1. Demyelinating, Metabolic & Degenerative Diseases of the CNS

2. Demyelinating diseases of the CNS
Acquired diseases characterized by:
Preferential damage to myelin
Relative preservation of axons
Reduced impulse conduction
Later in the Natural History secondary damage to axons may occur
Remember: the CNS has limited capacity to regenerate myelin

3. Mechanism of Demyelination Self-study
The upper part of the figure depicts a neuron with a myelinated axon. At the right corner, the neuron is magnified and cut in cross section, demonstrating the concentric lamellar structure of myelin.
The middle of the figure shows a neuron with a myelinated axon forming a synapse with another neuron. Two oligodendrocytes are shown; each cell myelinates multiple segments of more than one axon.
The bottom neuron has been partially demyelinated, and it is surrounded by T cells, which secrete inflammatory cytokines (interleukin-2 [IL-2], interferon gamma [IFN-and tumor necrosis factor- [TNF- ]), and by macrophages, which are stripping myelin from the axon.
The macrophages contain myelin debris in phagocytic vacuoles. Conduction in the demyelinated axon is blocked.
A blood vessel shows T cells adhering to the lumen and crossing from the vessel into the brain.

4. Effect of Demyelination on Nerve Conduction
Demyelination reduces the Velocity of Nerve conduction
Axonal degeneration reduces the Amplitude of Nerve conduction
Normal Amplitude - Low Velocity
Normal
Normal Velocity – low amplitude
Time in Milliseconds

5. Multiple Sclerosis (MS)
Autoimmune demyelinating disease
Distinct episodes of neurologic deficits Separated in
Time (the episodes)
Space (the white matter lesions)
Remember:
You need Two separate Episodes that affect Two different areas of the CNS to clinically diagnose MS

6. Multiple Sclerosis (MS) – Features
The Most common disease in this category
Risk higher as one moves away from Equator
1/1000 persons (US, Europe); Rare in Asians
Age: 20 to 50 years (peak = 30); rare in children
Gender: Women twice as men
Relapsing and remitting episodes are typical
Gradual, partial recovery of neurological function
Intervals: weeks to months

7. M S – Pathogenesis
Cellular immune response against components of myelin
Influenced by genetic/environment
Risk 15x if present in 1st degree relative
Risk 50x for monozygotic twins
Genetic linkage to HLA DR2

8. M S – Pathogenesis

9. M S – Pathogenesis
Initiated by reaction of CD4+ TH1 against self myelin Ag
due to microbial triggers?
susceptibility genes?
Secretions of cytokines (e.g. IFN-gamma)
Activation of Macrophages  damage to myelin

10. MS – Morphology Macro: Well circumscribed, irregular tan-gray plaques
Firmer consistency than surrounding white matter (sclerosis)
Microscopic foci to confluent & large

11. M S – Location of plaques
Commonly beside lateral ventricles
Also frequent in:
Optic nerve and chiasm
Brainstem tracts
Cerebellum
Spinal cord

12. M S – Histopathology Sharply defined lesions
Abundance of inflammatory cell (mainly Ma with PAS+ debris) especially around blood vessels (perivascular cuffs) and at the outer edge of the lesion
Depletion of myelin (illustrated by LFB stain)
Preservation of axons
Depletion of oligodendrocytes

14. M S – Clinical course Wide range of clinical manifestation
Certain patterns more common
Optic neuritis (Retro-Bulbar neuritis):
Frequent initial manifestation
Unilateral visual impairment
10-50% develops MS (after the 1st episode)
MS variants:
Neuromyelitis Optica (Devic Disease)
Acute MS (malignant MS; Marburg variant)

15. Neuromyelitis Optica (Devic Disease)
Especially Asians
Presents as:
Bilateral optic neuritis
Prominent spinal cord involvement
Three clinical forms:
Rapidly progressive
Relapsing-Remitting
Single episode
Plaques appear more destructive
Eugene Devic ( )

