The use of thalidomide to treat children with tuberculosis meningitis: A review.

Much of the morbidity and mortality caused by tuberculous meningitis (TBM) is mediated by a dysregulated immune response. Effective host-directed therapy is therefore critical to improve survival and clinical outcomes. Currently only one host-directed therapy (HDT), corticosteroids, is proven to improve mortality. However, there is no evidence that corticosteroids reduce morbidity and the mechanism of action for mortality reduction is uncertain. Further, it has no proven benefit in HIV co-infected individuals. One promising host-directed therapy approach is to restrict the immunopathology arising from tumour necrosis factor (TNF)-α excess is via TNF-α inhibitors. There are accumulating data on the role of thalidomide, anti-TNF-α monoclonal antibodies (infliximab, adalimumab) and the soluble TNF-α receptor (etanercept) in TBM treatment. Thalidomide was developed nearly seventy years ago and has been a highly controversial drug. Birth defects and toxic adverse effects have limited its use but an improved understanding of its immunological mechanism of action suggest that it may have a crucial role in regulating the destructive host response seen in inflammatory conditions such as TBM. Observational studies at our institution found low dosage adjunctive thalidomide safe in treating tuberculous mass lesions and blindness related to optochiasmatic arachnoiditis, with good clinical and radiological response. In this review, we discuss possible mechanisms of action for thalidomide, based on our clinico-radiologic experience and post-mortem histopathological work. We also propose a rationale for its use in the treatment of certain TBM-related complications.

Thalidomide Use for Complicated Central Nervous System Tuberculosis in Children: Insights From an Observational Cohort.

BACKGROUND: Much of the neurological sequelae of central nervous system (CNS) tuberculosis (TB) is due to an excessive cytokine-driven host-inflammatory response. Adjunctive corticosteroids, which reduce cytokine production and thus dampen the inflammation, improve overall survival but do not prevent morbidity. This has prompted investigation of more targeted immunomodulatory agents, including thalidomide. METHODS: We describe a retrospective cohort of 38 children consecutively treated with adjunctive thalidomide for CNS TB-related complications over a 10-year period. RESULTS: The most common presenting symptom was focal motor deficit (n = 16), followed by cranial nerve palsies and cerebellar dysfunction. Three of the 38 children presented with large dural-based lesions, manifesting as epilepsia partialis continua (EPC), 4 presented with blindness secondary to optochiasmatic arachnoiditis, and 2 children developed paraplegia due to spinal cord TB mass lesions. Duration of adjunctive thalidomide therapy (3-5 mg/kg/day) varied according to complication type. In children compromised by TB mass lesions, the median treatment duration was 3.9 months (interquartile range [IQR], 2.0-5.0 months), whereas in children with optic neuritis it was 2.0 months (IQR, 1.3-7.3 months) and in EPC it was 1.0 months (IQR, 1-2.5 months). Satisfactory clinical and radiological response was observed in 37 of the children. None of the children experienced rashes, hepatitis, or hematologic derangements or complained of leg cramps. CONCLUSIONS: This study is the largest cohort of adult or pediatric patients treated with adjunctive thalidomide for CNS TB-related complications. The drug has proved to be safe and well tolerated and appears to be clinically efficacious. The potential role of thalidomide or analogues in the treatment of other tuberculous meningitis-related complications requires further exploration.

Management of intracranial tuberculous mass lesions: how long should we treat for?

