Tuberculous meningitis is one of the most severe forms of tuberculosis in children. It typically occurs within one year after the primary tuberculosis infection, with the highest risk observed 3 to 6 months after initial exposure. Infants and young children under the age of 3 are most commonly affected. Since the widespread implementation of Bacillus Calmette-Guérin (BCG) vaccination and the use of effective anti-tuberculosis medications, the incidence of this disease has significantly decreased, and the prognosis has greatly improved. However, if the condition is not diagnosed in a timely manner or treated appropriately, the mortality rate and incidence of sequelae remain high. Therefore, early diagnosis and proper treatment are crucial for improving outcomes.
Pathogenesis
Tuberculous meningitis often represents part of a systemic miliary tuberculosis infection and arises via hematogenous dissemination. In infants, the immaturity of the central nervous system, incomplete development of the blood-brain barrier, and weakened immune function are closely associated with the development of this condition. Additionally, the disease may result from the rupture of tuberculous foci in the brain parenchyma or meninges, leading to the entry of Mycobacterium tuberculosis into the subarachnoid space and cerebrospinal fluid. Rarely, tuberculous lesions in the spine, skull, middle ear, or mastoid process can directly invade the meninges.
Pathology
Meningeal Lesions
The pia mater exhibits widespread congestion, edema, inflammatory exudation, and the formation of multiple tubercles. A large amount of inflammatory exudate accumulates in the subarachnoid space, predominantly in the basal cisterns due to gravity, the spacious cisternal anatomy, and the absorption properties of perivascular capillaries around the basal vessels and nerves. The exudate often contains epithelioid cells, Langerhans cells, and caseous necrosis.
Cranial Nerve Damage
Serofibrinous exudate involves the cranial nerve sheaths, compressing and impairing cranial nerves. This often results in facial nerve, hypoglossal nerve, oculomotor nerve, or abducens nerve dysfunction, producing corresponding clinical symptoms.
Cerebral Vascular Lesions
In the early stages, acute arteritis is predominant. In more advanced cases, proliferative tuberculous changes, including obliterative endarteritis, may develop. Severe cases can lead to cerebral infarction, ischemia, and softening, potentially causing hemiplegia.
Parenchymal Lesions
Inflammation may extend into the brain parenchyma or preexisting tuberculous lesions within the parenchyma, resulting in tuberculous meningoencephalitis. In rare cases, tuberculomas may form in the brain parenchyma.
Hydrocephalus and Ependymitis
Involvement of the ependyma and choroid plexus can lead to ventriculitis. If tuberculous lesions in the ependyma or choroid plexus cause adhesion or narrowing of the foramen of Monro, unilateral or bilateral ventricular dilation may occur. Obstruction of cerebrospinal fluid circulation due to exudates at the basal cisterns can result in hydrocephalus.
Spinal Lesions
Inflammation may spread to the spinal meninges, spinal cord, and nerve roots, leading to swelling, congestion, edema, and adhesion of the spinal meninges. Complete occlusion of the subarachnoid space may occur.
Clinical Manifestations
The onset of typical tuberculous meningitis is usually insidious. Based on clinical signs and symptoms, the disease course can be divided into three stages:
Early Stage (Prodromal Stage)
Lasting approximately 1–2 weeks, this stage is characterized by behavioral changes in children, such as reduced speech, lethargy, fatigue, irritability, and mood swings. Fever, loss of appetite, night sweats, weight loss, vomiting, and constipation (or diarrhea in infants) may also occur. Older children may complain of mild or intermittent headaches, while infants may exhibit facial grimacing, staring episodes, drowsiness, or developmental delays.
Middle Stage (Stage of Meningeal Irritation)
Lasting about 1–2 weeks, this stage is marked by increased intracranial pressure, leading to severe headache, projectile vomiting, drowsiness, irritability, and seizures. Signs of meningeal irritation become prominent. In infants, bulging fontanelles or widening cranial sutures may be observed. Cranial nerve involvement, particularly facial nerve palsy, is common, followed by oculomotor and abducens nerve palsies. Some children may develop encephalitic symptoms, such as disorientation, motor dysfunction, or speech impairment. Fundoscopic examination might reveal optic disc edema, optic neuritis, or choroidal miliary tubercles.
