MULTIFOCAL NEUROLOGICAL DISEASE AND ITS MANAGEMENT

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SECTION V MULTIFOCAL NEUROLOGICAL DISEASE AND ITS MANAGEMENT

BACTERIAL INFECTIONS – MENINGITIS

ACUTE BACTERIAL MENINGITIS

In most cases the infection causing meningitis arises in the nasopharynx; intravascular invasion (bacteraemia) and penetration of the blood–brain barrier follow mucosal involvement with entry into the CSF. Bacteria may invade the subarachnoid space directly by spread from contiguous structures, e.g. sinuses and fractures. Specific characteristics of the capsule determine whether meninges are breached. Humoral defences against bacteria are absent in the CSF offering little resistance to infection.

Causative organisms

In neonates

– Gram –ve bacilli, e.g. E. coli, Klebsiella.

Haemophilus influenzae. In children

– Haemophilus influenzae. Pneumococcus (Strep. pneumoniae).

Meningococcus. (Neisseria meningitidis). In adults

– Pneumococcus. Meningococcus.

Other bacteria – Listeria monocytogenes, Streptococcus pyogenes and Staphylococcus aureus – are occasionally responsible.

Host factors (congenital or acquired immune deficiency, hyposplenism and alcoholism) predispose to infection, as do environmental factors (overcrowding and poverty).

Infections of mixed aetiology (two or more bacteria) may occur following head injury, mastoiditis or iatrogenically after lumbar puncture.

Pathology

The presence of the blood–brain barrier limits host defence mechanisms and enables multiplication of organisms.

A purulent exudate most evident in the basal cisterns extends throughout the subarachnoid space.

The underlying brain, although not invaded by bacteria, becomes congested, oedematous and ischaemic.

The integrity of the pia mater normally protects against brain abscess formation.

The cytokines, interleukin, tumour necrosis factor, and prostaglandin E2 are released as part of an acute inflammatory response. They increase vascular permeability, cause a loss of cerebrovascular autoregulation and exacerbate neuronal injury.

The inflammatory exudate may also affect vascular structures crossing the subarachnoid space producing an arteritis or venous thrombophlebitis with resultant infarction. Similarly, cranial nerves may suffer direct damage.

Hydrocephalus can result from CSF obstruction.

Clinical

The classical clinical triad is fever, headache and neck stiffness.

Prodromal features (variable)	Meningitic symptoms
A respiratory infection otitis media or pneumonia associated with muscle pain	Severe frontal/occipital headache
	Stiff neck
	Photophobia.

Systemic signs: – High fever. Transient purpuric or petechial skin rash in meningococcal meningitis.

Associated neurological signs

– Impaired conscious level

– Focal or generalised seizures are frequent.

– Cranial nerve signs occur in 15% of patients.

– Sensorineural deafness (not due to concurrent otitis media but to direct cochlear involvement) – 20%

– Focal neurological signs – hemiparesis, dysphasia, hemianopia, papilloedema – occur in 10%.

Non-neurological complications

Features specific to causative bacteria

Haemophilus meningitis	Meningococcal meningitis	Pneumococcal meningitis
Generally occurs in small children. Preceding upper respiratory tract infection. Onset abrupt with a brief prodrome.

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

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.

Investigations

1. If patient has altered consciousness, focal signs, papilloedema, a recent seizure or is immunocompromised a CT brain should be done before LP. However, do not delay treatment – take blood cultures and commence antibiotics (see below) prior to scanning.

2. If above signs are absent or CT scan excludes a mass lesion → confirm diagnosis with a lumbar puncture and identify the organism.

– cell count is elevated, 100–10 000 cells/mm³(80–90% polymorphonuclear leucocytes).

– glucose is depressed.

– enzyme lactic dehydrogenase is elevated.

– culture CSF

Serological/immunological tests

The latex particle agglutination (LA) test, for the detection of bacteria antigen in CSF, has a sensitivity 80% for haemophilus and pneumococcus and 50% for meningococcus (100% specificity). The polymerase chain reaction (PCR), for the detection of bacteria nucleic acid in CSF, is available for all the suspected organisms. The specificity and sensitivity of PCR is unknown and the delay (3 to 5 days) to process results, makes the test less helpful than the combination of Gram’s stain, culture, and the LA test.

Treatment

Once meningitis is suspected, treatment must commence immediately, often before identification of the causative organism. Antibiotics must penetrate CSF, be in appropriate bactericidal dosage and be sensitive to causal organism once identified.

Initial therapy (before organism identification)

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

Meningococcus Benzylpenicillin or 3rd generation cephalosporin according to sensitivities

Chloramphenicol

Fluoroquinolone

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

Chloramphenicol

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.

– 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:

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).

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.

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.

A condition similar to Reye’s syndrome occurs in some children with family history of ‘sudden infant death’. A deficiency of medium chain acetyl-CoA dehydrogenase (an enzyme essential for fatty acid metabolism) is found. Carnitine deficiency results as a consequence of ‘alternative pathway’ fatty acid metabolism. Siblings of children with Reye’s syndrome should be screened for this disorder.

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

Similar to SSPE with a fatal outcome, caused by rubella virus.

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)

A similar disorder condition to CJD. Cases are familial and characterised by specific pathology of spongiform changes associated with amyloid plaques containing PrP immunoreactive proteins. Clinical features are nonspecific – ataxia, Parkinsonism, dementia. Death occurs within 5 years of contact.

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.

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