Often occurs in epidemics where the organism is carried in the nasopharynx. Septicaemia can occur with arthralgia; purpuric skin rash. When overwhelming, confluent haemorrhages appear in the skin due to disseminated intravascular coagulation.

Predominantly an adult disorder. Often associated with debilitation, e.g. alcoholism.

May result from pneumonia, middle ear, sinus infection or follow splenectomy. Onset may be explosive, progressing to death within a few hours.

Outcome

Generally good

Less than 5% mortality.

Gradual onset – good prognosis.

Sudden onset with septicaemia – poor outcome.

Overall mortality − 10%.

Mortality − 20%.

Poor prognostic signs – coma, seizures, increased protein in CSF.

Neonates (above 1 month)

– ampicillin, + aminoglycoside and cephalosporin

Children (under 5 years)

– vancomycin + 3rd generation cephalosporin

Adults

– vancomycin + 3rd generation cephalosporin

Immunocompromised patient

– vancomycin + ampicillin + cephalosporin

Steroids

A four-day regimen of dexamethasone, starting before or with the first dose of antibiotics, is now recommended in children with haemophilus and adults with bacterial meningitis likely to be pneumococcal. Meta-analysis found a risk reduction of neurological sequelae and mortality of about 30% in pneumococcal meningitis, with no clear difference with other organisms.

Therapy after organism identification

ORGANISM	ANTIBIOTIC	ALTERNATIVE THERAPY
Haemophilus	Ampicillin or 3rd generation cephalosporin according to sensitivities	Chloramphenicol Fluoroquinolone Cefepime

Pneumococcus Benzylpenicillin or 3rd generation cephalosporin according to sensitivities

Chloramphenicol

Fluoroquinolone

Meropenem

Meningococcus Benzylpenicillin or 3rd generation cephalosporin according to sensitivities

Chloramphenicol

Fluoroquinolone

Meropenem

E. coli 3rd generation cephalosporin Aztreonam, fluoroquinolone, meropenem, ampicillin Listeria

Duration

Pneumococcus – continue for 10–14 days after afebrile

Monitoring

In a deteriorating patient, CT scan will exclude the development of hydrocephalus, abscess or subdural empyema. In suspected sinus thrombosis MR venography may be required.

Remove any source of infection, e.g. mastoidectomy or sinus clearance.

In meningococcal meningitis the risk to household contacts is increased (500–800x) and chemoprophylaxis should be offered – rifampicin 600 mg b.d. for 48 hours. Vaccines are also available.

Meningitis/CSF shunts

Meningitis infection may follow CSF drainage operations for hydrocephalus. This may occur in the immediate postoperative period or be delayed for weeks or months. Clinical features of raised intracranial pressure may coexist due to shunt blockage. Bacteraemia is inevitable and blood cultures identify the responsible organism – usually Staphylococcus albus. The infection seldom resolves with antibiotic therapy alone and shunt removal is usually required.

BACTERIAL INFECTIONS – CNS TUBERCULOSIS

Tuberculosis is an infection caused in man by one of two mycobacteria – Mycobacterium tuberculosis and Mycobacterium bovis. The disease involves the nervous system in 10% of patients.

– which may obstruct the basal cisterns and result in hydrocephalus.

– Vasculitis

– secondary to inflammation around vessels, resulting in infarction of brain and spinal cord.

The basal meninges are generally most severely affected.

Clinical features

The majority of patients are adults; childhood TBM is now rare. Non-specific prodromal symptoms develop over 2–8 weeks.

Staging is useful for predicting outcome.

Seizures may occur at the onset. Involuntary movements (chorea, myoclonus) occur in 10%.

Atypically the illness may develop slowly over months presenting with dementia or rapidly like pyogenic (bacterial) meningitis. Occasionally cerebral features prevail rather than signs of meningitis.

Untreated, the illness may progress from phase 1 to death over a 3-week period.

Arachnoiditis inflammatory exudate may result in hydrocephalus/dementia/blindness.

TUBERCULOUS MENINGITIS

Investigations

• General: Anaemia, leucocytosis. Hyponatraemia (if inappropriate ADH secretion occurs).

• Cerebrospinal fluid

– Cell count, differential count, cytology (50–4000/mm³ – predominantly lymphocytes)

– Glucose, with a simultaneous blood sugar (<50% blood glucose)

– Protein (>1g/l)

– Acid-fast stain, Gram stain, appropriate bacteriologic culture and sensitivity, India ink (all causes of lymphocytic meningitis)

– Cryptococcal antigen, herpes antigen (other causes of lymphocytic meningitis)

– Culture for M. tuberculosis (50–80% positive)

– Polymerase chain reaction (PCR) to detect Mycobacterium DNA – specificity and sensitivity 100% and 70%.

• Tuberculin skin test: Positive in 50% of cases. (Negative if recent steroids or acquired primary infection.)

• Chest x-ray: – hilar lymphadenopathy/infiltrate/cavitations/effusion/scar.

• CT scan and MRI – hydrocephalus, basal meningeal thickening, infarcts, oedema, tuberculomas and obliteration of the subarachnoid space.

Diagnosis

Diagnosis is based on the clinical presentation with characteristic CSF findings.

DIFFERENTIAL DIAGNOSIS – Viral meningoencephalitis – Subacute/chronic meningitis (see pages 517–8).

Treatment

If suspect, commence antituberculous treatment.

Recommended treatment programme:

Normal regime:

Drug resistance suspected due to previous antituberculous therapy, e.g.

– Developing countries

– History of previous infection.

→ Add a fourth drug – streptomycin (1 g daily) or ethambutal (25 mg/kg daily).

Isoniazid and pyrazinamide penetrate meninges well; other drugs penetrate less well especially when the inflammation begins to settle.

Side effects:

– Isoniazid may produce peripheral neuropathy – protect with pyridoxine 50 mg daily.

– Ethambutol may produce optic atrophy – check colour vision.

– Streptomycin may cause 8th cranial nerve damage (vertigo and deafness).

– Nausea, vomiting, abnormal liver function and skin rashes may occur with all antituberculous drugs.

Evidence concerning the duration of anti-tuberculous treatment is conflicting. Conventionally therapy is given for 6–9 months, although some still recommend it for 24 months.

Intrathecal therapy: Since CSF penetration, especially with streptomycin, is poor, some recommend intrathecal treatment. Streptomycin 50 mg may be given daily or more frequently in seriously ill patients.

When obstructive hydrocephalus occurs, combined intraventricular (through the shunt reservoir or drainage catheter) and lumbar intrathecal treatment injections may be administered.

Steroid therapy: A recent Cochrane review reported that adjunctive steroids reduce neurological sequelae, hearing loss and mortality in patients with TBM without HIV. Insufficient data are available to recommend the use of steroids in HIV positive TBM.

Hydrocephalus

Progressive dilatation of the ventricles impairing conscious level requires CSF drainage – either temporarily with a ventricular catheter (permitting intraventricular drug administration) or permanently with a ventriculoperitoneal/atrial shunt. Surgery may also be considered for co-existent tuberculomas and tuberculous abscesses though these often resolve with drug therapy.

The course of treated tuberculous meningitis

Outcome is influenced by the patient’s age, general state of health, timing of initiation of treatment and the development of arachnoiditis and vascular complications.

Treatment in early stages is associated with a 10% mortality, in later stages with a 50% mortality. Of those who survive, neurological sequelae persist in 30% – hemiplegia, hypothalamic/pituitary dysfunction, blindness, deafness, dementia and epilepsy.

With treatment, CSF sugar quickly returns to normal; the cellular reaction gradually diminishes over 3–4 months; the protein level may take a similar time to return to normal.

Tuberculous meningitis in AIDS

Atypical mycobacteria such as M. avium and fortuitum should be considered. Response to treatment is generally good. TBM tends to occur in the earlier phases of immunodeficiency with CD4 T cell count, at <400 per mm³.

OTHER FORMS OF CNS TUBERCULOUS INFECTION

TUBERCULOMAS OF THE BRAIN

Tuberculomata may occur in cerebral hemispheres, cerebellum or brain stem with or without tuberculous meningitis, and may produce a space-occupying effect. They consist of caseating granulomas made up of epitheloid cells and macrophages containing mycobacteria. Lesions may be single or multiple. CT and MRI demonstrate lesions but appearances are not pathognomonic. Most resolve over a few weeks with antituberculous therapy.

POTT’S DISEASE

Chronic epidural infection follows tuberculous osteomyelitis of the vertebral bodies. This arises in the lower thoracic region, can extend over several segments and may spread through the intervertebral foramen into pleura, peritoneum or psoas muscle (psoas abscess).

TUBERCULOUS MENINGOMYELITIS

Infection of the leptomeninges results in an exudate that encases the spinal cord and nerve roots. This produces back pain, paraesthesia, lower limb weakness and loss of bowel and bladder control. Imaging may be normal while CSF shows high protein, lymphocytes and rarely acid fast bacilli. This disorder is now more frequent in AIDS patients. Differential diagnosis includes cytomegalovirus, cryptococcus, syphilis and lymphoma. Laminectomy and meningeal biopsy may be required to establish diagnosis. When suspected, empirical theory with antituberculous drugs is appropriate.

Clinical features:

SPIROCHAETAL INFECTIONS OF THE NERVOUS SYSTEM

SYPHILIS

This infectious disease is caused by the spirochaete Treponema pallidum. Entry is by:

– inoculation through skin or mucous membrane (sexually transmitted) – acquired syphilis.

– transmission in utero – congenital syphilis.

In the last 30 years, there has been a steady decline in incidence regardless of race and ethnicity. Despite this, it still remains an important health problem in certain geographic areas.

Up to 10% of patients with HIV will test positive for syphilis. All patients with neurosyphilis should be tested for this.

The chancre or primary sore on skin or mucous membrane represents the local tissue response to inoculation and is the first clinical event in acquired syphilis.

The organism, although present in all lesions, is more easily demonstrated in the primary and secondary phases.

In congenital syphilis fetal involvement can occur even though many years may elapse between the mother’s primary infection and conception.

Widespread recognition and efficient treatment of the primary infection have greatly reduced the late or tertiary consequences.

Not all patients untreated in the secondary phase progress to the tertiary phase.

In HIV patients the neurological complications occur earlier and advance more quickly.

Investigations

Spirochaetes can be demonstrated microscopically by dark field examination in primary and secondary phase lesions.

Serological diagnosis depends on detection of antibodies.

1. Non-specific (Reagin) antibodies (IgG and IgM).

Reagin tests involve complement fixation.

The Venereal Disease Research Laboratory (VDRL) test is the commonest and when strongly positive indicates active disease (may be negative in HIV).

