Tuberculous meningitis: what is it and what symptoms does it have?

It kills more people than AIDS, malaria and all tropical diseases combined. It affects mainly children, up to 300,000 a year.

The most effective form of defence against this disease is, above all, awareness among the general public and health professionals, early diagnosis, combating the emergence of multidrug-resistant strains of bacteria and, in some countries, the ongoing vaccination with a specific vaccine.

Tuberculous (TB) meningitis is the most serious form of extrapulmonary tuberculosis, a form that has spread to other organs of the body in addition to affecting the lungs.

It is also the most common form of bacterial meningitis in communities affected by the HIV and AIDS epidemics.

If diagnosed and treated early, up to 95% of patients can make a full recovery.

If the disease progresses to advanced stages despite antibiotic treatment, disability and, unfortunately, death are common consequences.

Tuberculous meningitis is most common in developing countries. Diagnosis there is often delayed due to confusion with other forms of bacterial meningitis, leading to incorrect treatment and loss of time.

In more developed communities, tuberculous meningitis occurs mainly in the elderly and in patients who are immunosuppressed. Immunosuppressed patients have reduced natural immunity due to other chronic diseases or are taking treatment that reduces their immunity.

Even in developed countries, diagnosis may be delayed or inaccurate. This is due to ignorance of the disease. Due to long-term vaccination, doctors today do not routinely encounter this disease or expect it in their patients.

Tuberculous meningitis is caused by Mycobacterium tuberculosis.

It is a Gram-positive, aerobic, non-sporulating, non-mobile rod that is distantly related to Actinomycetes.

The predisposing factors for tuberculous meningitis are similar to those for any other form of tuberculosis.

They include:

• Poverty
• overcrowding
• illiteracy
• malnutrition
• alcoholism
• substance abuse
• diabetes
• immunosuppressive treatment
• malignant tumour
• head injury
• Human immunodeficiency virus (HIV) infection

Transmission of Mycobacterium tuberculosis bacteria to a healthy person occurs primarily through airborne droplets that float freely in the air.

Once inhaled, they enter the lungs, where Mycobacterium tuberculosis multiplies in alveolar macrophages, which are the cells responsible for the immune defence of the lungs.

Within 2-4 weeks, they spread through the bloodstream to organs outside the lungs and form small granulomas. These sites may include the meninges and adjacent brain tissue.

These lesions are most common in the meninges and on the subpial or subependymal surface of the brain. Abundant foci of granulomas containing bacteria remain inactive for several years.

Granulomas that have been inactive for several years rupture and their contents spill into the subarachnoid space of the brain. Thus tuberculous meningitis occurs.

The exact cause of granuloma rupture is not known. Weakened immunity, including malnutrition and HIV infection, plays a significant role.

Direct dissemination from a tuberculous focus, for example from the middle ear or from vertebral inflammation (spondylitis), is relatively rare as a cause of TB meningitis.

In meningitis infection, meningeal effusion is produced, which contains a variety of bacteria.

The bacteria clog the narrow liquor pathways and openings through which the liquor flows and circulates around all parts of the brain - the brain stem, cerebral arteries and cranial nerves. The liquor also surrounds the spinal cord and spinal roots.

Obstruction of the flow of fluid beyond the tentorium (the boundary between the large lobes of the brain and the cerebellum) leads to communicating hydrocephalus. This is the most common type of hydrocephalus.

Blockage of the fourth ventricular outflow tract leads to non-communicating hydrocephalus. This is rarer but more severe. Unlike communicating hydrocephalus, it requires invasive neurosurgical treatment.

Tuberculous meningitis is usually preceded by a varied period of non-specific symptoms. The most common non-specific symptoms include:

• Nausea
• nausea
• fatigue
• weight loss
• fever
• muscle pain
• headache

At the first visit to the doctor, most patients are already in an advanced stage of the disease that has these symptoms:

• fever
• headache
• vomiting
• changes in sensitivity
• stiff neck

Cranial nerve opacities, loss of vision and other neurological deficits with signs of increased intracranial pressure, such as severe headache and vomiting, may occur. These are symptoms of an already advanced stage of tuberculous meningitis.

