Treatment Of Tuberculous Meningitis Research Articles

Clinical characteristics and treatment delay of cerebral infarction in tuberculous meningitis

Cerebral infarction (CI) complicating tuberculous meningitis (TBM) is a major risk factor of permanent disability. The prevention of this complication is an important issue in the quality care of TBM patients. Our aim was to evaluate the clinical characteristics of TBM patients with CI. Ninety-one adult patients with TBM were studied between 1999 and 2007. Clinical, neuroradiological and cerebrospinal fluid data of patients with CI were compared with those without CI. Thirty of the 91 patients had CI, including symptomatic CI occurring before admission in 10 patients, symptomatic CI occurring during hospitalisation in four and silent CI in 16 patients. When compared with non-CI patients, patients with CI were younger and associated with focal weakness on presentation, and had basal meningeal enhancement and hydrocephalus on brain images. Prolonged doctor delays of antituberculosis and steroid therapies, neurosurgical intervention, focal weakness and dementia as sequelae, and poor outcomes were associated with patients with CI than non-CI patients. Contrast-enhanced brain imaging is helpful to explore the basal meningeal enhancement in CI patients, and contributes to early diagnosis and treatment of TBM. Early antituberculosis and steroid therapies may help prevent CI in TBM patients.

066 The paradoxical response: the development of intracranial tuberculomas during treatment for tuberculous meningitis

Case ReportA 22-year-old Philipino man was admitted with a left 6th nerve palsy, confusion and acute urinary retention. This followed a 1 month history of headache, dizziness and double vision....

Tuberculous syringomyelia in an HIV-infected patient: a case report

A 37-year-old HIV-positive Gambian woman presented with spastic weakness of the right leg six years after receiving treatment for tuberculous meningitis (TBM). Magnetic resonance imaging (MRI) of the spine showed a multiloculated syrinx in the thoracic spinal cord extending from the T2 to the T11 level. Syringomyelia and syringobulbia have been reported as complications of TBM. We describe the first case of syringomyelia as an uncommon late complication of treated TBM in the setting of HIV infection. Early recognition of this rare entity may avoid irreversible neurological sequelae.

イソニアジド髄注療法およびステロイドパルス療法が奏効した難治性結核性髄膜炎の2例

Tuberculous meningitis (TbM) is a neurological emergency condition that requires prompt initiation of treatment. The standard initial treatment for TbM is often insufficient for producing remission because the anti-tuberculosis agent may cause severe side effects, or vasculitis and hydrocephalus may induce an intractable state. Moreover, it is difficult to distinguish paradoxical expansion from its own deterioration. We treated 2 cases of adult TbM by using multidisciplinary therapy, including methyl prednisolone pulse and intrathecal isoniazid administration. Both cases had not been diagnosed as pulmonary or other tuberculosis, and cerebrospinal fluid (CSF) culture and polymerase chain reaction at approximately 1 week after hospitalization identified the cases as TbM. We administered the standard initial treatment recommended by the British Infection Society guidelines for adults, but both cases deteriorated and showed elevation of intracranial pressure. We indwelled a lumbar drainage for Case 1 and an Ommaya reservoir for Case 2. We removed CSF and administrated isoniazid regularly using each of the drainage devices, added streptomycin, and increased the steroid dose including addition of steroid pulse therapy. Both cases improved, and their neurological dysfunction did not persist. After the induction of an intractable state occurs due to TbM, we are likely to assume poor prognosis and neurological sequelae. However, our experience in these cases showed amelioration of the symptoms leading to the rehabilitation of these patients in society.

Fulminant Tuberculous Meningitis

A 56-year-old Japanese male presented with tuberculous meningitis (TBM) manifesting as irrational behavior. He underwent lumbar puncture, which showed inflammatory cerebrospinal fluid (CSF) findings. Administration of anti-tuberculosis (TB) agents was started on the day after admission (Day 1) because delayed treatment of TBM might be fatal. On Day 4, magnetic resonance (MR) imaging and MR angiography showed fresh infarctions, hydrocephalus, and stenoses of arteries. CSF drainage and biopsy of brain tissue were performed, but the pathological findings were non-specific. Frequent CSF examinations, cultures, and polymerase chain reaction were performed, but no positive finding of TB was obtained. He died on Day 14. Brain autopsy showed Langerhans giant cells and Ziehl-Neelsen-positive TB bodies. Unfortunately, our patient suffered very poor outcome irrespective of early anti-TB treatment starting Day 1, suggesting the probability of delayed admission or drug-resistant TB. TB infection including TBM has become rare in developed countries, and diagnosis remains difficult. Corticosteroid therapy may be effective for TBM, but may be restricted and ameliorate mortality but not morbidity. Further study is required to establish second line treatment if TBM is resistant to anti-TB agents and corticosteroid administration.

