ABSTRACT
A. Definitions 1. No identifiable cause, except for neuromyelitis optica
(see below) 2. IIDDs need to be differentiated from other demyelinat-
ing disorders of known cause, such as leukodystrophies, progressive multifocal leukoencephalopathy, and central pontine myelinolysis
3. “Prototypical” IIDD is sometimes called “bout-onset” multiple sclerosis (BOMS) (this term is not preferred by some authorities, but implies a relapse at onset of the clinical disease)
4. Relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS): the continuum of BOMS
5. In most texts and discussions, the name “multiple sclerosis” is “loosely” used to entail RRMS, SPMS, or primary progressive multiple sclerosis (PPMS)
6. Other definitions included in the category of multiple sclerosis: relapsing-progressive and progressive-relapsing multiple sclerosis (they have no known bearing on prognosis or treatment decisions and are not used in this chapter)
7. IIDDs vary in number, size, and distribution (focal, multifocal, or diffuse) of lesions in the CNS and in pathologic features
8. Acute syndromes may be classified according to severity of the initial clinical presentation and initial pathologic features (e.g., amount of inflammation, demyelination, and necrosis)
9. Chronic syndromes may be classified according to clinical evolution, with accumulating disability and chronic pathologic features (e.g., oligodendrocyte damage, demyelination, remyelination, axonal loss, gliosis) (Fig. 14-1)
10. Some focal isolated IIDDs, and even diffuse fulminant Marburg forms of multiple sclerosis have potential to show dissemination in time and space and convert to “prototypical” BOMS
11. RRMS often evolves into SPMS (Fig. 14-1) 12. Identification of individual disorders as they stand
within the spectrum has prognostic and therapeutic implications
B. Isolated Syndromes 1. Focal isolated IIDDs
a. Are restricted to one area of the CNS b. Are self-limited c. May be responsive to high-dose corticosteroid therapy
during attacks (i.e., optic neuritis, acute transverse myelitis [ATM], and isolated brainstem or cerebellum inflammatory demyelination)
2. Isolated IIDDs may be postinfectious and postvaccinal like acute disseminated encephalomyelitis (ADEM) (see below)
3. May be recurrent (polyphasic) or nonrecurrent (monophasic) but not fulfilling the criteria for diagnosis of multiple sclerosis (Table 14-1) a. Neuroimaging (magnetic resonance imaging [MRI]) or
paraclinical (evoked potential studies) evidence of dissemination in space and time suggests diagnosis of BOMS 1) At 18 months from onset, 84% of patients with two
or more enhancing lesions at presentation meet McDonald criteria for BOMS (Table 14-1)
2) At 14 years from onset, only 19% who initially had normal MRI findings develop multiple sclerosis
b. Recurrent optic neuritis, recurrent ATM, and neuromyelitis optica may be related (see below)
4. Optic neuritis: the most common and benign IIDD (see Chapter 3) a. Long intracanalicular lesions of the optic nerve seen on
MRI are associated with poor recovery from attack of optic neuritis
b. For adults: overall risk of conversion to BOMS in 10 years, 38% 1) If two or more MRI lesions suggestive of multiple
sclerosis, 90% risk 2) If one MRI lesion is suggestive of multiple sclerosis,
56% risk 3) If normal MRI, 15% to 20% risk 4) No conversion to BOMS in short term if normal
MRI and no oligoclonal bands 5) Factors associated with lower risk of conversion to
BOMS: male sex, absence of pain, presence of optic disc swelling or peripapillary hemorrhages
5. ATM can be complete or partial a. Complete ATM
1) Symmetric, combined sensory and motor syndrome with sausage-shaped, swollen, and elongated enhancing spinal cord lesions (Fig. 14-2)
2) Presence of neuromyelitis optica antibodies (NMO IgG) predict evolution to neuromyelitis optica
b. Partial ATM 1) Asymmetric and generally milder multifocal myelitis
2) 58% to 80% of cases evolve to multiple sclerosis (sensory symptoms, posterolateral location of lesion in spinal cord, abnormal brain MRI, and oligoclonal bands in cerebrospinal fluid [CSF] predict conversion)
6. Other noninflammatory isolated demyelinating syndromes a. Central pontine myelinolysis: associated with rapid cor-
rection of hyponatremia, alcoholism, malnutrition, and organ transplantation (see Chapter 17) 1) Symptoms: decreased level of consciousness, tetra-
paresis, pseudobulbar palsy 2) Symptoms may be mild in some patients (despite
radiographic appearance) 3) There may be extrapontine myelinolysis 4) Fluid restriction is enough in some cases, but for saline
infusion, the rate is 12 mEq/L per day or 0.5 mEq/L per hour
b. Marchiafava-Bignami disease: focal demyelination of central area of corpus callosum seen in middle-aged chronic alcoholics (see Chapter 7) 1) Symptoms: dementia, dysarthria, weakness, seizures,
incontinence
C. Neuromyelitis Optica (Devic disease, Asian type multiple sclerosis)
1. Distinct IIDD with multifocal lesions that follow a restricted pattern of optic nerve and spinal cord involvement
2. Antibodies specific to neuromyelitis optica have been described: antigenic stimulus is thought to be against aquaporin-4 molecule
3. May be misdiagnosed as RRMS by existing clinical criteria at presentation (optic neuritis and myelitis may occur in either condition) (Table 14-1)
4. Neuromyelitis optica is differentiated from RRMS by a. Predilection for Asians and African Americans as well as
Caucasians in neuromyelitis optica b. Association with other systemic autoimmune disorders
in neuromyelitis optica c. Restricted syndrome of optic neuritis and “complete”
ATM (Fig. 14-2) generally lacking the typical brain lesions seen in RRMS
d. CSF oligoclonal bands generally absent (a neutrophilic pleocytosis may occur during attacks in neuromyelitis optica)
Table 14-1. Diagnostic Criteria for Multiple Sclerosis
Poser criteria McDonald criteria (new)
Clinical Objective Category Relapses Clinical Paraclinical* CSF (attacks) clinical lesion Additional
e. Specific neuromyelitis optica antibody absent in RRMS f. Relatively homogeneous pathologic features of neu-
romyelitis optica, suggesting a B-cell-mediated disorder with characteristics distinct from multiple sclerosis (Fig. 14-3 and 14-4)
g. Attacks of neuromyelitis optica are more severe and less often responsive to corticosteroid therapy than RRMS (morbidity and mortality from respiratory failure due to cervical myelopathy) 1) Monophasic course in 33% of patients (5-year survival,
90%); relapsing course in 67% (5-year survival, 68%) 2) Simultaneous optic neuritis and myelitis (within 1
month) predict monophasic and relatively benign course
3) Long interval between index events, female sex, older age at onset, and presence of other systemic autoimmune disease predict relapsing course and worse prognosis
5. Attacks of neuromyelitis optica may be resistant to initial high-dose corticosteroid therapy but may show improvement with plasma exchange
D. Fulminant IIDDs 1. Acute, generally monophasic syndromes characterized