17. Encephalomyelitis Acute disseminated encephalomyelitis (ADEM)
Monophasic demyelinating disease
Followed a week or two after:
Viral infection
Viral immunization (rarely)
Acute necrotizing hemorrhagic encephalomyelitis (ANHE)
Fulminant syndrome of CNS demyelination
Children and young adults
Preceded by URTI (e.g. Mycoplasma Pneumoniae)
Usually fatal

18. ADEM – Clinical Features
Diffuse (Not Focal) brain involvement
Headache
Lethargy
Coma
20% rapid progression & death
80% complete recovery

19. Other causes of Demyelination
Nutritional / metabolic
Machiafava-Bignami disease
(in alcoholics)
subacute combined degeneration
In Vit B-12 deficiency
central pontine myelinolysis
Complication after severe burns
Toxic
Others - HIV-1 myelopathy

20. Subacute Combined Degeneration
In subacute combined degeneration this is caused by vitamin B12 deficiency.
Similar demyelination pattern can be found in HIV-1 myelopathy (the cause in this demyelination is unknown)
Symptoms & Signs
Tingling
Numbness
Paresthesias
Unsteady gait
loss of vibration sense
loss of position sense
Leg weakness &
Pyramidal signs

21. Uncommon Diseases
Leukodystrophies are Inherited disorders of myelin synthesis & turnover
PML (progressive multifocal leukoencephalopathy)
Due to JC virus infection of oligodendrocytes
Results in loss of myelin

22. Inherited Demyelinating diseases
Secondary to a genetic defect in various metabolic and biochemical pathways
Breakdown of abnormal or immature myelin
Peripheral nervous system myelin involved in some of these disorders
Mostly pediatric, although adult forms exist

23. Inherited demyelinating diseases: 2 Examples
Metachromatic leukodystrophy
caused by a deficiency of the enzyme arylsulfatase A.
MLD is a lipid storage disease, resulting in the toxic build-up of lipids in cells in the nervous system, liver, and kidneys.
Symptoms: muscle wasting & rigidity, developmental delays, loss of vision, convulsions, paralysis, and dementia
Spongiform leukodystrophy
caused by a deficiency of the enzyme acetylaspartase
aspartate builds up in the neurons
accumulation of the aspartate in the white matter  leads to increased osmotic pressure there with consequent drawing of water & damage
Symptoms (Start in Infancy): mental retardation, feeding difficulties, abnormal muscle tone, poor head control, and abnormally enlarged head. Later – paralysis, blindness, or hearing loss

24. Acquired Metabolic Disorders

25. Acquired Metabolic Disorders – Classification with Examples
syndrome of confusion, stupor, or coma
Hypoglycaemia
Hypoxia / Hypercapnia
Hepatic Encephalopathy
Azotaemia
psychosis or dementia
Cushing disease and steroid encephalopathy
Hyperthyroidism
Hypothyroidism
progressive extra-pyramidal syndrome
Hyperbilirubinemia and kernicterus
cerebellar ataxia
Hypothyroidism

26. Degenerative Diseases of CNS
Lastly,
Degenerative Diseases of CNS

27. Degenerative Diseases
Two outstanding characteristics:
(1) selective involvement of anatomically and physiologically related systems of neurons
(2) begin insidiously and worsen gradually over many years, often a decade or longer

28. Syndromic Classification - 1
progressive dementia
Alzheimer disease
progressive dementia with other signs
Huntington chorea
“Parkinson’s Plus”
disordered posture and movement
Parkinson disease
Familial tremors
progressive ataxia
Spinocerebellar ataxias (early onset)
Friedreich ataxia
Cerebellar cortical ataxias
muscular weakness & atrophy (slow onset)
motor system disease

29. Stephen Hawking - A famous Scientist with Motor system disease

30. Syndromic Classification - 2
Hereditary neuropathies
peroneal muscular atrophy
progressive blindness or ophthalmoplegia
retinitis pigmentosa
Progressive external ophthalmoplegia
neurosensory deafness
Hereditary hearing loss

31. Thank You !