Treatment of Central Nervous System Tuberculosis Infections and Neurological Complications of Tuberculosis Treatment

Tuberculosis (TB) with central nervous system (CNS) manifestation is a form of TB with a high mortality and morbidity. Tuberculous meningitis (TM) is the most common form of CNS-TB. Although diagnosis of CNS-TB can be challenging, early treatment of CNS-TB is related to a better outcome. If CNS-TB is suspected, even though the clinical picture is not specific, it should be immediately treated. For the treatment of CNS-TB, knowledge of the penetration across the blood-brain barrier of the various antituberculosis agents used in TB treatment is important. These will be described here in order to serve as a guide in choosing a treatment for CNS-TB. Corticosteroids have an evidence-based value in the treatment of TM and so are recommended. As for thalidomide use in CNS-TB, sound evidence is still lacking. We will also include a description of the adverse neurotoxic effects of the various other agents including their psychiatric, ototoxic and ophthalmic adverse effects.

Meningitis tuberculosa: claves para su diagnóstico y propuestas terapéuticas

Diagnosis of tuberculous meningitis (TBM) is always a challenge. We must give importance for duration of clinical manifestations. Cerebrospinal fluid (CSF) has own characteristic and it have to be control several times during the treatment. Adenosin deaminase with cut off more than 15 UI/mL and M. tuberculosis polymerase chain reaction in CSF are the most relevant diagnostic tests. Radiologic test gives diagnostic clues but do not confirm the diagnosis. In the future we can structure a score with all these elements to support the clinician in the diagnostic process. The treatment of TBM because of its high morbidity and high mortality has to be necessarily more intensive and prolonged and we must select drugs with a good penetration into the central nervous system (SNC). A therapeutic scheme with duration of 12 months with two phases is proposed, the diary phase during the first three months of treatment includes isoniacid, rifampicin, pirazinamid and ethambutol or moxifloxacin. Streptomycin must not be included due to own erratic SNC penetration and its known toxicity. The second twice a week phase has to be changed by a three times per week phase during 9 months and it must include isoniacid, rifampicin and pirazinamide. Dexamethasone is added during the first 6 weeks of treatment. Patients with HIV infection than required treatment with antiretroviral drugs have to start ART treatment when diary phase has finished and must not include protease or integrase inhibitors.

Tuberculous meningitis: tips for diagnosis and proposals for treatment

Diagnosis of tuberculous meningitis (TBM) is always a challenge. We must give importance for duration of clinical manifestations. Cerebrospinal fluid (CSF) has own characteristic and it have to be control several times during the treatment. Adenosin deaminase with cut off more than 15 UI/mL and M. tuberculosis polymerase chain reaction in CSF are the most relevant diagnostic tests. Radiologic test gives diagnostic clues but do not confirm the diagnosis. In the future we can structure a score with all these elements to support the clinician in the diagnostic process. The treatment of TBM because of its high morbidity and high mortality has to be necessarily more intensive and prolonged and we must select drugs with a good penetration into the central nervous system (SNC). A therapeutic scheme with duration of 12 months with two phases is proposed, the diary phase during the first three months of treatment includes isoniacid, rifampicin, pirazinamid and ethambutol or moxifloxacin. Streptomycin must not be included due to own erratic SNC penetration and its known toxicity. The second twice a week phase has to be changed by a three times per week phase during 9 months and it must include isoniacid, rifampicin and pirazinamide. Dexamethasone is added during the first 6 weeks of treatment. Patients with HIV infection than required treatment with antiretroviral drugs have to start ART treatment when diary phase has finished and must not include protease or integrase inhibitors.

