Meningitis caused by Mycobacterium tuberculosis is characterized by low-grade fever, night sweats, headache, and loss of appetite in children under 5 years of age, tuberculosis patients, HIV-infected patients, and alcohol-dependent patients.
What is Tuberculous Meningitis?
Definition.
Tuberculous meningitis is a non-purulent meningitis caused by infection with Mycobacterium tuberculosis.
The surface of the brain is covered by the meninges, which are divided into three layers, from inner to outer: the soft meninges, the arachnoid, and the dura mater.
Mycobacterium tuberculosis invades the bloodstream, forms bacteremia, and circulates to the meninges, or choroid plexus vascular membranes, causing an inflammatory response.
Tuberculous meningitis may or may not be accompanied by systemic tuberculosis such as cornual tuberculosis, lymphatic tuberculosis, and osteoarticular tuberculosis.
Incidence
Globally, patients with tuberculous meningitis account for 1% to 5% of all tuberculosis, 5% to 10% of extrapulmonary tuberculosis, and about 70% of neurologic tuberculosis.
The co-morbidity rate of tuberculous meningitis and pulmonary tuberculosis can reach 29.4%~62.64%, and the morbidity and mortality rate or neurological disability rate is higher than 50%, and the incidence of the disease has been increasing in recent years.
Questions you may be concerned about
Can tuberculous meningitis cause epilepsy?
Tuberculous meningitis may cause epilepsy.
Tuberculous meningitis is a non-suppurative inflammatory disease of the meninges and spinal membranes caused by Mycobacterium tuberculosis.
Inadequate diagnosis and treatment of this disease can result in parenchymal brain damage, abnormal consciousness and mental health, seizures or persistent status epilepticus, paralysis of the limbs, confusion, and coma.
Seizures may also be caused by complications such as hydrocephalus and cerebral hemorrhage.
People with seizures can be treated with medications such as carbamazepine or sodium valproate.
Why is a lumbar puncture needed for tuberculous meningitis?
Characteristic changes in the cerebrospinal fluid are important for the diagnosis of tuberculous meningitis, so a lumbar puncture is needed.
The cerebrospinal fluid in this disease is turbid and grossly glassy. The white blood cell count is dominated by lymphocytes.
The biochemical features are high protein, low chloride, low glucose, and high protein. The glucose level may be less than 2.8 mmol/L, the protein level is greater than 450 mg/L, and the chloride is less than 120 mmol/L or less.
In addition adenosine deaminase and nucleic acid tests as well as culture of tuberculosis bacilli are helpful in making a definitive diagnosis.
How is tuberculous meningitis prevented?
Prevention of tuberculous meningitis mainly includes vaccination, treatment of primary tuberculous lesions, and strengthening of physical fitness.
BCG vaccination not only prevents the occurrence of tuberculosis, but also reduces the incidence of tuberculous meningitis when administered to newborns.
Thoroughly remove primary tuberculosis foci in the body, such as pulmonary tuberculosis, bone tuberculosis, etc., to prevent tuberculosis bacteria from destroying the blood-brain barrier through blood circulation.
Pay attention to nutrition, strengthen exercise, moderate work and rest, maintain optimistic mood, and enhance immunity.
Causes
Causes
Tuberculous meningitis is a disease that occurs when a person is infected with Mycobacterium tuberculosis through the respiratory tract.
Mycobacterium tuberculosis consists of four types: human, bovine, African and murine. Most of the pathogens of tuberculous meningitis are human-type Mycobacterium tuberculosis, and a few are bovine-type Mycobacterium tuberculosis.
Mycobacterium tuberculosis is elongated and slightly curved, about 0.4 micrometers × 0.4 micrometers, slightly blunt at both ends, unable to move, is an aerobic bacterium, and is naturally parasitic in humans.
Pathogenesis
Like infections in other parts of the body, Mycobacterium tuberculosis infection of the central nervous system results from respiratory inhalation of particles containing Mycobacterium tuberculosis.
After invading the body, Mycobacterium tuberculosis spreads to organs throughout the body, such as the meninges and adjacent brain tissue, within 2 to 4 weeks and activates the immune response.
Mycobacterium tuberculosis can be eliminated by activated macrophages and form tuberculosis nodules, which can lie dormant for several years.
When the body’s immunity is lowered, necrosis forms in the center of the nodule and Mycobacterium tuberculosis multiplies rapidly and is released into the subarachnoid space, leading to tuberculous meningitis.
