DEMYELINATING DISEASE

NEURO2 | Dr. Ruben Flores

03/12/2021, 10-12 NN

Contents MULTIPLE SCLEROSIS

I. Multiple Sclerosis  disease of young adults
a. Primary Progressive MS  more common in temperate climates
b. Symptoms  subacute disease
c. Course  relapses and remission
d. Etiology  objective evidence of anatomical lesions separated in space
e. Diagnosis and time
f. Treatment
g. Balo Sclerosis SCHUMACHER’S CRITERIA (1965)
h. Schilder Disease 1. There must be objective abnormalities on neuro exam
II. Guillain-Barré Syndrome attributable to dysfunction of the CNS
a. Pathogenesis 2. On neuro exam or by history, there must be evidence of
b. Pathophysiology involvement of two or more separate parts of the CNS
c. Epidemiology 3. The objective neurologic evidence of CNS disease must reflect
d. Clinical Features predominantly white matter involvement, i.e., fiber tract
e. Miller-Fisher Syndrome damage
f. GBS with Preserved Stretch Reflexes 4. The involvement of the neuraxis must have occurred
g. Bickerstaff’s Brainstem Encephalitis temporarily in one or the other of the following patterns:
h. Acute Ophthalmoparesis without Ataxia  In one or more episodes of worsening supported by a
i. Ataxic GBS period of one month or more, each lasting at least 24
j. Acute Oropharyngeal Palsy hours
k. Chronic Inflammatory Demyelinating Disease  Stepwise progression of signs. symptoms over a period of
l. Other Microbial Infections Causing GBS at least 6 months
m. Differential Diagnosis 5. Onset between 10 and 50 years of age inclusive
n. Evaluation 6. The patient’s signs and symptoms cannot be explained better
o. Prevention by some other disease process, a decision which must be
p. Management made by a physician competent in clinical neurology
q. Prognosis
r. Complications 2017 REVISED MCDONALD CRITERIA
 ≥2 clinical attacks
 with ≥2 lesions with objective clinical evidence
PATHOLOGIC CRITERIA  with no additional data needed
 destruction of myelin  ≥2 clinical attacks
 sparing of other elements of the nervous tissue  with 1 lesion with objective clinical evidence and a clinical
 infiltration of inflammatory cells, perivascularly history suggestive of a previous lesion
 specific distribution of lesions  with no additional data needed
 relative lack of Wallerian degeneration or secondary  ≥2 clinical attacks
degeneration  with 1 lesion with objective clinical evidence and no clinical
history suggestive of a previous lesion
CLASSIFICATION OF INFLAMMATORY DEMYELINATIVE  with dissemination in space evident on MRI
DISEASES  1 clinical attack (i.e., clinically isolated syndrome)
I. Multiple sclerosis  with ≥2 lesions with objective clinical evidence
A. Relapsing-remitting form  with dissemination in time evident on MRI or
B. Secondary progressive from demonstration of CSF-specific oligoclonal bands
C. Primary progressive form  1 clinical attack (i.e., clinically isolated syndrome)
D. Acute multiple sclerosis (Marburg disease and tumefactive  with 1 lesion with objective clinical evidence
MS)  with dissemination in space evident on MRI
E. Diffuse cerebral sclerosis (Schilder disease and concentric  with dissemination in time evident on MRI or
sclerosis of Balo) demonstration of CSF-specific oligoclonal bands
II. Neuromyelitis optica (Devic disease, NMO) and progressive
necrotic myelopathy Dissemination in Space
III. Acute disseminated encephalomyelitis (ADEM) and Acute  dissemination in space requires ≥1 T2-hyperintense lesions (≥3
hemorrhagic encephalitis (Weston Hurst disease) mm in long axis), symptomatic and/or asymptomatic, that are
IV. Demyelination in association with autoimmune disease (SLE, characteristic of multiple sclerosis in two or more of the four
Sjögren disease, and related conditions) following locations:
V. Sarcoid-related demyelination
VI. Graft-versus-host disease

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DEMYELINATING DISEASE
NEURO2 | Dr. Ruben Flores
03/12/2021, 10-12 NN

 periventricular (≥1 lesion, unless the patient is over the age

of 50 in which case it is advised to seek a higher number of
lesions)
 cortical or juxtacortical (≥1 lesion)
 infratentorial (≥1 lesion)
 spinal cord (≥1 lesion)
 T2-hyperintense lesions of the optic nerve, such as those in a
patient presenting with optic neuritis, cannot be used in
fulfilling the 2017 revised McDonald criteria