Intensified treatment with high dose Rifampicin and Levofloxacin compared to standard treatment for adult patients with Tuberculous Meningitis (TBM-IT): protocol for a randomized controlled trial

BackgroundTuberculous meningitis is the most severe form of tuberculosis. Mortality for untreated tuberculous meningitis is 100%. Despite the introduction of antibiotic treatment for tuberculosis the mortality rate for tuberculous meningitis remains high; approximately 25% for HIV-negative and 67% for HIV positive patients with most deaths occurring within one month of starting therapy. The high mortality rate in tuberculous meningitis reflects the severity of the condition but also the poor antibacterial activity of current treatment regimes and relatively poor penetration of these drugs into the central nervous system. Improving the antitubercular activity in the central nervous system of current therapy may help improve outcomes. Increasing the dose of rifampicin, a key drug with known poor cerebrospinal fluid penetration may lead to higher drug levels at the site of infection and may improve survival. Of the second generation fluoroquinolones, levofloxacin may have the optimal pharmacological features including cerebrospinal fluid penetration, with a ratio of Area Under the Curve (AUC) in cerebrospinal fluid to AUC in plasma of >75% and strong bactericidal activity against Mycobacterium tuberculosis. We propose a randomized controlled trial to assess the efficacy of an intensified anti-tubercular treatment regimen in tuberculous meningitis patients, comparing current standard tuberculous meningitis treatment regimens with standard treatment intensified with high-dose rifampicin and additional levofloxacin.Methods/DesignA randomized, double blind, placebo-controlled trial with two parallel arms, comparing standard Vietnamese national guideline treatment for tuberculous meningitis with standard treatment plus an increased dose of rifampicin (to 15 mg/kg/day total) and additional levofloxacin. The study will include 750 patients (375 per treatment group) including a minimum of 350 HIV-positive patients. The calculation assumes an overall mortality of 40% vs. 30% in the two arms, respectively (corresponding to a target hazard ratio of 0.7), a power of 80% and a two-sided significance level of 5%. Randomization ratio is 1:1. The primary endpoint is overall survival, i.e. time from randomization to death during a follow-up period of 9 months. Secondary endpoints are: neurological disability at 9 months, time to new neurological event or death, time to new or recurrent AIDS-defining illness or death (in HIV-positive patients only), severe adverse events, and rate of treatment interruption for adverse events.DiscussionCurrently very few options are available for the treatment of TBM and the mortality rate remains unacceptably high with severe disabilities seen in many of the survivors. This trial is based on the hypothesis that current anti-mycobacterial treatment schedules for TBM are not potent enough and that outcomes will be improved by increasing the CSF penetrating power of this regimen by optimising dosage and using additional drugs with better CSF penetration.Trial registrationInternational Standard Randomised Controlled Trial Number ISRCTN61649292

Tuberculous Meningitis: Diagnosis and Treatment Overview

Tuberculous meningitis (TBM) is the most common form of central nervous system tuberculosis (TB) and has very high morbidity and mortality. TBM is typically a subacute disease with symptoms that may persist for weeks before diagnosis. Characteristic cerebrospinal fluid (CSF) findings of TBM include a lymphocytic-predominant pleiocytosis, elevated protein, and low glucose. CSF acid-fast smear and culture have relatively low sensitivity but yield is increased with multiple, large volume samples. Nucleic acid amplification of the CSF by PCR is highly specific but suboptimal sensitivity precludes ruling out TBM with a negative test. Treatment for TBM should be initiated as soon as clinical suspicion is supported by initial CSF studies. Empiric treatment should include at least four first-line drugs, preferably isoniazid, rifampin, pyrazinamide, and streptomycin or ethambutol; the role of fluoroquinolones remains to be determined. Adjunctive treatment with corticosteroids has been shown to improve mortality with TBM. In HIV-positive individuals with TBM, important treatment considerations include drug interactions, development of immune reconstitution inflammatory syndrome, unclear benefit of adjunctive corticosteroids, and higher rates of drug-resistant TB. Testing the efficacy of second-line and new anti-TB drugs in animal models of experimental TBM is needed to help determine the optimal regimen for drug-resistant TB.

Concomitant tubercular and fungal cerebellar abscess in an immunocompromised girl

Concomitant tubercular and fungal cerebellar abscess is rare and we report the first concomitant recurrent multi-lobulated tubercular and fungal cerebellar abscess in an immunocompromised girl with Histiocytosis-X. She presented with cerebellar abscess history diagnosed during the ongoing treatment for tuberculous meningitis. The abscess was drained. Upon the detection of cerebellar abscess recurrence and pulmonary infection, she was referred to our clinic five weeks after the first surgical intervention. Patient was conscious, co-operating but confused. She had severe cachexia, stiff neck and fever. Fundus examination showed bilateral papilledema. Cranial MR images revealed multiple lobulated lesions. Suboccipital craniectomy was performed and abscess was evacuated in toto. Lesion was multi-lobulated. Thick, yellow-gray purulent material was drained. Histopathological examinations yielded Langhans giant cells,budding and branching fungal structures. Fungal infection was identified. We emphasize that posterior decompression and total resection should be considered first in the management of lesions with mass effect in the posterior fossa. Also the presence of concomitant fatal fungal abscess highlights that although the clinic and former diagnoses of the patient may direct the clinician to a certain pathogen, unusual resistant organisms should not be.

