Effectiveness of Adjunctive High-Dose Infliximab Therapy to Improve Disability-Free Survival Among Patients With Severe Central Nervous System Tuberculosis: A Matched Retrospective Cohort Study.

BACKGROUND: Few treatment options exist for patients with severe central nervous system (CNS) tuberculosis (TB) worsening due to inflammatory lesions, despite optimal antitubercular therapy (ATT) and steroids. Data regarding the efficacy and safety of infliximab in these patients are sparse. METHODS: We performed a matched retrospective cohort study based on Medical Research Council (MRC) grading system and modified Rankin Scale (mRS) scores comparing 2 groups of adults with CNS TB. Cohort A received at least 1 dose of infliximab after optimal ATT and steroids between March 2019 and July 2022. Cohort B received only ATT and steroids. Disability-free survival (mRS score ≤2) at 6 months was the primary outcome. RESULTS: Baseline MRC grades and mRS scores were similar between the cohorts. Median duration before initiation of infliximab therapy from start of ATT and steroids was 6 (IQR: 3.7-13) months and for neurological deficits was 4 (IQR: 2-6.2) months. Indications for infliximab were symptomatic tuberculomas (20/30; 66.7%), spinal cord involvement with paraparesis (8/30; 26.7%), and optochiasmatic arachnoiditis (3/30; 10%), worsening despite adequate ATT and steroids. Severe disability (5/30 [16.7%] and 21/60 [35%]) and all-cause mortality (2/30 [6.7%] and 13/60 [21.7%]) at 6 months were lower in cohort A versus cohort B, respectively. In the combined study population, only exposure to infliximab was positively associated (aRR: 6.2; 95% CI: 2.18-17.83; P = .001) with disability-free survival at 6 months. There were no clear infliximab-related side effects noted. CONCLUSIONS: Infliximab may be an effective and safe adjunctive strategy among severely disabled patients with CNS TB not improving despite optimal ATT and steroids. Adequately powered phase 3 clinical trials are required to confirm these early findings.

Distinguishing clinical characteristics of central nervous system tuberculosis in immunodeficient and non-immunodeficient individuals: a 12-year retrospective study.

BACKGROUND: Central nervous system tuberculosis (CNS TB) is a severe Mycobacterium tuberculosis (MTB) infection. It is unclear whether a patient's immune status alters the clinical manifestations and treatment outcomes of CNS TB. METHODS: Between January 2007-December 2018, chart reviews of CNS TB, including tuberculous meningitis (TBM), tuberculoma/abscess, and TB myelitis, were made. Subjects were categorized as immunodeficient (ID) and non-immunodeficient (NID). RESULTS: Of 310 subjects, 160 (51.6%) were in the ID group-132 (42.6%) had HIV and 28 (9.0%) had another ID, and 150 (48.4%) were in the NID group. The mean age was 43.64 ± 16.76 years, and 188 (60.6%) were male. There were 285 (91.9%) TBM, 16 (5.2%) tuberculoma/abscess, and 9 (2.9%) myelitis cases. The TBM characteristics in the ID group were younger age (p = 0.003), deep subcortical location of tuberculoma (p = 0.030), lower hemoglobin level (p < 0.001), and lower peripheral white blood cell count (p < 0.001). Only HIV individuals with TBM had an infection by multidrug-resistant MTB (p = 0.013). TBM mortality was varied by immune status -HIV 22.8%, other ID 29.6%, and NID 14.8% (p < 0.001). Factors significantly associated with unfavorable outcomes in TBM also differed between the HIV and NID groups. CONCLUSIONS: TBM is the most significant proportion of CNS TB. Some of the clinical characteristics of TBM, such as age, radiographic findings, hematological derangement, and mortality, including factors associated with unfavorable outcomes, differed between ID and non-ID patients.

Neuroimaging of central nervous system tuberculosis.

