Figure 58.1. Plain (A) and contrast (B) computed tomography (CT) showing hydrocephalus and basal meningeal enhancement.

Figure 58.2. Contrast magnetic resonance imaging (MRI) showing basal meningeal enhancement.

Figure 58.3. Plain CT showing mid hydrocephalus and multiple infarcts (dots).

Figure 58.4. Contrast MRI showing basal meningeal enhancement and intra-meningeal and adjacent parenchymal tuberculomas.

58.6 Treatment of Tuberculous Meningitis

58.6.1 Antituberculous Drug Treatment

There is a scarcity of controlled trials of antituberculous drugs in CNS tuberculosis. Most of the guidelines follow the model of short-course chemotherapy of pulmonary tuberculosis: an “intensive phase” of treatment with four drugs, followed by treatment with two drugs during a prolonged “continuation phase” [12]. The Infectious Disease Society of America, the Center for Disease Control and Prevention, and the American Thoracic Society guidelines recommend an initial 2-month induction therapy with isoniazid, rifampin, pyrazinamide, and ethambutol, followed by 7 to 10 months of additional isoniazid and rifampin for an isolate that is sensitive to these drugs (Table 58.1). Recent a systemic review suggests that a 6-month regimen might be sufficient if the likelihood of drug resistance is low [40].

Table 58.1. First-line antituberculous drugs.

58.6.2 Multi-drug Resistant Tuberculosis

Multi-drug resistant (MDR) (resistant to both isoniazid and rifampin) tuberculosis is a concern in high-burden countries. There were an estimated 500,000 cases of MDR tuberculosis in 2007, mostly from high-burden countries: 131,000 in India, 112,000 in China, 16,000 in South Africa, and 15,000 in Bangladesh. Furthermore, 55 countries had reported cases of extensively drug resistant (EDR) tuberculosis defined as MDR tuberculosis plus resistance to a fluoroquinolone and injectable second-line drugs by the end of 2008 [2]. In high-burden countries, the proportion of tuberculosis cases that are MDR may range from 1 to 14% or more [41]. Thus the probability of a patient with tuberculous meningitis in high-burden countries having MDR tuberculosis would be 0.1 to 1.4%. It will be extremely difficult clinically to suspect MRD tuberculous meningitis. MDR tuberculous therapy should be considered if there is a history of prior exposure to antituberculous drugs, contact with a patient with MDR tuberculosis, or poor clinical response to first-line drugs [13]. Resistance to isoniazid was associated with significantly longer times to CSF bacterial clearance [42]. In a prospective study of Vietnamese adults with tuberculous meningitis, isoniazid and/or streptomycin resistance was associated with slower CSF bacterial clearance but not with any difference in clinical response or outcome. However, combined isoniazid and rifampicin resistance was strongly predictive of death (RR of death 11.63, 95% CI 5.21-26.320) [43]. MDR tuberculosis requires extended treatment with second-line drugs that are less effective and have more adverse effects than isoniazid-based and rifampin-based regimens [44]. With the emergence of EDR tuberculosis, even the second-line drugs will be ineffective. Ethinomide and cycloserine have good CNS penetration and may be used as part of an “intensive phase” treatment regimen in patients with suspected MDR tuberculous meningitis [13]. Therapeutic drug monitoring has been used to assist in the management of MDR tuberculosis [45,46].

TMC207, an investigational diarylquinoline compound, acts by specifically inhibiting mycobacterial ATP synthase. In vitro, it inhibits drug-sensitive and drug-resistant M. tuberculosis isolates and is also bactericidal against dormant tubercle bacilli [47-50]. In a two-stage, phase 2, randomized, placebo-controlled trial consisting of an exploratory stage (8 weeks) followed by a separate proof-of-efficacy stage (24 weeks) in patients with newly diagnosed, smear-positive pulmonary infection caused by MDR M. tuberculosis, the addition of TMC207 to standard therapy reduced the time to conversion to a negative sputum culture as compared with placebo and increased the proportion of patients with conversion of sputum culture. The drug was well tolerated except for significant nausea [51].