Dissemination in Time
 dissemination in time can be established in one of two ways:
 a new T2-hyperintense or gadolinium-enhancing lesion SOME SUGGESTIVE SIGNS/ SYMPTOMS
when compared to a baseline MRI scan (irrespective of Positive Negative
timing) Combination of pyramidal, Early development of dementia,
 simultaneous presence of a gadolinium-enhancing lesion cerebellar, posterior column, & seizures, or extrapyramidal signs
and a non-enhancing T2-hyperintense lesion on any one brainstem signs Noncerebellar tremors, stupor, focal
Internuclear ophthalmoplegia atrophy
MRI scan
Aphasia and fasciculations
Hearing loss and uveitis
PRIMARY PROGRESSIVE MS
 ≥1 year of disability progression which can be determined ETIOLOGY
wither prospectively or retrospectively
 the cause is not known and an effective treatment has not
 with two of the following:
been identified
 ≥1 T2-hyperintense lesions characteristic of multiple
 much evidence now points to an immunological process as
sclerosis in one or more of the following regions:
one of the major elements in the disease
periventricular, cortical or juxtacortical, or infratentorial
 it is also likely that an environmental influence, possibly and
 ≥2 T2-hyperintense lesions in the spinal cord
infectious process, may contribute to the disease
 presence of CSF-specific oligoclonal bands
 it is now certain that genetic makeup influences susceptibility
to the disease (polygenic)
SYMPTOMS

DIAGNOSIS
Numbness, tingling 63.5%
Walking difficulty 48.9%
CSF STUDIES
Vision problems 40.2%
 normal RBS and glucose
Fatigue 40.1%  normal or mildly elevated protein
Weakness 25.3%  5-20 mononuclear cells
Dizziness 23.3%  intrathecal IgG synthesis
Pain 19.3%  increased IgG index or 24-hr synthesis rate
Muscle spasms 17.2%  increased kappa light chains
Depression 14.7%  oligoclonal bands
Cognitive dysfunction 13.4% - >90% of definite MS
Bladder dysfunction 11.1% - seen in other inflammatory disease
Bowel dysfunction 5.7% - seen in 7% of normal control

COURSE CSF Oligoclonal Bands

 exacerbations and remissions
 complete or nearly complete remission  chronic
 acute
 rapid progressive over a few weeks and months
 monophasic or short incomplete remission  severe
relapse
 progressive: gradual worsening without well-delineated
remission and relapses
 benign: few exacerbations (often mild) followed by complete
recovery
 subclinical: demyelination in asymptomatic patients (autopsy)

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DEMYELINATING DISEASE
NEURO2 | Dr. Ruben Flores
03/12/2021, 10-12 NN

 no significant side effects

EVOKED POTENTIAL  (+) Abs- no clinical significance
% PROLONGED POSSIBLE MS PROBABLE MS DEFIRNITE MS  mechanism of action- unknown
VEP 40 60 85
SSEP 50 70 80 TREATMENT FAILURE
BAEP 30 40 70
 severe side effects
 30 or more attacks per year
MS PLAQUES
 steady disease progression

INEFFECTIVE TREATMENTS
 linoleic acid supplementation or restriction
 hyperbaric oxygen
 long-term ACTH or corticosteroids- do not affect course of MS