by diffuse inflammatory demyelination of CNS that may be resistant to initial treatment with high-dose corticosteroids during attacks
2. Examples: ADEM, acute hemorrhagic leukoencephalitis (AHLE), Marburg variant of multiple sclerosis, Baló’s concentric sclerosis, focal tumefactive demyelinating lesions that may simulate brain tumors, myelinoclastic diffuse sclerosis (Schilder’s disease)
3. 44% of patients with acute fulminant attack unresponsive to corticosteroid therapy have moderate or marked improvement with plasma exchange
4. Specific diagnosis a. Based on clinical criteria b. There is no specific surrogate marker
5. ADEM a. Characterized by innumerable, diffusely enhancing,
subcortical white matter lesions on MRI (Fig. 14-5) b. Often follows vaccination (rabies, diphtheria, pertussis,
measles, rubella) or febrile illness (measles, Enterovirus, herpesvirus, influenza, Epstein-Barr virus, Mycoplasma, Borrelia)
c. Occurs in adolescents or children d. CSF: absence of oligoclonal bands chronically (they may
be present transiently), normal immunoglobulin content e. Clinical differentiation of ADEM from first attack of
RRMS or other fulminant form of IIDD may be difficult
f. Pathology: predominant perivenular inflammation, with relative lack of confluent demyelination (Fig. 14-6)
g. Most patients with ADEM recover h. Relapses and up to 20% mortality can occur in children
6. Acute hemorrhagic leukoencephalitis (Hurst disease) a. Characterized by abrupt fever, meningeal signs, seizures,
and impaired level of consciousness following upper respiratory tract infection in 50% of patients from all age groups
b. Possibly a form of ADEM c. Pathology: diffuse (sometimes asymmetric) edema and
herniation associated with diffuse perivascular hemorrhages and demyelinating lesions with neutrophilic infiltration of perivascular cuffs surrounding necrotic venules with fibrinous exudates (Fig. 14-7)
d. Usually fatal 7. Marburg variant of multiple sclerosis
a. Characterized by confluent areas of enhancing hemispheric demyelination, typically asymmetric, on MRI, with mass effect and herniation, in the absence of oligoclonal bands
b. Pathology: necrosis (Fig. 14-6), reflected in a more severe clinical course
c. Patients may die, may recover with marked morbidity, or may remain free of relapse
d. Disease may recur or evolve into RRMS after recovery from initial attack
8. Tumefactive multiple sclerosis a. Characterized by large tumor-like solitary demyelinating
lesions with concentric whorled appearance in some cases (Baló’s concentric sclerosis) (Fig. 14-6)
b. Course may be monophasic, but may also evolve into RRMS
c. Biopsy sometimes needed to differentiate from tumor (radiation is detrimental in demyelinating disease)
d. Tumefactive multiple sclerosis without Baló’s concentric sclerosis responds to corticosteroid therapy and has a more favorable course
9. Myelinoclastic diffuse sclerosis (Schilder’s disease) a. Characterized by bilateral symmetric, hemispheric
demyelinating lesions larger than 3×2 cm that can involve subcortical U fibers and adjacent cerebral cortex
b. A rare syndrome of children, who present with visual problems, blindness, headache, vomiting, seizures
c. Must be differentiated from leukodystrophy d. Pathology: mononuclear cellular infiltration maximal
in the center rather than periphery, with axonal injury, tissue necrosis, and cavitation
E. Prototypical Bout-Onset Multiple Sclerosis 1. Epidemiology
a. Prevalence decreases toward the equator and increases above 40 degrees north latitude and below 40 degrees south latitude
b. High prevalence: defined as more than 30/100,000 c. Based on population-based study in Olmsted County
Minnesota, in 2000, age-and sex-adjusted prevalence rate is 191/100,000; crude annual incidence rates are 4.5/100,000 for men, 10.4/100,000 for women, 7.5/100,000 overall
d. 250,000 to 350,000 cases of multiple sclerosis in U.S. e. Female-to-male ratio: 1.4 to 2.2/1 f. Peak age at clinical onset of disease: 25 to 30
2. Etiology a. Epidemiologic evidence for complex interplay of genetics
and environment but biologic relevance of individual genetic and environmental factors is not known
b. Epidemiologic evidence for genetic basis 1) Increased susceptibility in Caucasians 2) Excess occurrence in Northern Europeans relative to
indigenous populations of same region or virtual absence even in widely migrating populations such as gypsies
3) 15% to 20% of patients have history of familial multiple sclerosis
4) Excess concordance in monozygotic twins (31%) compared with dizygotic twins
5) Increased recurrence in relatives (3% to 5%): 20 to 40 times more in first-degree relatives; rapid decrease by degree of relatedness
6) No excess in adopted relatives of patients with multiple sclerosis
7) Human leukocyte antigen (HLA)-DR2 (DRB1*1501,DQ1*0602-chromosome 6p21): associated with three-to fourfold increased risk of sporadic and familial cases of multiple sclerosis (in Sardinians, HLA-DR3 and HLA-DR4)
8) Linkage to chromosome 12p12 in a large pedigree c. Epidemiologic evidence for environmental basis
1) Geographic variation in prevalence and mutable risk with migration from low to high as well as high to low prevalence areas
2) Pockets of increased prevalence and rare epidemics of multiple sclerosis (Faroe Islands, Iceland after World War II)
3) Incomplete concordance (<30%) in monozygotic twins 4) Emotional trauma: stress is associated with 1.9-fold
increase in exacerbations of multiple sclerosis 5) Physical trauma is not associated with onset or exacer-
bations of multiple sclerosis 6) Associated with increased risk of multiple sclerosis
a) Epstein-Barr virus: 2.1-to 5.5-fold b) Measles or mumps after age 15 c) Insufficient vitamin D intake d) Smoking: 1.4-to 1.9-fold (dose effect of pack years)
7) Decreased risk of multiple sclerosis: increased sun exposure between ages 6 and 15 and increased actinic sun damage
3. Pathology a. Early active lesion (Fig. 14-8)
1) Perivascular inflammation 2) Evidence of myelin breakdown, with lipid-laden
macrophages 3) Relatively preserved axons 4) Presence or absence of oligodendrocytes 5) Large hypertrophic-reactive astrocytes with
eosinophilic cytoplasm and granular mitosis (Creutzfeldt-Peters cells) (these can be differentiated from glioma by even distribution rather than clumping together)
6) Axonal ovoids indicative of newly transected axons may be seen in early active lesions
b. Chronic inactive lesion (Fig. 14-9 and 14-10) 1) Sharply circumscribed, hypocellular “plaque” with
variable degree of perivascular inflammation, lack of active myelin breakdown, decreased or absent mature oligodendrocytes, incomplete remyelination restricted
to the edge of the “plaque,” markedly reduced axonal density, and presence of fibrillary gliosis
2) Oligodendrocyte precursor cells, extensive remyelination can be present in some lesions but with reduced staining for myelin “shadow plaques”
c. Normal-appearing white matter is not disease-free 1) Diffuse axonal injury and wallerian degeneration,