The in-hospital case-fatality rate was 57% in patients with MDR tuberculous meningitis, with significant functional impairment in most of the survivors (Patel 2004) [52]. The morality was near 90% in patients with HIV-associated MDR tuberculous meningitis [53].

58.6.3 Adjunctive Steroid Therapy

A Cochrane systematic review concluded that overall adjunctive therapy with corticosteroids reduces the risk of death (RR, 0.78, 95% CI, 0.67-0.91). Data on disabling residual neurological deficits from three trials showed that corticosteroids reduce the risk of death or disabling residual neurologic deficit (RR, 0.82, 95% CI, 0.70-0.97). The review recommends the routine use of corticosteroids in HIV-negative people with tuberculous meningitis to reduce death and disabling neurological deficits amongst survivors. Corticosteroids should be used irrespective of age and disease stage [54]. A recent Vietnam adult study of adjunctive dexamethasone therapy in tuberculous meningitis demonstrated a significant reduction in mortality but not in morbidity [55]. A further subgroup analysis revealed that this benefit occurred among all severe grades of CNS tuberculosis and that this benefit was not seen in patients with HIV co-infection. The study also found that treatment with dexamethasone was associated with less severe adverse events, particularly hepatitis. The mechanism by which dexamethasone exerts its survival benefit is uncertain. Two possible mechanisms have been proposed: 1) the effect of dexamehasone on the deleterious aspects of the immune response in the CNS; and 2) the ability of dexamehtasone to prevent hydrocephalus and/or infarction [13,38]. Dexamethasone does not seem to improve outcome by attenuating immunological mediators of inflammation in the subarachnoid space or by suppressing peripheral T-cell response to mycobacterial antigens [15]. There is some evidence to suggest that adjunctive dexamethasone may affect outcome from tuberculous meningitis by reducing hydrocephalus and preventing infarction [38].

The initial dose of dexamethasone is 8 mg/day for children weighing <25 kg and 12 mg/day for children weighing ≥25 kg and for adults for 3 weeks and then decreased gradually during the following 3 weeks [56]. In the trails by Thwaites et al. [55], the initial dose was 0.3 mg/kg/day for grade I and 0.4 mg/kg/day for grades II and III, followed by gradual tapering over 6 weeks.

58.7 Treatment of Complications

In patients with tuberculous meningitis, potential neurologic complications requiring careful attention include altered mental status, elevated intracranial pressure (eICP), hydrocephalus, vasculitis, and acute seizures. Critical care of these patients should focus not only on treatment of the underlying infection and its immediate complications but also on minimizing secondary brain injury. Aggressive and appropriate care within the intensive care unit setting can minimize these complications and improve the chance of a good outcome [19].

58.7.1 Fever

Fever is a common feature in patients with tuberculous meningitis and the reported frequency varies between 60 and 95% [12]. Fever is regarded as a fundamental component of the acute-phase response to infection. Despite considerable research, it remains unclear whether infection-related fever is globally beneficial or harmful [57]. No data exist to determine the effect of fever on the pathology and ICP in tuberculous meningitis.

Fever management has become a common practice in neurologic and neurosurgical ICUs in patients with acute brain insult [58]. Fever exacerbates the degree of resulting neuronal injury in the presence of acute brain insult [58-60] and it also raises ICP [61]. However, there are several uncertainties with regard to infection-related fever management. There are very few studies that have looked into the effect of infection-related fever in patients with acute brain insult. Retrospective data indicate that stroke patients with preceding bacterial infections have poorer neurological and behavioural outcomes than do their uninfected counterparts [62,63]. In one experiment in which rats were injected with E. coli lipopolysaccharide prior to the induction of global brain hypoxia, fever was associated with increased neural damage [64]. Thus, fever management to achieve normothermia might be warranted in patients with severe grade tuberculous meningitis. However, one has to exercise caution in patients with associated sepsis. Low or normal temperature during bacteraemia has been shown to be associated with poor outcome [65]. Standard fever management consists of antipyretic drug therapy and external/physical cooling. Newer methods with surface cooling and intravascular cooling devices are more effective in lowering fever than standard fever management protocols [58].