Tuberculous intracranial mass lesions are common in settings with high tuberculosis (TB) incidence and HIV prevalence. The diagnosis of such lesions, which include tuberculoma and tuberculous abscesses, is often presumptive and based on radiological features, supportive evidence of TB elsewhere and response to TB treatment. However, the treatment response is unpredictable, with lesions frequently enlarging paradoxically or persisting for many years despite appropriate TB treatment and corticosteroid therapy. Most international guidelines recommend a 9-12 month course of TB treatment for central nervous system TB when the infecting Mycobacterium tuberculosis ( M.tb) strain is sensitive to first-line drugs. However, there is variation in opinion and practice with respect to the duration of TB treatment in patients with tuberculomas or tuberculous abscesses. A major reason for this is the lack of prospective clinical trial evidence. Some experts suggest continuing treatment until radiological resolution of enhancing lesions has been achieved, but this may unnecessarily expose patients to prolonged periods of potentially toxic drugs. It is currently unknown whether persistent radiological enhancement of intracranial tuberculomas after 9-12 months of treatment represents active disease, inflammatory response in a sterilized lesion or merely revascularization. The consequences of stopping TB treatment prior to resolution of lesional enhancement have rarely been explored. These important issues were discussed at the 3 rd International Tuberculous Meningitis Consortium meeting. Most clinicians were of the opinion that continued enhancement does not necessarily represent treatment failure and that prolonged TB therapy was not warranted in patients presumably infected with M.tb strains susceptible to first-line drugs. In this manuscript we highlight current medical treatment practices, benefits and disadvantages of different TB treatment durations and the need for evidence-based guidelines regarding the treatment duration of patients with intracranial tuberculous mass lesions.

Standardized Methods for Enhanced Quality and Comparability of Tuberculous Meningitis Studies.

Tuberculous meningitis (TBM) remains a major cause of death and disability in tuberculosis-endemic areas, especially in young children and immunocompromised adults. Research aimed at improving outcomes is hampered by poor standardization, which limits study comparison and the generalizability of results. We propose standardized methods for the conduct of TBM clinical research that were drafted at an international tuberculous meningitis research meeting organized by the Oxford University Clinical Research Unit in Vietnam. We propose a core dataset including demographic and clinical information to be collected at study enrollment, important aspects related to patient management and monitoring, and standardized reporting of patient outcomes. The criteria proposed for the conduct of observational and intervention TBM studies should improve the quality of future research outputs, can facilitate multicenter studies and meta-analyses of pooled data, and could provide the foundation for a global TBM data repository.

Clinicoradiologic response of neurologic tuberculous mass lesions in children treated with thalidomide.

Neurologic tuberculous pseudoabscesses that clinically progress despite conventional antituberculosis therapy may be responsive to adjuvant thalidomide, a potent tumor necrosis factor-α inhibitor. In this study, the addition of thalidomide provided substantial clinical benefit in the majority of patients, and magnetic resonance imaging evolution of lesions from early-stage "T2 bright" with edema to "T2 black" represented a marker of cure.

Host immune response to tuberculous meningitis.

BACKGROUND: Tuberculous meningitis (TBM) is a severe complication of tuberculosis predominantly affecting young children. Early treatment is vital to prevent morbidity and mortality, emphasizing the importance of early diagnosis. The lack of sensitive methods for early diagnosis is the most common cause of delay. Attempts have been made to develop simplified tests for tuberculosis, but their diagnostic power remains poor. The clinical picture of TBM is mainly driven by the host's immune response to Mycobacterium tuberculosis; therefore, identification of disease-specific biomarkers may have diagnostic and therapeutic value and improve our understanding of its pathogenesis. METHODS: We investigated disease-specific biomarkers of childhood TBM in a cohort of children aged 3 months-13 years with symptoms and signs suggestive of meningitis. Cerebrospinal fluid (CSF) and serum from 56 patients with and 55 patients without TBM were assessed for 28 soluble mediators. RESULTS: Unsupervised hierarchical clustering analysis revealed a disease-specific pattern of biomarkers for TBM relative to other types of meningitis. A biomarker-based diagnostic prediction model for childhood TBM based on CSF concentrations of interleukin 13 (cutoff value, 37.26 pg/mL), vascular endothelial growth factor (cutoff value, 42.92 pg/mL), and cathelicidin LL-37 (cutoff value, 3221.01 pg/mL) is presented with a sensitivity of 0.52 and a specificity of 0.95. CONCLUSIONS: These data highlight the potential of biosignatures in the host's CSF for diagnostic applications and for improving our understanding of the pathogenesis of TBM to discover strategies to prevent immunopathological sequelae.