A 20-month-old female, not immunized with Bacillus Calmette-Guérin (BCG) vaccine, was admitted due to a four-day history of fever and cough. In the past three months, she presented respiratory infections, weight loss and enlarged cervical lymph nodes. On day two of admission, she displayed drowsiness and positive Romberg's sign; cerebrospinal fluid (CSF) workout revealed 107/ul cells, low glucose and high protein levels. Ceftriaxone and acyclovir were initiated, and she was transferred to our tertiary hospital. Brain magnetic resonance imaging showed punctiform focal areas of restricted diffusion in left capsular lenticular region suggestive of vasculitis secondary to infection. Tuberculin skin test and interferon-gamma release assay were positive. She started tuberculostatic therapy, but two days later she presented tonic-clonic seizures and impaired consciousness. Cerebral computed tomography (CT) revealed tetrahydrocephalus (Figure 1), needing external ventricular derivation. She had a slow clinical improvement, requiring several neurosurgical interventions and developing a syndrome of inappropriate antidiuretic secretion alternating with cerebral salt wasting. Positive results for Mycobacterium tuberculosis were obtained by CSF culture and by polymerase chain reaction in CSF, bronchoalveolar lavage and gastric aspirate specimens. Repeated brain CT showed a large-vessel vasculitis with basal meningeal enhancement, typical of central nervous system (CNS) tuberculosis (Figure 2). She completed one month of corticosteroids and maintained antituberculosis treatment. At two years of age, she has spastic paraparesis and no language skills. Portugal had 1836 cases of tuberculosis (17.8 per 100000) in 2016 and was considered a low-incidence country; consequently, BCG vaccination is not universal (1). We present a severe case of CNS tuberculosis with intracranial hypertension, vasculitis and hyponatremia, associated with poorer outcomes (2). A high index of suspicion allowed prompt start of antituberculosis treatment. Diagnosis was corroborated by microbiological positivity and a typical triad in neuroimaging (hydrocephalus, vasculitis and basal meningeal enhancement) (3), which we wish to emphasize.

Time Elapsed from onset of symptoms to antituberculosis treatment in children with central nervous system tuberculosis in a tertiary hospital in South India: A mixed-methods pilot study.

A pilot study with a mixed-methods design was conducted to estimate the time for tuberculosis (TB) treatment initiation and associated factors among children with central nervous system-TB (CNS-TB). A total of 38 children were enrolled for the quantitative component, and 20 in-depth interviews were conducted. The median duration (interquartile range) from onset of symptoms to treatment initiation was 23 (11, 55) days. About 44% and 31% of the children presented with Stage II and Stage III of CNS-TB, respectively. The major reasons for delay were symptoms not taken seriously (50%) and too many referrals (21%). About 89% of the families went into catastrophic health expenditure due to the disease. The treatment delay may be due to both patient delay and health system delay. Tailoring approaches to target the pediatric population could further improve early detection and treatment initiation of CNS-TB.

Pelvic and central nervous system tuberculosis complicated by a paradoxical response manifesting as a spinal tuberculoma: a case report.

BACKGROUND: The post-partum period is a risk factor for tuberculosis (TB), possibly including the period after miscarriage as illustrated here. This case demonstrates how non-specific symptoms can hide widely disseminated TB. CASE PRESENTATION: A healthy 26-year-old female with a history of recent miscarriage presented to the emergency department with non-specific symptoms of headache, abdominal pain, and sub-acute fevers. She had immigrated to the United States from the Marshall Islands 9 years prior. Two months prior to presentation she had a miscarriage at 18 weeks of pregnancy. On admission, transvaginal ultrasound revealed retained products of conception and abdominal computed tomography revealed findings consistent with tubo-ovarian abscesses and peritonitis. The obstetrics and gynecology service performed dilation and curettage (D&C) to remove retained products of conception. Acid-fast bacilli cultures from cerebrospinal fluid as well as specimens from D&C and intra-abdominal abscesses subsequently all grew TB. She was diagnosed with TB meningitis, peritonitis, endometritis, and tubo-ovarian abscesses. Her treatment course was complicated by a paradoxical response resulting in a spinal tuberculoma causing lower extremity weakness. The tuberculoma was treated with surgical decompression as well as continuation of treatment with anti-tubercular chemotherapy and steroids. CONCLUSION: Disseminated and extrapulmonary TB can present with non-specific symptoms. Recognition of risk factors for TB is critical for prompt diagnostic evaluation and treatment of this deadly disease. A paradoxical reaction needs to be taken into consideration when any new neurological symptoms occur during TB treatment.

