Differential Diagnosis in Neurology

4.6. Enzyme and Metabolic Disorders Affecting the Spinal Cord

• Metachromatic leukodystrophy
• Krabbe's Disease
• Hyperlysinemia
• Pyruvate dehydrogenase deficiency (complex IV mtDNA)
• Leigh's Disease (COX deficiency complex III)

Homocarnosinosis

• General considerations:
  • AR
  • Abnormalities of histidine metabolism
  • Lack carnosinase activity
• Clinical features:
  • Spastic paraparesis
  • Mental retardation
  • Increased homocarnosine in the CSF

Abnormal Vitamin B12 Binding Protein

• General considerations:
  • Abnormal plasma vitamin B12 binding protein
  • High serum B12 level
  • Low CSF S-adenosylmethionine level
  • Low RBC B12 level
• Clinical features:
  • Spasticity of all extremities
  • Subacute combined posterior and corticospinal tract signs and symptoms

Combined System Degeneration (Corticospinal Tract and Posterior Column) after Nitrous Oxide Anesthesia

• General considerations:
  • Nitrous oxide anesthesia precipitates acute B12 deficiency
  • Cobalamin CO²⁺ inactivated to CO³⁺
  • Methyl cobalamine is a Co-factor for methionine synthetase; failure of conversion of homocysteine to methionine
• Clinical features:
  • Combined posterior and lateral column degeneration
  • Approximately six hours of exposure is required for those that are not B12 deficient prior to exposure; symptoms may appear 2–6 weeks after exposure

B12 Deficiency

• General considerations:
  • Multiple mechanisms are causative:
    • Malabsorption of B12 due to lack of intrinsic factor most commonly
    • 5 mcg is needed per day
    • Antibodies to gastric parietal cells may accompany all autoimmune diseases
    • May occur from tetrahydrobiopterin deficiency and B12 activator deficiency
    • The biochemical reactions that depend on B12 are:
      • Folate-dependent reaction that transfers a methyl group from methyltetrahydrofolate to homocysteine that produces methionine
      • Homocysteine to methionine reaction (methionine synthase required; cobalamin is a cofactor). Reduced cofactor activity leads to decreased DNA synthesis
    • Spongy degeneration with both myelin and axon destruction are seen in both the central and peripheral nervous system
• Clinical features:
  • Paresthesias with primarily large fiber greater than small fiber neuropathy
  • Dorsal column demyelination with loss of position, light touch and vibration sensitivity
  • Demyelination of subcortical frontal white matter that leads to frontal lobe personality charge
  • Loss of smell
  • Optic neuropathy
  • Cerebellar ataxia
  • Spasticity
  • An extremity that may be wasted with loss of sensation but has hyperactive reflexes
  • Absent reflexes in the ankle with pathological hyperactive reflexes at the knee and in the upper extremities

Selected Toxins Affecting the Spinal Cord

Lathyrism

• General considerations:
  • Consumption of the unripe chick pea or grass pea (Lathyrus sativus)
  • Contaminate; used instead of cereals or lentils during periods of great economic stress; need 15–150 mg/day for toxicity
  • Toxin: Beta-N-Oxolamine-L-Alazanine (BOAS)
• Clinical features:
  • Onset during the first four decades
  • Sudden onset of heaviness and leg weakness
  • Subacute onset over months can occur
  • Stiffness in lower extremities – 70%
  • Leg cramps – 50%
  • Paresthesias – 30%
  • Urinary symptoms – 5%
  • Nocturnal erections; ejaculations; urinary urgency may occur
  • Symmetrical spasticity; ankle clonus
  • Mild lower extremity weakness
  • Babinski sign is present; sparing of superficial reflexes (abdominal; cremasteric)
• Laboratory evaluation:
  • EMG:
    • Slow sural nerve conduction velocity; denervation of lower extremity muscles