Uniform research case definition criteria differentiate tuberculous and bacterial meningitis in children.

BACKGROUND: Tuberculous meningitis (TBM) research is hampered by low numbers of microbiologically confirmed TBM cases and the fact that they may represent a select part of the disease spectrum. A uniform TBM research case definition was developed to address these limitations, but its ability to differentiate TBM from bacterial meningitis has not been evaluated. METHODS: We assessed all children treated for TBM from 1985 to 2005 at Tygerberg Children's Hospital, Cape Town, South Africa. For comparative purposes, a group of children with culture-confirmed bacterial meningitis, diagnosed between 2003 and 2009, was identified from the National Health Laboratory Service database. The performance of the proposed case definition was evaluated in culture-confirmed TBM and bacterial meningitis cases. RESULTS: Of 554 children treated for TBM, 66 (11.9%) were classified as "definite TBM," 408 (73.6%) as "probable TBM," and 72 (13.0%) as "possible TBM." "Probable TBM" criteria identified culture-confirmed TBM with a sensitivity of 86% and specificity of 100%; sensitivity was increased but specificity reduced when using "possible TBM" criteria (sensitivity 100%, specificity 56%). CONCLUSIONS: "Probable TBM" criteria accurately differentiated TBM from bacterial meningitis and could be considered for use in clinical trials; reduced sensitivity in children with early TBM (stage 1 disease) remains a concern.

The value of transcranial Doppler imaging in children with tuberculous meningitis.

PURPOSE: Transcranial Doppler imaging (TCDI) is potentially a valuable investigational tool in children with tuberculous meningitis (TBM), a condition often complicated by pathology relevant to Doppler imaging such as raised intracranial pressure (ICP) and cerebral vasculopathies. METHODS: Serial TCDI was performed on 20 TBM children with the aim of investigating cerebrovascular haemodynamics and the relationship between pulsatility index (PI) and ICP. RESULTS: We observed a poor correlation between ICP and PI in children with communicating hydrocephalus (p = 0.72). No decline in PI was noted following 7 days of medical therapy for communicating hydrocephalus (p = 0.78) despite a concomitant decline in ICP. Conversely, a decline in PI was noted in all four children with non-communicating hydrocephalus who underwent cerebrospinal fluid diversion. High blood flow velocities (BFV) in all the basal cerebral arteries were observed in 14 children (70 %). The high BFV persisted for 7 days suggesting stenosis due to vasculitis rather than functional vasospasm. Complete middle cerebral artery (MCA) occlusion, subnormal mean MCA velocities (<40 cm/s) and PIs (<0.4) correlated with radiologically proven large cerebral infarcts. CONCLUSIONS: TCDI-derived PI is not a reliable indicator of raised ICP in children with tuberculous hydrocephalus. This may be attributed to individual variation of tuberculous vascular disease, possibly compromising cerebral vascular compliance and resistance. Basal artery stenosis secondary to vasculitis is observed during the acute stage of TBM in the majority of children.

Commercial nucleic acid amplification tests in tuberculous meningitis--a meta-analysis.

Although nucleic acid amplification tests (NAATs) promise a rapid, definitive diagnosis of tuberculous meningitis, the performance of first-generation NAATs was suboptimal and variable. We conducted a meta-analysis of studies published between 2003 and 2013, using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool to evaluate methodological quality. The diagnostic accuracy of newer commercial NAATs was assessed. Pooled estimates of diagnostic accuracy for commercial NAATs measured against a cerebrospinal fluid Mycobacterium tuberculosis culture-positive gold standard were sensitivity 0.64, specificity 0.98, and diagnostic odds ratio 64.0. Heterogeneity was limited; P value = 0.147 and I(2) = 33.85%. The Xpert MTB/RIF® test was evaluated in 1 retrospective study and 4 prospective studies, with pooled sensitivity 0.70 and specificity 0.97. The QUADAS-2 tool revealed low risk of bias, as well as low concerns regarding applicability. Heterogeneity was pronounced among studies of in-house tests. Commercial NAATs proved to be highly specific with greatly reduced heterogeneity compared to in-house tests. Sub-optimal sensitivity remains a limitation.

