Differences in cytokine and chemokine profiles in cerebrospinal fluid caused by the etiology of cryptococcal meningitis and tuberculous meningitis in HIV patients.

The roles of cytokines and chemokines in HIV-associated cryptococcal meningitis (HCM) and HIV-associated tuberculous meningitis (HTBM) are debatable. In sum, 34 HIV-infected patients without meningitis, 44 HCM patients and 27 HTBM patients were enrolled for study. The concentrations of 22 cytokines/chemokines in cerebrospinal fluid (CSF) were assayed at admission. Principal component analysis (PCA), Pearson's and logistic regression analyses were used to assess the role of cytokines/chemokines in HCM and HTBM. We found the levels of T helper (Th)17, Th1 [interleukin (IL)-12p40, interferon (IFN)-γ, tumor necrosis factor (TNF)-α and TNF-ß and Th2 (IL-2/4/5/6/10)] cytokines were elevated in patients with meningitis compared with those in HIV-infected patients without central nervous system (CNS) infection. Furthermore, the IL-1Ra, IL-12p40, IL-17α and monocyte chemotactic protein-1 (MCP-1) levels were higher in HCM patients, while the IFN-γ, regulated upon activation, normal T cell expressed and secreted (RANTES) and interferon-inducible protein-10 (IP)-10 levels were higher in HTBM patients. Elevated CSF concentrations of IL-17a, TNF-ß, IL-5, IL-12p40 and IL-1Rα were closely related to meningitis, but elevated IP-10, MCP-1, RANTES and IFN-γ levels and CSF white blood cells (WBCs) were protective factors against HCM. Our study suggested that HIV-infected patients with low CSF WBCs have a high risk of HCM. Th1, Th2 and Th17 cytokines/chemokines mediate differences in the pathogenesis of HCM and TBM. Overexpressed proinflammatory MCP-1, RANTES, IFN-γ and IP-10 in CSF are protective factors against HCM but not HTBM.

Elevation of CSF adenosine deaminase in HIV patient with meningitis from retroviral rebound syndrome, a case report.

Adenosine deaminase (ADA) in cerebrospinal fluid (CSF) is considered to be a useful biomarker in differentiating tuberculous meningitis (TBM) from other meningitis in non-HIV patients. However, its specificity decreases in patients with HIV, and other diseases such as cytomegalovirus encephalitis, toxoplasmosis or meningeal lymphomatosis can also elevate ADA in CSF. We here report a rare case of retroviral rebound syndrome in a HIV patient, whose ADA in CSF was elevated.

Complicaciones de meningitis tuberculosa en resonancia magnética en un paciente con lupus eritematoso sistémico / Complications of tuberculous meningitis in magnetic resonance imaging in a patient with systemic lupus erythematosus

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First case report of tuberculous meningitis secondary to endometrial tuberculosis following a clandestine abortion.

Tuberculous meningitis (TBM) is a medical emergency: it is the most severe, lethal and disabling clinical form of tuberculosis. We report the case of a 44-year-old woman who had undergone a clandestine abortion six weeks before admission. One week later, she had abnormal vaginal discharge. Three weeks prior to admission, headache, hyperpyrexia and mental alteration were added. At admission, a transvaginal ultrasound showed abnormalities of the uterine cavity. Sepsis and endometritis were diagnosed, and a hysterectomy was scheduled. During preoperative evaluation, meningeal signs were found. The first lumbar puncture (LP) showed a lymphomononuclear pleocytosis, hypoglycorrhachia and hyperproteinorrachia. After five days treatment with ceftriaxone, vancomycin and dexamethasone, only partial recovery occurred. A second LP showed AFB and PCR confirmed Mycobacterium tuberculosis. The histopathology of endometrial biopsy confirmed endometrial tuberculosis. Therapeutic response to anti-tuberculous treatment and corticosteroids was excellent. No other cause of immunosuppression apart from pregnancy was found. To the best of our knowledge, this is the first report of TBM secondary to endometrial tuberculosis and highlights an unusual clinical scenario in which severe and disseminated forms of TB could be present. TBM during and after pregnancy is rare, but compared with TBM in non-pregnant women, it has a poorer prognosis. Early diagnosis and treatment can be lifesaving in this life-threatening disease.

