Treatment of tuberculous meningitis in adults: Is the duration of intensive-phase therapy adequate?

Tuberculous meningitis (TBM) results in considerable morbidity and mortality, especially in developing countries such as South Africa. Treatment regimens have been extrapolated from treatment for pulmonary tuberculosis, and the intensive-phase duration of 2 months may be inadequate for treatment of patients with TBM. We highlight this situation with a case report of a patient with TBM whose illness progressed after institution of the maintenance phase of treatment. We propose that the intensive-phase treatment of TBM be revisited with regard to duration of treatment, choice of drugs during continuation-phase therapy, or both.

A study to assess the clinico-radiological presentation and outcome predictors in cases of tubercular meningitis.

INTRODUCTION: Tubercular bacterial meningitis continues to be an important cause of morbidity (especially neurologic handicap) in children from resource-poor countries. The present study was planned to assess the clinical and radiological presentation in cases of tubercular meningitis as well as to study the factors associated with mortality. METHODOLOGY: This study was done over a period of 12 months on children between 5 years and 13 years with suspected TBM. Staging of tubercular meningitis was done according to RNTCP Pediatric TB guideline 2019. RESULT: The study was conducted on a total of 47 pediatric patients with TBM. Mean age of children in present study was 8.77 ± 2.5 years. Our study documented male preponderance for TBM. Severe thinness was observed in 38.3% patients with TBM. Only 59.6% patients were immunized against tuberculosis and history of contact was documented in 40.5% patients. Maximum children belonged to stage I of TBM (59.6%) followed by stage III and stage II in 34% and 6.4% patients respectively. Montoux test positivity was observed in 14.9% patients only. CSF CBNAAT was positive in 6.4% patients. The most common finding was meningeal enhancement seen in 27.7% of patients followed by tuberculomas in 10.6%.Chest X ray was abnormal in 44.7% patients. In present study mortality was observed in 11 (23.4%) cases. Out of various risk factors, mortality was significantly associated with nutritional status and stage of TBM (p < 0.01). CONCLUSION: TBM is associated with high morbidity and mortality in children especially in India where Burden of TB is high. Our study emphasized on the risk factors associated with mortality in children with TBM and need for early diagnosis and appropriate treatment.

Brain MRI findings in relation to clinical characteristics and outcome of tuberculous meningitis.

Neuroradiological abnormalities in tuberculous meningitis (TBM) are common, but the exact relationship with clinical and inflammatory markers has not been well established. We performed magnetic resonance imaging (MRI) at baseline and after two months treatment to characterise neuroradiological patterns in a prospective cohort of adult TBM patients in Indonesia. We included 48 TBM patients (median age 30, 52% female, 8% HIV-infected), most of whom had grade II (90%), bacteriologically confirmed (71%) disease, without antituberculotic resistance. Most patients had more than one brain lesion (83%); baseline MRIs showed meningeal enhancement (89%), tuberculomas (77%), brain infarction (60%) and hydrocephalus (56%). We also performed an exploratory analysis associating MRI findings to clinical parameters, response to treatment, paradoxical reactions and survival. The presence of multiple brain lesion was associated with a lower Glasgow Coma Scale and more pronounced motor, lung, and CSF abnormalities (p-value <0.05). After two months, 33/37 patients (89%) showed worsening of MRI findings, mostly consisting of new or enlarged tuberculomas. Baseline and follow-up MRI findings and paradoxical responses showed no association with six-month mortality. Severe TBM is characterized by extensive MRI abnormalities at baseline, and frequent radiological worsening during treatment.

Tracking down the White Plague. Chapter two: The role of endocranial abnormal blood vessel impressions and periosteal appositions in the paleopathological diagnosis of tuberculous meningitis.