In addition, tuberculosis from neighboring tissues can invade directly into the skull or spinal canal, causing tuberculous meningitis.
High-risk groups
Infants and young children. The immaturity of the central nervous system, the imperfect function of the blood-brain barrier, and the low immune function of infants and young children are closely related to the occurrence of this disease.
Tuberculosis patients. Mycobacterium tuberculosis in patients with pulmonary tuberculosis can spread to the meninges through the bloodstream, causing tuberculous meningitis.
AIDS patients. AIDS patients are prone to a range of opportunistic infections, including tuberculous meningitis, due to immunodeficiency.
Patients with the presence of other risk factors such as diabetes mellitus, alcohol dependence, prolonged treatment with hormones and immunosuppressive agents, and malignant tumors.
Symptoms
Main Symptoms
Tuberculous meningitis has an insidious onset, or it may start acutely or subacutely, with a long course and varying severity of symptoms, the main symptoms of which are listed below:
Mycobacterium tuberculosis toxemia symptoms
Low-grade fever, night sweats, loss of appetite, generalized lethargy and weakness, and mental depression, often persistent.
Symptoms of increased intracranial pressure
Headache, nausea and vomiting are often present in children.
Signs of meningeal irritation
Severe headache, neck stiffness, limited neck movement.
Cerebral nerve damage
Unilateral or bilateral cerebral nerve involvement, with the spreading nerve being the most common, followed by the motor, buccal, and facial nerves.
Symptoms include dizziness, vision loss, diplopia, blurred vision, eye muscle paralysis, diplopia, head tilt, neck slant, and facial paralysis.
Symptoms gradually worsen as the disease progresses.
Symptoms of brain parenchymal damage
Mental depression, apathy, seizures, limb twitching, quadriplegia, impaired consciousness, learning and memory disorders, aphasia, etc.
Symptoms of complications
Various complications can occur due to late treatment or severe condition. The common complications and their manifestations are as follows.
Hydrocephalus: advanced cranial base meningeal adhesion obviously leads to obstructive hydrocephalus, which is manifested as headache, visual impairment, nausea, vomiting, etc. Children with hydrocephalus will have irritability, apathy, poor diet, eye fixation, and downward staring.
Cerebral hemorrhage: it can cause facial or limb paralysis, visual impairment, difficulty in walking, difficulty in speaking and comprehension.
If you experience unexplained headache, fever, dizziness, night sweats, generalized tiredness and weakness, nausea, vomiting, etc., it is recommended that you consult a doctor promptly.
Pediatrics
Infants and children with recurrent fever, vomiting, screaming, crying or drowsiness are advised to consult the doctor promptly.
Emergency Department
It is recommended to consult the Emergency Department or call 120 emergency number as soon as possible if there is neck stiffness and limitation of movement, severe headache, generalized convulsions, lethargy or coma.
Preparation
Preparation for medical consultation: registration, preparation of information, common problems
Tips for medical treatment
If the patient loses consciousness, clean up foreign objects in the patient’s mouth and tilt the patient’s head to one side to prevent choking.
If the patient’s whole body is convulsing, remove dangerous objects around, do not force open the mouth or stuff towels or chopsticks in the patient’s mouth.
Children are sometimes unable to accurately describe their symptoms. Parents can help to record the symptoms they have experienced so that they can give more reference to the doctor.
Preparation Checklist
症状清单
Is the headache severe? What makes it worse?
Do you have a fever? How long has the fever been present? What is the highest temperature?
Do you sweat a lot when you wake up from sleep?
Are there any limb twitches?
Is the child’s appetite normal? What is his mental state?
病史清单
Has the child ever had tuberculosis?
Has the child been in contact with a TB patient?
检查清单
Laboratory tests: blood count, blood biochemistry, tuberculin test
Diagnosis of tuberculous meningitis is based on history, clinical presentation, laboratory tests, and imaging studies. Imaging and cerebrospinal fluid tests are of greater significance in the diagnosis.
Medical history
Exposure to a person with tuberculosis or having had tuberculosis yourself.
Clinical manifestations
Patients may present with low-grade fever, night sweats, headache, and depression. On examination, there are signs of cerebral nerve damage and a positive meningeal irritation sign.
Symptoms of cerebral nerve damage
Paralysis of eye muscles: dilated or narrowed pupils, impaired movement of eyelids or eyeballs, diplopia.
