrocephalus, spina bifida, syringomyelia (due to increased CSF pressure within ependymal canal), and mental defects
• syringomyelia / hydrosyringomyelia / syringohydromyelia / hydrosyrinx / cystic myelopathy / Schneider central cord syndrome / syringomyelic syndrome : a chronic progressive disease of the spinal cord consisting of additional parallel cavities (mainly at cervical and thoracic level), which communicate or not with the main ependymal canal, causing compression of decussating spinothalamic nerve fibers and so regional (usually in upper limb) loss of thermic and pain sensitivities while deep (tactile and positional) sensitivity is spared (dissociated anesthesia), muscle atrophy, and spasticity, mainly of upper limbs
• syringobulbia : syringomyelia in which the cavity extends to involve the medulla oblongata
Symptoms & signs : Morvan's syndrome (a manifestation of syringomyelia in which the subcutaneous tissues of the hands become thickened, edematous, soft, swollen, cyanotic, and cold (Marinesco's succulent hand), associated with analgesic ulceration of the fingertips and paresthesias and atrophy of the hands and forearms.
• hydromyelia / hydrorachis : a pathological condition in which there is dilation of the central canal of the spinal cord with increased CSF accumulation.
• spinal arteriovenous malformation (AVM) => ischemia or compression
• extradural
• dural
• medullary
Laboratory examinations : DSA
• neoplasms
Symptoms & signs (acute or chronic) :
• sensory symptoms
• Lhermitte's sign : the development of sudden, transient, electric-like shocks spreading down the body when the patient flexes the head forward; seen mainly in multiple sclerosis but also in compression and other disorders of the cervical cord.
• motor symptoms (spinal shock => spastic paraplegia)
• Beevor's sign : upward deviation of the umbilicus on attempting to lift the head, caused by contraction of the upper but not the lower abdominal muscles and indicative of a SCI in the region of T6-T12
• sphincterial symptoms
• tache spinale : a bulla resembling a burn, and due to a SCI
• Kerr's sign : alteration of the texture of the skin below the somatic level in SCI
Laboratory examinations :
• EMG
• MEP
• SEP
• nerve conduction velocity (NCV)
• rachid MRI
• cerebrospinal fluid (CSF) examination
• myelography
Therapy : GR agonists
Bibliography : Spinal Cord Medicine: Principles and Practice. Lin, Vernon W., editor New York: Demos Medical Publishing, Inc.; ©2003. [Free at NCBI Bookshelf ! ]
• dermal sinus : a congenital sinus tract extending from the surface of the body, between the bodies of 2 adjacent lumbar vertebrae, to the spinal canal.
• myelitis : inflammation of the spinal cord, often part of a more specifically defined disease process (see also encephalomyelitis).
• periependymal myelitis : myelitis surrounding the central canal of the spinal cord.
• central myelitis: inflammation affecting chiefly the gray substance of the spinal cord
• poliomyelitis / polio : an acute infectious disease occurring sporadically or in epidemics and caused by a virus, usually a poliovirus but occasionally a coxsackievirus or echovirus. It is characterized clinically by fever, sore throat, headache, and nausea and vomiting, often with stiffness of the neck and back
• minor illness (abortive poliomyelitis) these may be the only symptoms
• major illness (infantile paralysis / acute anterior poliomyelitis / Heine-Medin disease), which may or may not be preceded by the minor illness, is characterized by involvement of the CNS, stiff neck, pleocytosis in the spinal fluid, and perhaps motor paralysis. There may be subsequent atrophy of groups of muscles, ending in contraction and permanent disability and deformity, and marked by inflammation of nerve cells in the ventral horns of the spinal cord (tends to be asymmetrical)
• nonparalytic poliomyelitis : the major illness of poliomyelitis when it does not involve paralysis.
• Colliver's symptom : a peculiar twitching, tremulous, or convulsive movement of the limbs, face, jaw, and sometimes of the entire body, seen in the preparalytic stage of poliomyelitis
• paralytic poliomyelitis : the major illness of poliomyelitis when it involves paralysis
• spinal paralytic or acute lateral poliomyelitis / infantile spinal paralysis : the classic form of the major illness of poliomyelitis, with the appearance of acute flaccid paralysis in one or more limbs
Therapy : Kenny treatment (a treatment formerly used for poliomyelitis consisting of wrapping of the back and limbs in hot cloths, followed, after pain has subsided, by passive exercise and instruction of the patient in exercise of the muscles).
Other varieties are :
• ascending poliomyelitis : poliomyelitis that is first manifested in the legs and rapidly ascends cephalad.
• bulbar poliomyelitis : a serious form of poliomyelitis in which the medulla oblongata is affected, and in which there may be dysfunction of the swallowing mechanism, and respiratory and circulatory distress.

Symptoms & signs : rope sign : acute angulation between chin and larynx, due to weakness of hyoid muscles, noted in bulbar poliomyelitis; systemic arterial hypertension
• cerebral poliomyelitis / polioencephalitis / poliomyeloencephalitis / polioencephalomyelitis / Strümpell's disease : poliomyelitis that extends into the brain
• endemic poliomyelitis : poliomyelitis occurring sporadically or in a small number of cases, particularly during periods of warm weather, in most countries throughout the world.
• epidemic poliomyelitis : poliomyelitis occurring in epidemic form.
• post-tonsillectomy poliomyelitis : acute poliomyelitis appearing within a short time after tonsillectomy.
• postinoculation or postvaccinal poliomyelitis : acute poliomyelitis appearing after a person has been vaccinated against poliomyelitis or some other disease. It may occur as a reaction to the vaccine or may be the result of infection by a new virus, usually another enterovirus or a resistant poliovirus.
• cornual myelitis : that which affects the horns of gray matter of the spinal cord
Symptoms & signs :
• Hoyne's sign: with the patient in the supine position, his head falls back when his shoulders are elevated.
• Morquio's sign : the patient lying supine resists all attempts to raise the trunk to a sitting posture until the legs are passively flexed
• pseudo-Babinski's sign : the Babinski's sign is modified so that only the big toe is extended, because all the foot muscles except the dorsiflexors of the big toe are paralyzed
• spine sign : disinclination to flex the spine anteriorly on account of pain
• leukomyelitis : inflammation of the white substance of the spinal cord.