Elderly patients have atypical clinical symptoms. This often leads to delayed diagnosis. Meningeal symptoms are less common in these patients. Fever, headache, vomiting, neck stiffness, altered sensitivity, seizures and local neurological deficits predominate.

Sometimes tuberculous meningitis in the elderly may manifest as subacute dementia with memory impairment and personality change.

In paediatric patients, the clinical findings are dominated by signs of increased intracranial pressure, convulsions, paralysis of the limbs and face, and even coma.

Generalized tonic and clonic seizures are the most common type of seizures in tuberculous meningitis.

A common metabolic abnormality in patients with tuberculous meningitis is hyponatraemia, i.e. low sodium content in the body. It is caused by repeated vomiting and malnutrition.

The most advanced stages of tuberculous meningitis are characterised by deep coma, hemiplegia (paralysis of half of the body) or paraplegia (paralysis of the arms or legs), decerebration with the body bent backwards, deterioration of vital signs and finally death.

Cranial nerve palsy occurs in approximately 25% of cases. The most commonly affected cranial nerve is the sixth cranial nerve, which is responsible for lateral eye movements.

Cranial nerve damage occurs either as a result of brainstem involvement or as a result of increased intracranial pressure.

Loss of vision is a very sad and serious complication of tuberculous meningitis.

There are several reasons why optic nerve damage occurs. One of them is the optic nerve oppression in the enlargement of the third ventricle in hydrocephalus, oppression by granuloma or the toxicity of ethambutol. Ethambutol is an antibiotic given in high doses in tuberculosis.

So-called optochiasmatic tuberculoma is a rare cause of visual failure in tuberculous meningitis. It is an involvement of the optic nerve and brainstem by ring-shaped lesions visible on magnetic resonance imaging of the brain.

Paraplegia (paralysis of the arms or legs) is a very common complication. It is caused either by tuberculous radiculomyelitis or by spinal cord involvement by granulomas.

The manifestations of tuberculous radiculomyelopathy include pain, tingling, bladder control disorders and muscle wasting. Muscle wasting is a late manifestation of nerve involvement.

Cerebral infarctions are also common in patients with tuberculous meningitis. These are sudden strokes caused by ischaemia, i.e. insufficient blood supply to the brain. They are often located in the basal ganglia responsible for movements and in the thalamus.

Tuberculous meningitis is classified into three stages according to the depth of unconsciousness. Three neurological categories are assessed using the GCS scale:

Eye opening

• Spontaneous eye opening (4 points)
• open on address (3 points)
• openness to painful action (2 points)
• not opening eyes (1 point)

Best vocal expression

• appropriate verbal response (5 points)
• inadequate verbal response (4 points)
• responds only with single words (3 points)
• unintelligible sounds (2 points)
• no answer (1 point)

Best motor response

• Performs an appropriate movement when prompted (6 points)
• performs an automatic defensive movement to a painful stimulus (5 points)
• performs an automatic escape movement to a painful stimulus (4 points)
• perform a non-specific limb flexion movement to a painful stimulus (3 points)
• perform a non-specific limb extension movement to a painful stimulus (2 points)
• no movement in response to pain (1 point)

A GCS score of 15 to 13 indicates no or mild impairment of consciousness.
A GCS of 12-9 indicates moderate impairment of consciousness.
A GCS less than 8 indicates severe impairment of consciousness and coma.

Grades of tuberculous meningitis according to the above GCS scale:

• Grade 1: GCS 15 with no focal neurological deficit.
• Grade 2: GCS 11-14 or GCS 15 with focal neurological symptoms
• Grade 3: GCS < 10

For a correct diagnosis, early detection of the cause, or at least a medical presumption of a diagnosis of TB, is most important. The patient must undergo several examinations, for example, a lumbar puncture with the aim of laboratory examination of the liquor.

The examination of the lymph is crucial to confirm the diagnosis of tuberculous meningitis. Characteristic changes in the lymph help to distinguish TB from other causes of chronic meningitis.

Typical changes in the liquor include, for example, multiplied cells, low glucose levels and increased protein levels.

The gold standard is also the detection of Mycobacterium tuberculosis bacteria in the liquor by microscopic examination. Unfortunately, the smear is positive in only 5-30% of patients.