Diagnosis of cryptococcal and tuberculous meningitis in a resource-limited African setting

Cryptococcal meningitis (CM) and tuberculous meningitis (TBM) are common in HIV-infected adults in Africa and difficult to diagnose. Inaccurate diagnosis results in adverse outcomes. We describe patterns of meningitis in a Malawian hospital, focusing on features which differentiate CM and TBM with the aim to derive an algorithm using only clinical and basic laboratory data available in this resource-poor setting. Consecutive patients admitted with meningitis were prospectively recruited, clinical features were recorded and cerebrospinal fluid (CSF) was examined. A total of 573 patients were recruited, and 263 (46%) had CSF consistent with meningitis. One hundred and twelve (43%) had CM and 46 (18%) had TBM. CM was associated with high CSF opening pressure and low CSF leukocyte count. Fever, neck stiffness and reduced conscious level were associated with TBM. A diagnostic index was constructed demonstrating sensitivity 83%and specificity 79% for the differentiation of CM and TBM. An algorithm was derived with 92% sensitivity for the diagnosis of CM, but only 58% specificity. Although we demonstrate features associated with CM and TBM, a sufficiently sensitive and specific diagnostic algorithm could not be derived, suggesting that the diagnosis of CM and TBM in resource-limited settings still requires better access to laboratory tools.

Approach to the Diagnosis and Management of Tuberculous Meningitis

Meningitis caused by Mycobacterium tuberculosis remains an important cause of morbidity and mortality worldwide, and presents particular challenges in terms of diagnosis and management. The nonspecific clinical presentation of tuberculous meningitis (TBM) has led researchers to develop newer molecular methods of making the diagnosis. Several of these methods have excellent sensitivity and specificity, although many are not yet available for clinical use. Successful treatment of TBM requires a combination of antimicrobial agents, with vigilance regarding the possibility of disease caused by resistant organisms. Adjunctive corticosteroids also have a role in treating this potentially devastating infection, as can neurosurgery. With proper therapy, morbidity and mortality can be minimized in patients with TBM.

Duration of anti-tubercular treatment in tuberculous meningitis: Challenges and opportunity

The duration of anti-tuberculous therapy in tuberculous meningitis is controversial. There is variation in recommendations by different societies and expert groups on this issue. To determine the strength of evidence for short-term therapy in tuberculous meningitis through review of literature and critical appraisal. Cochrane CENTRAL (Issue 4, 2010), TRIP database, and PubMed (from 1966 to present) were searched for relevant papers with keywords 'meningeal tuberculosis' and tuberculous meningitis' combined with 'chemotherapy'. A critical appraisal of a systematic review was done using standard criteria. A total of 10 relevant papers were identified. All papers were included in a systematic review. The systematic review did not specify study design of studies to be included, had only case series but no randomised controlled trial, and unclear definition of endpoints. The evidence base for short-term therapy for tuberculous meningitis is weak. There is a need to conduct a randomised controlled trial with non-inferiority hypothesis of adequate sample size with well-defined end points and adequate follow-up. This is a challenge as well as opportunity for Indian neurologists.

Corticosteroids (dexamethasoneversusintravenous methylprednisolone) in patients with tuberculous meningitis

As inflammatory changes play an important role in the neuropathogenesis of the disease, adjunctive corticosteroid treatment may be of benefit in tuberculous meningitis. In an open-label study in India, 97 patients with such meningitis were randomized into a control group, a dexamethasone group (with the drug given intravenously once a day for 4 weeks, and then orally, once daily, for another 4 weeks) and a methylprednisolone group (with the drug given intravenously once a day for 5 days). All the patients also received standard anti-tuberculosis drugs. The primary outcome measure was death or severe disability 6 months after the randomization, with a modified Rankin scale used to assess each patient's level of disability. The other outcome measures investigated were deterioration in vision, focal neurological deficits and new-onset seizures. Six patients (one of those given dexamethasone, three of those given methylprednisolone and two of those in the control group) were lost to follow-up. Although each corticosteroid was associated with a reduction in death or disability, this reduction did not reach statistical significance in either the dexamethasone group (relative risk of death=0.6, with a 95% confidence interval of 0.29-1.2; P>0.05) or the methylprednisolone group (relative risk of death=0.7, with a 95% confidence interval of 0.4-1.4; P>0.05), probably because of the small sample sizes. Among the patients who died within 10 months of randomization, the mean time to death (post-randomization) was 8.8 months in the dexamethasone group, 8.2 months in the methylprednisolone group, and 7.1 months in the control group (P>0.05). The prevalence of impaired vision, among all the patients evaluated, decreased from 41.8% at baseline to 29.9% (among the survivors) 6 months later. Adverse events were similar and equally reported in the two corticosteroid groups. Larger trials are still needed to determine if dexamethasone and/or methylprednisolone are useful in the treatment of tuberculous meningitis, at least in India.