diffuse lymphocytic infiltration (predominantly CD8+ T cells), and microglial activation
2) Magnetic resonance spectroscopy evidence of reduced N-acetylaspartate-to-creatine ratios and brain atrophy that is independent of T2 lesion load in MRI (see below)
d. Involvement of cerebral and cerebellar gray matter possible 4. Immunopathogenesis (Fig. 14-11)
a. Current working hypothesis of pathogenesis in BOMS is based on evidence from human disease and animal models of experimental allergic encephalomyelitis (EAE), canine distemper virus-induced demyelination, and Theiler’s virus-induced demyelination 1) Human disease: four patterns of immuno-
pathogenesis a) Pattern I: macrophage-associated demyelination b) Pattern II: antibody/complement-associated
demyelination c) Pattern III: distal dying-back oligodendrogliopathy d) Pattern IV: primary oligodendrocyte degeneration
2) The same pattern may persist in a patient 3) Pattern I and pattern II lesions resemble the EAE
model of multiple sclerosis b. Multiple sclerosis is a heterogeneous disease with multiple
pathologic pathways leading to a similar clinical disease c. One or more etiologic factors could be important in
pathogenesis 1) Evidence suggesting multiple sclerosis is a viral disease:
evidence for endemics, susceptibility of CNS to acute and latent viral diseases that can also present as attacks, resemblance to canine distemper virus-induced or Theiler’s virus-induced demyelination models
2) Evidence suggesting multiple sclerosis is an autoimmune disease: presence of immune activation in the absence of a specific viral agent linked to causality, presence of abnormal T-cell clones, association with MHC class II molecules, resemblance to EAE
d. Common “autoimmune hypothesis” favoring the presence of Th1 over Th2 type T cells in the pathogenesis of autoimmune diseases and multiple sclerosis 1) Protection from autoimmunity is achieved by self-
tolerance mechanisms
a) Central tolerance is achieved by thymic “negativeselection” of T cells sensitized to self (MHC class I molecules involved in recognition of self)
b) Peripheral tolerance is achieved by the type of the
costimulatory pathway used i) Th0 cell activation using CTLA4 can lead to
clonal anergy or generate a Th2-cell response (thought to be protective)
ii) Th0-cell activation using CD28 can lead to a Th1-cell response (thought to be detrimental)
c) Activation-induced apoptosis results from high intensity of the antigenic stimulus to Th0 cells, leading to increased production of interleukin (IL)-2 and activation of apoptotic Fas/FasL pathway i) Mutations in Fas lead to systemic autoimmunity
in mice and men (autoimmune lymphoprolifer-
ative syndrome) d) Cells that escape central and peripheral tolerance
become autoreactive T-cell clones, which are present in every person
2) A foreign antigen can lead to autoreactive T-cell activation due to molecular mimicry or a similar mechanism a) A uniform antigenic stimulus is not identified in
multiple sclerosis-against the autoimmune hypothesis
b) Initial event is presentation of an unknown antigen to naive Th0 cells by antigen-presenting cells (e.g., macrophages, microglia, B cells) via trimolecular complex (MHC class II, CD4, and T-cell receptor)
c) Autoreactive T-cell activation can happen in CNS or in the periphery with recruitment through blood-brain barrier via integrin (endothelial surface) and adhesion molecule (lymphocyte surface) interactions (VCAM/VLA-4, ICAM/LFA-4) and matrix metalloproteinase-9 (MMP-9) stimulation
3) Proinflammatory cytokines secreted by Th1 cells initiate the detrimental cascade of events leading to myelin injury and/or primary oligodendrocyte degeneration a) Autoreactive antibodies produced by B cells,
complement activation, microglia-induced myeloperoxidase (MPO) secretion and NOS2A activation, macrophage-induced demyelination, tumor necrosis factor α, nitric oxide (NO), reactive oxygen species (ROIs), and CD8 cellor Fas-induced apoptosis
4) Anti-inflammatory cytokines (e.g., IL-1, IL-4, IL-10) secreted by Th2 cells initiate the protective cascade of events leading to myelin repair and/or oligodendrocyte precursor activation a) Remyelination depends on antibodies produced by
B cells, ciliary neurotrophic factor produced by astrocytes, insulin-like growth factor-I produced by endothelial cells, apolipoprotein E, and glutathione synthetase family of molecules
5. Clinical syndromes and disease course a. An asymptomatic period of unknown duration precedes
initial presentation with an isolated syndrome, as may be evidenced by neuroimaging
b. Initial bout or attack: acute or subacute onset of isolated IIDD(s) evolving in several days, followed by stabilization and recovery (spontaneous or with treatment) 1) No specific signs or symptoms of multiple sclerosis 2) Typical onset: either monosymptomatic or poly-
symptomatic with sensory symptoms, unilateral optic neuritis (leading to relative afferent pupillary defect),
pyramidal symptoms, cerebellar symptoms, brainstem signs such as internuclear ophthalmoplegia (involvement of medial longitudinal fasciculus, most common reason in young adults), and bladder-bowel incontinence or retention
3) Less common presentations: Lhermitte’s sign (flexion of neck induces back or extremity paresthesias), cortical symptoms (aphasia, apraxia, recurrent seizures, visual field defects), or extrapyramidal syndromes (chorea and rigidity) presenting as individual attacks
c. Relapses, with complete remission or stepwise accumulation of deficit 1) Occurrence (on average): once every 2 years 2) Frequency decreases with time
d. Fatigue: worse in the afternoon with physiologic increase in body temperature
e. Uhthoff’s phenomenon: all symptoms may be exacerbated by overheating
f. Pseudoexacerbations: appear like a new “attack” and may occur with fever, exhaustion, or metabolic upset
g. Pain syndromes associated with multiple sclerosis: neuralgias (e.g., trigeminal neuralgia), dysesthesia, radicular pain, flexor and extensor spasms, optic neuritis, low back pain, osteoporosis-associated fractures
h. Recurrent, brief stereotypic paroxysmal symptoms (e.g., paroxysmal limb pain and paresthesias, myokymia, hemifacial spasm, trigeminal neuralgia, episodic clumsiness and dysarthria, tonic limb posturing) are likely due to ephaptic transmission and may respond to antiepileptic agents
i. Spasticity is a major problem in multiple sclerosis j. Overt dementia: present in about 5% of patients; neuro-
psychometric test abnormalities suggestive of subcortical dementia in 50% of patients
6. Diagnosis a. Based on clinical and paraclinical criteria of “dissemina-
tion in time and space” (Table 14-1) b. Differential diagnosis of BOMS: nongranulomatous
vasculitides, granulomatous disorders (Wegener’s granulomatosis, sarcoidosis), connective tissue disorders (rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome) Behçet’s syndrome, infections (Lyme disease, human T-cell lymphoma virus, human immunodeficiency virus, progressive multifocal leukoencephalopathy, neurosyphilis, Epstein-Barr virus, cytomegalovirus), CNS lymphoma