2. Specific treponemal antibodies (do not differentiate between past and present infection). Fluorescent treponemal antibody absorption (FTA) test and Treponema immobilisation (TPI) test.

3. Treponema pallidum DNA can be detected in the CSF of patients by PCR (sensitivity 60%).

SPIROCHAETAL INFECTION – NEUROSYPHILIS

The initial event in neurosyphilis is meningitis. Of all untreated patients 25% develop an acute symptomatic syphilitic meningitis within 2 years of the primary infection.

ACUTE SYPHILITIC MENINGITIS: Three clinical forms are recognised:

Late neurological complications occur in only 7% of untreated cases.

These forms are exceptionally rare and the clinical syndromes mentioned above seldom occur in a ‘pure’ form.

MENINGOVASCULAR SYPHILIS

‘Early’ late manifestation resulting in an obliterative endarteritis and periarteritis.

Presents as a ‘stroke’ in a young person – hemisphere, brain stem or spinal. Granulations around the base of the brain may produce cranial nerve palsies or even hydrocephalus.

CSF – lymphocytes 100/mm³, protein ↑, gammaglobulin ↑, positive serology. Penicillin arrests progression.

SPINAL SYPHILIS

Chronic meningitis with subpial damage to the spinal cord.

Presents as a progressive paraplegia, occasionally with radicular pain and wasting in upper limbs – ERB’s PARAPLEGIA. CSF – as meningovascular syphilis. Penicillin arrests progression.

OCULAR MANIFESTATIONS

Meningitis around optic nerve with subpial necrosis may be the only manifestation of late syphilis.

Presents as a constriction of the visual fields with a progressive pallor of the optic disc:

– if both eyes are affected, the vision is rarely saved.

– if only one eye is involved, treatment with penicillin will save the other.

Neuroretinitis, uveitis and chorioretinitis occur, especially in HIV patients.

GENERAL PARESIS

Characterised by dementia – with memory impairment, disordered judgement and disturbed affect – manic behaviour, delusions of grandeur (rare).

There are two phases:

1. Pre-paralytic – with progressive dementia.

2. Paralytic – when corticospinal and extrapyramidal symptoms and signs develop associated with involuntary movements (myoclonus).

Argyll Robertson pupils may be present (see page 146).

At autopsy, meningeal thickening, brain atrophy and perivascular infiltration with plasma cells and lymphocytes are evident; culture from the cortex may reveal an occasional treponema.

CSF – lymphocytes 50/mm³, protein ↑ 0.5–2 g/l, gammaglobulin ↑.

Reagin tests in CSF positive in the majority.

Treatment in the preparalytic phase will halt progression in 40%.

TABES DORSALIS

Posterior spinal root and posterior column dysfunction account for symptoms.

The CSF is more normal than in general paresis. The Reagin test may be negative in 30 per cent. Treatment may produce some improvement; it will not reverse joint destruction.

SYPHILITIC GUMMA presenting as an intracranial mass is extremely rare.

TREATMENT OF NEUROSYPHILIS

Penicillin G.	2–4 megaunits i.v.	(When patient sensitive to penicillin
or	4-hourly for 10 days.	↓
Procaine Penicillin	600 000 units i.m. daily for 15 days.	erythromycin or tetracycline may be given orally over 30 days.)
Benzathine Penicillin	2–4 megaunits i.m. weekly × 3.

To prevent congenital syphilis penicillin should be given to all neonates and infected mothers during the first 4 months of pregnancy.

The Jarisch-Herxheimer reaction – tachycardia/fever – occurs in one-third of patients within a few hours of commencing treatment; it is believed to be due to endotoxin release from killed organisms. Steroids should counter the reaction, especially in tertiary syphilis.

CSF follow up: CSF is checked initially and at 6 monthly intervals until normal.

Cell count and degree of positivity of VDRL are the best indicators of persistent infection.

Failure of treatment is common in HIV positive patients and more frequent retesting of blood and CSF is necessary.

SPIROCHAETAL INFECTION

LYME DISEASE (NEUROBORRELIOSIS)

Originally described in the community of Old Lyme, this is a disorder, caused by the spirochaete Borrelia burgdorferi, characterised by relapsing and remitting arthralgia associated with a characteristic skin rash (erythema chronicum migrans) and neurological features. The organism, related to the treponemes, is prevalent throughout Europe and North America and is carried by ixodes ticks.

Clinical features

Only a minority of persons bitten by an infected tick develop the disease. Spirochaetocidal activity in normal serum and the immune response normally provide protection. It rarely occurs in HIV patients.

Diagnosis

Treatment

Stage 1 – Oral antibiotics: penicillin, erythromycin or tetracycline.

Stage 2 – I.V. penicillin G. 20 million units for 10 days (or ceftriaxone).

Stage 3 – as stage 2.

If symptoms persist – wrong diagnosis with misleading titres, or – immune mediated damage.

Steroids can be used in late stages when symptoms have not responded to antibiotics.

LEPTOSPIROSIS

Leptospira interrogans is transmitted to man in the infected urine of wild and domestic animal carriers. Subclinical infection commonly occurs in high-risk occupations, e.g. sewer workers. Symptomatic illness is usually mild and only 10% of patients develop jaundice and haemorrhagic complications (Weil’s disease).

Clinical features

Diagnosis

A combination of abnormal liver and renal function with elevated creatine kinase suggest the diagnosis. Leptospirae can be isolated from blood and CSF (in the immune phase) but diagnosis is usually confirmed by demonstrating agglutinating antibodies (ELISA detected IgM).

Treatment

The disease is usually self limiting and therapy unnecessary. Early treatment in the leptospiraemic phase with Penicillin G 12 million units daily and tetracycline 500 mg four times per day may minimize the immune-mediated complications. Support of hepatic/renal failure and management of haemorrhagic complications may be life-saving.

PARASITIC INFECTIONS OF THE NERVOUS SYSTEM – PROTOZOA

TOXOPLASMOSIS

A world-wide parasitic infection affecting many species, including man.

Organism: An anaerobic intracellular protozoan, Toxoplasma gondii.

The majority of infections in man are asymptomatic (30% of the population have specific antibodies indicating previous exposure).

In the host

Transmission: Eating uncooked meat or contact with faeces of an infected dog or cat (definitive hosts).

There are two forms of toxoplasmosis:

ACQUIRED – symptomatic infection is uncommon and may be associated with underlying systemic disease or immunosuppression (e.g. AIDS).

Fever and fatigue with muscle weakness and lymphadenopathy result. Abnormal lymphocytes in peripheral blood leads to confusion with infectious mononucleosis. The neurological features are those of a meningoencephalitis with focal signs and depressed conscious level. Choroidoretinitis occasionally occurs.

Retinal pigment epithelium becomes hyperplastic – densely pigmented areas result.

Diagnosis:

Organisms are seldom identified.

IgG antibodies indicate previous exposure, positive IgM and high or rising IgG confirm active infection.

Serological tests may be negative in AIDS.

In acquired infection CT shows characteristic ring shaped contrast enhancement. MRI is even more sensitive. Brain biopsy is necessary for exclusion of CNS lymphoma and for definitive diagnosis.

N.B. Rubella, cytomegalovirus and herpes simplex can also spread transplacentally and cause jaundice and hepatosplenomegaly. Cytomegalovirus may also produce choroidoretinitis and intracranial calcification.

Treatment

Sulphadiazine and pyrimethamine (Dapaprim) with folinic acid for 6 weeks. In AIDS newer drugs, such as clarithromycin and azithromycin, have also been used with some success. In this patient group recurrence after discontinuation of therapy mandates life long treatment. Give steroids when choroidoretinitis is present.

MALARIA

Plasmodium falciparum, the agent of malignant tertiary malaria, is responsible for cerebral malaria. Infected red blood cells adhere to vascular endothelium and block the microcirculation. Endothelial damage produces cerebral oedema. Confusion, focal signs, convulsions and coma occur. Diagnosis depends on demonstrating parasites in peripheral blood. Parenteral anti malaria treatment (chloroquine), exchange transfusion and supportive therapy may be life saving. Overall mortality is 10%. Complete recovery without sequelae is expected in survivors.

VIRAL INFECTIONS

General principles

Invasion of the nervous system may occur as part of a generalised viral infection.

Occasionally nervous system involvement is disproportionately severe and symptoms of generalised infection are slight.

Viruses enter the body through the: respiratory tract, gastrointestinal tract, genitourinary tract or by inoculation through the skin.

After CNS penetration, the clinical picture depends upon the particular virus and the cells of the nervous system which show a specific susceptibility.

Some viruses cause a chronic, progressive infection, others remain dormant for many years within the nervous system before becoming symptomatic.

MENINGITIS

Meningitis is the commonest type of viral infection of the central nervous system. The term aseptic meningitis includes viral meningitis as well as other forms of meningitis where routine culture reveals no other organisms.

Common causal viruses –	Rare causal viruses –
ENTEROVIRUSES	LYMPHOCYTIC CHORIOMENINGITIS
MUMPS VIRUS	HUMAN IMMUNODEFICIENCY VIRUS (HIV)
HERPES SIMPLEX (subtype 2)	WEST NILE VIRUS
EPSTEIN-BARR VIRUS (EBV)

VIRAL INFECTIONS – MENINGITIS

Clinical features of acute aseptic meningitis

Enterovirus infection e.g. Coxsackie or echo viruses – affects children/young adults and occurs seasonally in late summer.

Spread is by the faecal/oral route.

Mumps – affects children/young adults. Winter/spring incidence.

Herpes simplex (type 2) – accounts for 5% of viral meningitis. Develops in 25% of patients with primary genital infection (suspect in sexually active adults). Can cause a recurrent meningitis (Mollaret’s meningitis).

Lymphocytic choriomeningitis – affects any age and is a consequence of airborne spread from rodent droppings.

Human Immunodeficiency Virus (HIV) – suspect in high risk groups (page 515). HIV antibodies are often absent and develop 1–3 months later during convalescence.

Investigations

The CSF cell count is elevated (lymphocytes or monocytes) with a normal glucose and protein. PCR detection of viral DNA/RNA in CSF though diagnostic, is rarely thought necessary. Virus may be cultured from throat swabs or stool. Serological tests on serum in acute and convalescent phases are especially valuable in detecting mumps and herpes simplex (type 2).

Differential diagnosis

From other causes of an aseptic meningitis which are usually subacute or chronic in onset:

– Tuberculous or fungal meningitis

– Leptospirosis

– Sarcoidosis

– Carcinomatous meningitis

– Partially treated bacterial meningitis

– Parameningeal chronic infection which evokes a meningeal response, e.g. mastoiditis.

