| disease | Tuberculous Meningitis |
| alias | Tuberculosis, Tuberculous Meningitis |
Tuberculous meningitis (abbreviated as TBM) is the most severe form of pediatric tuberculosis, often occurring within one year after initial infection. The incidence rate has significantly decreased in recent years.
bubble_chart Epidemiology
It is primarily seen in children aged 1 to 5 years. Among the 1,180 cases of tuberculous meningitis treated at Beijing Children's Hospital from 1964 to 1977, 56.7% were under 3 years old, with about half (48.5%) being infants under 1 year old. It occurs more frequently in spring and winter. Measles and whooping cough are common triggers for the onset of tuberculous meningitis. Head trauma, surgery, and overexertion can also occasionally serve as triggers.
It is mostly part of systemic foxtail millet-sized subcutaneous nodular disease, disseminated hematogenously. Among the 1,180 cases of tuberculous meningitis observed at Beijing Children's Hospital from 1964 to 1977, 44.2% were diagnosed with foxtail millet-sized pulmonary subcutaneous nodules. Over these 14 years, pathological examinations of 152 tuberculous meningitis cases revealed subcutaneous nodular disease in other systemic organs in 143 cases (94%); pulmonary subcutaneous nodules were found in 142 cases (93.4%) (with foxtail millet-sized pulmonary subcutaneous nodules being the most common). Approximately 62% had foxtail millet-sized subcutaneous nodules in the liver and spleen, 41% in the kidneys, and about 24% in the intestines and mesenteric lymph nodes. The involvement of the meninges by subcutaneous nodular lesions primarily occurs through the hematogenous-cerebrospinal fluid pathway. The occurrence of tuberculous meningitis is related to the body's high hypersensitivity. Additionally, tuberculous meningitis can be caused by the rupture of caseous foci in the brain parenchyma or meninges. Rarely, direct spread from subcutaneous nodular foci in the vertebrae, skull, or middle ear and mastoid can invade the meninges.
bubble_chart Pathological ChangesThe meninges are diffusely congested, and the cerebral gyri are generally flattened, with the most pronounced pathological changes at the base of the brain, hence the term basal meningitis. A significant amount of thick, turbid, grayish-white to grayish-green gelatinous exudate accumulates in the subarachnoid space of the medulla oblongata, pons, interpeduncular cistern, optic chiasm, and lateral cerebral fissure. The thick exudate and edema can compress and damage cranial nerves by surrounding them. The inflammation may extend to the brainstem, spinal cord, and nerve roots. Perivascular infiltration of plasma cells and lymphocytes is observed around cerebral blood vessels, with early manifestations primarily as acute arteritis. The longer the disease progresses, the more pronounced the proliferative vascular changes become, leading to obliterative endarteritis, which can result in cerebral infarction, softening, or hemorrhage.
bubble_chart Clinical Manifestations
The discovery of miliary skin papules is decisive for diagnosis. Fundus examination is also helpful in diagnosis. The detection of subcutaneous nodules on the choroid is equally valuable as the observation of miliary pulmonary subcutaneous nodules on chest X-rays.
1. Early diagnosis relies on detailed medical history, including close contact history and BCG vaccination history, thorough clinical observation, and high vigilance for the disease. For children with a history of subcutaneous node disease contact, positive tuberculin reaction, or existing subcutaneous node disease, the possibility of the disease should be considered when symptoms such as personality changes, mild fever, headache, unexplained vomiting, persistent constipation, or alternating drowsiness and dysphoria occur.
3. Chest X-rays are helpful for diagnosis. Among 1,180 children with tuberculous meningitis who underwent X-ray examinations, 86.9% showed active pulmonary subcutaneous nodes, including 454 cases (44.2%) of foxtail millet-type pulmonary subcutaneous nodes. However, it should be noted that 8.6% of the children had normal lungs, mostly older children.
4. Clinical manifestations: The discovery of skin foxtail millet-like rashes is decisive for diagnosis. Fundus examination is also helpful. Finding subcutaneous node nodules on the choroid membrane is equally valuable as observing foxtail millet-type pulmonary subcutaneous nodes on chest X-rays.