Paralysis of facial muscles: drooping of the corners of the mouth on the paralyzed side, disappearance of the nasolabial folds (commonly known as the lines separating the upper lip and the cheeks) when the teeth are exposed, and relaxation of facial muscles.
Paralysis of the optic nerve: blurred vision, etc.
Positive signs of meningeal irritation
Neck stiffness: spasmodic contraction and pain in the neck muscles, presenting a state of rigidity, with a sense of impedance when an external force pushes to make it bend, and the lower jaw cannot be close to the chest.
Positive Kernig’s sign: lying on the examination bed, one side of the hip and knee joint is bent at 90°, the examiner raises the patient’s calf to extend the knee, which can be up to 135° in normal people, and it is considered positive if there is resistance to extending the knee or if there is pain.
Positive Brudzinski’s sign: lying on the examination bed with both lower limbs straight, the examiner lifts the patient’s occiput and bends the head forward, if both knees bend automatically, it is positive for Brudzinski’s sign.
Laboratory tests
General Laboratory Tests
Most routine blood tests are normal or have mildly elevated white blood cells.
The erythrocyte sedimentation rate (sedimentation rate) may be increased in most patients, and hyponatremia and hypochloremia may be present.
Tuberculin test
The tuberculin test is used to determine the presence of Mycobacterium tuberculosis infection.
The test reagent is injected into the inside of the left anterior upper arm.
A positive result is evidence of active tuberculosis, BCG vaccination, or previous tuberculosis infection, while a negative tuberculin test may be seen in patients with malnutrition, severe systemic disease, or severe tuberculosis.
Cerebrospinal fluid examination
Routine examination of cerebrospinal fluid: the performance of cerebrospinal fluid is different in each stage of the disease.
Typical cerebrospinal fluid has a colorless, clear or cloudy, gross-glassy appearance, and a film may form after several hours of placement.
Intracranial pressure is often elevated.
Cell counts are elevated, and cerebrospinal fluid cytology is predominantly neutrophilic in untreated patients and lymphocytic in the recovery phase.
Sugar and chloride levels are decreased, with chloride decreased more markedly than in other types of meningitis.
Protein content is elevated.
Cerebrospinal fluid smear and culture: Positive antacid-stained smear of cerebrospinal fluid and culture of cerebrospinal fluid for Mycobacterium tuberculosis confirm the diagnosis.
Nucleic acid test: Detecting DNA fragments of Mycobacterium tuberculosis in cerebrospinal fluid by PCR is the fastest way to diagnose tuberculous meningitis at present, and second-generation sequencing of cerebrospinal fluid macro-genome also has some diagnostic value.
Adenosine deaminase (ADA): ADA is a nucleic acid metabolizing enzyme related to the cellular immune activity of the body. Elevated ADA in cerebrospinal fluid helps to diagnose tuberculous meningitis.
Imaging
Chest x-ray or chest CT
Tuberculous meningitis is often part of systemic tuberculosis, and some patients have pulmonary tuberculosis of the cornual type; therefore, a chest X-ray or chest CT should be performed to look for old tuberculous foci, calcifications, or pulmonary cornual lesions.
Cranial CT
A plain CT scan of the head may reveal ventricular dilatation and paraventricular hypodensity, and an enhanced CT scan may show meningeal enhancement.
Magnetic resonance (MRI)
MRI of intracranial tuberculous lesions may reveal the presence of non-caseating tuberculous spheres or liquefied foci of caseous necrosis. Enhancement scans show enhancement of the meninges, which may show significant enhancement in the form of irregular strips and nodules, and thickening of the cerebral nerves.
Magnetic resonance angiography (MRA) with angiography (CTA)
It can show stenosis of the distal internal carotid artery and proximal anterior and middle cerebral arteries.
Differential Diagnosis
Purulent meningitis
Similarities: Fever, headache, nausea, vomiting, may be accompanied by generalized convulsive seizures and impaired consciousness.
Differences: Septic meningitis has elevated leukocyte count and neutrophil count in routine blood tests, cloudy or purulent appearance in cerebrospinal fluid, markedly elevated leukocytes, and diffuse linear or striated enhancement of the supratentorial sulcus, the surface of the cerebral gyrus, and the arachnoid membranes in imaging.
Cryptococcal meningitis
Similarities: The clinical manifestations are similar, with severe headache and loss of vision as the main symptoms, and fever, nausea and vomiting will occur. There will be manifestations of cerebral nerve damage. Routine cerebrospinal fluid changes are similar.
Differences: Patients with cryptococcal meningitis are often associated with chronic wasting disease or systemic immunodeficiency disease. The detection of cryptococcus by ink staining can confirm the diagnosis of cryptococcal meningitis, but it is often necessary to carry out ink staining more than once to detect cryptococcus.
Viral meningitis
Similarity: fever, headache, vomiting, etc., and positive meningeal irritation sign.
Differences: Viral meningitis is a benign, self-limiting disease without cerebral nerve involvement or hydrocephalus. The two can also be differentiated by cerebrospinal fluid examination.
Carcinomatous meninges
Similarity: Both may present with signs of meningeal irritation and increased intracranial pressure, and cerebrospinal fluid examination may show low sugar and chloride levels.
Difference: Meningeal carcinoma is caused by the metastasis of cancer cells from other parts of the body to the meninges. Tuberculous meningitis is more common in middle-aged and older people and has a chronic onset; tuberculous meningitis is more common in younger people and has a more rapid onset. The diagnosis can be made on the basis of comprehensive examination (which can detect extracranial cancer foci) and cerebrospinal fluid cytology (which can detect cancer cells).
Treatment
The treatment of tuberculous meningitis is comprehensive and includes medication, systemic support, management of complications, and symptomatic treatment.
Anti-tuberculosis treatment is the core of treatment, and the earlier anti-tuberculosis treatment is started, the better the result will be. If the patient’s clinical manifestations, signs and laboratory tests are highly suspicious of the disease, empirical anti-tuberculosis treatment can be started as appropriate.
Anti-tuberculosis treatment
Principles of treatment
The principles of using anti-tuberculosis drugs are early, combined, adequate dosage and full course of treatment.
Early use of drugs: early application of anti-tuberculosis drugs will increase the sensitivity of tuberculosis bacteria to the drugs, and the drugs can easily penetrate into the lesions.
Combination of drugs: Combination of 3 or more drugs can enhance the efficacy of drugs and prevent and delay the development of bacterial drug resistance.
Adequate dosage: Adequate dosage can make the drug concentration in the blood and lesions reach a high level.
Adherence to a full course of medication: Adherence to a full course of regular medication can ensure and consolidate the effect of anti-tuberculosis treatment.
Commonly used drugs
Isoniazid (H), rifampicin (R), pyrazinamide (Z), streptomycin (S), and ethambutol (E) are the first-line anti-tuberculosis drugs.
Isoniazid: It can inhibit the DNA synthesis of Mycobacterium tuberculosis and destroy the enzyme activity in the bacillus, and it can kill Mycobacterium tuberculosis inside and outside the cell, and in the stationary or growth phase. The main adverse reactions are peripheral neuritis, liver damage and so on. When applying isoniazid treatment, vitamin B6 should be used simultaneously to prevent peripheral neuropathy.
Rifampicin: Binds to the RNA polymerase of bacteria, inhibits the growth and reproduction of bacteria, and leads to bacterial death. It has a killing effect on both intra- and extracellular Mycobacterium tuberculosis. The main adverse effects of rifampicin include hepatotoxicity and allergic reactions.
Pyrazinamide: It has a killing effect on intracellular tubercle bacilli in an acidic environment, especially more effective on the semi-dormant bacilli, and ineffective on extracellular bacteria. The main adverse reactions include liver damage, elevated blood uric acid, joint pain, swelling, ankylosis, and limitation of movement.
Streptomycin: only on the phagocytosis of extracellular tuberculosis bacteria have a killing effect, is a semi-effective bactericidal drugs. The main adverse reactions are ototoxicity and nephrotoxicity. Streptomycin can easily produce adverse effects on the fetal auditory nerve, pregnant women are prohibited. Streptomycin should be used in infants and young children to prevent ototoxicity.
Ethambutol: Inhibits bacterial RNA synthesis and growth of Mycobacterium tuberculosis. It is slow to produce drug resistance when used alone, and can be used in combination with other drugs to prevent the production of drug-resistant bacteria. Major adverse reactions include optic nerve damage, peripheral neuritis, and allergic reactions. Use with caution in pregnancy and lactation. It is easy to produce toxic effects on the optic nerve of children, so use with caution in children.
Methods of medication
Treatment of tuberculous meningitis is divided into an initial intensive phase and a consolidation phase.