TREATMENT OF ACUTE EXACERBATIONS

 IV methylprednisolone
 250-500 mg q12h x 3-7 days IV
 oral prednisolone 60-80 mg/day x 7 days
 taper x 1 month
 >85% improvement- R-R MS
 <50% improvement- chronic progressive MS
TREATMENT
 aimed at halting the progression BALO SCLEROSIS
 beta-interferon-1a (Avonex, Rebif)
 rare and progressive variant of MS
 beta-interferon-1b (Betasteron)
 symptom onset at early adulthood, except in some cases of
 Glatiramer acetate (Copaxone)
childhood onset
 intravenous immunoglobulin (IVIg)
 distinguishing features is the occurrence of alternating bands
 mitoxantrone (Novantrone)
of destruction and preservation of myelin in roughly a series of
concentric rings that represent alternating areas of myelin loss,
Beta-Interferon-1a
and preservation
 recombinant DNA technology
 clinical manifestations
 identical to naturally occurring interferon
 headache
 31% decrease in exacerbations
 disturbance of
 fewer enhancing active lesions than placebo (suggesting <new
communication
episodes of exacerbations)
 mental and behavioral
 Abs vs IFN-1a in 2 years (20%)
changes
 55% incidence of systemic, flu-like symptoms
 mutism
 given once a month (6M units IM)
 fever
 other findings
Beta-Interferon-1b
 disturbance of consciousness
 34% decrease in exacerbations
 bowel/bladder symptoms
 given every other day (8M units SC)
 paralysis
 40% develop Abs vs IFN-1b (Abs vs 1b usually neutralize 1a,
 long tract involvement
and vice versa)
 primitive reflexes
 flu-like symptoms (76%), tend to abate with time
 mechanism of action- unknown
SCHILDER DISEASE

Intravenous Immunoglobulin  most frequently involved: childhood and adolescents

 0.2 gm/kg, monthly
 disability scores improved; relapse cut in half
 well-tolerated, few side-effects
 small sample size (148 patients), expensive
Glatiramer Acetate (Copaxone)
 synthetic polypeptides designed to mimic MBP
 4 amino acids: glutamic acid, lysine, arginine, alanine, tyrosine
 29% reduction in exacerbations
 given daily (20mg SC)
 characteristically involve the cerebrum- diffuse and massive
demyelination
 progressive condition similar nature with MS
 prominent inflammatory reaction with axonal sparing
 hard to differentiate from “diffuse sclerosis”
GUILLAIN-BARRÈ SYNDROME

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DEMYELINATING DISEASE
NEURO2 | Dr. Ruben Flores
03/12/2021, 10-12 NN

PATHOGENESIS  the one most often reported is a benign upper respiratory

infection
 autoimmune disease resulting from aberrant immune
responses against various components of peripheral nerve
fibers ANTECEDENT EVENTS
 it involves both humoral and cell-mediated factors Viral Influenza
 circumscribed areas containing lymphocytes, macrophages, Cytomegalovirus*
and localized demyelination are present, scattered throughout Herpes
the PNS Epstein-Barr virus*
Hepatitis
MIMICRY Human immunodeficiency virus
 GBS after ganglioside injection Bacterial Campylobacter jejuni*
 ganglioside-like lipooligosaccharide Mycoplasma pneumoniae*
 passive transfer model Spirochetal Borrelia burgdorferi
Surgery
Vaccination Rabies (some strains)
Vaccinia
* stronger association

PATHOPHYSIOLOGY
 acute inflammatory demyelinating polyradiculopathy
(AIDP) form Paresthesias
 focal areas of demyelination
 conduction slowing or conduction block
 some minor associated axon loss
 acute axonal forms
 present as axon loss polyradiculoneuropathies
 affects motor, or motor and sensory fibers, depending
upon the subgroup
EPIDEMIOLOGY
Weakness
 relatively rare disorder
 1-2 cases per 100,000 population
 occurs worldwide, affects all races, attacks more males than
females, higher incidence in elderly
 most cases are sporadic and without reported seasonal
variation, but clusters have been observed
 acute axonal form of GBS (mostly in China)
- occurs primarily in epidemics
- during the summer months
- typically affects children and young adults
- Campylobacter jejuni infection implicated
CLINICAL FEATURES
 most patients are essentially well
 lack systemic symptoms, including fever, when PNS
symptoms begin
 initial neurological symptoms vary from patient to patient
 cardinal features of GBS:
 paresthesia
 weakness
 diminished or absent DTRs
 distal, usually symmetrical paresthesias involving the toes,
fingers, or both herald the onset of the disorder in at least 50%
of patients
 typically spreads proximally but seldom extends beyond the
ankles and wrists
 typically, vibration and proprioception are the most severely
affected
 sensory modalities mediated by large myelinated fibers
 weakness is often first noted a few days after the onset of
paresthesia
 typically, it begins in the lower extremities, especially in the
proximal muscles
 patients may have trouble climbing stairs and rising from
chairs
 weakness soon spreads (ascends) to the upper extremities
 less often, weakness begins simultaneously in the upper and
lower extremities
 lower extremities usually more severely affected