Nitrous Oxide

• General features:
  • Used as dental anesthetic and food propellants; abused as euphoric
  • Neuropathy and myelopathy occurs must frequently in B12 deficient patients
  • Mechanisms of pathology may be methionine synthetase inhibition
• Clinical presentation:
  • Initial systems are numbness of the distal arms and legs with poor finger dexterity; leg weakness and gait imbalance
  • Early stage of the neuropathy is accompanied by depressed reflexes impairment of fibration and pain sensibility
  • Lhermitte's sign may be noted
  • Severe intoxication causes lower extremity spasticity, severe loss of vibration, pain and position sensibility, hyperreflexia and Babinski signs are noted

Konzo

• General considerations:
  • Occurs in West Africa
  • Cyanide toxicity
• Clinical features:
  • Optic atrophy
  • Spastic paraparesis

Ethylene Oxide

• General considerations:
  • Used in gas sterilizations; operating room packs
• Clinical features:
  • Generalized spasticity

Subacute Myelo-Optic Neuropathy

• General considerations:
  • Caused by ingestion of outdated tetracycline
  • Major epidemics in Japan and Mexico
• Clinical features:
  • Optic neuritis
  • Spasticity from spinal cord involvement

Metabolic Causes of Spinal Cord Dysfunction

Hyperparathyroidism

• General considerations:
  • Occurs with primary and secondary hyperparathyroidisms (usually renal failure)
• Clinical features:
  • Proximal muscle weakness, fatigue and cramps
  • Rarely a fibrillating tongue has been noted
  • Rare urinary frequency
  • Severe hyperreflexia arms greater than legs
• Laboratory evaluation:
  • Erosion of the radial side of the index finger and the acromial head of the clavicle
  • EMG: neurogenic

Hyperthyroidism (Davidoff Syndrome)

• General considerations:
  • Syndrome is seen in the face of severe hyperthyroidism
• Clinical features:
  • Spastic paraparesis
  • Ophthalmoplegia
  • Babinski signs are present

Portocaval Shunt

• General considerations:
  • The spinal cord features are usually seen in a setting of severe liver failure
  • Hyperammonia is the rule; neurological features have been seen with normal ammonia levels
• Neurological features:
  • Relapsing intermittent encephalopathy
  • Spastic paraparesis
  • Generalized hyperreflexia
• MRI demonstrates
  • Increased T2 weighted signal in the caudate and putamen

Liver Failure

• General considerations:
  • Neurological features are seen from hepatic failure from all causes
  • Swelling of Alzheimer type II glia in the brain with increased intracranial pressure
  • MRI findings of increased signal on T2 weighted images (caudate and putamen)
• Neurological features:
  • Clinical stages:
    • Acute I:
      • Personality change (active psychosis)
      • Acute increased intracranial pressure
      • Reye's syndrome (increased ICP, vomiting, low glucose, decortication)
    • Subacute stage II:
      • Brainstem involvement
      • Reversible decerebration
      • Spasticity of all extremities
      • Pupils < 1 mm but are reactive to light
      • Babinski signs are present
    • Stage III:
      • Coma
      • Fetor hepaticus
      • Failure of Doll's eye and ice-water calorics
• Laboratory evaluation:
  • Increased serum ammonia may be the best clinical correlation; increased CSF glutamine occurs
• Pathology:
  • Increased prominence of Alzheimer type II glia

Cardiac Arrest and All Forms of Anoxia

• General considerations:
  • The following structures of the neuraxis are the most vulnerable to lack of oxygen:
    • Sumner's sector V of the hippocampal formation
    • Cortical layers III–V that receive thalamic projection
    • Purkinje cells of the cerebellum
    • Globus pallidus interna cells (GP)
    • Cranial nerves of the brainstem (particularly V in children)
    • Peripheral nerves
• Clinical features of spinal cord anoxia:
  • Severe rigidity of the extremities
  • Selective death of Renshaw cells (decreased glycine)
  • Loss of inhibitory interneurons of the spinal cord (GABAergic B cells)
  • Clinical spinal cord findings are over shadowed by deficits from other areas of the CNS