5. Brain CT scans: From 1986 to 1992, Beijing Children's Hospital performed brain CT scans on 50 children with tuberculous meningitis. The abnormalities observed in the CT scans closely resembled the pathological findings from 152 previous cases, indicating that brain CT scans are meaningful for diagnosing tuberculous meningitis.
6. Electroencephalogram (EEG) examination: During the acute phase, most children show abnormal EEGs, characterized by diffuse δ (below 3 Hz) and θ (4–7 Hz) slow-wave activity, often asymmetrical. Asymmetrical sporadic sharp waves, spike-and-slow, or sharp-and-slow waves may also be observed. In cases complicated by subcutaneous node tumors or localized cerebral infarction, space-occupying or focal changes may appear, such as localized δ waves. However, EEG changes are nonspecific and serve only as auxiliary clinical diagnostics, with limited value for pathogen differentiation. They are more useful for monitoring treatment efficacy, assessing prognosis, and identifying sequelae.
8. Additional early diagnostic methods for reference:
(1) CSF lymphocyte transformation test: Some researchers used 3H-thymidine incorporation to measure CSF lymphocyte transformation and found that under PPD stimulation, the transformation rate in tuberculous meningitis cases significantly increased, which has early diagnostic significance.
(2) CSF lactate measurement: This is meaningful for distinguishing tuberculous meningitis from viral encephalitis. CSF lactate measurement is highly significant for differentiating tuberculous meningitis from viral encephalitis and also has some value in distinguishing it from purulent meningitis.
(3) CSF adenosine deaminase (ADA) activity measurement: In most tuberculous meningitis patients, CSF ADA activity is higher than normal (normal individuals <9U/L），試驗的敏感性甚高，簡單易行，可做為早期診斷的協助。
(4) CSF immunoglobulin measurement: In tuberculous meningitis, CSF IgG levels are significantly elevated compared to viral encephalitis and purulent meningitis; IgA and IgM levels are slightly higher than in viral encephalitis but lower than in purulent meningitis.
Before obvious signs of meningeal irritation appear, it should be differentiated from general non-neurological diseases, including upper respiratory tract infections, pneumonia, indigestion, ascariasis, cold-damage disease, hand-foot convulsion syndrome, etc. At this time, even after lumbar puncture stimulation symptoms and signs, or even after cerebrospinal fluid examination, it still needs to be differentiated from a series of central nervous system diseases.
1. Purulent meningitis. The most easily confused is Haemophilus influenzae meningitis, as it is more common in children under 2 years old, and the cerebrospinal fluid (CSF) cell count is sometimes not very high. Next are meningococcal meningitis and pneumococcal meningitis. For differentiation, in addition to the history of subcutaneous node contact, tuberculin reaction, and chest X-ray examination, the most important is CSF examination. When the cell count exceeds 1000×106/L (1000/mm2), and polymorphonuclear neutrophils dominate in the differential count, purulent meningitis should be considered; but more importantly, cytological examination is crucial.
2. Viral central nervous system infections. Mainly viral encephalitis, viral meningoencephalitis, and viral myelitis can be confused with tuberculous meningitis, among which sporadic viral encephalitis requires more differentiation than epidemic cases.
The diagnostic points for various viral meningoencephalitis are: ① Often occurs in specific epidemic seasons. ② Each has its unique systemic manifestations, such as enteroviruses possibly accompanied by diarrhea, rash, or myocarditis. ③ CSF changes, apart from cell count and differential, differ in generation and transformation. In viral meningoencephalitis, CSF glucose and chloride levels are normal or slightly elevated, protein elevation is not significant, mostly below 1g/L (100mg/dl). ④ Each viral encephalitis or meningoencephalitis has specific laboratory diagnostic methods, such as serological tests and virus isolation (refer to relevant chapters).
Differentiating mild viral encephalitis from early-stage tuberculous meningitis is challenging. The management principles are: ① Start with anti-subcutaneous node drug treatment while conducting various tests, such as tuberculin tests and lung X-rays, to assist diagnosis. ② Avoid hormone therapy; if CSF returns to normal within a short period, it is more likely viral encephalitis rather than tuberculous meningitis. ③ Do not perform intrathecal injections of any drugs to avoid altering CSF composition and complicating differential diagnosis.