Short intensified treatment in children with drug-susceptible tuberculous meningitis.

BACKGROUND: The World Health Organization recommends 12-month treatment (2RHZE/10RH) for children with tuberculous meningitis (TBM). Studies evaluating length of antituberculous treatment for TBM report similar completion and relapse rates comparing 6-month treatment with 12-month treatment. METHODS: A prospective evaluation to determine whether short-course intensified treatment (6 RHZEth for HIV-infected and 9RHZEth for HIV-infected) is sufficient and safe in children with drug-susceptible TBM. RESULTS: Of 184 children with TBM, median age 58 months and 90 (49%) male, 98 children (53%) presented at stage II TBM, 64 (35%) at stage III TBM and only 22 (12%) at stage I TBM. Ninety (49%) children were treated at home after the first month of therapy; all others received their full treatment in hospital. The HIV prevalence was 14% (22/155 children tested). Anti-TB drug-induced hepatotoxicity occurred in 5% (8 of 143 children tested), all tested negative for viral hepatitis; in all 8 cases, the original regimen was restarted without recurrence. After treatment completion, 147 (80%) children had a good outcome, 7 (3.8%) died. There was no difference in outcome between HIV-infected and HIV-uninfected children who completed treatment (P = 0.986) nor between TBM-hydrocephalic children who were medically treated or shunted (P = 0.166). CONCLUSION: Short intensified treatment is safe and effective in both HIV-infected and HIV-uninfected children with drug-susceptible TBM.

Neurological manifestations of TB-IRIS: a report of 4 children.

INTRODUCTION: Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a potentially life-threatening complication in HIV infected children with tuberculosis (TB) of the central nervous system. HIV-associated TB-IRIS has not been previously described in children with neurotuberculosis. OBJECTIVE: To describe the neurological and neuro-radiological features of 4 consecutive cases of TB-IRIS in children with neurotuberculosis and to discuss possible management strategies. RESULTS: Three patients treated for tuberculosis of the central nervous system experienced paradoxical worsening of neurological symptoms when combination antiretroviral therapy (cART) was initiated. Intracranial tuberculomas were unmasked in the 4th patient. All patients developed new neurological signs within 10 days of cART initiation. Neurological symptoms and signs included headache, seizures, meningeal irritation, decreased level of consciousness, ataxia and focal motor deficit. Interventions included the temporary discontinuation of cART and the use of corticosteroids in all patients. Three patients received thalidomide and 1 chloroquine and mycophenolate mofetil. One patient died and the others experienced prolonged hospitalization. CONCLUSION: TB-IRIS should be considered when new neurological signs develop shortly after initiation of cART in children. There is little data to guide the timing of initiation of cART and the management of complications in children.

Impact of drug resistance on clinical outcome in children with tuberculous meningitis.