c. Paraclinical (laboratory) studies used in diagnosis: MRI, evoked potentials, CSF studies
d. Paraclinical studies may indicate disease activity even in absence of clinical activity
1) MRI a) 90% to 97% sensitive b) Typical lesions: localized to juxtacortical and
periventricular white matter, corpus callosum, brainstem, cerebellar peduncles (Fig. 14-12)
c) Lesions are usually ovoid d) “Dawson’s fingers”: lesions follow deep white
matter medullary veins from ventricle into centrum semiovale, best seen in sagittal images as flame-like lesions perpendicular to lateral ventricles
e) Acute multiple sclerosis lesions: typically isointense in T1-weighted images, hyperintense in FLAIR images (helpful in visualizing periventricular and juxtacortical lesions due to fluid suppression), and hyperintense in T2-weighted images (more sensitive than FLAIR for posterior fossa lesions)
f) Active lesions: enhancement i) Characteristic enhancement pattern with open
ring toward cerebral cortex, but can be solid ii) Enhancement represents blood-brain barrier
breakdown and may persist for up to 2 to 6 weeks without acute treatment
g) Chronic lesions: typically hypointense in T1weighted images (black holes); not usually seen in posterior fossa and should be differentiated from strokes (which are isointense with CSF in all sequences) i) Chronic corpus callosal atrophy, whole-brain
atrophy and ex-vacuo dilatation of ventricles correlate with disability and cognitive decline
ii) “Multiple sclerosis-like” lesions may be seen with hypertension or migraine headaches: typically, lesions are distributed randomly throughout white matter
2) Evoked potentials a) Sensitivity of evoked potentials in diagnosis of
multiple sclerosis i) Visual evoked potentials, 80% to 85% ii) Sensory evoked potentials, 75% iii) Brainstem auditory evoked potentials, 65%
b) Visual evoked potentials are abnormal in more than 90% of patients with previous optic neuritis despite normal visual acuity
3) CSF a) Usually normal cell count or mild lymphocytosis
(<50 cells) with normal or slightly increased protein and presence of oligoclonal bands (90%- 95% sensitive) and increased IgG index (sign of intrathecal antibody secretion independent of blood-brain barrier breakdown)
b) Oligoclonal bands may not be present initially but can appear later in the disease course
c) Oligoclonal bands can also be present in other conditions (7%) (e.g., subacute sclerosing panencephalitis, CNS measles and rubella, chronic meningitis, neurosyphilis, neurosarcoidosis, paraneoplastic disorders, acute idiopathic demyelinating polyneuropathy [Guillain-Barré syndrome] and sometimes stroke)
e. Diagnostic criteria for multiple sclerosis 1) Former diagnostic criteria (Poser criteria) did not
allow for diagnosis of RRMS in the setting of only one clinical attack or diagnosis of PPMS
2) Recently modified diagnostic criteria (McDonald criteria) included neuroimaging to expand clinical definition of dissemination in space or time that is required to diagnose prototypic RRMS
3) This modification helps with earlier diagnosis of RRMS and yields a fourfold increase in the diagnosis of definite RRMS in first 12 months after a clinically isolated event
7. Natural history and prognosis a. Benign multiple sclerosis: in about 15% of patients, all
neurologic systems remain fully functional 15 years after disease onset
b. Accumulation of disability over time 1) Disability is caused by progressive cognitive impairment,
depression, emotional lability, dysarthria, dysphagia, vertigo, progressive quadriparesis, sensory loss, ataxic tremors, pain, sexual dysfunction, spasticity, severe sphincter problems
2) Disability can accumulate in absence of clinical activity because of subclinical disease activity
3) Most commonly accepted clinical scales for defining disability in multiple sclerosis are Kurtzke Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC)
4) MSFC includes cognitive dysfunction and correlates better with MRI changes
c. Clinical predictors of relatively favorable course 1) Female sex 2) Young age at onset (<40) 3) Optic neuritis or sensory symptoms at onset 4) Monosymptomatic onset
d. Clinical predictors of unfavorable course 1) Male sex 2) Older age at onset (>40) 3) Motor, cerebellar, or sphincter symptoms at initial
presentation 4) Multifocal (polysymptomatic) disease at onset
5) Relatively frequent attacks within first 5 years 6) Short interval between first two attacks 7) Relatively short time to reach EDSS level 4 (out of 10) 8) Progressive course 9) High lesion load, apparent on early neuroimaging
10) Incomplete remission after first relapses e. Course in first 5 years usually predicts outcome f. During pregnancy: relapse rate decreases but postpartum
relapse rate initially increases and later decreases to preconception disease frequency
g. Cross-sectional MRI does not reliably predict long-term outcome (brain atrophy correlates with long-term cognitive dysfunction)
h. APOE genotype may correlate with long-term outcome (ε4 allele unfavorable, ε2 allele favorable)
i. Homozygosity for HLA-DR1501 alleles may be associated with more severe disease
j. Development of SPMS 1) May represent crossing of a clinical threshold of axon-
al damage resulting from previous or ongoing inflammatory demyelinating episodes
2) SPMS evolves from RRMS after a highly variable period
3) 75% of RRMS patients develop SPMS disease course by 25 years
4) Predictors of conversion to SPMS: male sex, older age at onset, polysymptomatic onset, sphincter symptoms at onset, recurrent motor or sphincter symptoms, early attainment of disability
k. 50% of multiple sclerosis patients die of causes other than multiple sclerosis
l. Mean survival: more than 25 years after disease onset
F. Primary Progressive Multiple Sclerosis 1. Characterized by insidious, progressive course and lack
of definite exacerbations, paucity of radiographic findings (e.g., gadolinium-enhancing lesions), laboratory, or pathologic evidence of inflammation
2. Differential diagnosis when presenting as progressive myelopathy: progressive myelopathic disorders, disorders with deficiency states (such as vitamin B12 deficiency), Arnold-Chiari malformation with syrinx, dural arteriovenous fistulas, spinocerebellar ataxias, hereditary spastic paraparesis, presenilin-1 mutation associated with spastic paraparesis, adrenomyeloneuropathy, and primary lateral sclerosis
3. Second most common form of IIDD after BOMS (7% in hospital-based cases and 20% in populationbased cases of multiple sclerosis) a. Features distinguishing PPMS from prototypical BOMS:
older age at onset, lack of female preponderance, predilection for chronic progressive myelopathy, paucity of intracranial lesions (only in 60%-70% and few lesions) found on MRI
b. PPMS has worse prognosis than BOMS (one-half of patients with PPMS require at least unilateral gait assistance by 8 years) 1) Involvement of three or more functional systems
(motor, cerebellar, sensory, or other) predicts a significantly worse outcome than involvement of two or fewer systems
