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Demylinating Diseases

Multiple Sclerosis 
  • Pathophysiology: 
    • Etiology: Unknown
    • Pathological Pattern: Not uniform
      • Macrophage infiltration
      • Microgial Activation
      • Lymphocyte Infiltration
      • Demylination
      • Oligodendrocytes loss
      • Axonal Damage / or Loss
  • Phenotypic Pattern: Varies
    • Imaging
      • MRI: 
        • Focal T2 Flair in brain and / or spinal cord (common after age 40 and in patients with migraine)
        • Transient gadolinium enhancement of acute active lesions
        • Facal T1 hypodensity
        • Brain and Spinal Cord Atrophy
        • None of these findings are Pathognomic 
  • Clinical Course: varies in each individual case
    • Typical 
      • 1996 Lublin-Reingold Classification of MS phenotype 
        • Relapsing Remiteting 85% 
          • Often has Benign MS presentation
        • Secondary progressive 50+% 
        • Primary progressive 10%
        • Progressive relapsing 5%
          • Note: 
            • Benign MS vs Malignant MS 
              • both are not a phenotypic descriptions of MS
              • Benign often can be designated accurately only in retrospective
              • Use these terms with caution
      • 2014 Update of Lublin-Reingold Classification Neurology 2014
        • Clinical Phenotype of MS 
          • Note: 
            • Radiographically Isolated Syndrome is not an MS phenotype
              • Risk predictors
                • Spinal cord lesions
                • Gd+ lesions
                • More than 9 T 2 lesions 
                • Abnormal CSF 
          • Clinically Isolated Syndromee (is an MS phenotype)
          • Relapsing Remitting MS 
            • Often has Benign MS presentation
          • Secondary progressive MS 
            • Baseline begins to worsen with each attacks
          • Primary progressive MS
            • Often has Malignant MS presentation
        • Modifiers of the Basic MS Phenotype 

Neurology 2014 Table 1 defines what is active vs progressive disease

          • Assessment of Activity
            • CIS
              • Active
              • Not-active
            • RRMS
              • Active
              • Not-active
          • Assessment of Progression (Primary progressive vs Secondary Progressive)
            • Active and with Progression
            • Active but without progression
            • Not active but with progression
            • Not active and without progression (Stable Disease)
      • References: 

    • Atypical Variants
      • Marburg’s Fulminant MS: Fulminent tumor like lesions
      • Tumefactive MS : Tumor like lesions in a patient with MS
      • ADEM
      • Shilder’s disease
      • Balo’s Concentric Sclerosis 
  • DDx: 
    • Diagnosis of MS requires ruling out alternative diagnoses, and clinical judgment is often needed to decide what is or what is not an attack BMJ 2014
  • Clinical Features BMJ 2014
    • Visual loss in one eye 17%
    • Ascending Sensory disturbance or weakness 36%
    • Altered balance and gait 18% 
    • Double vision 13%
    • Acute Myelitis 6% 
    • Lhermitte's symptoms
  • Diagnosis
    • Dissemination in space
      • At least 1 T2 lesion in at least 2 or 4 locations considered characteristic for MS
        • Periventricular 
        • Juxtacortical
        • Infratentorial (NOT the symptomatic region)
        • Spinal cord (NOT the symptomatic region)
    • Dissemination in time
      • If initial baseline MRI has both an asymptomatic gadolinium enhancing lesion(s) and non enhancing lesions, then diagnosis can be made with single MRI after a single clinical episode e
    • 2005 McDonald Criteria
        • 60% Sensitivity
        •  88% Specificity
        • 77% Positive Predictive Value 
    • 2010 Revision of McDonald Diagnostic Criteria (Diagnose accurately and early) 
BMJ 2014 Table 1 
      • Relapsing Disease
        • Systemic, Adaptive Immune System Mediated
      • Progressive Disease
        • Widespread degenerative process mediated by Innate Immune System restricted to CNS
        • One year of disease progression Plus 2 of 3 criteria:
          • Brain MRI meeting MS criteria
          • Spinal cord MRI with 2+ lesions
          • CSF showing oligoclonal bands or elevated IgG index by isoelectric focusing 
      • Incorporated the single MRI to meet both diagnostic criteria for dissemination in time and dissemination in space
      • Applies for Typical Clinically Isolated Syndrom (CIS) or symptoms constant with typical demylinating disease
      • Note
        • Determines what workup you consider
        • Determines what treatment options are available
        • Predict prognosis
        • Reflects underlying pathophysiology 
      • References
    • Treatment