BACKGROUND: Tuberculous meningitis (TBM) is associated with delayed diagnosis and poor outcome in children. This study investigated the impact of drug resistance on clinical outcome in children with TBM. METHODS: All children (0-13 years) were included if admitted to Tygerberg Children's Hospital, Cape Town, South Africa, from January 2003 to April 2009 with a diagnosis of either confirmed TBM, or probable TBM with mycobacterial isolation from a site other than cerebrospinal fluid. Mycobacterial samples underwent drug susceptibility testing to rifampin and isoniazid. Children were treated with isoniazid, rifampin, pyrazinamide and ethionamide according to local guidelines. RESULTS: One hundred twenty-three children were included; 13% (16 of 123) had any form of drug resistance, and 4% (5 of 123) had multidrug-resistant tuberculosis. Time from start of symptoms to appropriate treatment was longer in children with any drug resistance (median: 31 days versus 9 days; P=0.001). In multivariable analysis, young age (P=0.013) and multidrug-resistant tuberculosis (adjusted odds ratio: 12.4 [95% confidence interval: 1.17-132.3]; P=0.037) remained risk factors for unfavorable outcome, and multidrug-resistant tuberculosis remained a risk for death (adjusted odds ratio: 63.9 [95% confidence interval: 4.84-843.2]; P=0.002). We did not detect any difference in outcome between those with isolates resistant to only isoniazid and those with fully susceptible strains (adjusted odds ratio: 0.22 [confidence interval: 0.03-1.87]; P=0.17). CONCLUSION: Multidrug-resistant TBM in children has poor clinical outcome and is associated with death. We did not find any difference in the outcomes between children with isoniazid monoresistant TBM and those with drug-susceptible TBM. One explanation could be the local treatment regimen. Further investigation of this regimen is indicated.

Hemiconvulsion-hemiplegia-epilepsy syndrome in South African children: insights from a retrospective case series.

INTRODUCTION: Hemiconvulsion-hemiplegia-epilepsy (HHE) syndrome is a recognized sequel of febrile partial status in children younger than 4 years. OBJECTIVE: To describe the clinical features, neuroradiology and outcome in 8 South African children with HHE syndrome. METHOD: A retrospective descriptive study of 8 consecutive cases of HHE syndrome presenting to tertiary hospitals in the Western Cape over a 2 year period. RESULTS: The median age of onset of convulsive status was 16 months (range: 9-36 months). Gender distribution was equal. The duration of the initial episode of status exceeded 2 h in all children. All children were reported to have been developmentally normal prior to the onset of the first seizure and none previously suffered seizures or had a family history of febrile seizures and epilepsy. In 7 of the 8 cases the initial seizure was not associated with fever or preceding illness. Imaging demonstrated cerebral hemiatrophy in all and additional crossed cerebellar atrophy in 2 children. Moderate to severe intellectual disability ensued in the majority of children. The severity of the intellectual disability correlated with the degree of the motor deficit and occurred irrespective of the cerebral hemisphere involved. CONCLUSION: In contrast to developed countries, HHE syndrome is still prevalent in South Africa. The neurological morbidity in South African children is significant and highlights the need for improved emergency care of status epilepticus.

Tuberculous meningitis: barriers to adherence in home treatment of children and caretaker perceptions.

INTRODUCTION: In-hospital treatment of children with tuberculous meningitis (TBM) is not a feasible option in many resource-poor countries. Home-based treatment has shown to be a viable alternative. Adherence is an important factor determining success of treatment. OBJECTIVE: Identify possible barriers to adherence of home-based treatment and caretaker perception of the disease. METHOD: A qualitative study consisting of 11 in-depth semi-structured interviews was performed based on principles of the health belief model. RESULTS: Barriers of adherence identified include poor understanding of the disease and transmission route, difficulty with medication administration and side effects, lack of access to the health-care facility, long waiting times and hidden costs of transportation. Caretakers showed good appreciation of the adverse effects of noncompliance and benefits obtained from taking treatment in the home environment. CONCLUSION: Improved doctor-patient communication, information brochures, structural changes to hospital settings, provision of financial and peer support all contribute to optimal TBM home-based treatment.

The role of aspirin in childhood tuberculous meningitis.