3. Cryptococcal meningoencephalitis. Its clinical manifestations, chronic sexually transmitted disease course, and CSF changes can closely resemble tuberculous meningitis, but the course is longer and may include spontaneous remission. Chronic progressive intracranial hypertension symptoms are more prominent and disproportionate to other meningeal manifestations. This disease is rare in children and thus easily misdiagnosed as tuberculous meningitis. Definitive diagnosis relies on CSF smear with India ink staining under dark-field illumination, revealing round, thick-capsule-refractory cryptococcal spores, and growth of Cryptococcus neoformans on Sabouraud’s medium.
4. Brain abscess. Children with brain abscess often have a history of otitis media or head trauma, sometimes secondary to septicemia. Congenital heart disease is often associated. Besides meningeal and intracranial hypertension symptoms, focal brain signs are common. CSF changes, when not complicated by purulent meningitis, may range from normal to several hundred cells, mostly lymphocytes, with glucose and chloride levels usually normal, and protein normal or elevated. Differential diagnosis relies on ultrasound, EEG, brain CT, and cerebral angiography.
5. However, brain tumor differs from tuberculous meningitis in: ① Less fever. ② Spasms are rare, and even if present, consciousness is usually clear post-seizure, unlike advanced tuberculous meningitis where children fall into unconsciousness after spasms. ③ Unconsciousness is less common. ④ Intracranial hypertension symptoms are disproportionate to brain signs. ⑤ CSF changes are minimal or mild. ⑥ Tuberculin test is negative, and lungs are normal. For definitive diagnosis of brain tumor, timely brain CT scanning is necessary to assist diagnosis.
The diagnosis of typical tuberculous meningitis is relatively straightforward, but some atypical cases can be more challenging. Atypical tuberculous meningitis generally presents in the following scenarios: ①Infants and young children may experience an acute onset with rapid progression, sometimes presenting with convulsions as the first symptom. ②Early manifestation of brain parenchymal damage symptoms, such as chorea or psychiatric disorders. ③Early occurrence of cerebrovascular damage, presenting as limb paralysis. ④When combined with subcutaneous tuberculoma, it may mimic the presentation of an intracranial tumor. ⑤If subcutaneous tuberculous lesions in other parts of the body are extremely severe, they may mask the symptoms and signs of meningeal inflammation, making it difficult to recognize. ⑥Meningitis occurring during anti-tuberculosis treatment often presents as an abortive form. For all these atypical cases, diagnosis requires extra caution to avoid misdiagnosis.
bubble_chart Treatment Measures
1. General Therapy The following measures must be strictly implemented: ① Cut off contact with patients suffering from open subcutaneous nodes. ② Ensure strict bed rest and provide a nutrient-rich diet. ③ Provide meticulous care. Change the child’s position regularly. Pay close attention to the eyes, mucous membranes, and skin to prevent bedsores. Feed patiently to ensure adequate intake. For unconscious children, use nasogastric feeding. ④ Hospitalization is preferred. Outpatient treatment should only be considered when hospitalization is not feasible, but follow-up and adherence to treatment must be reinforced.
2. Anti-subcutaneous Node Drug Therapy The treatment principle is early and thorough therapy (continuous and long-term treatment). Currently, a combination of SM, INH, RFP, and PZA is commonly used. Among these, INH is the most critical drug and should be administered throughout the entire course of treatment. The treatment duration is 1–1.5 years, or no less than six months after cerebrospinal fluid (CSF) normalizes.
3. Hormone Therapy The treatment principle is that hormones must be used concurrently with effective anti-subcutaneous node drugs, with appropriate dosage and duration. In cases where hormone therapy is needed, the earlier it is administered, the better. Hormones have anti-inflammatory, anti-allergic, anti-toxic, and anti-fibrotic effects, which can rapidly alleviate toxic symptoms and meningeal irritation, reduce intracranial pressure, and mitigate or prevent hydrocephalus. Thus, hormones serve as an effective adjunct to anti-subcutaneous node therapy. Hormones are most effective for the basilar meningitis type. However, if the child has progressed to the meningoencephalitis type, reached an extremely advanced stage, developed subarachnoid space obstruction, or has concurrent subcutaneous node tumors, the efficacy of hormones diminishes significantly.