Late Stage (Comatose Stage)
Lasting approximately 1–3 weeks, the symptoms progressively worsen. Patients may transition from stupor to semiconsciousness and eventually to coma. Clonic or tonic seizures become more frequent. Severe emaciation, "boat-shaped" abdomen, and metabolic disturbances of water and electrolytes are common. In critical cases, a sudden increase in intracranial pressure may result in brain herniation, leading to respiratory and cardiovascular center failure, and ultimately death.
Atypical Manifestations
Atypical presentations of tuberculous meningitis include the following:
- Rapid onset and progression in infants, occasionally presenting primarily with seizures.
- Early involvement of the brain parenchyma, manifesting as chorea or psychiatric disturbances.
- Early vascular complications, leading to limb paralysis.
- Coexisting tuberculomas mimicking intracranial tumors.
- Severe extrameningeal tuberculosis masking meningeal symptoms, making diagnosis challenging.
- Development of meningitis during anti-tuberculosis treatment, presenting as an interrupted or relapsing course.
Diagnosis
Early diagnosis primarily relies on a detailed medical history, thorough clinical observation, and a heightened level of vigilance. Comprehensive analysis of all available information is necessary, with the most reliable diagnostic evidence being the detection of Mycobacterium tuberculosis in the cerebrospinal fluid (CSF).
Medical History
History of Tuberculosis Exposure
Most children with tuberculous meningitis have a history of contact with tuberculosis patients, particularly those with open pulmonary tuberculosis within the household, which is especially significant in diagnosing infants.
History of BCG Vaccination
The majority of affected children have not received BCG vaccination.
Previous History of Tuberculosis
A history of untreated tuberculosis within the past year is helpful for diagnosis.
Recent History of Acute Infectious Diseases
Recent illnesses such as measles or pertussis are common triggers for the exacerbation of tuberculosis.
Clinical Manifestations
Children with a history of the above factors who present with personality changes, headache, unexplained vomiting, alternating drowsiness and irritability, or intractable constipation should be considered potential cases of tuberculous meningitis. Fundoscopic examination revealing choroidal miliary tubercles can provide diagnostic clues.
Cerebrospinal Fluid Examination
CSF analysis is crucial for diagnosing this condition. Routine findings include elevated intracranial pressure, with the CSF appearing colorless and transparent or turbid like ground glass. When subarachnoid space obstruction occurs, the CSF may appear yellow, and a web-like film may form after 12–24 hours at rest. Microscopic examination of a smear prepared from this film and stained with acid-fast dye has a high detection rate for Mycobacterium tuberculosis.
White blood cell count is typically between 50–500×106/L, with lymphocytes predominating. During acute progression, new meningeal lesions, or tuberculomas rupture, the white blood cell count may exceed 1,000×106/L, and in one-third of patients, neutrophils predominate.
Glucose and chloride levels are both reduced, characteristic of tuberculous meningitis.
Protein levels are elevated, usually between 1.0–3.0 g/L, and can reach 40–50 g/L in cases of spinal obstruction.
Repeated CSF testing and dynamic observation are necessary when findings are atypical. Analysis of acid-fast stained smears prepared from 5–10 mL of CSF sediment can achieve a positivity rate of up to 30%.
Additional Tests
Detection of M. tuberculosis Antigens
The ELISA method for detecting M. tuberculosis antigens in CSF provides a sensitive and rapid diagnostic approach.
Anti-tuberculosis Antibody Detection
Measuring PPD-IgM and PPD-IgG antibodies in CSF using ELISA shows levels higher than those in serum. PPD-IgM antibodies appear 2–4 days after onset, peak at 2 weeks, and normalize by 8 weeks, providing early diagnostic evidence. PPD-IgG antibodies gradually rise 2 weeks post-onset, peak at 6 weeks, and normalize around 12 weeks.