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.

Central nervous system tuberculosis.

PURPOSE OF REVIEW: Central nervous system (CNS) tuberculosis is the most devastating form of tuberculosis (TB), with mortality and or neurological sequelae in over half of individuals. We reviewed original research and systematic reviews published since 1 January 2019 for new developments in CNS TB pathophysiology, diagnosis, management and prognosis. RECENT FINDINGS: Insight in the pathophysiology is increasing steadily since the landmark studies in 1933, focussing on granuloma type classification, the relevance of the M. tuberculosis bacterial burden and the wide range of immunological responses. Although Xpert/RIF has been recommended by the WHO for extrapulmonary TB diagnosis, culture is still needed to increase the sensitivity of TB meningitis diagnosis. Sequential MRIs can improve understanding of neurological deficits at baseline and during treatment. Pharmacokinetic/pharmacodynamic modelling suggests that higher doses of rifampicin and isoniazid in TB meningitis could improve survival. SUMMARY: Recent studies in the field of CNS-TB have largely focussed on TB meningitis. The outcome may improve by optimizing treatment dosing. This needs to be confirmed in clinical trials. Due to the important role of inflammation, these trials should be used as the platform to study the inflammatory and metabolomic responses. This could improve understanding of the biology of this disease and improve patient outlook by enabling individualised host-directed therapy.

Drug Resistance in Children with Central Nervous System Tuberculosis from a Tertiary Care Center in Mumbai.

INTRODUCTION: Central Nervous System tuberculosis (CNS-TB) is the most lethal form of extra-pulmonary TB, especially in children. In this study, we have discussed patterns of drug resistance in pediatric CNS-TB. MATERIALS AND METHODS: Prospective observational study conducted on 100 children at a tertiary care center. Diagnosed cases of CNS-TB were enrolled. GeneXpert MTB/RIF was used upfront for diagnosis, and in cases where TB MGIT culture was positive, a phenotypic Drug Susceptibility Test (DST) was done. Patients were divided into resistant to at least one drug (DR) and drug-susceptible (DS). Various parameters were compared between these groups. RESULTS: Mean age of participants was 5.84 ± 3.5 years, with a male-to-female ratio of 1.08 : 1; 14% of children had drug-resistant CNS TB (DR-CNS-TB). A higher proportion of children previously treated for TB were associated with drug resistance (p = 0.009), and those with disseminated TB also had a higher drug resistance (p = 0.002). Apart from this, the DR and DS groups had no statistically significant differences in demographic, clinical or epidemiological parameters. CONCLUSIONS: Previous history of being treated for TB and disseminated TB was an independent risk factor for DR-CNS-TB. Ensuring proper adherence and compliance to anti-tubercular treatment could help in preventing the emergence of DR TB.

Intensified adjunctive corticosteroid therapy for CNS tuberculomas.