The self-limiting and mild nature of viral meningitis should not lead to confusion with these more serious disorders.

Prognosis is excellent and treatment symptomatic.

VIRAL INFECTIONS – PARENCHYMAL

Viruses may act:

directly → acute viral encephalitis or meningoencephalitis, or indirectly via the immune system→ allergic or postinfectious encephalomyelitis and postvaccinial encephalomyelitis.

Also, a ‘toxic’ encephalopathy may develop during the course of a viral illness in which inflammation is not a pathological feature – REYE’S SYDNROME.

– Arthropod-borne – USA

– Arthropod-borne – Africa/India

– Arthropod-borne – eastern Europe

Encephalitis following childhood infections – measles, varicella, rubella – is presumed to be postinfectious and not due to direct viral invasion, though the measles virus has occasionally been isolated from the brain.

Clinical features:

Signs and symptoms:

General: pyrexia, myalgia, etc.

Specific to causative virus, e.g. features of infectious mononucleosis (Epstein-Barr).

Meningeal involvement (slight) → neck stiffness, cellular response in CSF.

Signs and symptoms of parenchymal involvement – focal and/or diffuse.

In general, the illness lasts for some weeks.

Prognosis is uncertain and depends on the causal virus as do neurological sequelae.

Herpes Simplex (HSV) and Varicella-Zoster (VZV) commonly cause disease in humans.

HERPES SIMPLEX ENCEPHALITIS

HSV-1 is the commonest cause of sporadic encephalitis.

One third occur due to primary infection; two thirds have pre-existing antibodies (reactivation).

Clinical features

A world-wide disorder occurring during all seasons and affecting all ages.

Incidence: 1/250 000

General symptoms at onset – headache, fever – with evolution over several days to seizures and impaired conscious level.

Investigations

MR imaging: T2 weighted MRI showing temporal and orbitofrontal hyperintensities typical of herpes simplex encephalitis.

CSF examination reveals 5–500 lymphocytes. The protein is mildly elevated and the glucose is normal.

EEG examination shows generalised slowing with bursts of ‘periodic’ high voltage slow wave complexes over the involved temporal lobe.

Polymerase chain reaction (PCR) on CSF may be negative in the first 48 hours. The quantity of HSV DNA then increases and, if initially negative and the clinical course is suggestive, the examination should be repeated. Also paired sera and CSF should be sent for HSV antibody (CSF HSV-specific antibody can still be detected up to 30 days).

Brain biopsy seldom required in view of the above new diagnostic techniques.

Treatment: Acyclovir inhibits DNA synthesis, is relatively non-toxic and significantly reduces morbidity and mortality. When the diagnosis is considered, treatment must start without delay.

Varicella-Zoster Virus (VZV) encephalitis may complicate chicken pox, or a cutaneous zoster eruption. CSF shows a mild lymphocytosis (<100 cells/mm³), a slight increase in the protein and a normal glucose. PCR detects VZV DNA. The virus can be grown from CSF and antibodies detected. Treatment with acyclovir or famciclovir is effective. Vasculitis may complicate.

VIRAL INFECTIONS – REYE’S SYNDROME

REYE’S SYNDROME

This rare encephalopathy, associated with fatty changes in the liver and other viscera, is almost exclusively confined to children. It is due to aspirin useage in infection with Influenza A, Influenza B or varicella–zoster viruses.

Incidence

Since 1980 the incidence of this condition has dropped dramatically, in part due to avoidance of salicylates in children.

Pathology

Neurons and glial cells are swollen; the liver, heart and kidney show fatty infiltration.

Pathogenesis

Viral synergism with an environmental factor, e.g. salicylates, may be responsible.

Morphological changes in mitochondria indicate a central role.

Death results from raised intracranial pressure.

Investigations

– Raised liver enzymes (ALT & AST)

– Elevated serum ammonia

– Hypoglycaemia (in infants)

– Prolonged prothrombin time

– Increase in serum fatty acids Aminoaciduria

CT/MRI show appearances of diffuse cerebral oedema

Differential diagnosis

Consider other causes of raised intracranial pressure in childhood, especially

– lead encephalopathy,

– lateral sinus thrombosis, e.g. following mastoiditis.

Treatment

Treatment aims at lowering intracranial pressure with the aid of intracranial pressure monitoring (see page 52). In addition, blood glucose must be maintained and any associated coagulopathy treated. Reduction of ammonia may be achieved by peritoneal dialysis or exchange transfusion.

Prognosis

Early diagnosis and supportive treatment has reduced the mortality from 80% to 30%.

When raised intracranial pressure is present, mortality increases to 50% and a high proprotion of survivors have cognitive disorders.

VIRAL INFECTIONS – CHRONIC DISORDERS

In these disorders the infection results in a chronic progressive neurological condition.

The evidence of a viral etiology is:

Direct – finding of inclusion bodies, demonstration of viral particles or isolation of virus.

Indirect – relationship of onset of symptoms to a preceding viral illness, transmission of illness from one host to the next

N.B. Not all these features are present in any one illness

SUBACUTE SCLEROSING PANENCEPHALITIS (SSPE)

Caused by measles-like paramyxovirus – isolated from brain biopsy.

Less common with the availability of widespread primary measles vaccination.

Clinical features: A world-wide disorder. Incidence: 1 per million per year. Onset: between ages 7–10 years.

Stage 1: Behavioural problem, declining school performance, progression → dementia

Stage 2: Chorioretinitis, myoclonic jerks, seizures, ataxia, dystonia

Stage 3: Lapses into rigid comatose state

The illness may occur after measles vaccination or following clinical infection at an early age (under 2 years).

Accompanying features of infection, i.e. pyrexia, leucocytosis, are absent.

Investigations

EEG – shows periodic high voltage slow wave complexes on a low voltage background trace.

Pathology

Changes involve both white and grey matter, especially in the posterior hemispheres. Brain stem, cerebellum and spinal cord are also affected. Oligodendrocytes contain eosinophilic inclusion bodies. Marked gliosis occurs with perivascular lymphocyte and plasma cell cuffing.

Treatment: There is no effective treatment. Since the introduction of measles vaccination there has been a marked reduction of SSPE.

Subacute measles encephalitis may follow measles infection in children on immunosuppressive drug treatment or with hypogammaglobulinaemia. The clinical course is different however from SSPE and EEG and CSF findings are less specific.

PROGRESSIVE RUBELLA PANENCEPHALITIS

Presents at a later age (10–15 years)	CSF shows high γ globulin.
Progressive dementia.	Antibodies elevated in serum and CSF to rubella.
Ataxia. Spasticity. Myoclonus.	Biopsy does not show inclusion bodies.
Treatment: No effective treatment

PRION DISEASES

Fatal conditions characterised by the accumulation of a modified cell membrane protein – Prion protein or PrP (proteinaceous infectious particle) within the central nervous system.

Clinical features are dependent on site and rate of deposition of PrP. A similar disorder in cattle, bovine spongiform encephalopathy (BSE) may be a source of infection in man.

The Prion theory

Experimental and epidemiological evidence supports transmissibility. Physical properties of the infective agent – heat and radiation resistance and absence of nucleic acid – suggests it is comprised solely of protein. This infectious protein when innoculated modifies normal cell membrane protein which acts as a template for further conversion to abnormal protein. This host-encoded protein accumulates without any inflammatory or immune response. In familial cases a point mutation in the prion gene explains disease susceptibility.

Creutzfeldt-Jakob disease (CJD)

A worldwide disorder with incidence 1:1 000 000. Approximately 90% of cases are sporadic and 10% familial caused by mutations in the prion protein (PRNP) gene on chromosome 20. Age of onset 50–60 years. Non specific symptoms at onset (anxiety and depression) are rapidly followed by myoclonus, ataxia, akinetic rigid state, dementia. Death within 12 months is usual. Iatrogenic disease occurs following corneal or dural grafts, depth electrodes and cadaveric derived human growth hormone treatment.

Investigation

EEG – 1–2 Hz triphasic sharp waves with periodic complexes

CSF – increase in protein 14–3–3 (a protein kinase inhibitor)

[The combined EEG and CSF findings, where positive, have diagnostic sensitivity/specificity of 97%]

Pathology

– Neuronal degeneration occurs with marked astrocytic proliferation and amyloid plaque formation. Vacuolation of glial cells results in a characteristic spongiform appearance.

Treatment – supportive.

New Variant CJD (vCJD)

Generally affects younger age group. Psychiatric symptoms of depression, anxiety, or withdrawal are common early manifestations. Neurological symptoms appear approximately 6 months later, with paraesthesias an early feature. Eventually sufferers exhibit ataxia, progressive dementia and involuntary movements (myoclonus, chorea, or dystonia).

Only 50% of patients have protein 14–3–3 proteins in CSF. EEG reveals non-specific slowing (the periodic complexes of sporadic CJD are absent).

PRNP gene mutations are found with patients homozygous for methionine at the 129 codon. Neuropathological changes – ‘florid’ plaques in the cerebral and cerebellar cortex, severe thalamic gliosis, and spongiform change with diffuse accumulation of prion proteins.

Gerstmann Straussler syndrome (GSS)

Kuru

An extensively studied disorder of Papua New Guinea. It is of interest in view of man to man spread from cannibalism.

VIRAL INFECTIONS – MYELITIS AND POLIOMYELITIS

MYELITIS

Acute viral transverse myelitis is rare. It can occur in association with measles, mumps, Epstein-Barr, herpes zoster/simplex, enterovirus infections HIV, HTLV-1 and 2 and smallpox. Fever, back and limb pain precede paralysis, sensory loss and bladder disturbance. Initially paralysed limbs are flaccid, but over 1–2 weeks spasticity and extensor plantar responses develop. Good recovery occurs in 30%. Death from respiratory failure is rare (5%).

Investigations

Myelography when performed is normal. MRI may demonstrate focal cord signal changes. CSF shows elevated protein with a neutrophil or lymphocytic response. Serological tests will occasionally identify the causal virus. Electrophysiology distinguishes from Guillain-Barré syndrome.

Treatment

Supportive; the place of steroids remains unproven.

It is not clear whether the pathological effects (perivenous demyelination) result from direct or delayed (immunological) reactions to the virus.

POLIOMYELITIS

An acute viral infection in which the anterior horn cells of the spinal cord and motor nuclei of the brain stem are selectively involved. A major cause of paralysis and death 30 yrs ago, now rare with the introduction of effective vaccines and improved sanitation.

Causative viruses:

The poliovirus is a picornavirus (RNA virus).

Three immunological distinct strains have been isolated. Immunity to one does not result in immunity to the other two.

Coxsackie and echoviruses (also picornaviruses), may produce a clinically identical disorder. West Nile virus can produce a polio-like flaccid paralysis.