G. Treatment of Idiopathic Inflammatory Demyelinating Diseases
1. Treatment of relapses a. High-dose corticosteroid therapy
1) Alleviates symptoms faster than natural history of the attack
2) Transiently restores blood-brain barrier 3) Does not affect long-term outcome
a) Two or three annual courses of methylprednisolone intravenously may slow accumulating clinical disability or cerebral atrophy seen on MRI
4) Intravenous “pulse” of methylprednisolone 500 to 1,000 mg daily for 3 to 7 days with gastrointestinal prophylaxis is the accepted practice
5) Tapered oral dose may be continued but is not necessary 6) Lower dose oral prednisone alone may increase the
risk of recurrent episodes of disease activity in optic neuritis
7) Other intravenous corticosteroids such as dexamethasone or adrenocorticotropic hormone may be administered instead
8) Minimally symptomatic attacks limited to nondisabling systems (e.g., sensory symptoms) do not need to be treated
9) Chronic or frequent use of corticosteroids may increase the risk of osteoporosis, but osteoporosis may develop independently of corticosteroid use in prototypical RRMS
b. Natalizumab (Tysabri) is a humanized anti-α4-integrin antibody that inhibits the trafficking of leukocytes across endothelium: approved but marketing was suspended in March 2005 because of cases of progressive multifocal leukoencephalopathy
c. Plasma exchange may benefit patients with severe attacks with marked acute disability in whom acute corticosteroid therapy fails 1) 7.1-fold increased chance of moderate or better recovery
over sham treatment
2) Seven exchanges administered every other day is accepted regimen
2. Chronic immunomodulatory and immunosuppressant treatments a. Several immunomodulatory treatments are available
(Table 14-2): none are curative b. All the listed medications are approved by U.S. Food and
Drug Administration (FDA) c. Interferons and glatiramer acetate: approved for RRMS
but not any of the progressive forms d. Mitoxantrone hydrochloride (immunosuppressant)
1) Approved for SPMS and worsening RRMS, specifically during rapid progression from RRMS to SPMS
2) Important dose-dependent cardiotoxicity, which is less than its analogue, doxorubicin
3) The risk for chronic cardiomyopathy limits the approved cumulative dose of mitoxantrone for treatment of multiple sclerosis to 140 mg/m2
e. Effects of immunomodulatory treatments 1) Decreased number of attacks (variable rate, approach-
ing 30% for interferons) 2) Decreased number of enhancing lesions on MRI 3) Reduced enlargement rate of lesions on MRI 4) Likely help to decrease long-term atrophy 5) None have been studied long enough to address long-
term clinical benefit f. Interferons produce neutralizing antibodies that may
hamper their effectiveness; the frequency of this differs by agent
g. Mechanism of action of these agents is incompletely understood 1) Interferons
a) Reduce overall T-cell proliferation and production of tumor necrosis factor α
b) Decrease antigen presentation c) Shift T-cell response to a Th2 type response d) Increase IL-10 and IL-4 secretion e) Reduce immune cell trafficking through the
blood-brain barrier by inhibiting adhesion molecules, chemokines, and proteases involved in the trafficking
2) Glatiramer acetate a) Synthetic polypeptide mix containing alanine,
lysine, tyrosine b) May promote proliferation of Th2 cytokines c) Competes with myelin basic protein for presenta-
tion on MHC class II molecules d) Alters macrophage function e) Induces antigen-specific suppressor T cells
3) Mitoxantrone hydrochloride
a) Potent immunosuppressant with important dosedependent cardiotoxicity, which is less than its analogue, doxorubicin
b) Suppresses proliferation of T cells, B cells, and macrophages
c) Impairs antigen presentation d) Decreases secretion of proinflammatory cytokines e) Enhances T-cell suppressor function f) Inhibits B-cell function and antibody production g) Inhibits macrophage-mediated myelin degradation
h. Controlled High-Risk Subjects Avonex Multiple Sclerosis Study (CHAMPS) and Early Treatment of Multiple Sclerosis (ETOMS) trial 1) Onset of treatment with interferon beta-1a after the
first attack of isolated demyelinating syndrome delays conversion to clinically definite multiple sclerosis by Poser criteria (Table 14-1) and lowers the risk of subsequent attack from 50% (placebo treated) to ~35% (low-dose interferon-treated) over 2 to 3 years
Table 14-2. Chronic Treatment Options for Multiple Sclerosis
Multiple sclerosis type Therapeutic agent Dose
2) Beneficial effect in CHAMPS is different for different clinically isolated syndromes and should not be generalized a) Prevention of conversion to clinically definite mul-
tiple sclerosis is evident in an isolated spinal cord syndrome more than a brainstem-cerebellar syndrome
b) In case of isolated optic neuritis, the effect is marginal
c) For patients defined as “high risk” for converting to multiple sclerosis by having at least nine T2weighted hyperintense lesions and at least one enhancing lesion in initial MRI study, predicts a two-thirds reduction in conversion to definite multiple sclerosis in 2 years, but 44% in this group do not convert to definite multiple sclerosis in 2 years without any treatment
3) Follow-up time is short for both studies and there is no evidence that delayed conversion to BOMS prevents long-term disability
3. Symptomatic treatment a. Fatigue
1) Mainstay treatment: organization of daily chores with intermittent rest periods
2) First-choice medical treatment: amantadine 100 mg twice daily
3) Alternatives: modafinil 200 mg once or twice daily, pemoline 18.75 mg daily (short-term use associated with liver toxicity, often not recommended), or selective serotonin reuptake inhibitors (SSRIs) (little evidence for the latter)
4) Aspirin has been suggested recently b. Spasticity
1) Mainstay treatment: physical and occupational therapy
2) Overtreatment of spasticity may lead to loss of beneficial posture to overcome weakness
3) First choice: oral baclofen 10 mg daily before sleep and titrated to 60 mg daily or higher; if refractory, intrathecal baclofen pump
4) Alternatives: tizanidine up to 8 mg four times daily, dantrolene 25 mg daily and titrated to symptoms, or benzodiazepines
c. Paroxysmal symptoms and pain 1) First choice: carbamazepine 2) Alternatives: phenytoin, gabapentin, or other
antiepileptics 3) Tricyclic antidepressants 4) Rhizotomy for refractory trigeminal neuralgia 5) Hydroxyzine for itching
6) Botox injections for spasms d. Depression: SSRIs or tricyclic antidepressants e. Cerebellar tremor
1) Clonazepam, valproic acid, or isoniazid 2) Thalamic stimulator for contralateral tremor for
refractory cases 3) Overall, difficult to manage effectively
f. Bladder dysfunction 1) Characterized by urodynamic studies (and urology
consultation if necessary) 2) Most common urologic issue: frequency and urgency
due to hyperreflexic bladder with small capacity and early detrusor contraction a) Chronic medical management with anticholiner-
