CHAPTER OUTLINE

Despite the significant advances seen in laboratory and imaging diagnostics, many of the conditions seen by neurologists are still diagnosed on purely clinical grounds. In neurology, there remains no substitute for a meticulous clinical history and careful examination.

Neurological investigations include all imaging modalities, neurophysiological tests of both the central and peripheral nervous system, and laboratory based investigations, including haematology, biochemistry, immunology, histopathology and cytology. This chapter will focus on the neurological conditions for which biochemical abnormalities are pertinent. Separate chapters cover the biochemistry of cerebrospinal fluid and muscle disease and other conditions that overlap with general neurological practice.

‘Encephalopathy’ is a term for any diffuse disease of the brain that alters brain function or structure. It is a common condition that encompasses coma, acute confusional state, delirium and dementia. The hallmark of encephalopathy is an altered mental state.

For patients presenting with altered consciousness, a detailed history often has to be taken from family, friends and other healthcare professionals, to determine pre-existing medical conditions and time of onset of altered mental state. For example, patients presenting with altered consciousness following apnoea or cardiac arrest are likely to be suffering from a hypoxic–ischaemic encephalopathy but alternative causes need to be excluded. Access to medication, previous psychiatric problems or use of illicit drugs may suggest intoxication. If the patient is known to have diabetes, hypo- or hyperglycaemia is likely. Patients on diuretics are at risk of hyponatraemia.

Both a general systemic examination and detailed neurological examination are required to determine the cause of encephalopathy. Specific breath smells suggest certain causes, e.g. ammonia-like (uraemia); fruity-smelling (ketoacidosis); musty or fishy (acute hepatic failure); onion (paraldehyde), and garlic (organophosphates). Hypertension may indicate amfetamine or cocaine intoxication or a hypertensive encephalopathy. Examination of the skin may show signs of chronic liver disease, haemodialysis fistula, previous sternotomy scars from cardiac surgery or injection marks from intravenous drug use.

Other global neurological signs include generalized seizures, tremor, asterixis (abnormal jerking tremor in hands seen in liver flap) and myoclonus (involuntary brief jerk-like twitching, often multifocal). Focal signs indicate a localized problem within one part of the brain, for example visual or language disturbance from cerebral cortex pathology or eye movement disturbance, slurred speech or swallowing problems from brainstem pathology. Focal neurological signs usually suggest a primary neurological cause of encephalopathy.

This colourless and odourless gas is the most common cause of accidental poisoning in Europe and North America, as well as being a major cause of suicidal deaths. When 20–30% of total haemoglobin is bound to carbon monoxide, it causes headache, nausea and shortness of breath; when 50–60% is bound, coma results. Carbon monoxide exposure is detected by measuring the carboxyhaemoglobin concentration in blood. Carbon monoxide poisoning is treated with oxygen, using hyperbaric facilities in severe cases, if available.

Alcohols, including ethanol, produce an altered mental state by central nervous system depression. Methanol and ethylene glycol similarly cause direct central nervous system depression but are also toxic via metabolism in the liver to formic acid (methanol) and glycolic and oxalic acids (ethylene glycol).

Methanol and ethylene glycol concentrations can be measured in the blood but usually the suspicion is raised by other biochemical abnormalities. Poisoning with either causes a high anion gap metabolic acidosis. Treatment is by blocking the action of alcohol dehydrodenase with ethanol or fomepizole to decrease the production of toxic metabolites.

Overdose causes coma, pinpoint pupils and respiratory depression. This can be from iatrogenic, accidental or suicidal overdose (e.g. morphine) or from use of illicit drugs (e.g. heroin). Diagnosis is usually suspected from the clinical triad but a rapid urine screening test can confirm opioid exposure. Treatment is with naloxone, given as a bolus dose followed by an infusion if the patient responds, in addition to supportive care.

Wernicke–Korsakoff encephalopathy is a clinical triad of confusion, ataxia and ophthalmoplegia (eye movement disorder). It comprises two syndromes. First, Wernicke encephalopathy, an acute or subacute confusional state with ataxia and ophthalmoplegia and second, Korsakoff dementia, characterized by severe amnesia and confabulation. The former is often reversible but the latter is irreversible and persistent. Wernicke–Korsakoff encephalopathy is caused by thiamin deficiency and is most commonly seen in alcoholics but can also occur in patients with anorexia, hyperemesis gravidarum, those receiving total parenteral nutrition, or in the context of malabsorption and refeeding syndrome. The role of measurement of plasma thiamin concentrations in diagnosis and monitoring remains controversial and functional assessment by assay of red cell transketolase is no longer used by most laboratories for diagnosis. Therefore, laboratory tests are aimed at excluding other conditions and providing evidence of risk factors (e.g. macrocytosis and deranged liver function tests in alcoholism). Brain magnetic resonance imaging (MRI) can show signal change in the thalami, mammillary bodies, tectal plate and periaqueductal grey matter. Treatment is with parenteral thiamin. In the UK, normal practice is to give thiamin in a vitamin complex of riboflavin, nicotinamide, pyridoxine and ascorbic acid. Early treatment can reverse the symptoms rapidly and prevent dementia. Administration of intravenous glucose (including as part of parenteral nutrition) to patients who are severely malnourished, can exhaust their (already depleted) supply of thiamin and precipitate Wernicke–Korsakoff encephalopathy. Thiamin should therefore be administered before starting a glucose infusion in patients at high risk.