Pathology

Initially – inflammatory meningeal changes, followed by – inflammatory cell infiltration (polymorphs and lymphocytes) around the brain stem nuclei and anterior horn cells. Neurons may undergo necrosis or central chromatolysis.

Microglial proliferation follows.

Mode of spread

Spread by faecal/oral route. Once ingested the virus multiplies in the nasopharynx and gastrointestinal tract.

Epidemiology

A highly communicable disease which may result in epidemics.

Seasonal incidence – late summer/autumn.

World-wide distribution, although more frequent in northern temperate climates.

Prophylactic vaccination has produced a dramatic reduction in incidence in the last 25 years. In developing countries without a vaccination programme, the disease remains a problem.

Clinical features

Infection may result in:

– Subclinical course + resultant immunity (majority)

– Mild non-specific symptoms of viraemia + resultant immunity

– Meningism without paralysis (PREPARALYTIC) + resultant immunity

– Meningism followed by paralysis (PARALYTIC) + resultant immunity.

VIRAL INFECTIONS – POLIOMYELITIS

Diagnosis

During the meningeal phase, consider other causes of acute meningitis.

Once the paralytic phase ensues, distinguish from the Guillain-Barré syndrome and transverse myelitis.

The clinical picture + CSF examination (polymorphs and lymphocytes increased; protein elevated with normal glucose) are sufficient to reach the diagnosis.

Poliovirus RNA can be detected in faeces or CSF by PCR.

Prognosis

In epidemics, a mortality of 25% results from respiratory paralysis. Improvement in muscle power usually commences one week after the onset of paralysis and continues for up to a year.

Only a proportion of muscles remain permanently paralysed; in these, fasciculation may persist. In affected limbs, bone growth becomes retarded with shortening as well as thinning.

Treatment

The patient is kept on bed rest and fluid balance carefully maintained.

Respiratory failure may require ventilation.

Avoid the development of deformities in affected limbs with physiotherapy and splinting.

Post-Polio Syndrome

A significant proportion of polio patients develop late sequelae often 30 yrs after initial illness – fatigue, myalgia and progressive muscle atrophy with weakness are characteristic.

Prophylaxis

VIRAL INFECTIONS – VARICELLA-ZOSTER INFECTION

Varicella (chickenpox) and herpes zoster (shingles) are different clinical manifestations of infection by the same virus – Varicella–Zoster, a DNA human herpes virus.

Conditions caused:

– an acute encephalitis

– viral meningitis

– myelitis

– postinfectious encephalomyelitis

– postinfectious polyneuropathy (Guillain-Barré syndrome).

SHINGLES

This occurs after virus reactivation, dormant after the primary infection (chickenpox).

Clinical features

Patients are usually over 50 years of age. Sexes are affected equally. Recurrence is rare. Often occurs in immunocompromised patients e.g. lymphoma. Also associated with spinal/nerve root trauma.

Initial feature:

Motor weakness occurs in 20% due to damage of the anterior horn cell. More widespread spinal (myelitis) or encephalic involvement occurs in the immunodeficient. In these patients extensive cutaneous lesions are common (disseminated zoster).

Cranial nerve ganglia involvement:

– Trigeminal: usually ophthalmic division with vesicles above the eye and associated corneal ulceration – HERPES ZOSTER OPHTHALMICUS.

– Geniculate: vesicles within the external auditory meatus and ear drum. Ipsilateral deafness and facial weakness result. – RAMSAY HUNT SYNDROME.

Diagnosis: Based on clinical features. Virus DNA can be detected in vesicular fluid by PCR.

Treatment

This depends on the severity and location of skin lesions. Mild disease requires symptomatic treatment only. Severe disease, involvement in immunocompromised patients, or ophthalmic vesicles require acyclovir either orally or intravenously.

POST HERPETIC NEURALGIA

This is a condition which occurs in 10% of all patients. The incidence rises with age. A chronic, uncomfortable, burning pain presents in the territory of the involved dermatome. The pathogenesis is unknown.

Treatment with antidepressants, anticonvulsants, e.g. carbamazepine, transcutaneous stimulation (TCS) or sympathetic ganglion block may help, but results are unpredictable.

Varicella and Herpes Zoster CNS involvement

Patients with AIDS and other immunocompromising disorders risk severe, life-threatening CNS involvement – encephalitis, cerebral vasculitis, myelitis or brain stem encephalitis. Herpes Zoster ophthalmicus can be associated, in the middle aged, with delayed major cerebral artery territory infarction. This presents 4–6 weeks after infection. Stroke also occurs as a remote complication of childhood varicella, usually within 12 weeks of clinical chickenpox. These are both due to virus-induced damage to cerebral arteries (vasculitis). The role of anti-viral drugs and steroids is uncertain.

OPPORTUNISTIC INFECTIONS

These infections occur in immunocompromised patients. Certain types of immunological deficiency tend to be associated with specific forms of infection.

CLINICAL SYNDROMES, DIAGNOSIS AND TREATMENT

ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS)

Human immunodeficiency virus (HIV-I) has lymphotropic (CD4 lymphocytes) and neurotropic (microglial) properties. Neurological features develop in 80% of infected individuals manifesting as either direct effects of the HIV virus or infections, tumours and associated vascular disorders due to immunodeficiency. AIDS is the end stage of chronic infection.

Prevalence of AIDS and HIV infection

Certain individuals are ‘at risk’ of infection:

The incidence of HIV infection in ‘at risk’ groups varies considerably.

Sex education, supply of clean needles to addicts, active drug-dependence programmes and specific precautions in the preparation of blood products are necessary to limit its spread.

Current prevalence of HIV – USA 450/100,000

CLINICAL COURSE OF HIV INFECTION

NEUROLOGICAL PRESENTATIONS OF HIV INFECTION

Treatment

Opportunistic infection – treatment of specific infection (see page 514).

With known HIV + ve patients, invasive procedures such as biopsy are often avoided and trials of therapy are administered, e.g. cerebral toxoplasmosis – trial of pyrimethamine and sulphadiazine, monitored with CT/MRI. If lesions do not resolve → biopsy (? lymphoma).

Highly active antiretroviral therapy (HAART) with effective treatment for infections and neoplastic complications has significantly improved outcome. Mean survival time for HIV-infected persons currently exceeds 10 years. The prolonged survival of HIV-infected persons increases their risk of developing PML or CNS lymphoma (these responding poorly to treatment).

HAART management comprises two nucleoside reverse transcriptase inhibitors (e.g. zidovudine and didanosine) and a protease inhibitor (e.g. ritonavir or indinavir), or a nonnucleoside reverse transcriptase inhibitor (nevirapine). This combination is given to HIV-infected individuals with detectable viral loads or immunologic dysfunction (less than 500 CD4+ cells/mm³). HAART results in immunological and neurocognitive improvement, even when HIV is advanced. Treatment aims at reducing the viral load to undetectable levels, PCR having a central role in monitoring therapy and identifying drug resistance.

SUBACUTE/CHRONIC MENINGITIS

This entity is characterised by symptoms and signs of meningeal irritation which persist and progress over weeks without improvement. Unlike acute meningitis, the onset is insidious; cranial nerve signs and focal deficits such as hemiparesis, dementia and gradual deterioration of conscious level may predominate. Predisposing factors include immunosuppression or immunocompromised host. The outcome depends upon aetiology and the early instigation of appropriate treatment.

Chronic meningitis is associated with certain CSF findings.

– Lymphocytosis + low glucose (relative to serum level)

– Lymphocytosis + normal glucose.

Diagnosis depends upon CSF examination.

Lumbar puncture should be performed in suspicious cases as soon as CT scan has ruled out a mass lesion.

SUBACUTE/CHRONIC MENINGITIS WITH A LOW CSF GLUCOSE

Western herbs shown to suppress or inhibit pro-inflammatory cytokine production

Despite extensive investigation, a group of patients with chronic meningitis exists in whom no cause is found.

DEMYELINATING DISEASE

Demyelinating disorders of the central nervous system affect myelin and/or oligodendroglia with relative sparing of axons.

The central nervous system is composed of neurons with neuroectodermal and mesodermal supporting cells.

The neuroectodermal cells comprise:

astrocytes

ependymal cells

oligodendrocytes.

The oligodendrocytes, like Schwann cells in the peripheral nervous system, are responsible for the formation of myelin around central nervous system axons.

One Schwann cell myelinates one axon but one oligodendrocyte may myelinate several contiguous axons, and the close proximity of cell to axon may not be obvious by light microscopy.

Oligodendrocytes are present in grey matter near neuronal cell bodies and in white matter near axons.

Myelin is composed of protein and lipids. Protein accounts for 20% of total content. The lipid fraction may be divided into:

cholesterol

glycophosphatides (lecithins)

sphingolipids (sphingomyelins).

The laying down of myelin in the central nervous system commences at the fourth month of fetal life in the median longitudinal bundle, then in frontal and parietal lobes at birth. Most of the cerebrum is myelinated by the end of the 2nd year. Myelination continues until the 10th year of life.

Myelin disorders may be classified as diseases in which:

1. Myelin is inherently abnormal or was never properly formed – these disorders generally present in infancy and early childhood and have a biochemical basis, e.g. leukodystrophy.

2. Myelin which was normal when formed breaks down as a consequence of pathological insult, e.g. multiple sclerosis.

MULTIPLE SCLEROSIS

Multiple sclerosis (MS) is a common demyelinating disease, normally characterised by focal disturbance of function and a relapsing and remitting course.

The disease occurs most commonly in temperate climates and prevalence differs at various latitudes:

	Latitude (°N)	Rate/100 000 (adjusted)
Orkneys and Shetland………	60	309
England (Cornwall)…………	51	63
Italy (Bari)……………	41	13

The disease usually occurs in young adults with a peak age incidence of 20–40 years. Slightly more females than males are affected. There is a 3% risk of disease if a sibling or parent is affected.

PATHOLOGY

Scattered lesions with a greyish colour, 1 mm to several cm in size, are present in the white matter of the brain and spinal cord and are referred to as plaques. The lesions lie in close relationship to veins (postcapillary venules) – perivenous distribution.

PATHOGENESIS

Immune deficiency has been suggested. This might explain the possible persistence of a latent virus and variations in immune status could be the basis of ‘relapses and remissions’. T lymphocytes and macrophages found in plaques may be sensitized to myelin antigens.

Hereditary/genetic factors appear significant. There is an increased familial incidence of multiple sclerosis. This has led to the study of histocompatibility antigens (HL-A). An association between A3, B7, B18 and DW2/DRW2 and multiple sclerosis has been demonstrated. Concordance rate in monozygotic twins is 30% and in dizygotes 5%. Affected women transmit MS to offsping more frequently than affected men suggesting that mitochondrial genes contribute to inheritance.

Viruses may be important in the development of multiple sclerosis, infection perhaps occurring in a genetically/immunologically susceptible host.

Elevated serum and CSF antibody titres have been found to:

– varicella zoster, measles, rubella and herpes simplex during relapse.

Biochemical: No biochemical effect has been demonstrated – myelin appears normal before breakdown and the proposed excess of dietary fats or malabsorption of unsaturated fatty acids is unproven.

In summary – the causation is probably multifactorial.

CLINICAL FEATURES

Peak age of onset

– 20–25 years

Childhood onset rare

– 2%

Patients presenting >50 years

– 5%

Patients presenting >60 years

– 1%

Multiple sclerosis is usually characterised by:

– Signs and symptoms of widespread white matter disease.

– A relapsing and remitting or progressive course.

Symptoms at onset

1. Vague symptoms: lack of energy, headache, depression, aches in limbs – may result in diagnosis of psychoneurosis. These symptoms are eventually associated with:

Trigeminal neuralgia may be an early symptom of multiple sclerosis, and this should be considered in the young patient with paroxysmal facial pain.

Sensory symptoms

Numbness and paraesthesia are common and often minor and transient. Paraesthesia is more often due to posterior column demyelination than to spinothalamic tract involvement.

Posterior column lesions result in impaired vibration sensation and joint position sensation. In such cases a limb may be rendered ‘useless’ by the absence of positional awareness.

Lhermitte’s sign: with cervical posterior column involvement sudden neck flexion will evoke a ‘shock-like’ sensation in the limbs.

Spinothalamic lesions result in dysaesthesia – an unpleasant feeling of burning, coldness or warmth, with associated sensory loss to pain and temperature contralateral to the lesion.

Motor symptoms

Monoparesis and paraparesis are the most common motor symptoms. Hemiparesis and quadriparesis occur less commonly.

Paraparesis is the result of spinal demyelination, usually in the cervical region.

Signs: – Increased tone

– Hyperactive tendon reflexes, extensor plantar response and absent abdominal reflexes

– Pyramidal distribution weakness.

Loss of vision

Acute optic neuritis (Retrobulbar neuritis): Visual loss associated usually with a central scotoma and recovery over some weeks. This commonly occurs in young adults. The visual loss develops over several days and is often associated with pain on ocular movement (irritation of the dural membrane around the optic nerve). In milder forms, only colour vision is affected. Typically only one eye is affected, although occasionally both eyes simultaneously or consecutively are involved.

On examination: Disturbance of visual function ranges from a small central scotoma to complete loss. Fundal examination reveals swelling – papillitis – in up to 50% of patients, depending upon the proximity of the plaque to the optic nerve head.

‘Sheathing’ from an inflammatory exudate around peripheral retinal venules is common. Reduced visual acuity distinguishes papillitis from papilloedema.

Investigation: Visual evoked responses (VERs) show delay. High resolution CT or MRI of the optic nerve excludes tumour. MR confirms the presence of plaque.

Treatment: The optic neuritis study group showed that IV or oral steroids compared with placebo accelerated recovery though at 2 years there was no significant difference in eventual visual function. Oral steroids were associated with a higher risk of recurrent optic neuritis. Intravenous steroids appeared (within the next 2 years) to reduce the risk of subsequent MS.

Outcome: 90% of patients recover most vision, although symptoms may transiently return following a hot bath or physical exercise – Uhthoff’s phenomenon. Following recovery the optic disc develops an atrophic appearance with a pale ‘punched out’ temporal margin.

Subsequent course: The optic neuritis study group reported 12% of cases had developed clinically definite MS within 2 years (4% with a normal and 30% with an abnormal cranial MRI). Thereafter the risk is 5–6% per annum.

Acute bilateral optic neuritis: less common than unilateral disease and progression to MS not as likely. Occasionally followed by a transverse myelitis (Neuromyelitis optica, page 529). Examination of mitochondrial DNA distinguishes from Leber’s hereditary optic neuropathy (page 551).

Disturbance of ocular movement

Diplopia may result from demyelination affecting the brain stem pathway of the III, IV or VI cranial nerves. Abnormality of eye movements with or without diplopia occurs when supranuclear or internuclear connection are involved. The latter results from a lesion in the medial longitudinal fasciculus – internuclear ophthalmoplegia (I.N.O.) – and in young persons is pathognomonic of MS.

Nystagmus may be an incidental finding on neurological examination. It is unusual in multiple sclerosis when the eyes are in the primary position, and is commonly seen on lateral gaze. Pupillary abnormalities may occur from:

– sympathetic involvement in the brain stem (Horner’s syndrome)

– III nerve involvement, or

– II nerve involvement.

The swinging light test is a sensitive test of impaired afferent conduction in the II nerve. Alternating the light from one eye to the other results eventually in ‘pupillary escape’ – the pupil dilates despite the presence of direct light.

OTHER FEATURES

Vestibular symptoms: Vertigo of central type may be a presenting problem or it may develop during the course of the illness. Hearing loss is rare.

Ataxia of gait and limb inco-ordination are frequently present. The gait ataxia may be cerebellar or sensory type (see Romberg’s test). Limb inco-ordination, intention tremor and dysarthria indicate cerebellar involvement.

Sphincter disturbance with urgency or precipitancy of micturition and eventual incontinence occurs. Conversely urinary retention in a young person may be the first symptom of disease. On direct questioning, impotence is frequently found.

Mental changes: Mood change – euphoria or depression occur. Cognitive impairment develops in advanced cases. Generalised fatigue is common.

Emotional lability: Uncontrolled outbursts of crying or laughing, result from involvement of pseudobulbar pathways.

Paroxysmal (symptoms occurring momentarily throughout any stage of the disease): paraesthesia, dysarthria, ataxia, pain, e.g. trigeminal neuralgia, photopsia (visual scintillations), epilepsy.

CLINICAL COURSE

The pattern of illness in individual sufferers cannot be predicted. Several different rates of disease activity and progression have been defined.

1. Relapsing and remitting Of all patients with MS, 70% pass through this stage. With each attack recovery is virtually complete. This phase of illness may persist for many years. The explanation of why relapses take place is unknown.

2. Secondary progressive and relapsing/remitting secondary progressive After a period of time, relapsing and remitting MS attacks are followed by incomplete recovery and cumulative loss of function and disability. At any one time, the chronic progressive stage accounts for 20% of all sufferers. Converting from relapsing and remitting to secondary progressive occurs on average 6–10 years after the initial symptoms.

3. Primary progressive This form is common in late onset MS (>45 yrs) and accounts for 15% of all patients. Symptoms and signs are usually spinal and relapses absent in the context of insidious progression.

4. Benign This is defined as low disability (EDSS <3) 10 years after onset. The true incidence of such cases is difficult to define and patients may still progress in time to major disability. Some support for a benign form comes from the occasional incidental autopsy finding of MS.

Recognition of different phases of MS is essential in selecting patients for new disease-modifying treatments. The degree of disability can be recorded using specific scales such as the Kurtzke score or the Extended Disability Status Score (EDSS).

[This is a 10 point non-linear scale where 1 = no symptoms or signs, 6 = a walking aid to achieve a short distance, 8 = restricted to bed/wheelchair and 10 = death due to MS.]

INVESTIGATIONS

The development of imaging and laboratory testing has advanced diagnostic accuracy.

Neurophysiological: may detect a second asymptomatic lesion (see page 54).

2. Somatosensory evoked response (SSEP) may detect central sensory pathway lesions.

3. Brain stem auditory evoked potential (BAEP) may detect brain stem lesions.

Cerebrospinal fluid examination by lumbar puncture

A mild pleocytosis (25 cells/mm³), mainly lymphocytes, is occasionally found. The total protein may be elevated, although this rarely exceeds 100 mg/l. An increase in gammaglobulin occurs in 50–60% of cases. Electrophoresis of CSF using agar or acrylamide shows discrete bands which are not present in serum.

These bands are found in up to 95% of patients with established disease and in 50-60% after the first attack. Oligoclonal bands (OCBs) are not specific to MS but persist indefinitely, unlike other inflammatory neurological diseases (see following page).

MRI

This has contributed enormously to the diagnosis and understanding of MS. Normal white matter appears dark with low signal intensity in T2 weighted images. Myelin breakdown produces a longer relaxation time and increased signal on T2. Gliosis produces similar changes. The presence of white matter abnormalities with a periventricular distribution is suggestive but not diagnostic of MS. Paramagnetic contrast (Gadolinium) will show active inflammation. A combination of MRI and CSF (oligoclonal band) will rule out MS if both are negative. MR may predict long term outcome – following a single episode of demyelination (e.g. optic neuritis or transverse myelitis). Those with cranial MR abnormalities will relapse sooner than those without. At present MRI does not correlate well with disability, but newer techniques may be more sensitive measures of disease progression.

Diagnosis requires two or more episodes of symptoms attributable to demyelination, at least 30 days apart at different sites in the central nervous system, and the exclusion of alternative pathologies. Research criteria have been developed for clinical studies which combine clinical features with investigation findings. The McDonald criteria (2001) allow for MRI scan evidence of the development of new lesions to lead to a diagnosis after a single clinical episode.

Primary progressive MS can be diagnosed after 1 year of progressive deficit, with brain or spine plaques along with CSF unmatched oligoclonal bands and exclusion of alternative diagnoses.

Conditions with similar CSF profile to MS (presence of oligoclonal bands)

– Subacute sclerosing panencephalitis (SSPE)

SYMPTOMATIC

Spasticity	Drugs: baclofen (GABA derivative); dantrolene (direct action on muscle); tizanidine (α₂ adrenergic agonist); botulinum toxin
	Physiotherapy and splinting
	Intrathecal baclofen
Urinary symptoms	Detrusor instability – anticholinergics (oxybutinin, tolterodine); if severe intravesical botulinum toxin injections
	Nocturia – desmopressin spray
	Incomplete bladder emptying – intermittent self catheterisation
Bowel symptoms	Dietary manipulation; laxatives; suppositories/enemas
Pain	Analgesics; anticonvulsants; antidepressants; NSAIDs; transcutaneous electrical nerve stimulation
Paroxysmal symptoms	Seizures – anticonvulsants
Fatigue	Amantadine; modafinil
Depression	Clinical psychology; antidepressants, tricyclic or SSRI
Tremor	Betablockers; primidone; if severe deep brain stimulation
Ataxia	Walking aids; physiotherapy

Symptom management will often require a coordinated multidisciplinary approach, particularly as the disease progresses.