Extensive meningeal and prenchymal calcified tuberculoma as long-term residual sequelae of tuberculous meningitis

A 51-year-old woman presented with progressive cognitive decline of 1 year duration. Her past medical history revealed that she received treatment for tuberculous meningitis and milliary tuberculosis at the age of twenty. At that time cerebrospinal fluid (CSF) and sputum were positive for M. tuberculosis. During that illness she had suffered from recurrent seizures. Neurological examination revealed right optic atrophy with total blindness and right spastic hemiparesis. Neuropsychological tests revealed visuospatial, verbal and visual memory deficits, and also deficits in frontal executive functions. Brain computed tomography (CT) scan and magnetic resonance imaging (MRI) showed multiple extensive popcorn-like calcifications in the basal cisterns, insula, hippocampus, and frontal corticomedullary junction along the meninges protruding into the brain prenchyma [Figures 1 and 2]. The masses showed hypointensity in all spin-echo sequences of the brain MRI [Figure 2]. These findings suggest extensive meningeal and parenchymal calcified tuberculoma as long-term sequelae of tuberculous meningitis. A large calcified nodule in the right crus cerebri was probably responsible for the blindness in her right eye and a right hippocampal head compression by the calcified lesion may relate to some of her cognitive deficits [Figure 3].

Temporal evolution of cerebrospinal fluid following initiation of treatment for tuberculous meningitis.

Clinicians often perform follow-up lumbar punctures (LPs) on patients with tuberculous meningitis (TBM) to document changes occurring in the cerebrospinal fluid (CSF). Normalisation of the CSF then serves as indirect confirmation of the diagnosis. However, changes occurring in CSF following the initiation of anti-tuberculosis (TB) treatment are not well described. We undertook a retrospective study to determine the temporal evolution of CSF in patients with TBM on anti-TB treatment in an attempt to provide a more rational basis for the interpretation of repeat LPs. Patients diagnosed with TBM at King George V Hospital in Durban from 1994 to 2003 were identified. Demographic, clinical, laboratory and radiological data were recorded. We examined the change in CSF lymphocyte cell count, polymorphonuclear (PMN) cell count, glucose concentration and protein concentration. Initially, scatter plots of the data modelled over time were produced and random effects models were then used to model the predicted changes in CSF over time. Ninety-nine patients were identified, and a total of 327 LPs were done. The average number of LPs per patient was 3 (range 3 - 9). Statistically significant changes in all four variables (lymphocytes, PMN cells, glucose and protein) were demonstrated, with a p value < 0.001. The predicted models showed that lymphocyte count and protein concentration change slowly over time. PMN cells and glucose concentration changed rapidly in an exponential manner. Our results demonstrate the tendency for CSF to normalise over time. The slow change in lymphocyte count and protein concentration limits clinical use. The rapid change in PMN cells and glucose concentration allows us to make reasonable clinical decisions. If a repeat LP does not show definite improvement in these two parameters, it should be considered atypical for TBM.

Robert McLaren Todd

Robert McLaren Todd’s life and work can be divided into four main parts: education and medicine, the Church, music and his other interests, and of course his family. Education and...

Evidence Behind the WHO Guidelines: Hospital Care for Children: What is the Most Appropriate Anti-microbial Treatment for Tuberculous Meningitis?

The World Health Organization (WHO) has produced guidelines for the management of common illnesses in hospitals with limited resources. This series reviews the scientific evidence behind WHO’s recommendations. The WHO guidelines, and more reviews are available at http://www.ichrc.org This review addresses the question: What is the most appropriate anti-microbial treatment for tuberculous meningitis? The WHO Pocketbook of Hospital Care for Children recommends as the optimal treatment regimen, where there is no drug resistance:

Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults

Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults