14248_C04.qxd 7/7/0610:12AMPage111 4. 3. 2. 2. 3. 1. (ADEM) Encephalomyelitis Disseminated Acute IV. (possibly) (possibly) and meningismus, fever, encephalopathy, has typically ADEM cord; and spinal brain the of part anyinvolve may that and days few a over severity in increase that abnormalities neurological multifocal acute-onsetSymptoms: children in common Epidemiology: astrocyte reactive and hyperplasia;demyelination lymphocytesinvolvesoften junction cortical–subcortical the with cuffing perivascular in- volving sparing axonal with demyelination extensive and diffuse Histology: e. a. sclerosis multiple of variant Marburg’s c. b. e. d. a. sclerosis concentric Balo’s c. b. e. d. vciain rbe o salo vcie) atog a preceding a. a although diagnosis vaccines),the establish to necessary not smallpox is vaccination or infection or (rabies vaccination a after or chickenpox, or smallpox, rubella, measles, pre- with a infection ceding of weeks 2 within or during develops typically Pathophysiology: tract infection are rare associations rare are infection tract relapsing-remitting disease relapsing-remitting survivalin 5-year70% disease; fulminant survivalin 5-year 90% prognosis: i. protein basic Marburg’s that of evidence form modified or immature an is expressionof thereto related is variant although sclerosis, multiple for that as same the be topathophysiology:generally pathophysiologyconsidered is the ii. i. testing diagnostic pressureintracranial in increasedrapidly torelate symptoms:predominantly rgoi: otlt i uuly u t ms efc ad enain o to process demyelinating or the in brainstem herniation, the and effect of involvement mass to due usually is mortality prognosis: phamide cyclophos- , plasmapheresis, IVg, glucocorticoids, treatment: i. the from distance increasing center with severity preserved decreasing of of areas are that with myelin alternate that rings concentric in occur mation inflam- demyelinationand wherein leukocytes, inflammatory of collection perivascular a around centered are that lesions demyelinating histology: ii. i. testing diagnostic seizures function, behavioralcognitive and impaired symptoms:headache, multiple develop reliably not do survivors possible; is remission spontaneous although weeks, few a within outcome fatal a has usually prognosis: sclerosis multiple per as treatment: up, nuna and influenza, mumps, 6% fcss ta rpdy nrae i sz ad s soitd with associated is and edema size to due in effect mass increases rapidly that cases) of hemisphere(60% single a of lesion demyelinating acute large, a histology: the lesion contrast enhances and shrinks after steroid treatment steroid after shrinks and enhances contrast lesion the neuroimaging: lesionsare often mistaken fortumororcerebritis because pleocytosis minimal a for except normal usually is fluid cerebrospinal or else a lesion involving acute and chronic demyelination chronic and acute involving lesion a else or demyelination of process disease the amounts of suppression remyelination,active suggesting small and exhibit myelin preserved of areas occasionally oligoclonal bands oligoclonal occasionally and pleocytosis monocyte exhibits usually fluid cerebrospinal observable multiple also are typical lesions sclerosis 4–3); (Fig. ring-enhancing effect mass have concentric may that lesions multiple demonstrates neuroimaging Box 4.2) (Box yolsa pneumoniae Mycoplasma pe respiratory upper 191:818, Fig. 2A. Reprinted by permission.) by Reprinted 191:818, 2A. Fig. 1994; Antemortem Radiology sclerosis. concentric Balo of diagnosis GH. Collins LB, Poe AM, Gharagozloo a as (Fromarrow). demyelinationof (curved wellarea confluent as arrow), (straight myelin preserved and demyelination of layers alternating hallmark the ing 4–3 Figure ✧ ✧ Schilder’s Disease Box 4.2 enhancing lesionswithmasseffect. Neuroimaging often demonstrates large intracranial pressure. elevated and injury neurological focal thought to have a monophasic course of is typically entity disease unclear This aos ocnrc ceoi demonstrat- sclerosis concentric Balo’s 111 Acute Disseminated Encephalomyelitis (ADEM) 14248_C04.qxd 7/7/06 10:12 AM Page 112

5. Diagnostic testing a. cerebrospinal fluid exhibits mild lymphocytosis and increased pro- tein but a normal opening pressure i. differentiate ADEM from Reye syndrome, which has normal cerebrospinal fluid and elevated serum ammonia levels; oligo- clonal bands are likely to be present in postinfectious ADEM ii. serology also for measles, mumps, varicella zoster, and herpes simplex virus (HSV) b. neuroimaging: unlike the MRI lesions of multiple sclerosis, ADEM may involve the basal ganglia and thalamus, and have large confluent Figure 4–4 Acute disseminated encephalomyelitis. lesions with mass effect (Fig. 4–4) (From McKhann GM et al. Q&A Color Review of 6. Treatment: High-dose glucocorticoids; IVg, cyclophosphamide, or plasma- Clinical and Neurosurgery. Stuttgart, Germany: Georg Thieme; 2003:145, Fig. 146a. pheresis in refractory cases Reprinted by permission.) 7. Prognosis: 20% mortality and at least 35% eventually will develop multiple sclerosis a. focal neurological deficits generally improve but 95% survivors with infec- tious ADEM and 30% with postvaccine ADEM have residual psychiatric disorders, dementia, or epilepsy

V. Acute Necrotizing Hemorrhagic Encephalomyelitis 4 Disorders of Myelination 1. Pathophysiology: essentially a hyperacute form of ADEM that may be associ- ated with Mycoplasma pneumoniae upper respiratory tract infection a. histology: intense lymphocytic perivascular inflammation with necrosis and hemorrhage from small blood vessels, causing petechiae; progresses to liquefactive destruction of the white matter of both hemispheres, brain- stem, and cerebellar peduncles 2. Symptoms: initially meningitis-like symptoms but rapidly develops seizures and focal neurological injury; progresses to coma that rapidly is fatal 3. Diagnostic testing a. systemic evidence of infection (e.g., increased WBC count) b. cerebrospinal fluid exhibits increased opening pressure, monocytosis, increased protein, and normal glucose c. neuroimaging: large areas of increased T2 signal intensity with small areas of reduced T2 signal representing hemorrhage; lesions have significant edema and mass effect 4. Treatment: as per multiple sclerosis 5. Prognosis: usually fatal within several days

VI. Nutrition- and Electrolyte-Related Demyelinating Disorders

1. Central pontine myelinosis a. pathophysiology: usually occurs as a reaction to the rapid correction of severe, long-standing (i.e., 2-day duration) hyponatremia i. prolonged systemic hyponatremia causes loss of sodium and potas- sium from the brain interstitial fluid into the cerebrospinal fluid, and the loss of intracellular organic molecules (e.g., myoinositol, taurine, glutamate) that maintain cellular tonicity; rapid increases in the extracellular tonicity do not permit water equilibration with the in- tracellular environment, thereby causing cell death ii. particularly at risk are alcoholics (e.g., 10% occurrence after Wernicke’s Figure 4–5 Central pontine myelinosis. (From McKhann GM et al. Q&A Color Review of encephalopathy), burn victims, patients with liver failure or trans- Clinical Neurology and Neurosurgery. Stuttgart, plantation, anorexics, malnourished patients, and patients on pro- Germany: Georg Thieme; 2003: 11, Fig. 2. 112 longed diuretic therapy Reprinted by permission.) 14248_C04.qxd 7/7/0610:12AMPage113 2. 1. 4.4) (Box Disorder Dysmyelinating VII. d. a. disease Marchiafava-Bignami d. c. b. b. c. a. disease Pelizaeus-Merzbacher prognosis: unpredictable recovery unpredictable prognosis: i. 13) Chapter see pellagra; defi- (i.e., ciency niacin with associated although deficiency, nutritional to known relation no patient; malnourished or alcoholic any in occur may but wine red drink who alcoholics chronic in described pathophysiology:classically prognosis: often remits but may be acutely fatal acutely be may but remits often prognosis: supplementation vitamin treatment: demyelination of tion loca- the upon dependant and variable highly is course clinical its but tia demen- lobe frontal rapid-onset a resembles commonly most symptoms: iii. ii. i. daysseveralover progresses that course biphasic a has usually symptoms: no more than 8 mmol/L in 24 hours using 3% saline 3% using hours 24 in mmol/L 8 than more no example, hyponatremia,for of correction gradual treatment:preventionwith ii. i. myelin compaction myelin minor for (a necessary are protein (which which protein), DM-20 PLP and protein) myelin produces gene of this 50% for accounts of splicing alternative 4.5); (Box gene (PLP) proteinproteolipid the of abnormalities by caused pathophysiology: wherein 1 mL of 3% saline has 0.5 mmol Na mmol 0.5 has saline 3% of mL 1 wherein occur in any other region of white matter including the optic optic the including matter white may of region demyelinationother any in necrosis; occur involving frequently more but nosis myeli- pontine central to similar changes corpus histological the with in callosum develop demyelination of areas symmetric histology: (1) injury after days severaldevelops inflammation loss; axonto lead not does that axonswelling some with splitting sheath myelin of areas symmetric histology: (1) syndrome} {locked-in quadriparesis flaccid to progressing monatremia, nor- to correction after daysseveraldeveloping and normonatremia to correction with remit which hyponatremia, by caused seizures and encephalopathy required sodium in mmol in sodium required (1) in chromosome to X leads females heterozygous the of inactivation mosaic inheritance; X-linked (4) (3) (2) (1) gene PLP the in abnormalities in the brain the in the involving not does elsewhere demyelinatinghavelesions 10% also 4–5); and (Fig. tectum tegmentum the pons the of rim a of spares that center the in lesion demyelinating large a involves motor abnormalities motor ocular and pupillary in result may tegmentum the involvementof healthy oligodendrocytes healthy oligodendrocyte by replaced causes areoligodendrocytes dead few gene the because apoptosis PLP abnormal the if symptoms no mild is phenotype dys-myelination; causes production; PLP prevents deletion: gene complete severe oligo- is phenotype causes apoptosis; dendrocyte folding: PLP incorrect cause that mutations point mild is phenotype tion; dysmyelina-causes translation: PLP prevent that mutations point genes surrounding of involvement upon depending severity, variable of is phenotype overproduction; PLP cause aberrations: segmental ([Na] target [Na] actual Box 4.3 ) (Box L) (30 • ) 30 Lisestimated bodyvolume Box 4.3 paraplegia (SPG-2) spastic hereditary a in mutated also is PLP Box 4.5 by abnormalmyelin. these diseasesarenot always characterized misnomer— a is disease” “Dysmyelinating Box 4.4 113 Dysmyelinating Disorder 14248_C04.qxd 7/7/06 10:12 AM Page 114