Adenosine Deaminase (ADA) Activity
ADA exists predominantly in T cells. CSF ADA activity is elevated (>9 U/L) in approximately 63–100% of patients with tuberculous meningitis. Levels are markedly increased within the first month of the disease and significantly decrease after 3 months of treatment.
Tuberculin Skin Test
A positive result is helpful for diagnosis, although up to 50% of children may show a negative response.
CSF Culture for M. tuberculosis
This is the most definitive method for diagnosing tuberculous meningitis.
Polymerase Chain Reaction (PCR)
PCR amplification of unique M. tuberculosis DNA fragments from CSF allows accurate detection of minimal amounts of M. tuberculosis DNA.
IGRAs, GeneXpert, and Next-Generation Sequencing (NGS)
These advanced techniques are now being utilized to analyze CSF samples.
Imaging (X-ray, CT, or MRI)
Approximately 85% of children with tuberculous meningitis show evidence of tuberculosis on chest radiographs, with 90% demonstrating active disease, including 48% with miliary tuberculosis. Chest X-rays confirming hematogenous dissemination of tuberculosis are highly indicative of tuberculous meningitis. Early brain CT scans may appear normal but can show basal ganglia enhancement, increased density, blurring or calcification of basal cisterns, ventricular dilation, cerebral edema, or early focal infarctions as the disease progresses.
Differential Diagnosis
Tuberculous meningitis needs to be differentiated from conditions such as pyogenic meningitis, viral meningitis, cryptococcal meningitis, and brain tumors.
Complications and Sequelae
The most common complications include hydrocephalus, cerebral parenchymal damage, intracranial hemorrhage, and cranial nerve dysfunction. Among these, the first three are the leading causes of mortality in tuberculous meningitis. Severe sequelae include hydrocephalus, limb paralysis, intellectual disability, blindness, aphasia, epilepsy, and diabetes insipidus. Approximately two-thirds of children with late-stage tuberculous meningitis develop sequelae, whereas early-stage cases rarely result in lasting complications.
Treatment
Treatment focuses on two key aspects: anti-tuberculosis therapy and intracranial pressure reduction.
General Therapy
Bed rest is required, with attentive nursing care. For comatose patients, enteral nutrition via nasogastric feeding or parenteral nutrition may be provided to ensure adequate caloric intake. Frequent repositioning can help prevent pressure ulcers and hypostatic pneumonia. Proper hygiene of the eyes, oral cavity, and skin is important.
Anti-Tuberculosis Therapy
The combined use of bactericidal anti-tuberculosis drugs capable of crossing the blood-brain barrier is adopted, following a phased treatment approach.
Intensive Phase
A combination of isoniazid (INH), rifampin (RFP), pyrazinamide (PZA), and streptomycin (SM) is utilized for 3–4 months. Dosages include:
- INH: 15–25 mg/kg/day
- RFP: 10–15 mg/kg/day (not exceeding 450 mg/day)
- PZA: 20–30 mg/kg/day (not exceeding 750 mg/day)
- SM: 15–20 mg/kg/day (not exceeding 750 mg/day)
During the first 1–2 weeks of treatment, half of the daily dose of INH is administered via intravenous infusion (diluted in sodium chloride injection or 5% glucose injection), while the other half is taken orally. Once the condition improves, the full daily dose is switched to oral administration.
Consolidation Phase
Treatment continues with INH, RFP, or ethambutol (EMB). This phase lasts for 9–12 months, and the total course of anti-tuberculosis therapy is at least 12 months, or for at least 6 months after CSF parameters return to normal. For early cases, a 9-month short-course regimen (3HRZS/6HR) is effective.
Intracranial Pressure Reduction
Controlling intracranial pressure is critical, and various measures may be applied:
Dehydration Therapy
Mannitol (20%) is commonly used at a dose of 0.5–1.0 g/kg per injection, administered intravenously over 30 minutes every 4–6 hours. In cases of brain herniation, the dose may be increased to 2 g/kg per injection. Gradual dose reduction begins after 2–3 days, with discontinuation after 7–10 days.