58.7.2 Fluid and Sodium Disturbances

Disturbances of sodium, intravascular volume, and water are common in tuberculous meningitis. The reported frequency of hyponatremia in patients with tuberculous meningitis varies between 35 and 65% [66-68]. Hypotonic hyponatremia causes the entry of water into the brain, resulting in cerebral edema [69]. Hyponatremia without eICP may be associated with altered mental status. In patients with tuberculous meningitis, both hyponatremia and altered mental status are independent predictors of death or severe disability [70].

In tuberculous meningitis it is often difficult to precisely determine the cause of hyponatremia. The differential diagnosis includes the central salt wasting syndrome (CSWS), the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), and adrenal insufficiency. The CSWS is defined as renal loss of sodium during intracranial disease, leading to hyponatremia, excessive natriuresis, volume depletion and clinical response to volume and salt replacement [71]. The available evidence suggests that the cause of hyponatremia in tuberculous meningitis is due to CSWS [72-77]. The CSWS involves renal salt loss resulting in hyponatremia and hypovolaemia, whereas SIADH involves a physiologically inappropriate secretion of ADH or increased renal sensitivity to ADH, leading to renal conservation of water and euvolaemic or hypervolaemic hyponatremia [71].

At presentation, many patients with tuberculous meningitis have compromised volume status. The first step is to assess the volume status and replace the volume with normal saline and simultaneously investigate the patient for hyponatremia. The therapy in CSWS is volume and sodium replacement (0.9% sodium chloride or 3% if necessary). The rapidity of sodium replacement depends on the rate at which the hyponatremia developed. Treatment of hyponatremia developing at a rate of >0.5 mmol/l/h should be aggressive, as it is a life-threatening complication and may cause death from severe cerebral edema and herniation (Kroll 1992) [78]. Mineralocorticoid or fludrocortisone supplementation has also been shown to be effective in returning serum sodium levels to normal [79,80]. Volume restriction is the treatment of choice in SIADH and in patients with symptomatic hyponatremia; 3% sodium chloride is usually combined with frusemide to facilitate free water excretion and correct hyponatremia.

58.7.3 Acute Seizures

Acute seizures occur in about 50% of children with tuberculous meningitis and in 5% of adults [12]. New-onset acute symptomatic seizures are not uncommon in patients with HIV-associated tuberculous meningitis [81]. Rarely convulsive status epilepticus (CSE) [82] and non-convulsive (NCSE) [83] status epilepticus (SE) may complicate tuberculous meningitis. Patients with the first acute symptomatic seizure caused by CNS infection are at a higher risk for 30-day mortality [84].

In patients with CNS infections, recurrent seizures are common after the first acute seizure [85]. Probably, these patients will need AED prophylaxis to prevent seizure recurrence, at least for the period of resolution or stabilization of an acute CNS insult. The plan in such patients would be acute abortive treatment with benzodiazepines, followed by a loading dose of phenytoin/fosphenytoin and subsequent maintenance therapy. An alternative drug is levetericetam. Studies using levetericetam in SE and NCSE, both in children and adults, suggest the efficacy of the drug when administered early, and a dose of <3000 mg daily is likely to provide benefits [86-88]. AEDs may be continued if there is a high risk of recurrence for a period of 3 to 6 months [89].

While using AEDs, interactions with other co-medications, particularly anituberculous drugs, should be considered. Isoniazid inhibits phenytoin, carbamazepine and valproic acid, producing high serum levels of these AEDs and thus toxicity [90,91]. Rifampin lowers the concentration of valproic acid, phenytoin, carbamazepine, lamotrigine, making some of these drugs relatively ineffective [90]. When combined with isoniazid, rifampicin counters the former’s inhibitory effect on the metabolism of phenytoin. Isoniazid, rifampin, pyrazinamide and valproic acid are all hepatotoxic drugs. When used together, they may potentiate hepatotoxicity. Preferably, valproic acid should be avoided; if given, liver function should be monitored at regular intervals.

58.7.4 Vasculitis

Vascular pathology associated with tuberculous meningitis, arteritis, arterial spasm, intraluminal thrombus, and external compression of proximal vessels by exudates in the basal cisterns, all compromise cerebral perfusion and oxygen delivery to the brain [10,11,92]. In an autopsy study, arteritis and infarcts were seen in 70% of brains. Arteritis mostly involved the perforating branches of the major arteries at the base of the brain [10,11].