The hormone dosage should be moderate: prednisone or prednisolone at 1.5–2 mg/(kg·d), with a maximum dose not exceeding 45 mg/d; dexamethasone is five times more potent than prednisone, so the dosage should be 1/5 of the latter; hydrocortisone can be administered intravenously during the acute phase for 1–2 weeks at 5 mg/(kg·d). During hormone tapering, adrenocorticotropic hormone (ACTH) can be supplemented at 12.5–25 U intramuscularly daily. Hormones should be tapered slowly after 4–6 weeks of use and discontinued within 2–3 months based on the patient’s condition.
For children with existing or impending CSF circulation obstruction, intrathecal hormone injection may be considered, but extreme caution must be exercised regarding the type of preparation, injection dosage, and necessary dilution.
4. Treatment of Hydrocephalus In the antimicrobial therapy for pediatric tuberculous meningitis, controlling hydrocephalus is often the primary concern. Hydrocephalus can be clinically diagnosed within 1–2 weeks of the disease course and confirmed via CT scans, lateral ventricle puncture, or drainage. In addition to the routine use of therapeutic hormones, the following measures can be taken to treat hydrocephalus.
(1) Lateral Ventricle Drainage: Indicated for acute hydrocephalus when other measures to reduce intracranial pressure fail or when cerebral herniation is suspected. Continuous drainage typically lasts 1–3 weeks, and 1–2 procedures are usually sufficient to control the condition. The drainage volume can reach 50–200 ml daily. During drainage, ensure the lateral ventricle puncture needle is securely fixed to avoid injuring brain tissue. Monitor CSF pressure regularly to prevent excessively low pressure, which may cause cerebral hemorrhage. Special attention must be paid to preventing secondary infections.
(2) Hypertonic Solutions: The mechanism involves rapid intravenous infusion of hypertonic solutions to create an osmotic gradient between blood and CSF, thereby reducing intracranial pressure. This is suitable for rescuing children with severe cerebral edema due to cerebral herniation or those over 3 years old for whom lateral ventricle drainage is challenging. Commonly used hypertonic solutions include 30% urea, 20% mannitol, 25% sorbitol, and 50% glycerol syrup (oral). Administer 1–1.5 g/(kg·d) intravenously over 30 minutes, repeating 2–3 times if necessary.
(3) Acetazolamide: As a carbonic anhydrase inhibitor, it may reduce the production of cerebrospinal fluid by inhibiting the action of carbonic anhydrase in the choroid plexus of the brain ventricles, thereby lowering intracranial pressure. Its effect is relatively slow. The dosage is 20–40 mg/(kg·d), divided into 2–3 oral doses per day. The treatment course should be prolonged, ranging from several weeks to half a year. It can be used before or after treatments such as lateral ventricle drainage or hypertonic solution intravenous infusion to compensate for the inability to sustain these treatments long-term. It is particularly suitable for chronic hydrocephalus when other pressure-reducing measures are difficult to maintain. In younger infants, a possible side effect is metabolic acidosis, which may be prevented by concurrently administering sodium bicarbonate if necessary. Rare side effects include hematuria accompanied by abdominal pain, which resolves quickly after discontinuation. The most severe side effects are anuria and acute renal failure.
(4) Shunt surgery. If obstructive hydrocephalus occurs due to adhesion and obstruction of the basal meninges, the above treatments are difficult to be effective. Long-term application of lateral ventricle drainage only serves as symptomatic treatment and is difficult to sustain for an extended period. In such cases, when anti-subcutaneous node drug therapy has basically controlled the inflammation, ventriculoperitoneal shunt surgery may be considered.
5. Symptomatic treatment. When high fever and persistent convulsions occur, Wintermin II or other sedatives can be used. To improve the metabolic processes of the nervous system, glutamic acid, compound vitamin B, vitamin B12, and large doses of vitamin C can be administered. For malnourished children or those with extremely slow recovery, small amounts (25–50ml) of multiple blood transfusions may be performed.
If clinical symptoms disappear, cerebrospinal fluid returns to normal, and there is no recurrence within 2 years after the treatment course, the condition can be considered cured. However, continued observation is still necessary until 5 years after the cessation of treatment.
1. Infection with primary drug-resistant strains: Primary drug resistance in pediatric tuberculous meningitis has become a major challenge in clinical treatment, severely affecting the prognosis and increasing the mortality rate.