INTRODUCTION: Central nervous system (CNS) tuberculomas are a challenging manifestation of extrapulmonary tuberculosis often leading to neurological complications and post-treatment sequelae. The role of adjunctive corticosteroid treatment is not fully understood. Most guidelines on management of tuberculosis do not distinguish between tuberculous meningitis and CNS tuberculomas in terms of corticosteroid therapy. METHODS: We describe five patients with CNS tuberculomas who required intensified dexamethasone treatment for several months, in two cases up to 18 months. RESULTS: These patients were initially treated with the standard four-drug tuberculosis regimen and adjuvant dexamethasone. Neurological symptoms improved rapidly. However, multiple attempts to reduce or discontinue corticosteroids according to guideline recommendations led to clinical deterioration with generalized seizures or new CNS lesions. Thus, duration of adjunctive corticosteroid therapy was extended eventually leading to clinical cure and resolution of lesions. CONCLUSION: In contrast to tuberculous meningitis, the treatment for CNS tuberculomas appears to require a prolonged administration of corticosteroids. These findings need to be verified in controlled clinical studies.

Tuberculosis treatment in children: The changing landscape.

Traditionally children have been treated for tuberculosis (TB) based on data extrapolated from adults. However, we know that children present unique challenges that deserve special focus. New data on optimal drug selection and dosing are emerging with the inclusion of children in clinical trials and ongoing research on age-related pharmacokinetics and pharmacodynamics. We discuss the changing treatment landscape for drug-susceptible and drug-resistant paediatric tuberculosis in both the most common (intrathoracic) and most severe (central nervous system) forms of disease, and address the current knowledge gaps for improving patient outcomes.

Multi-spectral Pattern of Clinical Presentation and the Resultant Outcome in Central Nervous System Tuberculosis: A Single Center Study on the Ubiquitous Pathogen.

Central nervous system (CNS) tuberculosis (TB) is a great medical masquerader having a multi-spectral pattern of clinical presentation, thereby complicating early diagnosis and appropriate management. This review article describes clinical presentation of CNS TB in a group of 47 patients, who were managed in the Nobel Medical College and Teaching Hospital in Biratnagar, Nepal during the last 2 years. We evaluated demographic profile, mode of management, and clinical outcome in these patients. The findings were that intracranial TB was present in 27 (57.5%) patients and the spinal involvement was in 20 (42.5%) patients. The most frequent presentation of the former was TB meningitis with hydrocephalus (55.5%) and that of the latter was Pott's spine with abscess in 50% of cases. TB meningitis with hydrocephalus was the commonest cause of mortality (83.3%) among the patients. CNS TB should be considered in the differential diagnosis in patients presenting with equivocal neurological signs and symptoms, especially in TB endemic regions. It seems prudent to commence early antitubercular therapy for safeguarding such patients from poor neurological outcome as well as mortality it harbingers.

[Central nervous system tuberculosis : don't miss the diagnosis !] / Errance diagnostique dans un cas de tuberculose du système nerveux central Nebie A (1), Ali D (1), Bosquee L (2), Gorur Y (3), Cardos B (4).

We are presented a 35-year-old patient with no previous relevant medical history who was admitted to the emergency department for fever, altered mental status and diffuse abdominal pain. Initial evaluation failed to the demonstrated the presence of thoracic or abdominal deep infection. The clinical course was marked by a deterioration of the neurological condition. The cerebral MRI showed diffuse and extensive involvement of the brainstem and cerebellar hemispheres associated with hydrocephalus consistent with tuberculous meningoencephalitis. Antituberculous therapy was started with some delay but no clinical improvement was achieved and the patient died.

Une patiente âgée de 35 ans, sans antécédents médicaux particuliers, est admise au service des urgences pour fièvre accompagnée d'un syndrome confusionnel et de douleurs abdominales diffuses. La prise en charge initiale ne permet pas de mettre en évidence une infection profonde au niveau thoracique et abdominal. L'évolution clinique est marquée par une détérioration de son état neurocognitif. L'IRM cérébrale montre une atteinte diffuse et étendue des hémisphères cérébraux, du tronc cérébral et du cervelet, associée à une hydrocéphalie, liée à une probable méningo-encéphalite tuberculeuse. Un traitement antituberculeux est instauré avec un certain délai, mais aucune amélioration clinique n'est observée et la patiente finit par décéder.