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.

Characteristics of miliary tuberculosis in pregnant women after in vitro fertilisation and embryo transfer.

OBJECTIVE: To analyse the clinical characteristics of miliary tuberculosis (TB) in pregnant women after in vitro fertilisation and embryo transfer (IVF-ET). METHODS: Six pregnant women with miliary TB after IVF-ET between October 2010 and July 2015 were retrospectively analysed. RESULTS: The patients were aged between 29 and 39 years. Fever, cough and dyspnoea were the main symptoms, and started during the first and second trimesters of pregnancy. Erythrocyte sedimentation rate and C-reactive protein were increased. White blood cell count was normal or slightly increased. Tuberculin purified protein derivative and acid-fast smear of sputum tests were negative. T-SPOT®.TB was performed in two cases and the results were positive. Chest computed tomography showed typical miliary nodules. One patient had tuberculous meningitis. Although all patients were cured, the foetuses died. CONCLUSIONS: The principal symptoms of miliary TB in pregnant women after IVF-ET were fever and dyspnoea. Physicians should consider the occurrence of miliary TB, particularly in the case of fever of long duration, respiratory symptoms and no response to antibiotic treatment.

Central Nervous System Tuberculosis : Etiology, Clinical Manifestations and Neuroradiological Features.

PURPOSE: As a result of multilateral migration and globalization in times of humanitarian crises, western countries face a possible increase in the incidence of central nervous system tuberculosis (CNS TB). The diagnosis of CNS TB is challenging and often delayed due to the manifold and often non-specific presentation of the disease. The aim of this review is to analyze and summarize imaging features and correlated clinical findings of CNS TB. METHODS: The different manifestations of CNS TB are explained and illustrated by characteristic neuroradiological as well as neuropathological findings. An overview on diagnostic and therapeutic approaches is provided. For clarity, tables summarizing the lesion patterns, differential diagnoses and diagnostic hints are added. RESULTS: The CNS TB can be manifested (1) diffuse as tuberculous meningitis (TBM), (2) localized as tuberculoma or (3) tuberculous abscess or (4) in extradural and intradural spinal infections. Information on clinical presentation, underlying pathology and the distinguishing features is demonstrated. The TBM is further described, which may lead to cranial nerve palsy, hydrocephalus and infarction due to associated arteritis of the basal perforators. The differential diagnoses are vast and include other infections, such as bacterial, viral or fungal meningoencephalitis, malignant causes or systemic inflammation with CNS. Complicating factors of diagnosis and treatment are HIV coinfection, multi-drug resistance and TB-associated immune reconstitution inflammatory syndrome (IRIS). CONCLUSIONS: Neurologists and (neuro-)radiologists should be familiar with the neuroradiological presentation and the clinical course of CNS TB to ensure timely diagnosis and treatment.

A fatal case of tuberculous meningitis in a child with juvenile idiopathic arthritis: a diagnostic challenge.

The prognosis of tuberculous meningitis, a rare form of extrapulmonary tuberculosis, depends on the stage of treatment initiation. We report a fatal case of tuberculous meningitis. The patient had received successive tumor necrosis factor (TNF) antagonists and abatacept to treat juvenile idiopathic arthritis, with negative results for polymerase chain reaction and acid-fast bacilli on smear, had normal cerebrospinal fluid (CSF) adenosine deaminase and glucose levels. Six weeks post-admission, the CSF culture demonstrated Mycobacterium tuberculosis. The altered immunological responses caused by anti-TNF treatment made the diagnosis challenging. Clinicians should bear this in mind and, if suspected, treatment should be initiated immediately.