2. Timing of treatment: The later the treatment, the higher the mortality rate. Among 979 cases, no deaths occurred in early-stage cases, while the mortality rate was 3.3% in intermediate-stage [second-stage] cases and 24.9% in advanced-stage cases.
3. Age: The younger the child, the faster and more severe the progression of meningeal inflammation, leading to a higher mortality rate. For cases of similar severity, children under 3 years old have a poorer prognosis compared to those over 3 years old.
4. Disease type: Cases with severe brain parenchymal damage have a worse prognosis. The mortality rate is zero for serous type, 6.4% for basal meningitic type, and 21.5% for meningoencephalitic type, which accounts for 78.2% of all deaths.
5. Presence of hydrocephalus: This is also related to the stage of the disease. The mortality rate is significantly higher in cases with hydrocephalus (20%) compared to those without (3.9%). Some children may die from brain herniation before the anti-subcutaneous node drugs take full effect during treatment.
6. Initial or retreatment: Retreatment cases, including relapsed or worsened cases, have a poorer prognosis.
7. Treatment method: With insufficient doses or inappropriate methods, the disease course of early or intermediate-stage [second-stage] cases, which should have a better prognosis, may become prolonged or chronic. This can lead to extensive adhesions in the subarachnoid space, resulting in hydrocephalus or spinal cord dysfunction, or prolonged disease progression causing cerebrovascular lesions and cerebral infarction, leading to irreversible damage, sequelae, or even death.
Relapses mostly occur within 2 years after the end of treatment, though they may occasionally happen within 3–5 years. Most relapses occur once, but some may recur multiple times. If detected early and treated promptly, relapsed cases can still be completely cured. However, some relapsed cases respond less effectively to treatment compared to initial cases, yielding poorer outcomes.
The most fundamental way to prevent tuberculous meningitis is to prevent children from being infected with subcutaneous nodes. Effective measures are as follows:
1. Ensure proper initial and booster BCG vaccinations. Experience has shown that effective BCG vaccination can prevent or reduce the occurrence of tuberculous meningitis.
2. Early detection and active treatment of infection sources. Detect adult subcutaneous node patients early, especially among those in close contact with children, such as parents, nursery caregivers, and teachers in kindergartens and primary schools. Strengthen tuberculosis prevention efforts and enhance the management and treatment of adult subcutaneous nodes.
3. Improve children's immune resistance. Provide proper feeding, establish a reasonable daily routine, and adhere to planned immunizations to enhance physical resistance and reduce acute infectious diseases.
4. Early detection and thorough treatment of primary subcutaneous node disease in children. Early and complete cure of primary subcutaneous node disease in children can significantly reduce the incidence of tuberculous meningitis.
The most common complications include hydrocephalus, brain parenchymal damage, cerebral hemorrhage, and cranial nerve disorders. The first three are often the causes of death in tuberculous meningitis. Clinical manifestations include hydrocephalus, decerebrate rigidity, limb paralysis, epilepsy, blindness, aphasia, etc. Severe sequelae include hydrocephalus, limb paralysis, blindness, intellectual disability, diabetes insipidus, and epilepsy. Based on our analysis of 203 cured children, 11.8% had grade I sequelae, while 34% had severe sequelae. Among children with sequelae, advanced-stage patients accounted for about two-thirds, while early-stage cases were rare.
Before the appearance of obvious meningeal irritation signs, it should be differentiated from general non-neurological diseases, including upper respiratory tract infections, pneumonia, indigestion, ascariasis, cold-damage disease, hand-foot convulsion syndrome, etc. At this stage, a lumbar puncture to examine the cerebrospinal fluid can confirm the diagnosis. After the appearance of meningeal irritation symptoms and signs, and even after cerebrospinal fluid examination, it still needs to be differentiated from a series of central nervous system diseases.
1. Purulent meningitis: The most easily confused is Haemophilus influenzae meningitis, as it is more common in children under 2 years old, and the cerebrospinal fluid cell count is sometimes not very high. Next are meningococcal meningitis and pneumococcal meningitis. For differentiation, in addition to subcutaneous nodule contact history, tuberculin reaction, and lung X-ray examination aiding diagnosis, the most important is cerebrospinal fluid examination. When the cell count is above 1000×106/L (1000/mm3), and the majority of the differential count is polymorphonuclear neutrophils, purulent meningitis should be considered; but more importantly, bacteriological examination is crucial.