It is not clear how to treat this serious complication of tuberculous meningitis or the compromised cerebral perfusion and infarction. Recently delayed abnormalities of cerebral oxygenation, despite ICP control and full conventional therapy, have been shown in two patients with tuberculous meningitis, confirming the progressive nature of the vascular insult [93]. Corticosteroids may be beneficial. How corticosteroids exert their beneficial effect in tuberculous meningitis is not clear. One of the mechanisms may be an anti-inflammatory effect. However, this effect is difficult to prove [94]. The Vietnam adult study suggests that dexamethasone might improve survival from tuberculous meningitis by reducing the incidence of infarction and speeding the resolution of hydrocephalus [38]. Corticosteroids might antagonize vascular endothelial growth factor (VEGF) β and thereby reduce vasogenic cerebral edema [95]. Gujjar et al. [96] studied the efficacy of triple-H therapy in patients with tuberculous arteritis and suggested that it is safe and may be beneficial in the management of patients with tuberculous arteritis.

58.7.5 Intracranial Pressure

In patients with tuberculous meningitis, elevated intracranial pressure (eICP) is one of the predictors of poor outcome. The relative risk of poor outcome in children with clinical features of eICP was 1.7 (95% CI, 1.7–2.2; p 0.002). In this study, the stage of the disease at admission was found to be an independent risk factor for poor outcome (odds ratio [OR], 4.8, 95% CI, 2.7-8.7; p <0.001) [21]. The presence of hydrocephalus usually signifies eICP; in patients with hydrocephalus, the stage of the disease at admission is a predictor of poor outcome [97-100].

Pathogenesis of ICP

Understanding the pathogenesis of eICP is essential for formulating appropriate therapeutic interventions. The pathological substrate of eICP includes: 1) diffuse edema consequent to encephalitic processes; 2) micro- and macroinfarcts secondary to vasculitis of both small and large vessels and the associated edema and space-occupying effect; 3) hydrocephalus due to CSF blockage by adhesion formation of the basal subarachnoid cisterns; 4) a space-occupying effect of associated tuberculoma(s) [10,11]. Rarely, mostly in children, tuberculous encephalopathy may contribute to eICP. Tuberculous encephalopathy is an immune-mediated allergic process with no appreciable inflammatory reaction; the pathology includes demyelination and edema [24].

In addition to the pathological substrate, other players in the pathogenesis of eICP in tuberculous meningitis include fever and hyponatremia. Hyponatremia is a common finding in such patients and results in osmotic water shifts, leading to an increase in intracellular fluid (ICF) volume, especially brain cell swelling or cerebral edema [69]. An increase in brain temperature in the presence of acute cerebral damage is associated with a significant raise in ICP [61].

Management

The clinical presence of papilledema may help to diagnose eICP. The GCS is a reliable scale to assess brain injury severity. A GCS <8 suggests serious pathology and possible eICP. In addition to clinical evaluation, neuroimaging is an essential component in the management of eICP in patients with tuberculous meningitis. It provides a good idea about the possible pathological substrate of eICP. The imaging evaluation usually begins with a contrast CT scan as an emergency procedure: 1) to identify intracranial lesions, tuberculomas and space-occupying infarcts that may need surgical correction; 2) to identify CSF obstruction, hydrocephalus; and 3) to appreciate the severity of cerebral edema or the presence of brain shift.

There are no established guidelines for when to institute ICP monitoring in patients with tuberculous meningitis and eICP. In one study in children with hydrocephalus and eICP, response to therapy was assessed by means of repeated lumbar CSF pressure monitoring and CT scanning. No correlation was observed between lumbar opening pressure and the degree of hydrocephalus as measured by CT [101]. Studies in children with other CNS infections, encephalitis and bacterial meningitis have shown the usefulness of ICP monitoring in the optimal management of ICP [102,103]. It will be appropriate to monitor ICP in patients with tuberculous meningitis with features of ICP and grade II and III disease.