ACUTE RELAPSE

Methylprednisone 3 g i.v. over 3 days. Check for infection beforehand, monitor blood glucose and consider an H₂ blocker for ulcer prophylaxis. Methylprednisone can also be given orally.

MODIFY NATURAL HISTORY

Relapsing remitting MS

Betainterferon and glatiramer acetate reduce the relapse rate by about 30%. The evidence that this reduction translates into reduced disability is less clear. In the UK ambulant patients with two clinically significant relapses in the last 2 years would be eligible for treatment.

Natalizumab, a monoclonal antibody, reduces the relapse rate by over 60% with reduction in disability but is associated with a risk of developing progressive multifocal leucoencephalopathy (1 in 1000). As a result it is available only for patients with aggressive disease. Mitoxantrone is a chemotherapy agent which can be used in aggressive disease with risk of cardiotoxicity and leukemia.

A range of further agents are undergoing trials.

Primary progressive MS and secondary progressive MS

There are no effective disease modifying drugs currently available.

OTHER DEMYELINATING DISEASES

NEUROMYELITIS OPTICA (Devic’s disease)

A subacute disorder characterised by simultaneous or consecutive demyelination of the optic nerves and spinal cord. Whether a distinct entity or variant of MS is uncertain. Pathologically demyelination is associated with marked cavitation and necrosis (possibly due to severe oedema confined and compressed by the pia of the optic nerves and spinal cord). Systemic lupus erythematosus, Behçet’s disease and sarcoidosis produce a similar picture.

Clinical features

Visual loss is rapid, bilateral and occasionally total.

Spinal cord symptoms follow – hours, days or occasionally weeks later.

Back pain and girdle pain. Paraesthesia in lower limbs.

Paralysis may ascend to involve respiratory muscles.

Urinary retention is common.

Recovery is complete in 60–70% of patients. When recurrent attacks occur, this results in an aggressive course with a high fatality.

Examination

Investigations

Anti-aquaporin 4 antibody is positive in over 90% of patients.

Visual evoked responses are prolonged. The CSF shows an elevated protein with a lymphocytosis occasionally as high as 1000 cells per mm³. Gammaglobulin may be elevated and OCBs absent. MRI shows cord swelling with enhancement over several levels.

Treatment

Patients may respond to i.v. methylprednisone or plasma exchange. Supportive treatment is required to minimise complications (DVT/PE, decubiti, contractures). Ventilatory support is sometimes required and may be permanent. There appears to be a case for using immunosuppressive drugs (azathioprine, cyclophosphamide) to prevent relapses though evidence is as yet limited.

TRANSVERSE MYELITIS

This occasionally occurs as the first manifestation of MS but this also occurs with viral infection (e.g. herpes virus), vasculitis and atherosclerotic vascular disease. Only 4% of patients with normal cranial MRI progress to MS. Investigations should exclude other causes of acute spinal cord syndrome – spinal cord compression – by MRI.

ACUTE DISSEMINATED ENCEPHALOMYELITIS (ADEM) (postinfectious encephalomyelitis)

ADEM is an acute immune-mediated demyelinating disorder in which small foci of demyelination with a perivenous distribution are scattered throughout the brain and spinal cord. Lesions are 0.1–1.0 mm in diameter.

This disorder may follow upper respiratory and gastrointestinal infections (viral), viral exanthems (measles, chickenpox, rubella, etc.) or immunisation with live or killed virus vaccines (influenza, rabies).

Measles is the commonest cause occurring in 1 per 1000 primary infections; next Varicella zoster (chickenpox), 1 per 2000 primary infections.

Clinical features: Within days or weeks of resolution of the viral infection, fever, headache, nausea and vomiting develop. Meningeal symptoms (neck stiffness, photophobia) are then followed by drowsiness and multifocal neurological signs and symptoms – hemisphere brain stem/cerebellar/spinal cord and optic nerve involvement. Myoclonic movements are common.

Predominantly spinal, cerebral or cerebellar forms occur, though usually the picture is mixed. Optic nerve involvement takes the form of optic neuritis. Rarely the peripheral nervous system is involved.

Diagnosis: No diagnosis test. CSF – 20–200 mononuclear cells. Total protein and γ globulin raised. Peripheral blood may be normal or show neutrophilia, lymphocytosis or lymphopenia.

The electroencephalogram (EEG) shows diffuse slow wave activity. CT scan is normal. MRI shows small focal white matter changes, simultaneously enhancing with contrast indicating that all are of the same degree of acuteness (unlike MS).

Diagnosis is straightforward when there is an obvious preceding viral infection or immunisation. When viral infection immediately precedes, distinction from acute encephalitis is often impossible.

Separation from acute MS may be difficult. Fever, meningeal signs with elevated CSF protein above 100 mg/ml with cell count greater than 50 per mm³ suggest ADEM.

Pathology: demyelination is limited to perivascular areas and lesions do not approach the same size as in MS.

Outcome: The illness is typically monophasic.

The mortality rate is 20%.

Full recovery occurs in 50%.

Poor prognosis is associated with an abrupt onset and the degree of deficit.

Treatment: Steroids are used, although no controlled trials have been conducted. Large dosage is recommended during the acute phase. Cyclophosphamide may be used in refractory cases.

ACUTE HAEMORRHAGIC LEUKOENCEPHALITIS

This is a rare demyelinating disease. It is regarded as a very acute form of postinfectious/acute disseminated encephalomyelitis.

Clinical picture: Antecedent viral infection, depression of conscious level and multifocal signs and symptoms. Focal features may suggest a mass lesion or even herpes simplex encephalitis.

The diagnosis is only really possible at biopsy or autopsy, but elevated CSF pressure, lymphocytosis and erythrocytes in CSF and xanthochromic appearance of fluid are all suggestive.

Pathology: Perivascular polymorph infiltration. Microscopic and macroscopic haemorrhage. Perivascular demyelination and necrotising changes in vessels.

Treatment: Steroids in high dosage should be used though evidence of value in this rare condition is scant.

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

This is a demyelinative disease occurring in association with systemic illness in which cell-mediated and occasionally humoral immunity is depressed, e.g. AIDS (4% of cases), lymphoma, sarcoidosis, systemic lupus erythematosus. The disorder is due to reactivation of previous papovavirus (SV40 or JC virus) infection.

Clinical picture: Features of diffuse process – personality change, hemiparesis, cortical visual loss, seizures, etc. Duration of illness: 3–6 months. Non-remitting and fatal.

Pathology: Demyelination without inflammatory response, especially in subcortical white matter. Electron microscopy – papovavirus in oligodendroglia.

Diagnosis: CT scanning and MR reveal widespread multifocal white matter damage. Definitive diagnosis is made from brain biopsy. Virus can be isolated by inoculation on to glial tissue culture.

Treatment: reversal of any underlying immune deficit (for example highly active antiretroviral therapy (HAART) in patients with AIDS) may slow progression.

LEUKODYSTROPHIES

Inborn errors of metabolism may affect the normal development of myelin. These genetic disorders usually present in infancy or childhood but occasionally produce their first manifestations in adult life.

3 specific types are recognised

– Metachromatic leukodystrophy

– Globoid cell leukodystrophy

– Adrenomyeloneuropathy or adrenoleukodystrophy (ADL).

The last condition is sex linked, characterised by adrenal insufficiency and disordered myelin in brain, spinal cord and peripheral nerve. The clinical picture is highly variable and results from a defect in beta oxidation of very long chain fatty acids (VLCFA) which build up in blood and skin fibroblasts. Dietary treatments (Lorenzo’s oils) lower these and may slow progression of this fatal disorder. Heterozygote female carriers may become symptomatic with a late onset progressive myelopathy.

NEUROLOGICAL COMPLICATIONS OF DRUGS AND TOXINS

History and examination

When acute intoxication is suspected, the following clinical features are supportive.

Also: Note

– Puncture marks in narcotic addicts

– The presence of a snout area rash in solvent abusers

– Rashes in barbiturate poisoning

– Respiration rate in salicylate poisoning

– Skin colour in carbon monoxide poisoning.

Clinical features:

While the neurological picture is generally diffuse, certain pronounced symptoms occur with one drug or toxin and not with another. The following table should act as a guide to diagnosis and alert the clinician to the possible offending substance.

For treatment, the reader is advised to consult an appropriate pharmacology or general medical text.

DRUG-INDUCED NEUROLOGICAL SYNDROMES

HEADACHE

Vasodilators: antihistamines, sympathomimetics, calcium channel blockers, bronchodilators, ergotamine, cocaine

Dopamine agonists

Non-steroidal anti-inflammatories

SEIZURES

Antidepressants, antimicrobials: cycloserine, isoniazid, metronidazole, penicillin

Antineoplastics: vincristine, methotrexate.

Analgesics: pentazocine, fentanyl, opiates

Anaesthetics: ketamine, halothone, althesin

Bronchodilators. Sympathomimetics

Miscellaneous: amphetamine, baclofen, lithium, iodinated contrast media, insulin

CONFUSION/DELIRIUM

Anticholinergics. Anticonvulsants

Antimicrobials: iosiazid, rifampicin

Antineoplastics: vincristine

Dopamine agonists. Tranquillisers

Miscellaneous: cimetidine, ranitidine, lithium

PERIPHERAL NEUROPATHY

Antimicrobials: ethambutol, isoniazid, nitrofurantoin, metronidazole, dapsone

Antineoplastics: cytosine arabinoside, cisplatin, procarbazine, vincristine (and other vinca alkaloids)

Antirheumatics: colchicine, D-penicillamine, gold, indometacin

Miscellaneous: cimetidine, phenytoin

RETINOPATHY

Antimalarials: chloroquine, mepacrine

VIII NERVE DAMAGE

Aminoglycoside antibiotics: gentamicin, kanamycin, neomycin, streptomycin

Miscellanous: cisplatin, ethycrinic acid, quinine, salicylates

VISUAL DISTURBANCE

Phenothiazines Miscellaneous: ethambutol, indometacin, tamoxifen

OPTIC NEURITIS

Antimicrobials: chloramphenicol dapsone, isoniazid, streptomycin

Miscellaneous: chlorpropamide

MOVEMENT DISORDERS

Antiemetics: metoclopramide

Butyrophenones: haloperidol, droperidol

Dopamine agonists. Phenothiazines: chlorpromazine, thioridazine

Tricyclic antidepressants

ATAXIA

Anticonvulsants: carbamazepine, phenytoin, primidone

Antineoplastics: cytosine arabinoside, fluoracil

Phenothiazines: sedatives; barbiturates, chloral hydrate. Tranquillisers: diazepam

MUSCLE PAIN AND WEAKNESS

Antineoplastics: cytosine arabinoside, methotrexate, thiotepa

Statins

Miscellaneous: clofibrate, D-penicillamine, danazol, L-tryptophan.