Although endocranial abnormal blood vessel impressions (ABVIs) and periosteal appositions (PAs) have been considered as paleopathological diagnostic criteria for tuberculous meningitis (TBM) based on findings of previous studies, they are not pathognomonic for tuberculosis (TB). Therefore, their utilization in the paleopathological practice can be questioned, especially in consideration that most of the previous studies were not performed on identified skeletal collections but on osteoarchaeological material and did not include statistical data analysis. To fill the aforementioned research gap, for the first time, a macroscopic investigation was conducted on identified pre-antibiotic era skeletons from the Terry Collection. A sample set of 234 individuals who died of TB (TB group) and 193 individuals who died of non-tuberculous causes (NTB group) were examined. The frequency of ABVIs and PAs, as well as other probable TB-related lesions was recorded. To determine the significance of difference (if any) in the frequencies of ABVIs and PAs between the two groups, χ2 testing of our data was performed. We found that ABVIs, PAs, and their co-occurrence with each other and with other probable TB-related lesions were more common in the TB group than in the NTB group. In addition, the χ2 comparative frequencies of ABVIs and PAs revealed a statistically significant difference between individuals who died of TB and individuals who died of NTB causes. Our findings strengthen those of previous studies that ABVIs and PAs are not specific to TBM but can be of tuberculous origin. Therefore, they do have a diagnostic value in the identification of TB in human osteoarchaeological material, especially when they simultaneously occur with other probable TB-related lesions. Their prudent utilization provides paleopathologists with a stronger basis for diagnosing TB and consequently, a more sensitive means of assessing TB frequency in past human populations.

Progressive quadriparesis and inflammation: A common disease, a rare presentation.

A previously healthy, 10-years-old girl presented with progressively worsening pain and weakness of the limbs for the past 2 weeks. It initially started with low-grade fever lasting for 4 days followed by severe pain over bilateral lower and upper limbs. Gradually she became bed-ridden. On examination, she had severe neck rigidity, generalized tenderness all over the body, generalized hyperalgesia, hyporeflexia, bilateral extensor plantar response and toe-walking. An initial clinical diagnosis of Landry-Guillain Barry syndrome was considered. Nerve conduction study showed generalized, demyelinating polyneuropathy. She was administered IVIG and was evaluated for other causes of arachnoiditis. MRI brain and spine showed enhancement and clumping of nerve roots in the conus and cauda equina. CECT chest showed necrotic mediastinal lymphnodes. A final diagnosis of disseminated tuberculosis with tuberculous arachnoiditis was considered and she was administered ATT, pulse methylprednisolone followed by maintenance oral corticosteroids. Currently, after 5 months of therapy, she has recovered clinically.

Lessons learnt from an old foe.

Neurotuberculosis usually responds well to standard antitubercular therapy. Some; patients have prolonged course A 11 year old boy diagnosed TBM, an immunocompetent patient, had an unusual course of illness in the form of prolonged fever, persistent hyponatremia and CSF; pleocytosis despite adequate treatment. Clinical course in the management of TBM can be; protracted with complications despite adequate therapy.

Inclusion of Mechanical Ventilation in Severity Staging of Tuberculous Meningitis Improves Outcome Prediction.

Patients with tuberculous meningitis (TBM) in any stage of the British Medical Research Council (BMRC) scale, if requiring mechanical ventilation (MV), are likely to have a poor outcome. We report the usefulness of BMRC, BMRC-MV, and BMRC-hydrocephalus (BMRC-HC) staging, and Haydarpasa Meningitis Severity Index (HAMSI) scoring in predicting the outcome of TBM. One hundred ninety-seven TBM patients were analyzed from a prospectively maintained TBM registry. The severity of meningitis was categorized using BMRC (stages I-III), BMRC-MV (I-IV [MV patients were grouped as stage IV]), and BMRC-HC (I-IV [BMRC stage III patients with hydrocephalus were grouped as stage IV]). Haydarpasa Meningitis Severity Index scoring was categorized as < 6 and ≥ 6. The outcome was defined at 6 months using the modified Rankin Scale (mRS) as death, poor (mRS score > 2), or good (mRS score ≤ 2). Forty-nine (25%) patients died. BMRC-mechanical ventilation stage IV had the highest predictive value for defining death, with a sensitivity of 88% and a specificity of 86%. About 81.7% of surviving patients had a good outcome at 6 months. BMRC-mechanical ventilation stages I-III had the highest predictive value for defining good outcome, with a sensitivity of 93% and a specificity of 61%. In TBM, BMRC-MV staging has the best predictive value for defining death and disability.

Tuberculous meningitis manifesting with neuroregression in a eleven month child.