CSF Secretion Reduction
Acetazolamide is introduced 1–2 days before discontinuing mannitol, at an oral dose of 20–40 mg/kg/day (not exceeding 750 mg/day). The medication may be used for 1–3 months or longer, either continuously or intermittently (e.g., 4 days on, 3 days off). In infants, metabolic acidosis may occur, and sodium bicarbonate can be given prophylactically if necessary.
Ventricular Puncture and Drainage
This approach is suitable for acute hydrocephalus unresponsive to other measures or when brain herniation is suspected. The drainage volume should correspond to the severity of hydrocephalus, typically 50–200 mL per day, for a duration of 1–3 weeks. In the presence of ventriculitis, intraventricular drug administration may be considered. Infection prevention is essential during this procedure.
Lumbar Puncture and Intrathecal Administration
This method is appropriate for:
- High intracranial pressure unresponsive to corticosteroids and mannitol, but without the immediate need or availability for ventricular drainage.
- Poorly controlled meningeal inflammation resulting in difficult intracranial pressure management.
- CSF protein levels exceeding 3.0 g/L.
A specific volume of CSF is removed to reduce intracranial pressure. For children over 3 years old, injections of 20–50 mg INH and 2 mg dexamethasone are administered into the subarachnoid space. For children under 3 years, doses should be halved. Initially performed daily, the frequency is gradually reduced to every other day, twice weekly, and then once weekly over a 2–4 week course.
Shunt Surgery
In cases of obstructive hydrocephalus caused by basal meningeal adhesions that fail to respond to ventricular drainage, and when CSF parameters have returned to normal, ventriculocisternal shunting (ventriculoperitoneal shunt) may be considered to resolve elevated intracranial pressure.
Corticosteroids
Corticosteroids suppress inflammatory exudation, reduce intracranial pressure, alleviate toxic and meningeal irritation symptoms, facilitate CSF circulation, and reduce adhesions, thereby diminishing or preventing hydrocephalus. Early administration produces better outcomes. Prednisone is often used at a daily dose of 1–2 mg/kg (not exceeding 45 mg/day) and gradually tapered off over 8–12 weeks.
Symptomatic Treatment
Management of Convulsions
Management of Water and Electrolyte Disturbances
Dilutional Hyponatremia
Stimulation of the hypothalamic supraoptic and paraventricular nuclei by tuberculous exudates leads to increased antidiuretic hormone (ADH) secretion, resulting in excessive water reabsorption in the renal tubules. This causes dilutional hyponatremia, and severe cases can lead to water intoxication, with symptoms such as oliguria, headaches, vomiting, convulsions, or coma. Treatment involves intravenous infusion of 3% sodium chloride solution at 6–12 mL/kg, which raises serum sodium by 5–10 mmol/L, along with restricted water intake.
Cerebral Salt-Wasting Syndrome
Damage to the hypothalamus or midbrain can disrupt aldosterone regulation, reducing its secretion. Excess natriuretic hormones result in substantial sodium loss through the kidneys, along with water loss, leading to cerebral salt-wasting syndrome. Blood and urinary sodium levels should be monitored. Isotonic fluids supplemented with 3% sodium chloride solution can be used to restore sodium levels.
Hypokalemia
Potassium depletion may be addressed by administering isotonic solutions with 0.2% potassium chloride intravenously or oral potassium supplements.
Follow-Up
Relapses occur only within four years of discontinuing therapy, with most cases within 2–3 years. Post-treatment follow-up for at least 3–5 years is necessary. A cure is considered when no clinical symptoms are present, CSF is normal, and no relapse occurs within two years of completing therapy.
Prognosis
The prognosis depends on several factors:
- Timing of Treatment: Mortality rates increase with delayed treatment.
- Age: Younger patients experience faster, more severe disease progression, with higher mortality rates.
- Disease Stage and Type: Early, serous-type cases have better prognoses, while late-stage or meningoencephalitic cases have worse outcomes.
- Drug Resistance: Primary resistant M. tuberculosis strains significantly impact prognosis.
- Treatment Approach: Inadequate dosages or improper treatment methods may prolong the disease course and increase complications.