Drug screen in suspected overdosage

Too often the clinician, when managing drug or toxin overdosage, requests a ‘drug screen’. The techniques used in detection, e.g. gas chromatography, thin-layer chromatography and immunological tests, are sophisticated and time-consuming and may require samples of serum, urine or both.

The clinician must ‘narrow down the field’ from the history and presenting symptoms/signs and discuss with the laboratory the class of drug or toxin he suspects. A knowledge of the blood level of some drugs, e.g. salicylates, barbiturates, is important in deciding the approach to treatment.

SPECIFIC SYNDROMES OF DRUGS AND TOXINS

NEUROLEPTIC MALIGNANT SYNDROME

A rare life-threatening disorder induced by initiation, increase or reintroduction of neuroleptic drugs (e.g. chlorpromazine, haloperidol). The condition appears to result from acute dopamine receptor blockade and is characterised by hyperpyrexia, bradykinesia, rigidity, autonomic disturbance, alteration of consciousness and high serum muscle enzymes (creatine kinase). The causal drug should be withdrawn and the patient cooled. Give dopamine agonists with dantrolene sodium to control bradykinesia and rigidity respectively. Death occurs in 15% from renal failure and/or cardiovascular collapse.

SEROTONIN SYNDROME

SSRIs can cause dystonia and occasionally low-grade fever, confusion, autonomic disturbance, restlessness and rigidity. Early recognition and drug withdrawal is vital for good outcome.

Treatment of acute intoxication is symptomatic; there are no specific antidotes.

Industrial exposure to hydrocarbons produces similar symptoms.

ORGANOPHOSPHATES

These are widely used as insecticides (sheep dip) and herbicides. They cause symptoms by phosphorylation of the enzyme acetyl cholinesterase. Acute intoxication produces seizures, autonomic disturbance and coma.

LEAD EXPOSURE

Lead has no biological function. It is present in normal diet as well as in the atmosphere from automobile fumes and in the water supply of old buildings containing lead tanks and piping. Occupation exposure occurs in plumbers, burners and smelters. Lead excess interferes with haem synthesis. This results in the accumulation of ‘blocked’ metabolites such as aminolevulinic acid (ALA) in serum and urine. It also inhibits oxidative enzymes (e.g. Superoxide dismutase). Anaemia occurs with a characteristic finding in the blood film (basophilic stippling). Both the peripheral and central nervous systems are affected.

Treatment

Chelating agents (e.g. calcium disodium edetate – EDTA – or D-penicillamine) and i.v. mannitol in acute encephalopathy with papilloedema.

In acute fulminating encephalopathy the mortality has been reduced to 5%, but neurological sequelae are common.

COMPLICATIONS OF RECREATIONAL DRUG ABUSE

The problems of drug abuse are of epidemic proportions. An increasing number of neurological syndromes are recognised.

All recreational drugs are associated with increased risk of cerebral or spinal infarction or intracerebral haemorrhage. (Mechanisms are varied – drug-induced hypertension, coagulopathies, foreign body (talc) embolisation and septic emboli from infective endocarditis.)

All intravenous drug abusers are at risk of HIV infection and its complications (page 515)

METABOLIC ENCEPHALOPATHIES

In general terms, the clinical features of metabolic encephalopathy are relatively stereotyped reflecting a generalised disturbance of function of both hemispheres.

These features are characteristic but exceptions occur in specific encephalopathies –

Beware of the possibility of multiple pathology, e.g. an alcoholic patient with a chronic subdural haematoma may also have liver failure and thiamine deficiency.

CLASSIFICATION AND BIOCHEMICAL EVALUATION

Many metabolic disturbances cause an acquired encephalopathy in adults.

The most frequently encountered are:

Less commonly:

– Hyponatraemia. Hypernatraemia.

– Hypokalaemia. Hyperkalaemia.

– Hypocalcaemia. Hypercalcaemia.

– Hypothyroidism. Lactic acidosis.

– Addison’s disease.

Drugs and toxins producing encephalopathy are dealt with separately (page 533).

Laboratory assessment of suspected metabolic encephalopathy

All patients should have a basic biochemical screen:

– Serum urea and electrolytes.

– Liver function (albumin, globulin, bilirubin, alkaline phosphatase and enzymes) and random blood glucose.

– Blood gases (pH, PO₂ PCO₂).

– Serum ammonia.

– Electroencephalography – slow wave activity (theta or delta) supports the diagnosis of a diffuse dysfunction: hepatic encephalopathy shows a specific triphasic slow wave configuration.

– CT scan – if the above tests are normal or coexisting structural brain disease is suspected.

Calculation of the anion gap may be helpful in the diagnosis of encephalopathies, especially lactic acidosis. The sum of the anions (Cl ⁻ and HCO ⁻₃) normally equals the sum of the cations (Na⁺ and K⁺). An increase in the gap in the absence of ketones, salicylates and uraemia suggests lactic acidosis or ethylene glycol poisoning.

HYPOXIC ENCEPHALOPATHY

Impaired brain oxygenation results from:

– Reduced arterial oxygen pressure – lung disease.

– Reduced haemoglobin to carry oxygen – anaemia or blood loss.

– Reduced flow of blood containing oxygen (ischaemic hypoxia) – due to reduced cardiac output (with reduced cerebral blood flow).

– Biochemical block of cerebral utilisation of oxygen – rare (e.g. cyanide poisoning).

When cerebral arterial PO₂ falls below 35 mmHg (4.5 kPa), anaerobic metabolism takes over; this is not efficient and a further drop in PO₂ will result in neurological dysfunction. The extent of hypoxic damage depends not only upon the duration of hypoxia but also on other factors, e.g. body temperature – hypothermia protects against damage. The irreversibility of hypoxic damage is explained by the ‘no flow phenomenon’ – after 3–5 minutes the endothelial lining of small vessels swells – even with reversal of hypoxia, flow through these vessels is no longer possible.

SPECIFIC ENCEPHALOPATHIES

Pathology

As a consequence of high metabolic demand, some areas are more susceptible than others.

Microscopic changes depend upon the delay between the hypoxic event and death.

Immediate:	At 48 hours:	At several days/weeks:
Scattered petechial haemorrhages.	Cerebral oedema associated with petechial haemorrhage.	Necrosis in cortical grey matter and globus pallidus with associated astrocytic proliferation. The cerebellum and brain stem may also be affected.

Clinical features:

e.g. Severe hypoxia from circulatory arrest

Delayed hypoxic encephalopathy refers to the rare occurrence of a full clinical recovery followed after some weeks by a progressive picture → deterioration of conscious level → death. Widespread subcortical demyelination is found at autopsy.

HYPERCAPNIC ENCEPHALOPATHY: the consequence of an elevated arterial carbon dioxide level.

Clinical features:

Headache, confusion, disorientation, involuntary movements.

Papilloedema, depressed limb reflexes, extensor plantar responses.

Diagnosis: A PCO₂ greater than 50 mmHg (6 kPa) with a reduced PO₂ is found on arterial blood sampling.

The presence of headache, confusion and papilloedema may suggest intracranial tumour. If hypercapnia has not been diagnosed, such patients inevitably are referred for CT brain scan.

HYPOGLYCAEMIA ENCEPHALOPATHY: the consequence of insufficient glucose reaching the brain and may result from – overdosage of diabetic treatment

– insulin secreting tumour – insulinoma

– hepatic disease with reduction of liver glycogen.

Serum glucose levels of 1.5 mmol/l are associated with the onset of encephalopathy. Levels at 0.5 mmol/l are associated with coma.

Pathology: Changes occur in the cerebral cortex – focal necrosis surrounded by neuronal degeneration. Subcortical grey matter (caudate nucleus) and cerebellum are vulnerable.

Clinical features: These, as with hypoxia, depend upon the duration and severity of hypoglycaemia.

Repeated mild to moderate episodes may result in a chronic cerebellar ataxia.

Repeated severe attacks may result in a mixed myelopathy/peripheral neuropathy which is distinguished from motor neuron disease by the presence of sensory signs.

HYPERGLYCAEMIC ENCEPHALOPATHY

Two types of encephalopathy develop as a consequence of hyperglycaemia:

Diabetic ketoacidotic coma	Diabetic hyperosmolar non-ketotic coma
Accumulation of acetone and ketone bodies in blood results in acidosis. Hyperventilation ensues with a reduction in PCO₂ and HCO⁻₃ Osmotic diuresis due to hyperglycaemia results in dehydration.	This results from the hyperosmolar effect of severe hyperglycaemia. Reduction of the intracellular compartment results. Involuntary movements, seizures and hemiparesis may occur. Vascular thrombosis is not uncommon. Ketoacidosis is mild or does not occur.
The neurological presentation is that of confusion, progression to coma and, if untreated, death.

HEPATIC ENCEPHALOPATHY

Neurological signs and symptoms secondary to hepatic dysfunction may arise in:

– acute liver failure.

– chronic liver failure complicated by infection or gastrointestinal haemorrhage.

– chronic liver failure producing characteristic hepatocerebral degeneration.

Clinical features:

The encephalopathy is progressive.

Pathology

Neuronal loss with gliosis is noted in the cerebral cortex as well as basal ganglia, cerebellum and brain stem. Astrocytes with irregular and enlarged nuclei are characteristic.

Hepatocerebral degeneration (Wilson’s disease) (see page 373) is an abnormality of copper metabolism and leads to a deposition of copper in the brain, particularly the basal ganglia, and the liver. This leads to a slowly progressive neurological disorder. This can vary but the predominant features include dementia, dysarthria and ataxia, primitive reflexes, choreoathetosis, myoclonus, tremor and pyramidal signs.

Consciousness is not impaired.

URAEMIC ENCEPHALOPATHY

Clinical features:

Pathology:

Uraemia may produce non-specific pathological findings in the nervous system. Peripheral nervous system involvement occurs in chronic renal failure.

Dialysis encephalopathy is encountered in persons on renal dialysis exposed to high aluminium levels in the dialysate. The features are those of dementia, behavioural changes, seizures and myoclonus. The condition progresses unless aluminium levels are controlled.

Specific investigations and treatment of individual metabolic encephalopathies do not come within the scope of this book.

NUTRITIONAL DISORDERS

INTRODUCTION

Nutritional deficiency presents a massive problem in the developing world. In Western countries, alcoholism is the major cause of the neurological syndromes resulting from dietary deficiency with faddism and malabsorption disorders accounting for only a small number.