Tuberculosis (TB) is a disease of diverse manifestations. In children, neurotuberculosis is the severest form, which when left untreated can have deleterious consequences. There has been reports on pediatric TB meningitis manifesting with fever and seizures, altered sensorium or focal deficits. There are reports on TB meningitis presenting with cognitive decline in adults. We are reporting a eleven month old girl child who presented with acute regression of attained developmental milestones of one month duration as the only presenting complaint and MRI brain revealed basal exudates with hydrocephalus which nailed the diagnosis of tuberculous meningitis. CSF (Cerebro Spinal Fluid) tested by CBNAAT (Cartridge Based Nucleic Acid Amplification Testing) for TB was negative, but gastric aspirate tested for the same, came positive. Tuberculin skin testing was also positive. Chest X-ray was normal. The child had not received BCG (Bacillus Calmette Guerin)vaccine, thereby increasing her risk of complicated TB. The contact couldn't be traced. The child was started on ATT (Anti Tubercular Treatment) as soon as the diagnosis was made and she improved, thus signifying the better outcome with early initiation of ATT. This case reporting is intended to highlight the unusual presentation of TB meningitis in children, which when clinicians are aware of will lead to early treatment and better prognosis.

Clinical, Imaging, and Laboratory Characteristics of Adult Mexican Patients with Tuberculous Meningitis: A Retrospective Cohort Study.

Tuberculous Meningitis (TBM) is the most common form of central nervous system Tuberculosis (TB), accounting for 5-6% of extrapulmonary TB cases. Nowadays, TBM continues to be a major topic in public health because of its high prevalence worldwide. This retrospective study aimed to describe the clinical, laboratory, and imaging characteristics at admission; and in-hospital outcome of adult Mexican patients with TBM. We collected data from medical records of patients aged ≥18 years diagnosed with TBM according to the uniform case definition for clinical research who were treated at Tijuana General Hospital between January 2015 and March 2018 and compared them according to the subtype of diagnosis. We included 41 cases (26 males, median age 28 years, range 18-57 years), 13 (31.7%) patients were HIV positive, and 21 (51.2%) were illicit drug users. At admission, 7 (17.1%) patients were in stage I, 22 (53.6%) in stage II, and 12 (29.3%) in stage III. A definitive diagnosis was established in 23 (56.1%) patients, probable in 14 (34.1%), and possible in four (9.8%). Molecular testing was positive in 83% of the cases, yielding significantly higher positive results than other microbiological studies. There were eight (19.5%) deaths, without statistical difference between mortality and not having a definitive diagnosis (p = 0.109). We found that the baseline characteristics of our population were similar to those described by other authors worldwide. In this series, molecular testing showed to be very useful when used in the early stages, particularly in subjects with subacute onset of headache, fever, weight loss, and altered mental status.

Tubercular meningitis in patients with systemic lupus erythematosus: clinical characteristics, risk factors, and outcomes of 10 patients.

Tubercular meningitis (TBM) is a rare condition in patients with systemic lupus erythematosus (SLE). The aim of this study is to describe the clinical characteristics, possible risk factors, and outcomes of SLE patients with TBM. We systematically reviewed medical records from10 SLE patients with TBM admitted to our hospital from December 2008 to December 2018. A total of 100 cases in the same period were randomly selected as controls from SLE inpatients without infection. In patients with TBM, the mean age at presentation was 35.2 years (range 19.8-45.2); the mean duration of SLE was 34.6 months (range 4-84 months). Patients with TBM had significantly longer SLE duration, higher ESR and CRP level, and lower CD4+ cell counts and albumin level than those without infections (p < 0.05 for all). There were no differences in prednisone dose at the time of symptom onset or cumulative dose over the preceding year between the two groups. Logistic regression analysis showed that patients with a lower CD4+ cell count were more likely to have TBM compared with controls (OR = 3.67, p = 0.020). TBM should be considered when SLE patients have central nervous system (CNS) symptoms with a longer duration, higher ESR and CRP level, and lower CD4+ cell counts and albumin level, even if the patients are receiving a low prednisone dose.Key Points• Patients with TBM have significantly longer SLE duration and lower CD4+ cell counts and albumin level than those without infections; lower CD4+ cell count was an independent risk factor to have TBM in patients with SLE.

Extrapulmonary Tuberculosis: Pathophysiology and Imaging Findings.

Extrapulmonary tuberculosis (TB) represents approximately 15% of all TB infections. It is difficult to diagnose on the basis of imaging characteristics and clinical symptoms, and biopsy is required in many cases. Radiologists must be aware of the imaging findings of extrapulmonary TB to identify the condition in high-risk patients, even in the absence of active pulmonary infection. In extrapulmonary TB, the lymphatic system is most frequently affected. The presence of necrotic lymph nodes and other organ-specific imaging features increases the diagnostic probability of extrapulmonary TB. Disseminated infection and central nervous system involvement are the most frequent manifestations in immunosuppressed patients. Renal disease can occur in immunocompetent patients with very long latency periods between the primary pulmonary infection and genitourinary involvement. In several cases, gastrointestinal, solid-organ, and peritoneal TB show nonspecific imaging findings. Tuberculous spondylitis is the most frequent musculoskeletal manifestation. It is usually diagnosed late and affects multiple vertebral segments with extensive paraspinal abscess. Articular disease is the second most frequent musculoskeletal manifestation, and synovitis is its predominant imaging finding.©RSNA, 2019.

Clinical features, outcomes and prognostic factors of tuberculous meningitis in adults worldwide: systematic review and meta-analysis.

BACKGROUND: Tuberculous meningitis (TBM) is one of the most life-threatening infectious diseases. We performed a systematic review and meta-analysis of the clinical features, outcomes, and prognostic factors for TBM in adults. METHODS: PubMed, EMBASE, Cochrane CENTRAL, and Web of Science were searched for studies that reported the clinical outcomes and/or risk factors for death in adults with TBM between January 1990 and July 2018. A random-effects meta-analysis model was used to pool data on clinical features, outcomes, and risk factors for death. RESULTS: Thirty-two studies that examined 5023 adults who had TBM met the inclusion criteria. Overall, the mortality was 22.8% [95% confidence interval (CI) 18.9-26.8] and the risk of neurological sequelae was 28.7% (95% CI 22.8-35.1). The major risk factors for death (OR > 2 and P < 0.05) were advanced stage of disease (OR = 6.06, 95% CI 4.31-8.53), hydrocephalus (OR = 5.27, 95% CI 2.25-12.37), altered consciousness (OR 3.33, 95% CI 1.51-7.36), altered sensorium (OR 3.31, 95% CI 2.20-4.98), advanced age (> 60 years; OR = 2.64, 95% CI 1.27-5.51), and cerebral infarction (OR = 2.35, 95% CI 1.63-3.38). The clinical features and diagnostic findings present in more than four-fifths of the patients were fever (86.3%, 95% CI 82.4-89.8) and low CSF/serum glucose ratio (80.6%, 95% CI 64.8-92.6). CONCLUSIONS: Adults with TBM have high rates of mortality. Clinicians should maintain a high clinical suspicion for patients who present with certain clinical features, and should pay more attention to prognostic factors.

Oxidative and endoplasmic reticulum stress in tuberculous meningitis related seizures.

BACKGROUND AND PURPOSE: High oxygen consumption and high polyunsaturated fatty acid content in the brain may render it vulnerable to oxidative stress and endoplasmic reticulum (ER) stress. We report the role of these parameters in tuberculous meningitis (TBM) patients with seizures and correlate these with clinical radiological, and laboratory findings. METHODS: Serum oxidative stress markers ; Catalase, Superoxide dismutase (SOD), Glutathione (GSH), Protein-carbonyl, Malonaldehyde (MDA) were measured using spectrophotometer and ER stress markers-ATF4, CHOP, XBP1 and GRP-78 using RT-PCR in TBM patients, 29 with seizures, 20 without seizures and 20 matched controls. In 10 patients, sequential estimation of oxidative stress and ER stress markers was also measured. RESULTS: In comparison to controls, TBM patients had significant difference in the expression of oxidative stress and ER stress markers. Serum MDA (P=0.02), protein-carbonyl (P < 0.01) were significantly higher and SOD (P=0.02) and GSH (P < 0.01) significantly lower in the patients with seizures compared to those without seizures. The ER stress markers were insignificantly elevated in TBM patients with seizures. On sequential evaluation, oxidative stress and ER stress markers increased following seizures and returned to baseline at the time of discharge. CONCLUSION: The results suggest some role of oxidative stress and ER stress in TBM, but do not predict its outcome.

Clinical characteristics of tuberculous meningitis combined with cranial nerve palsy.