Management of eICP should be carried out in a stepwise fashion as in any other clinical setting. The initial steps should include optimal head positioning to allow for venous drainage and adequate analgesia and sedation. Additional basic measures should focus on optimizing hemodynamic status and oxygenation (airway and ventilation control).

Osmotherapy

The administration of osmotic agents is one of the principal strategies to lower eICP. Commonly used agents are mannitol and hypertonic saline. Osmotic agents, most often mannitol, have been used in patients with CNS infections to treat eICP [104-106]. But none of the studies systematically evaluated the efficacy of the osmotic agents. Similarly, there are few studies in which eICP was treated with an ICP-targeted approach [107]. Hypertonic saline can be used as an alternative to mannitol. It may also be used in otherwise refractory intracranial hypertension to treat eICP. The safety and efficacy of hypertonic saline in the treatment of eICP in other clinical settings has been well established. However, caution is advised with high osmolar loads because they carry an increased risk for potentially deleterious consequences of hypernatremia or may induce osmotic blood-brain barrier opening, with possibly harmful extravasation of the hypertonic solution into the brain tissue [108].

Hyponatremia is a common complication of tuberculous meningitis, and hypovolaemia is often present early in the course of the disease. Fluid therapy should aim at avoiding hypovolaemia and hypo-osmolality. When such a clinical situation is associated with eICP, hypertonic saline may be an appropriate choice [19]. Hypertonic saline is devoid of the risks of dehydration and tubular damage as occur with mannitol.

Hydrocephalus

Hydrocephalus can be treated with diuretics, osmotic agents, serial lumbar puncture, external ventricular drainage or ventriculoperitoneal shunt. The addition of acetazolamide and furosemide was significantly more effective in achieving normal ICP than antituberculous drug treatment alone [109]. In a series of 217 children with tuberculous meningitis and hydrocephalus, medical treatment obviated the need for shunt surgery in over 70% of children [110]. However, patients on medical treatment should be closely monitored to detect worsening or lack of improvement, and shunt surgery should be considered if medical management fails. Ventriculoperitoneal shunt is associated with favourable outcome. The grade of the disease at presentation is a predictor of outcome after shunt surgery [97-100]. In mild and moderate hydrocephalus, early shunt surgery (2 days after diagnosis) was associated with better outcomes compared with delayed surgery (3 weeks after diagnosis [111].

Tuberculomas

The reported frequency of tuberculoma(s) on the initial CT scan varies between 2 and 38% [19]. A growing body of evidence suggests that most often tuberculomas resolve with antituberculous treatment [19].Surgical excision is indicated in: 1) tuberculomas causing obstructive hydrocephalus and significant eICP; 2) tubuerculomas causing obstructive hydrocephalus and not resolving on medical treatment; 3) large space-occupying tuberculomas with eICP; 4) tuberculomas with associated compartmental shifts and not resolving with medical treatment [19].

Prognosis

The reported mortality associated with treated tuberculous meningitis varies between 20 and 50% [13]. In a recent, large retrospective cohort study of all the children with tuberculous meningitis in the Western Cape of South Africa, the mortality was 13% [21]. This very low mortality has been explained by directly observed treatment, active treatment of hydrocephalus, and low rate of HIV co-infection and MDR tuberculosis in the study population. However, the morbidity was quite high, and only 16% of patients had a normal outcome. The morbidity reported in other series varied between 20 and 30% [13]. A major prognostic indicator for mortality and morbidity was disease stage at presentation [21,112]. In the South African study in children, ethnicity, disease stage, headache, convulsions, motor function, brainstem dysfunction, and cerebral infarction were independently associated with poor outcome on multivariate logistic regression analysis. The area under curve (AUC) of the model was 0.84 (95% CI, 0.80-0.89) [21].

58.8 Conclusion

Tuberculous meningitis is a serious CNS infection with significant mortality and high morbidity among survivors. Most factors found to correlate with poor outcome can be directly traced to the degree of disease progression at the time of diagnosis. The only way to reduce mortality and morbidity is by early diagnosis and timely recognition of complications. Aggressive and appropriate care within the intensive care unit setting can minimize associate brain injury and improve the chance of a good outcome.

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