Clinically Isolated Syndrome
  • DDx: 
    • Stroke
    • Infection
    • Tumor
NMO Spectrum Illness (NOT MS any more; its a NEW entity) or Devic's Syndrome or NMO
Misc: MS Charcot Triad
    • Nystagmus
    • Scanning Speech
    • Intention Tremor
Case Based Learning 

51 yo F with DM, HTN, HLD presented for AMS. Details of history not known.  MRI shows the following. Unclear of diagnosis of MS. LP is done. No inflammatory cells, or oligoclonal band is seen. Working diagnosis is microvascular disease. 

CPK, Lactic Acid is elevated on admission. HIV is negative. B12 level is normal. MMA and Homocystein is not checked. 

What is the DDx. 



Further work up reveals absence of proteinuria, and retinopathy. 
MMA and Homocysteine, 


Autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL):  osmiophilic material accumulates between the smooth-muscle cells

MS: including the relatively rapid onset of symptoms, a relapsing–remitting course, fatigue, depression, HA, ocular symptoms, autonomic dysfunction, evidence of brainstem or cerebellar symptoms (including slurring of speech), seizure-like activity. Higher cortical features may be spared early in the disease, but may be affected later in the days; female predominance; On MRI, lesions primarily affecting the white matter of the brain and spinal cord are found; corpus callosum is commonly affected; lesions may or may not enhance with contrast; CSF is normal mostly except for mild elevation of protein, Oligoclonal Bands, and leucocytes, mostly Monocytes; Visual or auditory evoked potential; 

Other Demylinating disease

B12 Deficiency


Lyme Disease: Affects CNS in 15 % of the time; this diagnosis should always be considered if white mater lesions are present; B/L CN VII is the key feature; Lymphocytic meningitis can occur; painful radiculitis can occur; rarely focal encephalomyelitis or myelopathy can occur. 

HIV: progressive apathy, depression, psychomotor retardation, and memory loss can occur; There is often focal subcortical involvement, with infection of macrophages in the subcortical white matter and the basal ganglia.

Maligancy: glioma (Gliomas can in- filtrate the corpus callosum) or a lymphoma (Lymphoma of the central nervous system tend to affect the deep structures, including the corpus callosum) 

MELAS: typically begin before 40 yr but can occur after that; encephalomyopathy, seizures, and dementia often occur with headaches and vomiting; DM is frequently seen; Stroke affect cortical and sub-cortical white matter, but do not confer the vascular area; 

Case 36-2005: A 61-Year-Old Woman with Seizure, Disturbed Gait, and Altered Mental Status (DDx of MELAS)

Migraine: White-matter abnormalities called “unidentified bright objects” are associated with migraine; The number of white-matter abnormalities in- creases with an increasing frequency of migraines; 

Cerebral Vasculopathies 

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy: Subcortical ischemic strokes, particularly in the anterior temporal lobes, begin in the fifth or sixth decade, often in the absence of traditional vascular risk factors; Psychiatric symptoms, dementia, and migraine headaches are common; MRI shows multiple subcortical infarcts, with diffuse leukoencephalopathy; 

Cerebral Vasculitis: 

Susac’s syndrome, also known as retinoco- chleocerebral vasculopathy, is a microangiopathy that affects the brain, retinal arteries, and cochlea, causing headaches, personality changes, dementia, bilateral branch retinal artery occlusions, and deaf- ness. It occurs predominantly in women 20 to 40 years of age and is thought to be immune-medi- ated. Chronic lesions, described as “snowball le- sions,” can be confluent and can affect large areas of the corpus callosum; Patients with primary angiitis of the central nervous system have an elevated erythrocyte sedimenta- tion rate, a characteristic angiographic appearance, and evidence of inflammation in the cerebrospinal fluid; 

Binswanger’s disease, or subcortical leukoencephalopathy : progressive subcortical white-matter disease associated with progressive cognitive and motor decline; 4th - 7th decade; HTN; small discrete infarcts and larger areas of diffuse and incomplete infarction and demyelination with thickening and hyalinization of arterioles

Lacunar infarcts are deep white-matter infarcts, typically less than 15 mm in diameter, that are due to occlusion of a penetrating artery; The occlusion may be caused by multiple processes, most commonly hypertension, diabetes, advanced age, ischemic heart disease, and cigarette smoking;