OBJECTIVE: To retrospectively analyze the data of 72 patients with tuberculous meningitis (TBM) combined with cranial nerve palsy, to explore the incidence, clinical features, CSF assay changes and outcome in patients with TBM. PATIENTS AND METHODS: A total of 72 patients were diagnosed as TBM with cranial nerve palsy. The gender, age, clinical manifestations, CSF examinations, cerebral magnetic resonance imaging (MRI) enhancement scan were collected. All these patients had completed at least 2 months of follow up after anti-tuberculous treatment. RESULTS: This study retrospectively evaluated 486 patients; include 254 (52.3%) men and 232 (47.7%) women. The mean age was 35.2 ±â€¯17.0 years. 72 patients (14.8%) were diagnosed as TBM with cranial nerve palsy. Among them, 38 cases (52.8%) had optic nerve palsy (the 2nd nerve), 41 cases (56.9%) had oculomotor nerve palsy (the 3rd nerve), 3 cases (4.2%) had abducens nerve palsy (the 6th nerve), and 10 cases (13.9%) had auditory nerve palsy (the 8th nerve). 16 patients (22.2%) had two groups of cranial nerve involvement (oculomotor nerve and optic nerve in 10 cases, optic nerve and auditory nerve in 5 cases, and optic nerve and abducens nerve in 1 case). Two patients (2.8%) had three groups of cranial nerve involvement (oculomotor nerve, optic nerve and abducens nerve). CSF MTB was detected by acid fast bacilli (no patient was positive), MTB DNA detection by multiplex polymerase chain reaction (PCR) (3 patients were positive) and MTB cultures (2 patients were positive). There was no significant difference of CSF cells and biochemistry investigations between the patients with or without cranial nerve palsy. Magnetic resonance imaging (MRI) enhancement scan were done in 66 (91.7%) patients after admission. It was abnormal in 57 (86.3%) patients. 15 cases (26.3%) had meningeral enhancement, 25 cases (43.9%) had tuberculoma, 11 cases (19.3%) had hydrocephalus and 6 cases (10.5%) with infarct. All patients were followed up after 2 months of anti-tuberculous treatment. 70 patients (97.2%, 70/72) with the cranial nerve palsy were fully recovered without obvious sequel. CONCLUSION: The complications of cranial nerve palsy in TBM patients are not uncommon, and the rate of misdiagnosis is high, which makes them vulnerable to emergencies such as disturbance of consciousness. Effective anti-tuberculous treatment can restore most cranial nerve palsy.

The neurocritical care of tuberculous meningitis.

Tuberculous meningitis is the most severe form of tuberculosis and often causes critical illness with high mortality. Two primary management objectives are reducing intracranial pressure, and optimising cerebral perfusion, while killing the bacteria and controlling intracerebral inflammation. However, the evidence base guiding the care of critically ill patients with tuberculous meningitis is poor and many patients do not have access to neurocritical care units. Invasive intracranial pressure monitoring is often unavailable and although new non-invasive monitoring techniques show promise, further evidence for their use is required. Optimal management regimens of neurological complications (eg, hydrocephalus and paradoxical reactions) and of hyponatraemia, which frequently accompanies tuberculous meningitis, remain to be elucidated. Advances in the field of tuberculous meningitis predominantly focus on diagnosis, inflammatory processes, and antituberculosis chemotherapy. However, clinical trials are required to provide robust evidence guiding the most effective supportive, therapeutic, and neurosurgical interventions for tuberculous meningitis that will improve morbidity and mortality.

The pathogenesis of tuberculous meningitis.

Tuberculosis (TB) remains a leading cause of death globally. Dissemination of TB to the brain results in the most severe form of extrapulmonary TB, tuberculous meningitis (TBM), which represents a medical emergency associated with high rates of mortality and disability. Via various mechanisms the Mycobacterium tuberculosis (M.tb) bacillus disseminates from the primary site of infection and overcomes protective barriers to enter the CNS. There it induces an inflammatory response involving both the peripheral and resident immune cells, which initiates a cascade of pathologic mechanisms that may either contain the disease or result in significant brain injury. Here we review the steps from primary infection to cerebral disease, factors that contribute to the virulence of the organism and the vulnerability of the host and discuss the immune response and the clinical manifestations arising. Priorities for future research directions are suggested.