2. Viral central nervous system infections: Mainly viral encephalitis, viral meningoencephalitis, and viral myelitis can be confused with tuberculous meningitis, among which sporadic viral encephalitis requires more differentiation than epidemic cases.
The diagnostic points for various viral meningoencephalitides are: ① Often have specific epidemic seasons. ② Each has its unique systemic manifestations, such as enteroviruses possibly accompanied by diarrhea, rash, or myocarditis. ③ Cerebrospinal fluid changes, apart from cell count and differential count being difficult to differentiate from tuberculous meningitis, the generation and transformation changes are different. In viral meningoencephalitis, cerebrospinal fluid glucose and chloride are normal or slightly elevated, protein increase is not significant, mostly below 1G/L (100mg/dl). ④ Various viral encephalitides or meningoencephalitides have specific laboratory diagnostic methods, such as serological tests and virus isolation (refer to relevant chapters).
Differentiating mild viral encephalitis from early-stage tuberculous meningitis is relatively difficult. The management principles are: ① First, use anti-subcutaneous nodule drug treatment while conducting various tests, such as tuberculin test, lung X-ray, etc., to assist diagnosis. ② Avoid hormone treatment; if cerebrospinal fluid returns to normal in a short time, it is more likely viral encephalitis rather than tuberculous meningitis. ③ Do not inject any drugs intrathecally to avoid altering cerebrospinal fluid components and complicating differential diagnosis.
3. Cryptococcal meningoencephalitis: Its clinical manifestations, chronic sexually transmitted disease course, and cerebrospinal fluid changes can closely resemble tuberculous meningitis, but the course is longer and may include spontaneous remission. Chronic progressive intracranial hypertension symptoms are more prominent and do not parallel other meningeal manifestations. This disease is less common in children, so it is easily misdiagnosed as tuberculous meningitis. Definitive diagnosis relies on cerebrospinal fluid smear, using India ink staining under dark-field illumination to reveal round, thick-capsulated, refractile cryptococcal spores. Sabouraud's medium may show growth of Cryptococcus neoformans.
4. Brain abscess: Children with brain abscess often have a history of otitis media or head trauma, sometimes secondary to septicemia. It is often associated with congenital heart disease. Besides meningeal and intracranial hypertension symptoms, children with brain abscess often have focal brain signs. Cerebrospinal fluid changes, when not complicated by purulent meningitis, may range from normal to several hundred cells, mostly lymphocytes, with glucose and chloride mostly normal, and protein normal or elevated. When differential diagnosis is difficult, ultrasound, electroencephalogram, lung CT, and cerebral angiography can assist.
5. Brain tumor: However, brain tumor differs from tuberculous meningitis in: ① Less fever. ② Spasms are rarer, and even if spasms occur, consciousness is usually clear afterward, unlike advanced-stage tuberculous meningitis where children fall into unconsciousness after spasms. ③ Unconsciousness is less common. ④ Intracranial hypertension symptoms do not parallel brain signs. ⑤ Cerebrospinal fluid changes are minimal or slight. ⑥ Tuberculin test is negative, and lungs are normal. To confirm brain tumor, timely brain CT scan should be performed to assist diagnosis.
The diagnosis of typical tuberculous meningitis is relatively easy, but for some atypical cases, diagnosis can be more challenging. Atypical tuberculous meningitis may present in the following scenarios: ①Infants and young children may have an acute onset with rapid progression, sometimes presenting with convulsions as the first symptom. ②Early symptoms of brain parenchymal damage may manifest as chorea or mental disorders. ③Early cerebrovascular damage may present as limb paralysis. ④When combined with a subcutaneous tuberculoma in the brain, it may mimic the presentation of an intracranial tumor. ⑤If subcutaneous tuberculous lesions in other parts of the body are extremely severe, they may mask the symptoms and signs of meningeal inflammation, making it difficult to recognize. ⑥When meningitis occurs during anti-tuberculosis treatment, it often presents as an abortive form. For all these atypical cases, diagnosis requires special caution to prevent misdiagnosis.