Deep Tendon Reflexes

ANTECEDENT EVENTS
 on clinical examination. one of the earliest findings is
 antecedent events, so-called ‘triggers,’ are associated in ~70%
decreased or absent DTRs
of cases
 these may either precede or follow by a few days the
 they usually occur 1-3 weeks before the onset of clinical
demonstration of weakness on physical exam
symptoms, rarely as much as 6 weeks earlier

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DEMYELINATING DISEASE
NEURO2 | Dr. Ruben Flores
03/12/2021, 10-12 NN

DISEASE PROGRESSION  presence of anti-GQ1b IgG antibodies

 progressive phase of the illness lasts from a few days to a ACUTE OPHTHALMOPARESIS WITHOUT ATAXIA
month  acute onset of external ophthalmoplegia
 ~50% of patients reach the nadir of clinical function by 2  AO without ataxia is a mild form of FS
weeks and 80% by 3 weeks  also carry the anti-GQ1b IgG antibody
 flaccid weakness is ultimately present and varies considerably
in severity and distribution
ATAXIC GBS
 often is profound, involving all four limbs, the respiratory
 severe ataxia of the cerebellar type with no or minimal
muscles, and the face
ophthalmoplegia
 facial diplegia, or bilateral facial weakness, is seen in ~50%
 hyporeflexia or areflexia, distal paresthesias with CSF
of the patients
albuminocytological dissociation
 presence of anti-GQ1b IgG antibodies
ANTI-GM1 ANTIBODY
 patients are more likely to have axonal degeneration
 less sensory disturbance ACUTE OROPHARYNGEAL PALSY
 associated with severe neuropathy predominantly distal  characterized by oropharyngeal weakness without
distribution of weakness without sensory disturbance ophthalmoplegia and limb weakness
 presence of anti-GQ1b/ GT1a IgG antibodies
ANTI-GD1A ANTIBODY
 most specific for AMAN CHRONIC INFLAMMATORY DEMYELINATING
 associated with the need for prolonged artificial ventilation POLYNEUROPATHY
with poor recovery after 3 months  presence of anti-GD3 antibodies

ANTI-GA1NAC-GD1A ANTIBODY
OTHER MICROBIAL INFECTIONS CAUSING GBS
 also associated with AMAN
 Haemophilus influenzae
 associated with a rapidly progressive and more severe course
 Mycoplasma pneumoniae
with predominantly distal weakness, and little sensory or
 Cytomegalovirus
cranial nerve involvement
 affects younger groups, earlier course with high frequency
of respiratory insufficiency and often with CN involvement
ANTI-GM1B ANTIBODY
and severe sensory loss
 associated with a more rapidly progressive and more severe
 AIDP pattern
weakness
 less common cranial nerve and sensory involvement
 slower recovery DIFFERENTIAL DIAGNOSIS
 hysteria/ conversion reaction  critical illness
MILLER-FISHER SYNDROME  hexacarbons  poliomyelitis
 malingering  tranverse myelitis
 the Miller-Fisher syndrome triad
 diphtheria  myasthenic syndrome
 ophthalmoplegia
 brainstem infarction  focal compression
 ataxia
 drugs  myasthenia gravis
 areflexia
 (locked-in syndrome)  cauda equina lesions
 antecedent symptoms: upper respiratory symptoms such as
 Lyme disease  snake venom
sore throat
 vasculitis  sea urchin venom
 CSF protein is usually elevated, but the NCS findings are more
 rabies  hypermagnesemia
suggestive of axon loss then SD
 neuromuscular transmission  heavy metals, arsenic,
 associated with anti-GQ1b IgG
disorders thallium, gold
 generally a benign disorder and does not require specific
 enteroviruses  muscle disorders
immune therapy
 botulism  alcohol
 median interval: 10 days
 acute myelopathies  hypokalemia
 tick bite paralysis  organophosphates
GBS WITH PRESERVED STRETCH REFLEXES  peripheral neuropathies  hyperkalemia
 AMAN  acute intermittent porphyria
 Anti-GM1 IgG antibodies
 Anti-GD1 IgG antibodies EVALUATION
 routine hematologic studies are usually normal
BICKERSTAFF’S BRAINSTEM ENCEPHALITIS  the critical laboratory studies are:
 disturbance of consciousness, ophthalmoplegia, and ataxia  CSF analysis