gics: oxybutynin (Ditropan), tolterodine (Detrol), or hyoscyamine (Levsinex)
3) Less common urologic issue: flaccid bladder a) Mainstay treatment: self-catheterization b) Medical treatments: cholinergic agents (bethane-
chol and baclofen can be used) 4) Sphincter-detrusor dyssynergia: α-adrenergic blockers
such as prazosin (Minipress) used to relax the sphincter
5) Acute worsening could be due to urinary tract infections and should be managed appropriately
A. Systemic Lupus Erythematous (SLE) 1. Systemic manifestations of SLE: malar rash, photosen-
sitivity, arthritis, serositis (pleuritis or pericarditis), nephritis, mucosal ulcers, hematologic depression (anemia, leukopenia, thrombocytopenia), hypocomplementemia, false-positive VDRL (differentiate from neurosyphilis)
2. Neuropsychiatric presentation (50% of SLE patients) can be acute (e.g., antiphospholipid antibody syndrome and stroke), subacute, or chronic progressive with relapses a. 30% reduced 5-year survival for patients with neurologic
involvement b. Psychiatric and behavioral CNS manifestations (most
common): acute confusional states, psychosis, dementia (must rule out opportunistic infections)
c. Stroke (arterial and venous) 1) Most important neurologic manifestation 2) Due to cardiac emboli, coagulopathy, degenerative
vasculopathy, venous sinus thrombosis
Table 14-3. Common Systemic Autoimmune Vasculitis and Nonvasculitic Inflammatory Disorders With Neurologic Complications*
Symptoms
Type Systemic CNS PNS Diagnosis Treatment
Table 14-3. (continued)
Symptoms
Type Systemic CNS PNS Diagnosis Treatment
Table 14-3. (continued)
Symptoms
Type Systemic CNS PNS Diagnosis Treatment
Table 14-3. (continued)
Symptoms
Type Systemic CNS PNS Diagnosis Treatment
3) One cause of cardiac emboli in this setting: LibmanSacks endocarditis
d. Aseptic meningitis: rare (has been described in association with use of nonsteroidal antiinflammatory drugs or azathioprine)
e. “Cerebral lupus”: direct antibody-mediated angiitis of CNS with fibrinoid necrosis of small vasculature, is rare
f. Noncompressive myelopathy and transverse myelitis (must rule out opportunistic infections)
g. Cranial neuropathies (e.g., optic neuritis, trigeminal sensory neuropathy)
h. Movement disorders: parkinsonism, ataxia, chorea (see Chapter 8)
i. Seizures
d. Interstitial fibrosis e. Pleuritis f. Pneumonitis g. Pericardial effusions h. Skin lesions
5. Cervical compression myelopathy due to atlantoaxial subluxation (anterior, posterior, ventral, lateral)—careful with hyperextension of neck during endotracheal intubation
6. Rheumatoid nodules: extradural spinal canal, leptomeningeal
7. Neuromuscular involvement a. Chronic progressive compression neuropathies (most
common) b. Most common compression neuropathy: median
neuropathy at the wrist c. Distal symmetric sensory polyneuropathy d. Distal symmetric sensorimotor polyneuropathy e. Asymmetric axonal polyneuropathy, mononeuritis multiplex f. Vasculitic peripheral nerve manifestations are secondary
to systemic fulminant vasculitis or obliterative vasculitis (microvascular occlusive disease) and secondary ischemia: acute or subacute presentation
g. Muscle disease: vasculitic myositis, idiopathic overlap polymyositis syndrome, steroid-induced myopathy
8. Neurologic complications of specific rheumatoid arthritis treatments: gold (neuropathy), penicillamine (drug-induced myasthenia gravis, myopathy), chloroquine (retinopathy, neuropathy, myopathy)
9. Treatment: no standard treatment, corticosteroids and immunosuppressant agents such as cyclophosphamide, azathioprine, methotrexate, or mycophenolate may be tried (controlled trials lacking)
C. Sjögren’s Syndrome 1. Systemic manifestations: xerostomia and keratocon-
junctivitis sicca (due to destructive lymphocytic inflammation of exocrine glands), arthritis, interstitial nephritis, skin involvement
2. Neurologic manifestations: predominantly involvement of peripheral nervous system a. High frequency of positive anti-Ro (SSA) antibodies
(sensitive and specific to general autoimmunity), present in SLE, Sjögren’s syndrome, SLE-Sjögren overlap syndrome, and primary biliary cirrhosis
b. Low frequency of anti-La (SSB) antibodies are more specific to Sjögren’s syndrome
c. Therefore, presence of only anti-Ro antibodies marks general systemic autoimmunity but not Sjögren’s syndrome as the cause of neurologic complications
1) May occur from foci of infarction, opportunistic infection, drug intoxication, others
2) 30% to 54% of SLE patients have seizures at some point 3. Neuromuscular manifestations of SLE
a. Vasculitis-induced mononeuropathies (mononeuritis multiplex)
b. Symmetric, axonal, distal sensorimotor (or primarily sensory) neuropathy
c. Polyradiculopathy d. Polyradiculoneuropathy (a chronic inflammatory
demyelinating polyradiculoneuropathy) e. Myositis or vasculitic myopathy
4. Serologic features a. Antinuclear antibody (ANA): nonspecific b. Extractable nuclear antigen (ENA)
1) Constitutes antibodies to native double-stranded DNA, Sm antigen, and ribonucleoprotein antigen
2) Good evidence for SLE in appropriate clinical context c. Antiphospholipid antibodies with procoagulant proper-
ties: lupus anticoagulant and anticardiolipin antibodies d. Antiphospholipid antibodies are present in all patients
with antiphospholipid syndrome and in 30% of patients with SLE, but may also be present in up to 29% of patients with BOMS
e. Presence of antiphospholipid antibodies predicts 50% chance of recurrence of SLE and greater likelihood of valvular and cardiac disease
f. Presence of antiphospholipid antibodies and active SLE during second trimester predict increased risk of abortion and stroke
g. Low complement levels: may be used to determine disease activity
5. Treatment a. High-dose intravenous corticosteroids, followed by oral
prednisone b. Immunosuppressant, steroid-sparing agents: cyclophos-
phamide, azathioprine, methotrexate c. Antimalarial agents (e.g. hydroxychloroquine) not well-
studied in the peripheral nervous system or CNS disease
B. Rheumatoid Arthritis 1. The most common connective tissue disorder, rare
CNS involvement 2. Most common mechanism of disease: widespread
arthropathy with secondary compression neuropathies 3. Course: chronic, progressive 4. Systemic manifestations
a. Symmetric polyarthritis b. Subcutaneous nodules c. Pulmonary nodules
d. Peripheral nervous system manifestations: sensory ataxic neuronopathy (ganglionopathy), sensory or sensorimotor symmetric polyneuropathy, cranial neuropathies (most commonly trigeminal neuropathy); high female prevalence
e. CNS manifestations (less common): aseptic meningoencephalitis, diffuse and focal CNS syndromes (including myelopathy) should be considered in the differential diagnosis of recurrent isolated transverse myelitis
f. Trimethoprim-sulfamethoxazole (Bactrim)–associated aseptic meningitis is more common in patients with Sjögren’s syndrome
3. Associated with other autoimmune neurologic disorders (e.g., myasthenia gravis, polymyositis)
D. Progressive Systemic Sclerosis 1. Systemic manifestations