Bacteriologically confirmed extra pulmonary tuberculosis and treatment outcome of patients consulted and treated under program conditions in the littoral region of Cameroon.

BACKGROUND: Extra-pulmonary tuberculosis (EPTB) is defined as any bacteriologically confirmed or clinically diagnosed case of TB involving organs other than the lungs. It is frequently a diagnostic and therapeutic challenge with paucity of data available. The aim of this study was to assess the prevalence of bacteriologically confirmed EPTB; to determine the most affected organs and to evaluate the therapeutic outcome of EPTB patients treated under program conditions in the littoral region of Cameroon. METHODS: A descriptive cross-sectional laboratory-based epidemiological survey was conducted from January 2016 to December 2017 and 109 specimens from 15 of the 39 diagnosis and treatment centers in the littoral region were obtained. Two diagnostic methods (Gene Xpert MTB and culture (LJ and MGIT) were used for EPTB diagnosis. Determine HIV1/2 and SD Biolinewere used for HIV diagnosis. Confirmed EPTB cases were treated following the national tuberculosis guide. RESULTS: The prevalence of bacteriologically confirmed EPTB was 41.3% (45). All 45 cases were sensitive to rifampicin. Males were predominately more infected [26 (57.8%)] likewise the age group 31-45 years with 15 (33.3%) cases. The overall prevalence for HIV was 33.6% (36). HIV infection was present in 28.9% (13) of patients with EPTB. The most affected sites with EPTB were: Lymph nodes (66.5%), pleural cavity (15.6%), abdominal organs (11.1%), neuromeningeal (2.2%), joints (2.2%) and heart (2.2%). Overall, 84.4% of the study participants had a therapeutic success with males responding better 57.9% (p = 0.442). Therapeutic success was better (71.7%) in HIV negative EPTB patients (p = 0.787). CONCLUSION: The prevalence of bacteriologically confirmed EPTB patients treated under program conditions in the littoral region of Cameroon is high with a therapeutic success of 84.4% and the lymph nodes is the most affected site.

Primary pituitary tubercular abscess as a differential diagnosis for sellar suprasellar mass.

Only four cases of primary pituitary tubercular abscess have been reported. A 20-year-old ladypresented to us with headache and pituitary dysfunction. Radiology showedsellar tubercular abscess with suprasellar extension. Microscopic examination of pus collected during surgery showed granulomatous tissues and Acid Fast Bacilli. The response to antitubercular therapy was remarkable.

Clinical perspectives into the use of thalidomide for central nervous system tuberculosis.

BACKGROUND AND PURPOSE: Central nervous system (CNS) tuberculosis (TB) accounts for over 4% of all TB notifications in the UK and causes death or significant disability in over half of those affected. Tumour necrosis factor alpha is a critical cytokine involved in the neuropathogenesis of CNS TB. Thalidomide has been trialled in CNS TB due to its immunomodulatory and immune reconstitution effects through the inhibition of tumour necrosis factor alpha. Despite animal models demonstrating dramatic improvement in survival, studies in paediatric patients have been associated with higher levels of mortality. The effects of thalidomide have not yet been studied in adults with CNS TB. This narrative case series guides clinicians through a range of CNS TB clinical cases seen in a large London teaching hospital, serving a region with a high incidence of TB (32 per 100 000) with 55% of TB cases manifesting as extrapulmonary disease. We aimed to illustrate our experiences of using thalidomide to treat a range of severe CNS TB complications. METHODS: Five inpatients at The Royal London Hospital, London, UK treated with thalidomide in addition to standard TB treatment are described in detail. The rationale for treatment initiation with thalidomide is explained. RESULTS: The case examples are used to guide our reflections and lessons learnt regarding the use of thalidomide. Responses to treatment and functional outcomes suggest that thalidomide may be a useful adjunct to standard TB therapy in selected adult cases. CONCLUSIONS: The experience gained from using thalidomide in this small case series may provide evidence leading to more research into using thalidomide to treat severe CNS TB.