(2) minimal, transient symptoms during childhood if abnormal PLP gene only causes abnormal myelin compaction iii. histology (1) with oligodendrocyte apoptosis: patchy, tiger skin-like (“tigroid”) myelination with a reduced number of oligoden- drocytes (Fig. 4–6); severity may be such that no myelin or oligodendrocytes are present in affected areas (2) with abnormal oligodendrocyte myelination: diffusely reduced myelin staining of the white matter with a normal number of oligodendrocytes b. symptoms (Table 4–2) c. diagnostic testing: genetic testing for PLP duplications i. neuroimaging: large, symmetric areas of increased T2 signal in the white matter with diffuse atrophy d. treatment: none specific e. prognosis: severe disease with stridor causes death by 10 years of age

2. Alexander’s disease Figure 4–6 T2-weighted MRI scans through the a. pathophysiology: caused by mutations in centrum semiovale demonstrate inhomogeneous signals corresponding to areas of myelination in i. glial fibrillary acidic protein (GFAP) (in 90% cases): mutations otherwise widely unmyelinated white matter cause a toxic gain-of-function that disrupts the normal ability of {tigroid myelination}. (From Plecko B et al. Degree astrocytes to maintain oligodendrocyte viability of hypomyelination and magnetic resonance spec- 4 Disorders of Myelination troscopy findings in patients with Pelizaeus ii. nicotinamide adenine dinucleotide (NADH) ubiquinone oxidore- Merzbacher phenotype. Neuropediat 2003; 34:132, ductase flavoprotein-1: an uncommon association that has yet to Fig. 4A. Reprinted by permission.) be substantiated by autopsy confirmation b. histology i. infants: a failure of normal myelination fol- lowed by demyelination that is associated with eosinophilic inclusion bodies in swollen astrocyte processes {Rosenthal fibers}; areas with these abnormalities develop in a perivascular and subependymal distribution ii. adult form: central nervous system demyelination is minimal; the key histological feature is a predominance of Rosenthal fibers that contain GFAP, heat-shock proteins, and --crystallin (1) difficult to distinguish from multiple sclerosis or conditions with reactive gliosis, which also have Rosenthal fibers c. symptoms (Box 4.6) Box 4.6 i. infantile form: onset of symptoms 2 years of age Symptomatically, Alexander’s disease is indistinguishable from Canavan’s disease (1) developmental regression; with progressive head enlargement that can be (but is not always) due to underlying hydrocephalus (2) (3) seizures

Table 4–2 Symptoms of Diseases with Proteolipid Protein (PLP) Abnormalities

Spastic paraplegic Neonatal PMD Classic PMD type 2

Intellectual impairment Severe Mild Mild Motor impairment Severe Mild Mild Speech acquisition None Normal Motor aphasia Severe Mild Mild Present Present Absent Other features Stridor, seizures Dystonias Vision loss

Abbreviations: PMD, Pelizaeus-Merzbacher disease. 114