a. Raynaud’s phenomenon b. Renal involvement, including glomerulonephritis:
leading cause of death c. Diffuse or limited cutaneous scleroderma: symmetric
skin thickening d. Systemic fibrosis: cardiac, pulmonary (interstitial pul-
monary fibrosis, pericarditis, congestive heart failure) e. Gastrointestinal mucosal lesions f. Keratoconjunctivitis g. Associated with CREST (calcinosis, Raynaud’s phenom-
enon, esophageal dysmotility, sclerodactyly, telangiectasias) syndrome
2. CNS involvement: rare 3. Peripheral nervous system involvement: most common
neurologic involvement a. Fibrosis can cause cranial neuropathies: most common,
isolated trigeminal neuropathy b. Peripheral neuropathy: rare, often due to other organ
involvement c. Compression mononeuropathies (e.g., median neuropa-
thy at the wrist) from fibrotic thickening of surrounding tendon sheaths
d. Mononeuropathy multiplex most frequently with CREST (vasculitic neuropathy with perivascular inflammation) syndrome
4. May present as part of mixed connective tissue disorder 5. Mechanism of damage due more often to fibrosis than
vasculitis 6. Treatment: penicillamine, azathioprine, colchicine,
corticosteroids (short-term only)
E. Mixed Connective Tissue Disease: heterogeneous, variable features of other connective tissue disorders (Table 14-3)
A. Polyarteritis Nodosa, Churg-Strauss Syndrome, and Wegener’s Granulomatosis
1. All are necrotizing vasculitides 2. Polyarteritis nodosa and Churg-Strauss syndrome
involve small-and medium-sized vessels; Wegener’s granulomatosis involves smaller vessels
3. Polyarteritis nodosa a. CNS manifestations
1) Common (40%-45% of patients) but have delayed onset after initial symptoms of the disease (2-3 years)
2) Diffuse encephalopathy with seizures (40%), hypertensive encephalopathy, focal vasculitic lesions (50%), isolated cranial neuropathies (most common, cranial nerves II, III, VIII) (10%-15%)
b. Peripheral nervous system manifestations 1) Common and early (50%-60% of patients) 2) Predominantly mononeuritis multiplex, mixed
sensorimotor distal symmetric polyneuropathy, plexopathy, radiculopathy, inflammatory myopathy
c. Systemic vasculitic manifestations: most commonly kidneys, skin, mesenteric vessels
d. Gastrointestinal tract angiography: sometimes needed to make diagnosis
e. 30% of patients may have hepatitis B surface antigen f. Polyarteritis nodosa is not associated with antineutrophil
cytoplasmic antibodies (ANCA) 4. Churg-Strauss syndrome
a. Asthma, allergic rhinitis, and nasal polyposis b. Peripheral eosinophilia, increased IgE levels c. Extravascular granulomas d. Granulomatous or nongranulomatous eosinophilic
necrotizing vasculitis (involving arteries and veins) e. Higher predilection for hemorrhages than polyarteritis
nodosa (more venous involvement) f. Associated with perinuclear ANCA
5. Wegener’s granulomatosis a. Classic triad: segmental glomerulonephritis, granulomas
of respiratory tract, necrotizing vasculitis b. Nervous system involvement
1) Granulomatous spread from paranasal sinuses leading to exophthalmos (ocular pseudotumor), optic nerve involvement, oculomotor and other cranial neuropathies, cavernous sinus syndrome, pituitary syndromes
2) Granulomatous vasculitis: peripheral neuropathy, vasculitic stroke, encephalopathy, intracerebral or subarachnoid hemorrhage, optic neuritis
c. Approximately 5% of patients have intracranial hemorrhage d. Associated with cytoplasmic ANCA against proteinase-3
in most patients 6. Renal failure: most common cause of death in necro-
tizing vasculitides 7. Treatment: corticosteroids, cyclophosphamide
B. Giant Cell Arteritis: temporal arteritis and Takayasu’s arteritis
1. Temporal arteritis a. Systemic panarteritis affecting older adults (almost all
older than 50) b. Affects medium-or large-sized arteries, primarily the
intracranial and extracranial vessels c. Visual disturbance d. Temporal throbbing headache with radiation to the ear,
jaw, tongue, and ipsilateral or contralateral bifrontal or occipital head regions
e. Scalp tenderness f. Jaw claudication g. Constitutional symptoms (low-grade fever, fatigue, night
sweats, anorexia) h. Other symptoms: blindness due to optic neuropathy,
ocular muscle dysfunction, strokes, seizures i. Other intracranial vessels (vertebral and carotid arteries)
can be involved j. Half of the patients have polymyalgia rheumatica k. Diagnosis: erythrocyte sedimentation rate more than
50 mm/h and temporal artery biopsy (in 70% of cases diagnosis is made after biopsy) even if the disease involves other parts of CNS vasculature
l. Treatment 1) Oral prednisone should be started without awaiting
biopsy results because of risk of blindness 2) Treatment usually continued for 2 years
2. Takayasu’s arteritis a. Large-vessel arteritis involving aorta and its branches b. Predominantly affects young Asian women c. May present with unexplained systemic illness and fever
of unknown origin d. Often, nonspecific symptoms at presentation:
headaches, dizziness, arthralgias e. Features related to the large-vessel arteritis: stroke,
syncope, subclavian steal syndrome, amaurosis fugax and other transient ischemic events, claudication, chest and abdominal angina
f. Bruits often heard from involved vessels g. Treatment: oral prednisone, cyclophosphamide,
methotrexate, or cyclosporine
C. Behçet’s Disease 1. Endemic in countries along the ancient “Silk Road”
(Japan, Korea, Middle East, Mediterranean basin), with highest incidence in Turkey
2. Associated with HLA-DR5 3. Affects men more than women 4. A systemic vasculitis characterized by arterial and venu-
lar involvement of different size vessels 5. Systemic manifestations: predominantly venulitis lead-
ing to hallmark oral and genital aphthous ulcers a. Ocular manifestations: uveitis, retinal vasculitis b. Cutaneous manifestations: oral and genital ulcers,
erythema nodosum, papulopustular lesions c. Venous involvement: superficial thrombophlebitis, deep
venous thrombosis, cerebral venous sinus thrombosis, superior vena cava syndrome
d. Pulmonary vascular complications can be fatal e. Gastrointestinal tract ulcers (need to be differentiated
from inflammatory bowel disease) f. Arthritis g. Diagnostic hallmark: a skin reaction called “pathergy
phenomenon,” which is also responsible for delayed wound healing
h. Diagnostic criteria: recurrent oral ulcers plus two of the following: 1) Recurrent genital ulcers 2) Uveitis, retinitis 3) Skin lesions, including erythema nodosum
6. CNS complications affect 10% to 30% of patients and are common causes of morbidity and mortality a. Most common presentation: headache followed by long
tract signs b. Aseptic meningitis (rare, but before MRI era, it was
thought to be common) c. Venous sinus thrombosis and resultant intracranial
hypertension d. CNS parenchymal disease likely due to venulitis involv-
ing diencephalic regions with characteristic MRI findings of inflammation and edema responsive to corticosteroids
e. Spinal cord involvement (predilection for thoracic cord) f. Brainstem involvement: cranial neuropathies (e.g.,