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DEMYELINATING DISEASE
NEURO2 | Dr. Ruben Flores
03/12/2021, 10-12 NN

 NCS examination  improvement begins earlier in the course

CSF ANALYSIS  less mechanical ventilation is required
 increased protein concentration with a normal cell count  both ICU and hospitalization time is decreased
 considered one of the diagnostic finding s in GBS  must be instituted early during the disorder to be effective
 cytoalbuminologic dissociation (within the 1st week)
 no precise regimen though most have used
NERVE CONDUCTION STUDIES  150 to 120 ml/kg over 7-10 days of treatment
 assessment of one, or more often several, nerves show  the drawbacks
changes strongly suggestive of SD  expensive and invasive
 conduction block  rare complications such as hypotension and sepsis
 differential slowing  potential blood product exposures
 focal slowing
 these changes are much more apparent on motor NCS than IV Immunoglobulin Treatment
sensory NCS  advantages over plasmapheresis:
 simpler to administer
PREVENTION  costs slightly less
 drawback:
 there is no known prevention for sporadic GBS
 the transmission of viral infections, including HIV, is a
 whenever GBS occurs in epidemic form, its incidence may be
significant concern, because IVIg is made from plasma
reduced by improved public health measures
pooled from many donors

MANAGEMENT
Corticosteroids
 the treatment of GBS has two components:
 both corticosteroids, in conventional doses, and
 supportive care
adrenocorticotropic hormone (ACTH) are ineffective in the
 specific therapy
treatment of GBS
 supportive care remains the cornerstone of therapy
 ACTH is shown to be detrimental in some studies
 most patients recover function if they advance past the
 high-dose corticosteroids (?)
acute phase of the illness
 if shown to be effective, they will be very appealing
 the major reduction in deaths from GBS over the past few
treatment options compared with plasmapheresis
decades has been due to advances in supportive care
- relatively inexpensive and easy to administer
- particularly in mechanical ventilation
 potential serious complications
- bowel perforations
SUPPORTIVE CARE
- fulminant infections and sepsis
 patients with suspected GBS should be hospitalized, regardless
of how mild their disorder appears initially
PROGNOSIS
 rapid deterioration occurring over a brief period of time
 most patients are hospitalized for at least 1 month
can occur
 ~5% of patients die
 ICU admissions occurs in ~30% of GBS patients who are
 mortality rate of 15-20% in ICUs (ARDS)
hospitalized
 ~75% of patients recover without serious neurological
 patients must be assessed and monitored to avoid the major
sequelae, including
life-threatening complications of GBS
 bilateral footdrop
 respiratory failure
 intrinsic hand muscle weakness and wasting
 dysautonomia
 sensory ataxia
 venous thromboembolism
 burning dysesthesias

SPECIFIC THERAPY
 the specific treatment of choice for GBS since 1978 has been COMPLICATIONS
plasmapheresis
 beneficial in patients of all agents RESPIRATORY FAILURE
- only anecdotal reports, rather than large-scale studies  the most serious complication and most common
- some preliminary studies using intravenous  weakness of the respiratory muscles, particularly the
immunoglobulin (IVIg) treatment for GBS have diaphragm, is most often responsible
produced encouraging results  assessment of respiratory function
 neither therapy has shown beneficial effects either on mortality  arterial blood gas analysis
or relapse rates  bedside spirometry
 vital capacity measurements (most useful)
Plasmapheresis  generally, intubation is required whenever the vital capacity
 objective improvement in at least 50% of patients falls to 15 ml/kg

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DEMYELINATING DISEASE
NEURO2 | Dr. Ruben Flores
03/12/2021, 10-12 NN

DYSAUTONOMIA
 occurs more frequently and more severely in GBS patients with
respiratory failure and severe motor deficits
 difficult complications to manage include
 severe paroxysmal hypertension
 orthostatic hypotension
 various cardiac arrhythmias

OTHER COMPLICATIONS
 neurogenic bladder/ urinary tract infections
 gastrointestinal disorders
 bleeding secondary to stress ulcers and erosive gastritis
 ileus and fecal impaction
 hyponatremia
 usually in ventilated patients
 due to inappropriate releases of antidiuretic hormone
 responds to fluid restriction
 complications of protracted paralysis
 non-life-threatening complications
 pain and psychological trauma

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