"Growing" the bacteria on specific soil in the laboratory and confirming the diagnosis in this way is also not always positive and can take up to several weeks.

A faster result with comparable sensitivity can be obtained by using a special test.

The so-called BacTec mycobacteria detection system is a fully automated system. It detects carbon dioxide produced during microbial metabolism.

The carbon dioxide causes the pH of the medium to drop and changes the colour of the sensor from dark green to yellow. The colour change is continuously monitored and immediately reported by the instrument itself.

The detection of tuberculosis bacteria in the liquor still remains a major diagnostic challenge.

Therefore, several newer diagnostic tests have been developed. These include the ELIspot test or the detection of cells secreting anti-Bacillus Calmette-Guérin antibodies in the liquor.

Neuroimaging

Both computed tomography (CT) and magnetic resonance imaging (MRI) are valuable imaging modalities in the diagnosis of tuberculous meningitis and in the evaluation of disease complications and treatment.

Characteristic changes on CT include the presence of effusions, hydrocephalus, increased meninges signal and periventricular infarcts (around the ventricles), and cerebral edema.

The presence of hydrocephalus is associated with a higher risk of stroke and indicates a poor prognosis of the disease.

A more sensitive imaging method for tuberculous meningitis is brain MRI. The examination, performed together with the contrast agent gadolinium, can reveal meningeal involvement early in the disease.

Enlarged nodules, lungs dotted with tuberculous granulomas and effusion may be present on chest X-rays of patients.

Tuberculosis does not manifest itself within a short time after infection like other infectious diseases. It has a very long incubation period.

After infection, clinically silent granulomas (tuberculomas) form in the body and remain 'silent' for several years. This stage of the disease is called the latent stage of tuberculosis.

After an outbreak, the spread of CNS bacteria is relatively rapid. For doctors, the diagnostic period is crucial, when they can detect the causative agent of infectious meningitis.

Antibiotic treatment effective against mycobacteria is highly specific, with up to four drugs in combination. Correct identification of the bacterium is therefore crucial for treatment.

The outcome of treatment is closely related to the age of the patient and the stage of the disease at the time of diagnosis.

Modern treatment has reduced the death rate from tuberculous meningitis to less than 15%. However, this is still a relatively high figure for a disease for which there is a cure.

Neurological sequelae are even more numerous after tuberculous meningitis has been overcome.

The most common sequelae include:

• Cognitive and thinking disorders (80%)
• personality and behavioural changes (40%)
• motor disorders (25%)

Blindness and deafness are rarer complications of modern, relatively potent and toxic treatments.

A worse treatment effect is expected in HIV-infected patients who do not take antiretroviral drugs against the virus and the development of its disease, i.e. AIDS.

Prevention

Prevention of tuberculosis consists of the following basic proven measures:

• isolation of the source of infection
• BCG vaccination
• chemoprophylaxis
• X-ray depistisiton
• Bacteriological depistribution
• Thorough public and health professional awareness

The most important thing is to protect the youngest children from contracting TB. In fact, TB in childhood occurs in almost half of families with a known incidence of TB.

TB is spread, for example, when grandparents who are TB carriers babysit their grandchildren.

Tuberculosis vaccination - calmetisation

This is an active immunisation where the body itself makes antibodies against TB.

The TB vaccine is due to two French microbiologists, L.C.A. Calmette and C. Guérin, who in 1906 in Paris produced a strain of cow-type mycobacteria that had a greatly reduced infectivity but a good immunizing capacity.

Administration of the BCG vaccine fixes the tuberculous mycobacteria at the point of entry into the body. The vaccine is injected intradermally, preferably into the arm.

Vaccination is best started from day 4 to week 6 of the newborn's life. This is only valid if the newborn has reached a birth weight of more than 2 500 g.

This is followed by re-vaccination at 11 years if the child is tuberculin negative.

Chemoprophylaxis

It is used in children who are in contact with active tuberculosis. It is also used in people with a high tuberculin reaction who also have another chronic disease that weakens the body's immunity. This may include diabetes, stomach and duodenal ulcers, HIV infection or corticosteroids.

It consists of the administration of the antituberculosis drug isoniazid at a dose of 300 mg per day for a maximum of 6 months. In addition, pyridoxine or rifampicin tablets are administered.