Endovascular treatment of HIV-associated spontaneous common carotid artery pseudoaneurysm in a case of miliary and CNS tuberculosis.

HIV and tuberculosis infections are known to be associated with vasculopathy including occlusive disease and aneurysm formation. We report a case of 43-year-old male with miliary and central nervous system (CNS) tuberculosis; recently, diagnosed as HIV seropositive, on antiretroviral and antitubercular treatment presenting with painful neck swelling. He was found to have common carotid artery (CCA) pseudoaneurysm that was managed by endovascular stent grafting. HIV vasculopathy-related CCA pseudoaneurysm is a potentially life-threatening rare entity. Treatment of an immunocompromised patient by endovascular approach minimizes hospital stay and avoids wound-related complications. To the best of our knowledge, there has been no case report describing endovascular treatment of CCA pseudoaneurysm in an HIV-positive patient with low CD4 count and coexistent disseminated tuberculosis.

Magnetic resonance imaging characteristics and treatment aspects of ventricular tuberculosis in adult patients.

BACKGROUND: Ventricular involvement in neurotuberculosis is rare. The literature regarding the characteristics of magnetic resonance imaging (MRI) in ventricular tuberculosis is very limited. PURPOSE: To describe MRI characteristics of ventricular tuberculosis and discuss the medical treatment along with the clinical outcome. MATERIAL AND METHODS: Ten patients (6 men, 4 women; average age, 39 years) were diagnosed with ventricular tuberculosis during a period of 3 years. Four patients had the history of pulmonary/pleural tuberculosis. The clinical and MRI features of these patients were reviewed retrospectively. RESULTS: On a brain MRI, three patients showed ependymitis associated with contrast enhancement of the ependymal lining of the ventricular walls. One patient had choroid plexitis associated with prominent swollen and marked enhancement of the choroid plexus. One patient had intraventricular tuberculoma associated with an intraventricular nodule. Two patients had both ependymitis and choroid plexitis. Three patients had both intraventricular tuberculoma and choroid plexitis. Four patients had hydrocephalus. All patients underwent intrathecal injection of isoniazid and dexamethasone combined with multidrug anti-tuberculosis treatment. All patients had a good clinical recovery, except for one who developed hemi-paralysis due to cerebral infarction. On the repeated MRI of eight patients after therapy, all lesions disappeared or decreased in size, apart from in one patient who showed ventricular separation. CONCLUSION: MRI characteristics of ventricular tuberculosis included ependymal enhancement, swelling, and enhancement of the choroid plexus and intraventricular tuberculomas. Intrathecal injection of isoniazid and dexamethasone along with multidrug chemotherapy showed good efficacy in ventricular tuberculosis.

Pregabalin-induced first degree atrioventricular block in a young patient treated for pain from extrapulmonary tuberculosis.

Pregabalin, widely used in the treatment of several pain disorders, is usually well tolerated. Uncommonly, the drug may induce cardiac side effects, rarely prolongation of the PR interval. The latter has never been described in patients with healthy heart or normal renal function. We characterize a unique case of a young man with extrapulmonary tuberculosis and no detectable or known cardiac or kidney diseases, treated with pregabalin to control the severe pain due to the involvement of the spinal cord by the tuberculosis, showing an atrioventricular (AV) block due to pregabalin administration. The reported case emphasizes the need of monitoring PR interval during treatment with pregabalin, even in patients without background of cardiac or renal diseases.

Joint failure after steroid therapy in tuberculous encephalitis.

We report a case of multifocal avascular osteonecrosis (AVN) following steroid administration in a case of tuberculous encephalitis in a young patient. The risk of joint-related AVN as a side effect of adjunctive steroid therapy should be taken into consideration when evaluating the dosage and treatment duration in tuberculous encephalitis.