recurrent facial palsies), long tract signs g. Peripheral neuropathy h. Necrotizing myopathy (sometimes due to chemothera-
peutic agents) i. CNS arterial involvement: rare; may cause stenosis,
aneurysm formation, dissection of intracranial vessels 7. Disease course: single attack, relapsing-remitting, or
secondary progressive 8. MRI: T2 hyperintense lesions in brainstem, basal
ganglia, internal capsule, subcortical white matter (no
predilection for periventricular regions, as in multiple sclerosis)
9. CSF: elevated opening pressure (may be only abnormality with isolated venous sinus thrombosis), pleocytosis, increased protein level, normal glucose, and, infrequently, oligoclonal bands
10. Treatment (Table 14-3)
D. Isolated CNS Vasculitis (see Chapter 11)
A. Features 1. Multisystem, idiopathic, noncaseating granulomatous
disease 2. Most prevalent in African Americans and women 3. 50% of patients with neurologic involvement present
with neurologic disease
B. Systemic Manifestations 1. Pulmonary involvement: bilateral hilar adenopathy and
pulmonary infiltrates 2. Cutaneous manifestations: erythema nodosum 3. Uveitis 4. Arthritis
C. Nervous System Involvement (3%-5% of patients): diverse, may affect CNS, peripheral nervous system, and muscle
1. Cranial neuropathies (from basal meningitis) a. Facial neuropathy: most common b. Optic neuropathy: may be acute and resemble idiopathic,
demyelinating optic neuritis (to be differentiated from uveitis, which may also be present)
c. Rarely due to cerebellopontine angle mass lesion 2. Pituitary-hypothalamic dysfunction (e.g., diabetes
insipidus, somnolence, obesity, hypopituitarism) 3. Meningoencephalitis: usually aseptic meningitis with
increased opening CSF pressure, mononuclear CSF pleocytosis, increased CSF protein level, possibly oligoclonal bands
4. Increased intracranial pressure (often with aseptic meningitis), and, occasionally, hydrocephalus
5. Intracranial parenchymal disease: may be due to inflammatory infiltration of parenchyma from leptomeningeal and/or ependymal surfaces
6. Spinal cord parenchymal disease a. Transverse myelitis due to sarcoidosis should be differen-
tiated from isolated transverse myelitis, neuromyelitis
optica, multiple sclerosis, human T-cell lymphotropic virus-1 (HTLV1), and Sjögren’s syndrome
b. Resistance to steroids and plasma exchange, with persistent inflammation, should further suggest sarcoidosis especially in African American patients
7. Peripheral nerve involvement a. Symmetric distal polyneuropathy or, less commonly,
polyradiculoneuropathy (especially with cauda equina leptomeningeal involvement)
b. Asymmetric polyneuropathy: mononeuritis multiplex 8. Myopathy
a. More than 50% of patients have muscle involvement, most are asymptomatic
b. Acute or chronic myositis (with proximal more than distal muscle weakness), pain, tenderness
c. Nodular, patchy myositis
D. Histopathology (Fig. 14-13) 1. Noncaseating granulomas consisting of epithelioid
macrophages, monocytes, lymphocytes, fibroblasts; sometimes have fibrotic (rarely necrotic) centers
2. Perivascular inflammation may cause thickening of intima and media of affected vessels and tissue ischemia; may spread to involve parenchyma
3. Fibrosis may eventually develop: treatment goal is to diminish irreversible fibrosis and resultant ischemia
E. Ancillary Testing 1. MRI: parenchymal lesions with increased T2 signal
and leptomeningeal, parenchymal, and nerve root enhancement
2. CSF examination may show any combination of the following: increased opening pressure, increased protein level, decreased glucose level, mononuclear pleocytosis, elevated IgG index and oligoclonal bands, and increased CSF angiotensin-converting enzyme (nonspecific marker, with questionable sensitivity because negative CSF angiotensin-converting enzyme does not exclude the diagnosis)
3. Evoked potentials, electromyography, nerve conduction studies in selected cases
4. 30% to 70% of patients have increased serum levels of angiotensin-converting enzyme (nonspecific)
5. Endocrine testing 6. Serum and urine calcium: concentration may be
increased 7. Kveim testing: not available 8. Biopsy of relevant tissues (skin, conjunctiva, lymph
node, lung) necessary for diagnosis in clinically suspected cases
9. Nerve root or nerve biopsy may be necessary for diagnosis in selected cases
F. Disease Course 1. Monophasic in two-thirds of patients, progressive or
relapsing-remitting course in one-third 2. Poor prognostic factors: hydrocephalus; spinal cord,
brainstem, or cerebral mass lesions; epilepsy; encephalopathy; optic nerve involvement
G. Treatment 1. Prednisone 2. Methotrexate, azathioprine, cyclosporine,
cyclophosphamide
1-5. Match the disease (1-5) with the corresponding feature (a-e)
1. Systemic lupus erythematosus
2. Wegener’s granulomatosis
3. Takayasu’s arteritis
4. Giant cell arteritis
5. Polyarteritis nodosa
a. Predominantly affects aortic arch in young Asian women
b. Associated with seropositivity for hepatitis B
c. Associated with cytoplasmic (c)-ANCA reactivity
d. Occurs in patients older than 50 years, often with an increased erythrocyte sedimentation rate
e. Aseptic meningitis may be induced by use of nonsteroidal anti-inflammatory drugs
6. All the following are typical brain MRI lesions of multiple sclerosis except: a. Well circumscribed b.Appear hyperintense (bright) on T1-and T2-
weighted MRI c. Round or ovoid appearance d.Typically are a few millimeters to 1 cm in diameter
7. Patients with a clinically isolated symptom of demyelination: a. Have clinically definite multiple sclerosis regardless
of what MRI demonstrates b.Have approximately an 85% chance of developing
clinically definite multiple sclerosis in the next 10 years if two or more cerebral lesions are seen on MRI at onset
c. Have approximately a 45% chance of developing clinically definite multiple sclerosis in the next 10 years if two or more cerebral lesions are seen on MRI at onset
d.Have approximately a 50% chance of developing clinically definite multiple sclerosis in the next 10 years if two or less cerebral lesions are seen on MRI at onset
e. MRI is not indicated because it has no prognostic value for these patients
8. Which of the following is associated with a favorable long-term prognosis for patients with multiple sclerosis? 1) Male sex 2) Onset before age 30 3) T1 hypointense lesions on initial MRI of head 4) Optic neuritis as presenting symptom Choices are a=1,3; b=2,4; c=1,2,3; d=4 only
9. Interferon beta therapy for multiple sclerosis is not associated with: a. Injection site reactions b.Pancreatitis c. Increased liver enzyme levels d.Risk of worsening depression e. Flulike symptoms
10. Glatiramer acetate is: a. Composed of amino acids making up myelin basic
protein b.Approved for treating secondary progressive multiple
sclerosis c. Associated with worsening of attacks of multiple
sclerosis d.Associated with flulike symptoms after injection e. Used to alter the predominant immune response
from Th2 to Th1 type
For questions 11-13, mark all responses that are correct.