Vitamins appear important nutrients and certain disorders such as Wernicke Korsakoff syndrome (thiamine) or subacute combined degeneration (vit. B₁₂) are attributed to a single deficiency. Others such as polyneuropathy result from multiple deficiency.

Vitamin deficiency in itself does not always produce symptoms; a dietary excess of carbohydrate seems essential for the development of the neurological features of thiamine deficiency.

As a rule, nutritional disorders of the nervous system present clinically in a symmetrical manner.

WERNICKE KORSAKOFF SYNDROME

This syndrome is comprised of an acute and a chronic phase:

Patients often demonstrate additional features of nutritional deficiency – peripheral neuropathy, trophic skin changes and autonomic dysfunction (arrhythmias, postural hypotension and hypothermia). Features of acute alcohol withdrawal often co-exist.

N.B. Korsakoff’s psychosis may also be caused by head injury, anoxia, epilepsy, encephalitis and vascular diseases.

WERNICKE’S SYNDOME

Diagnosed in 0.1–0.4% of hospital admissions.

Pathology:

Neuronal, axonal and myelin damage occur symmetrically in the mamillary bodies, the walls of the third ventricle, thalamus and periaqueductal grey matter. Secondary vascular proliferation and haemorrhages occur within these lesions.

WERNICKE KORSAKOFF SYNDROME

Investigation

• Serum B₁ levels may be low.

• Pyruvate is elevated.

• Transketolase activity is decreased (enzyme in hexose monophosphate shunt).

• MRI may show mamillary body atrophy.

Treatment

Intravenous (i.v.) Pabrinex containing thiamine (B₁), riboflavin (B₂), pyridoxine (B₆), is the only available treatment. Oral treatment is ineffective. Treatment must be given immediately to persons with a suggestive clinical picture and evidence of chronic alcohol use. Those with a history of alcohol abuse requiring IV glucose should be treated prophylactically (thiamine is critical for the metabolism of carbohydrate and levels can be exhausted by a sudden load).

With treatment – Eyes improve – in days, though nystagmus may persist for months.

– Ataxia improves – in weeks.

Overall mortality: 15% → coma → death.

Failure to recognise and promptly treat can result in Korsakoff’s syndrome or psychosis.

There is a disturbance of memory in which information cannot be stored. In addition the normal temporal sequence of established memories is disrupted, resulting in a semifictionalised account of the circumstances which the patient may find him/herself in (confabulation). This memory disturbance can only be tested for when the confusion of Wernicke’s disease has cleared.

Treatment

Acute treatment is with vitamin replacement as for Wernicke’s – there is no other specific treatment. The loss of short term memory causes significant disability and patients will often require closely supervised care.

B₁₂ DEFICIENCY – SUBACUTE COMBINED DEGENERATION OF THE SPINAL CORD

B₁₂ deficiency produces the specific neurological syndrome of subacute degeneration of the spinal cord (SADC). Two cobalamin-dependent enzymatic reactions occur in humans. The first reaction converts methylmalonyl-coenzyme A (CoA) to succinyl-CoA. The second involves the synthesis of methionine from homocysteine. Deficiency in B₁₂ therefore results in an accumulation of homocysteine. Despite the importance of methionine to myelin sheath phospholipid methylation, the basis of neurological damage remains uncertain.

Causes

• Inadequate diet (e.g. strict vegans)

• Increased need – pregnancy

• Defective absorption – Pernicious anaemia

– decreased intrinsic factor (necessary for absorption)

– malabsorption (pancreatitis, coeliac disease, gastric surgery, tapeworm infestation etc.)

– Plantar responses are extensor.

– Sensory loss: loss of vibration and joint position sensation in the lower limbs. Stocking/glove sensory loss is found when peripheral nerves are involved.

– Reflex findings are variable and depend on the predominance of peripheral nerve or corticospinal tract involvement.

Mini mental status examination (MMSE) test may suggest dementia.

Optic pallor and centrocaecal scotoma can be demonstrated.

Diagnosis

Suspect in paraparesis with combined upper and lower motor neuron signs with ‘stocking/glove’ sensory loss.

Differentiate from other causes of acute myelopathy, e.g. cord compression, multiple sclerosis.

Investigation

Peripheral blood film – may show a megaloblastic anaemia

Serum B₁₂/Folate – low B₁₂. (If folate low – investigate causes: diet/drugs/malabsorption) If serum B₁₂ low (normal > 190 ng/l)

– measure intrinsic factor antibody

– Schilling test (measure of capacity to absorb)

– if normal – dietary

– if low – repeat with intrinsic factor (normal = pernicious anaemia, abnormal = malabsorption and investigate accordingly)

MRI – may show spinal and cerebral white matter hyperintensity on T2 images Nerve conduction studies – may show axonal neuropathy

Treatment

Consider treatment for patients who have serum B₁₂ level of less than 130 ng/l (neurological dysfunction normally occurs with levels < 100 ng/l).

Initiate treatment with vitamin B₁₂, 1000 micrograms intramuscularly given daily for 3 to 7 days, then weekly for 4 weeks.

Continue maintenance therapy for life.

Course and progression

Untreated, the disorder is progressive, the patient eventually becoming bed-bound and comatose. If diagnosed and treated early (within 2 months of onset), complete recovery can be anticipated. In established cases, only progression may be halted.

Caution: When folic acid is prescribed alone, it will improve the haematological picture of B₁₂ deficiency but cause rapid often irreversible neurological deterioration.

Tocopherol (vit. E).

In its active form – D α tocopherol – it acts as a membrane stabilizer and anti-oxidant. Deficiency occurs in chronic fat malabsorption (e.g. coeliac disease or cystic fibrosis) and results in widespread neurological disturbances – ataxia, ophthalmoplegia, seizures and corticospinal tract dysfunction. These are halted and often reversed by i.m. vit. E. It has been speculated that the antioxidant effect might make vitamin E a candidate for cytoprotection and repair within the nervous system. Studies in Parkinson’s disease, multiple sclerosis and stroke are disappointing.

Abetalipoproteinaemia (Bassen-Kornzweig syndrome) predisposes to vit. E deficiency (the vitamin is transported by low-density lipoproteins). These patients have acanthocytes in the peripheral blood and a pigmentary retinopathy.

NUTRITIONAL POLYNEUROPATHY

Deficiency of vitamin B complex – B₁ (Thiamine), B₂ (Riboflavin), B₃ (Nicotinic acid), B₅ (Pantothenic acid) or B₆ (Pyridoxine) – results in peripheral nerve damage.

The combination of polyneuropathy and cardiac involvement is referred to as BERI-BERI. When oedema is also present it is termed wet beri-beri and, when absent, dry beri-beri. Beri-beri occurs in rice eating countries.

In Western countries, alcoholism is the major cause of nutritional polyneuropathy with or without cardiac involvement, otherwise world wide famine and starvation is responsible.

Pathology

The distal portions of nerves are initially affected.

Anterior horn cells and dorsal root ganglion cells undergo chromatolysis.

Vagus nerve and sympathetic trunk involvement occurs in severe cases.

Associated signs

Shiny skin on legs with poor distal hair growth. ‘Hyperpathic’ painful soles of feet. Evidence of liver failure.

Diagnosis

Supported by investigation such as peripheral blood film (elevated MCV) and disturbed liver function tests.

Nerve conduction studies reveal mildly reduced motor and sensory conduction velocities.

Differential diagnosis

Consider other causes of subacute or chronic sensorimotor neuropathy (see page 436).

Treatment

A high calorie (3000) diet should be supplemented daily with Thiamine (25 mg), Niacin (100 mg). Riboflavin (10 mg), Pantothenic acid (10 mg) and Pyridoxine (5 mg).

Burning paraesthesia may respond to gabapentin, pregabalin or carbamazepine.

Recovery may be very slow and incomplete but with the withdrawal of alcohol and adequate vitamin supplementation some improvement should occur.

TOBACCO–ALCOHOL AMBLYOPIA

A large number of toxic substances can produce impaired vision. Methyl alcohol causes sudden and permanent blindness. Chronic painless visual loss from optic neuritis develops in malnourished patients with a high tobacco consumption (Tobacco-alcohol amblyopia). This is caused by exposure to cyanide from tobacco smoking associated with low vitamin levels due to poor nutrition and absorption associated with drinking alcohol. Other potential toxins include methyl alcohol (moonshine) and ethylene glycol (antifreeze).

ALCOHOL RELATED DISORDERS

ALCOHOL MYOPATHY

Muscle damage (elevated creatine phosphokinase) is not uncommon in alcoholics following acute ingestion. The cause of alcoholic myopathy is uncertain; mitochondrial disturbances, potassium depletion, rhabdomyolysis (due to seizures or local compression) have all been suggested.

There are two forms of alcoholic muscle disease

2. Chronic myopathy Painless proximal weakness sometimes associated with cardiomyopathy. Muscle biopsy showing type 2 fibre atrophy.

Management is abstinence, vitamin supplementation and IV saline in acute necrotizing myopathy with myoglobinuria to prevent renal failure.

ALCOHOLIC DEMENTIA

Experimentally, chronic alcohol consumption results in neuronal loss. CT evidence of atrophy and neuropsychological impairment is common in alcoholics. However, whether or not these result from the direct toxic and dementing effect of alcohol remains uncertain.

ALCOHOLIC CEREBELLAR DEGENERATION

Probably the commonest cause of acquired ataxia, alcoholic patients may develop a chronic cerebellar syndrome either as a sequel of Wernicke’s syndrome or as a distinct clinical entity. A long history of alcohol abuse is obtained. Males are predominantly affected. Onset is gradual and symptoms often stabilise. Ataxia of gait with lower limb inco-ordination predominates. The upper limbs are spared. Nystagmus is rarely present. Cerebellar dysarthria is usually mild. Coexistent signs of peripheral neuropathy are often found.

Investigations:

– Abnormal liver function tests e.g. elevation of enzymes – γ GT.

– Macrocytosis in peripheral blood film.

– CSF examination normal.

– CT and MRI reveal cerebellar vermal atrophy.

Progression

may evolve rapidly and reverse with improved nutrition and alcohol withdrawal. may evolve subacutely. may evolve chronically and slowly progress over many years. Pathology:

– All the cellular elements of the cerebellar cortex are affected, but particularly Purkinje cells of the anterior and superior vermis and the anterior portion of the anterior lobes.

Pathogenesis:

– The disorder may be due to nutritional deficiency, especially thiamine, or else result from the direct toxic effect of alcohol or electrolyte disturbance on the cerebellum.

Differential diagnosis:

– Distinguish from hereditary and other acquired ataxias, e.g. hypothyroidism.

Treatment:

– Alcohol withdrawal, a well balanced diet and adequate vitamin supplementation.