Metabolic and demyelinating disorders

(I) Adrenoleukodystrophy: It is a X-linked disorder characterized by accumulation of very long chain fatty acids or VLCFAs in peroxisomes. There is a defect in beta oxidation of VLCFAs which leads to immune mediated destruction of myelin causing cerebral demyelination, peripheral neuropathy, adrenocortical and testicular insufficiency. Clinical manifestations are seizures, spastic tetraplegia, dementia, hyperactivity and features of Addison’s disease features. Most cases present in childhood. Characteristically, lamellar cytoplasmic inclusions are seen in brain macrophages, Schwann cells, Leydig cells, and adrenocortical cells. These lamellar inclusions consist of cholesterol esterified with VLCFAs. Periventricular demyelination is seen in the occipital region .

(II) Metabolic encephalopathies: They are caused by the effects of systemic illnesses on the brain causing impaired cerebral metabolism. Common causes are as follows:

Common causes of metabolic encephalopathies

• Hypoglycemia
• Ischemia
• Hypoxia
• Hypercapnia
• Vitamin deficiency like Vit B1 or thiamine
• Hepatic encephalopathy
• Uremia
• Renal failure
• Drug adverse effects and alcohol
• Infective causes
• Sepsis
• Electrolyte imbalances like hyponatremia

Functions of the neocortex and ascending reticular activating system from the brainstem are affected leading to change in the level of consciousness which may present as confusion, altered sensorium, small pupils, slow respiration, asterixis (flapping tremor), seizures and coma.

(III) Multiple sclerosis or MS: It is a chronic, inflammatory and demyelinating disease of the CNS. It is more common in women of Northern European ancestry. It is caused by a combination of factors such as genetic predisposition combined with previous viral infection and/or environmental triggers that lead to autoimmune attack and destruction of myelin sheath and oligodendrocytes. Previous infections with EBV, HHV 6, Chlamydia pneumoniae and HLA DR2 increase the risk of MS. It can be either type IV or type II hypersensitivity. Some studies have found that patients suffering from MS are deficient in linolenic acid.

Types of MS

MS is diagnosed on the basis of at least two different lesions like white matter plaques plus at least two different episodes in the disease course plus laboratory evidence of chronic CNS inflammation. On biopsy, multiple, discrete pink or gray areas are seen with a rubbery texture, showing loss of myelin and oligodendrocytes and an inflammatory exudate containing CD4+ T cells. Axons and neurons are preserved. Clinical features include sensory disturbances like tingling-numbness, “pins and needles” sensation,fatigue, diplopia, vertigo, tremors, ataxia, numbness in limbs, optic neuritis and bladder incontinence and constipation. Babinski sign is positive and internuclear ophthalmoplegia may be present due to demyelination of the medial longitudinal fasciculus. CSF shows normal glucose, increased proteins especially gamma globulins and MBP or myelin basic protein and increased CD4+ T cells. CSF electrophoresis shows oligoclonal bands.

(IV) Central pontine myelinolysis (CPM): It is characterized by myelin destruction in the pons following rapid correction of hyponatremia. It presents 2-3 days after the correction of hyponatremia as altered sensorium, dysarthria, dysphagia followed by flaccid and later spastic quadriplegia and in severe cases by “locked-in syndrome”, coma and death. Malnourished and alcoholic individuals are at greater risk of CPM. Microscopically the lesion shows degeneration and loss of oligodendrocytes with preservation of axons. Rapid correction of hyponatremia causes the neurons to shrink and damages the blood-brain barrier which causes osmotic stress, activation of plasminogen, proteases and cytokines, which lead to oligodendrocyte loss and demyelination.

(V) Guillain-Barre syndrome (acute inflammatory polyneuropathy or post-infective polyneuritis or GBS): It is a rapidly progressive, autoimmune polyneuritis that typically follows an infection of the gastrointestinal or respiratory tract. Common pathogens associated are Mycoplasma pneumoniae, Campylobacter jejuni, HIV, EBV, CMV, Zika, HEV and influenza viruses. It presents as a bilateral ascending paralysis described as weakness in the feet that spreads up to involve the arms and trunk, tingling, “pins and needles” sensation, numbness, muscle pain and in severe cases by respiratory paralysis and difficulty swallowing. “Glove and stocking” paresthesias are seen. Autonomic imbalances like pulse and blood pressure variations and arrhythmias may occur. Deep tendon reflexes are lost. Molecular mimicry or sharing of epitopes in myelin or Schwann cell membrane, with antecedent infective agents leads to autoimmune response to peripheral nerves. Myelin loss from Schwann cells and axons of peripheral nerves is seen. CSF examination shows albuminocytologic dissociation meaning increased CSF protein with normal cell count and normal glucose levels.