A Diagnostic Formula for Discrimination of Tuberculous and Bacterial Meningitis Using Clinical and Laboratory Features.

Background: The discrimination of tuberculous meningitis and bacterial meningitis remains difficult at present, even with the introduction of advanced diagnostic tools. This study aims to differentiate these two kinds of meningitis by using the rule of clinical and laboratory features. Methods: A prospective observational study was conducted to collect the clinical and laboratory parameters of patients with tuberculous meningitis or bacterial meningitis. Logistic regression was used to define the diagnostic formula for the discrimination of tuberculous meningitis and bacterial meningitis. A receiver operator characteristic curve was established to determine the best cutoff point for the diagnostic formula. Results: Five parameters (duration of illness, coughing for two or more weeks, meningeal signs, blood sodium, and percentage of neutrophils in cerebrospinal fluid) were predictive of tuberculous meningitis. The diagnostic formula developed from these parameters was 98% sensitive and 82% specific, while these were 95% sensitive and 91% specific when prospectively applied to another 70 patients. Conclusion: The diagnostic formula developed in the present study can help physicians to differentiate tuberculous meningitis from bacterial meningitis in high-tuberculosis-incidence-areas, particularly in settings with limited microbiological and radiological resources.

Thalidomide and Phosphodiesterase 4 Inhibitors as Host Directed Therapeutics for Tuberculous Meningitis: Insights From the Rabbit Model.

Tuberculous meningitis (TBM) is the most devastating form of extrapulmonary Mycobacterium tuberculosis infection in humans. Severe inflammation and extensive tissue damage drive the morbidity and mortality of this manifestation of tuberculosis (TB). Antibiotic treatment is ineffective at curing TBM due to variable and incomplete drug penetration across the blood-brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barriers. Adjunctive corticosteroid therapy, used to dampen the inflammation, and the pathologic manifestation of TBM, improves overall survival but does not entirely prevent the morbidity of the disease and has significant toxicities, including immune-suppression. The rabbit has served as a fit for purpose experimental model of human TBM since the early 1900s due to the similarity in the developmental processes of the brain, including neuronal development, myelination, and microglial functions between humans and rabbits. Consistent with the observations made in humans, proinflammatory cytokines, including TNF-α, play a critical role in the pathogenesis of TBM in rabbits focusing the attention on the utility of TNF-α inhibitors in treating the disease. Thalidomide, an inhibitor of monocyte-derived TNF-α, was evaluated in the rabbit model of TBM and shown to improve survival and reduce inflammation of the brain and the meninges. Clinical studies in humans have also shown a beneficial response to thalidomide. However, the teratogenicity and T-cell activation function of the drug limit the use of thalidomide in the clinic. Thus, new drugs with more selective anti-inflammatory properties and a better safety profile are being developed. Some of these candidate drugs, such as phosphodiesterase-4 inhibitors, have been shown to reduce the morbidity and increase the survival of rabbits with TBM. Future studies are needed to assess the beneficial effects of these drugs for their potential to improve the current treatment strategy for TBM in humans.

Seizures in tuberculous meningitis.

OBJECTIVE: We report the frequency of seizure, its possible mechanisms and effect of seizure on the outcome of tuberculous meningitis (TBM). METHODS: Seventy-nine patients with TBM admitted during 2014-2017 were evaluated. The seizures were categorized as per International League Against Epilepsy as well as into early (within 1 month of meningitis) and late (>1 month) seizure. The possible association of seizures was recorded and the outcome was assessed using modified Rankin Scale (mRS ≤ 2 as good, and mRS > 2 as poor). RESULTS: The median age was 27 (18-76) years and 43 (54.4%) of whom were females. Tuberculous meningitis was definite in 31 (39.2%) and highly probable in the remaining. Seizures occurred in 27 (34.2%): early onset in 8 (29.6%) and late in 19 (70.4%) patients. The seizures were focal in 11(13.9%), focal to bilateral in 9 (11.4%), generalised tonic clonic in 7 (8.9%) and status epilepticus in 6 (7.6%) patients. Early seizures were associated with meningeal irritation and late seizures with tuberculoma, infarction and hyponatremia (P = 0.01). Seizure did not affect the mortality but were associated with worse six months outcome (P = 0.03). CONCLUSION: Seizures occurred in 34% patients with TBM and were associated with poor outcome at six months.