The World Health Organization (WHO) recommends initial treatment with a combination of at least three drugs, commonly isoniazid, rifampicin, and pyrazinamide. In mild cases, pyrazinamide can be discontinued after 3 months of treatment and isoniazid and rifampicin can be continued for another 7 months.
A fourth agent, such as streptomycin or ethambutol, may be added for resistant strains; a total course of 9 months is sufficient for rifampin-intolerant strains; rifampin-resistant strains need to be treated continuously for 18 to 24 months.
Liver function should be monitored during treatment because rifampin, isoniazid, and pyrazinamide are hepatotoxic. If liver levels are mildly elevated but the patient does not have clinical signs of liver damage, treatment should continue to be adhered to.
Adjuvant therapy
Glucocorticoids
The use of glucocorticoids in addition to effective anti-tuberculosis therapy can reduce symptoms of toxicity, inhibit inflammatory reactions and cerebral edema, lower intracranial pressure and inhibit meningeal fibrosis to prevent adhesions.
Glucocorticoid therapy is required when the following conditions are present
Marked increase in intracranial pressure.
Tuberculous meningitis combined with hydrocephalus and cerebral vasculitis.
High protein concentration in the cerebrospinal fluid, with the risk of clot formation causing blockage of the spinal canal.
The application of hormones is preferable to early, small doses, short courses of treatment.
Adults can use prednisolone, dexamethasone.
Dehydrating agents
Due to the increase in intracranial pressure, antihypertensive treatment is often required. Osmotic diuretics, such as 20% mannitol, glycerol fructose or glycerol saline, can be used, and the lost fluids and electrolytes need to be replaced in time.
Antiepileptic drugs
Some patients with tuberculous meningitis complicated by seizures can be treated with carbamazepine or sodium valproate.
Surgery
Tuberculous meningitis secondary to adhesions at the base of the skull and obstructive or traffic hydrocephalus requires surgical treatment.
Lateral ventricular puncture and drainage: can slow down symptoms and is indicated in acute hydrocephalus, when treatment by other intracranial pressure treatments fails or when there is brain herniation formation.
Shunt surgery: for patients with severe cases of obstructive hydrocephalus, effective in reducing cerebral edema and lowering intracranial pressure.
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Prognosis
Cure
The prognosis of tuberculous meningitis is related to the age of the patient and the severity of the disease.
Early diagnosis, early treatment, appropriate use of medications, and prompt management of increased intracranial pressure can improve the cure rate.
Improvement of symptoms or signs and normal cerebrospinal fluid tests suggest a favorable prognosis.
Hazard
Coma at the onset of the disease usually indicates a critical condition, and infants, young children and the elderly generally have a poorer prognosis.
Death
A small number of people may die even after receiving good treatment.
Sequelae
If left untreated, the complications of meningitis can be long-lasting, with varying degrees of sequelae.
Less severe ones include strabismus, facial nerve palsy, mild limb paralysis, headaches, mild mental and behavioral disorders (e.g., excitability, polyphasia, mental retardation, poor memory) and endocrine disorders (e.g., mild obesity).
Severe sequelae include hydrocephalus (headache, visual disturbances, nausea, vomiting), limb paralysis, epilepsy, blindness, aphasia, mental retardation, and urolithiasis (profuse urination, extreme thirst).
Daily
Daily life
Diet
There are generally no special dietary requirements, and it is sufficient to ensure adequate nutritional intake.
If there are symptoms such as nausea and vomiting, you can eat some easy-to-digest foods, such as vegetable porridge, rice soup, egg soup and noodle sheets.
Eat more protein-rich foods, such as meat, eggs, dairy products, soy products, etc., and consume more vegetables and fruits to replenish enough vitamins and trace elements.
Prohibit spicy, greasy and other stimulating foods and alcohol.
Lifestyle habits
Exercise appropriately, pay attention to rest and ensure enough sleep.
When there is neck stiffness, soft pillows can be used to relieve it.
Maintaining a good mood can help the body restore its resistance.
Rehabilitation
People with limb paralysis need to insist on daily rehabilitation training.
For those who are bedridden for a long time, family members or caregivers need to pay attention to the dryness and cleanliness of the bed, change clothes and sheets in time, and clean the skin with lukewarm water every day.
For those who are unconscious, family members or caregivers need to turn them over and massage them every day.
Follow the doctor’s instructions for regular checkups or when there is any physical discomfort.