Arterial stroke is the main cause of poor outcome in childhood tuberculous meningitis. Aspirin has an antithrombotic action at low dose and anti-ischemic and anti-inflammatory properties, which are dose-related. The aim of the study was to explore the possible benefits of aspirin in children with tuberculous meningitis. A total of 146 consecutive children with a diagnosis of probable tuberculous meningitis were studied. Patients were randomized into 3 groups: (1) placebo group, (2) low-dose aspirin group, and (3) high-dose aspirin group. Twenty-nine additional patients who received aspirin before admission were excluded from the randomized study, but continued on low-dose aspirin. Aspirin, irrespective of dose, did not show any significant benefit regarding morbidity (hemiparesis and developmental outcome) and mortality. Aspirin was well tolerated, but 1 death was probably related to aspirin. The fact that the outcome of the high-dose aspirin group compared favorably with the other treatment groups despite younger age and more severe neurological involvement at baseline needs further investigation.

Tuberculous meningitis: a uniform case definition for use in clinical research.

Tuberculous meningitis causes substantial mortality and morbidity in children and adults. More research is urgently needed to better understand the pathogenesis of disease and to improve its clinical management and outcome. A major stumbling block is the absence of standardised diagnostic criteria. The different case definitions used in various studies makes comparison of research findings difficult, prevents the best use of existing data, and limits the management of disease. To address this problem, a 3-day tuberculous meningitis workshop took place in Cape Town, South Africa, and was attended by 41 international participants experienced in the research or management of tuberculous meningitis. During the meeting, diagnostic criteria were assessed and discussed, after which a writing committee was appointed to finalise a consensus case definition for tuberculous meningitis for use in future clinical research. We present the consensus case definition together with the rationale behind the recommendations. This case definition is applicable irrespective of the patient's age, HIV infection status, or the resources available in the research setting. Consistent use of the proposed case definition will aid comparison of studies, improve scientific communication, and ultimately improve care.

Tuberculous meningitis-related optic neuritis: recovery of vision with thalidomide in 4 consecutive cases.

Blindness is an uncommon but devastating complication of tuberculosis meningitis. The main causes are chronically raised intracranial pressure (hydrocephalus and/or tuberculomas) or direct involvement of the optic chiasm or optic nerves by the basal arachnoiditis (inflammation and/or compression). Antituberculosis therapy combined with corticosteroids and control of intracranial pressure constitutes the mainstay of therapy for tuberculous meningitis. Despite these treatment measures, some patients develop blindness, mainly as a result of progressive optochiasmatic arachnoiditis. This led us to explore the role of adjuvant thalidomide therapy, and we describe the dramatic recovery of vision in 4 consecutive cases. Clinical recovery was accompanied by marked radiological improvement on magnetic resonance imaging (MRI) of the brain.

Iron status in children with recurrent episodes of tumefactive cerebral demyelination.

Iron is a vital element in the multifactorial initiation of myelination. It is required for cholesterol and lipid biosynthesis, both key components of myelin. Iron also plays an important role in energy production by mitochondrial oxidative metabolism which occurs in myelin-producing oligodentrocytes at a higher rate than in any other cell. Iron deficiency can, therefore, result in decreased oligodendrocyte survival and defective myelination. This led us to investigate iron status in 2 consecutive children with multiple sclerosis who presented with recurrent episodes of tumefactive demyelination. Testing revealed nonanemic iron deficiency in both patients. Discontinuation of iron supplementation in both children resulted in recurrent decreased iron parameters which can indicate mutations in proteins responsible for regulation of iron uptake. Further studies are warranted to explore the association of low iron in children presenting with recurrent episodes of tumefactive demyelination.

Update on tuberculosis of the central nervous system: pathogenesis, diagnosis, and treatment.

Tuberculous meningitis is the most dangerous form of tuberculosis, yet our understanding of disease pathogenesis is based upon studies performed in the 1920s, our diagnostic methods are dependent upon those developed in the 1880 s, and our treatment has advanced little since the introduction of isoniazid in the 1950s. The authors focus this review on three important questions. First, how does Mycobacterium tuberculosis reach the brain? Second, what is the best way of identifying patients who require early empiric antituberculosis therapy? Third, what is the best way of managing tuberculous hydrocephalus?