Hypoxic–ischaemic encephalopathy is caused by hypoxaemia and/or reduced blood flow to the brain from failure of the cardiac system, the respiratory system or both (e.g. myocardial infarction, drowning). When cerebral perfusion pressure falls, there is a failure of autoregulation leading to ischaemia and hypoxia and to cell death by both necrosis and apoptosis. The diagnosis is usually evident from the history. Myoclonus is common (Lance–Adams syndrome). There is a wide spectrum of clinical outcomes depending on the degree and duration of the insult from full recovery to severe prolonged disability and death.

Severe extracranial infection can be associated with an impaired mental state. The pathophysiological mechanism involves reduced cerebral blood flow and oxygen extraction by the brain, cerebral oedema, disruption of the blood–brain barrier owing to inflammatory mediators acting on the cerebrovascular endothelium, and abnormal neurotransmitter compositions. Diagnosis of sepsis can be aided by the finding of a raised white blood cell count and raised inflammatory markers, and by blood cultures. Treatment is of the underlying infection with supportive care.

Hashimoto encephalopathy presents with seizures, behavioural and psychiatric manifestations, movement disorders and coma and is associated with the presence of high titres of anti-thyroglobulin or anti-thyroid peroxidase (TPO, antimicrosomal) antibodies. The condition can present without any features of thyroid disease. It is unclear whether the anti-thyroid antibodies are pathogenetic or simply represent an immune epiphenomenon but it is important not to miss this diagnosis as the condition responds to treatment with steroids.

Folate deficiency is usually associated with other nutritional deficiencies. Folate antagonists (e.g. methotrexate, trimethoprim and pyrimethamine) are also potential causes. Neurological manifestations are rare and the same as with vitamin B₁₂ deficiency. Treatment is by folate replacement, although any vitamin B₁₂ deficiency should be treated first to prevent exacerbation of spinal cord degeneration.

Copper deficiency is rare and causes both haematological and neurological disease. Neurological manifestations include myelopathy, peripheral neuropathy and optic neuropathy. Copper deficiency was recognized in ruminants (swayback disease) long before it was identified in humans. The presentation can be similar to that of subacute combined degeneration of the spinal cord. It is usually secondary to gastric surgery, gastrointestinal diseases or total parenteral nutrition, or to excess intake of zinc or iron, which reduce copper absorption in the gut. Copper deficiency myelopathy has been attributed to ingestion of zinc contained in denture cream in some patients. Treatment is with oral or intravenous copper replacement.

Hepatic myelopathy is a rare complication of chronic liver disease. It has been suggested that it is caused by the neurotoxicity of ammonia or other metabolites bypassing normal liver metabolism. It is characterized by spastic paraparesis with minimal sensory and sphincteric involvement. Diagnosis is a process of exclusion requiring normal CSF analysis and brain imaging. Liver transplantation may result in improvement, especially if performed early in the course of the disease.

This is a progressive neurodegenerative disease with variable age of onset and rate of progression and hence variable prognosis. The clinical presentation of the chronic form of hexosaminidase A deficiency may mimic spinocerebellar degeneration, Friedreich ataxia, or amyotrophic lateral sclerosis (see below).

This is the commonest clinical variant of adrenoleukodystrophy, a disorder of peroxisomal fatty acid oxidation causing the accumulation of very long chain fatty acids in myelin, adrenal cortex and Leydig cells of the testes. Patients with an adrenomyeloneuropathy presentation of this X-linked recessive disorder present in their third decade with a progressive spastic paraparesis and sphincter dysfunction. A sensorimotor peripheral neuropathy may be a feature and ataxia and dementia are seen occasionally. Adrenal insufficiency will often have been present since childhood and there may be hypogonadism. Around 50% of heterozygous females will show some symptoms later in life. The clinical findings and magnetic resonance imaging point to the diagnosis, which is confirmed by demonstrating hypoadrenalism and elevated concentrations of very long chain fatty acids (VLCFAs) in plasma and cultured skin fibroblasts. Genetic testing is available. The only gene in which mutations are known to cause adrenoleukodystrophy is ABCD1, which codes for a peroxisomal membrane transporter protein, although molecular genetic testing is rarely required to confirm the disease, especially in a male. Treatment is with steroid replacement, symptomatic management and supportive care.