A fatal case of tuberculous meningitis in a child with juvenile idiopathic arthritis: a diagnostic challenge

Abstract The prognosis of tuberculous meningitis, a rare form of extrapulmonary tuberculosis, depends on the stage of treatment initiation. We report a fatal case of tuberculous meningitis. The patient had received successive tumor necrosis factor (TNF) antagonists and abatacept to treat juvenile idiopathic arthritis, with negative results for polymerase chain reaction and acid-fast bacilli on smear, had normal cerebrospinal fluid (CSF) adenosine deaminase and glucose levels. Six weeks post-admission, the CSF culture demonstrated Mycobacterium tuberculosis. The altered immunological responses caused by anti-TNF treatment made the diagnosis challenging. Clinicians should bear this in mind and, if suspected, treatment should be initiated immediately.

Neurological manifestations of HIV-AIDS at a tertiary care institute in North Eastern India.

BACKGROUND: The nervous system is among the most frequent and serious targets of human immunodeficiency virus (HIV) infection. The infection usually occurs in patients with profound immunosuppression. In 10 - 20% of the patients, the presence of a neurological disease is the first manifestation of symptomatic HIV infection. AIMS AND OBJECTIVE: Despite the wide prevalence of neurological manifestations in HIV, there is no study examining the clinical manifestations of this disease in the resource- limited communities from north-eastern parts of India. To characterize the neurological involvement in patients with HIV infection at a tertiary care institute in northeast India, we studied various neurological presentations of HIV. SETTING AND DESIGN: This was a retrospective observational study done at a tertiary care institute in northeast India over a period of 6 years from August 2008 to September 2014. MATERIAL AND METHODS: A total of 91 HIV seropositive patients of both genders, aged >18 years, showing clinical evidence of central nervous system (CNS) involvement, and admitted in a tertiary care institute were included. Their clinical manifestations, laboratory investigations, and imaging were studied. RESULT: Tuberculous meningitis was the most common presentation as secondary CNS illness (43.9%), followed by cryptococcal meningitis (14.2%) and cerebrovascular accidents (5.49%). Furthermore, 6.59% had neurosyphilis, 6.59% had acquired immune deficiency syndrome (AIDS) - associated dementia, and peripheral neuropathy occurred in 16.4% of the patients. Headache was the most common neurological symptom seen in 25% of the patients. Seizures were noted in 25% of the pateints. CD4 was significantly low in most of the patients with progressive multifocal leukoencephalopathy, HIV associated encephalopathy (HAD) and cryptococcal meningitis compared with other neurological manifestations. CD4 counts in tuberculous meningitis and HAD were 110.3/µl and 95/µl, respectively. CONCLUSION: CNS tuberculosis was the most common secondary infection seen in HIV patients followed by cryptococcal meningitis. A high index of clinical suspicion of neurological involvement in HIV patients helps in the early diagnosis and early institution of specific treatment, which in turn decreases the morbidity and mortality considerably.

Clinical presentations, diagnosis, mortality and prognostic markers of tuberculous meningitis in Vietnamese children: a prospective descriptive study.

BACKGROUND: Tuberculous meningitis in adults is well characterized in Vietnam, but there are no data on the disease in children. We present a prospective descriptive study of Vietnamese children with TBM to define the presentation, course and characteristics associated with poor outcome. METHODS: A prospective descriptive study of 100 consecutively admitted children with TBM at Pham Ngoc Thach Hospital, Ho Chi Minh City. Cox and logistic regression were used to identify factors associated with risk of death and a combined endpoint of death or disability at treatment completion. RESULTS: The study enrolled from October 2009 to March 2011. Median age was 32.5 months; sex distribution was equal. Median duration of symptoms was 18.5 days and time from admission to treatment initiation was 11 days. Fifteen of 100 children died, 4 were lost to follow-up, and 27/81 (33 %) of survivors had intermediate or severe disability upon treatment completion. Microbiological confirmation of disease was made in 6 %. Baseline characteristics associated with death included convulsions (HR 3.46, 95CI 1.19-10.13, p = 0.02), decreased consciousness (HR 22.9, 95CI 3.01-174.3, p < 0.001), focal neurological deficits (HR 15.7, 95CI 1.67-2075, p = 0.01), Blantyre Coma Score (HR 3.75, 95CI 0.99-14.2, p < 0.001) and CSF protein, lactate and glucose levels. Neck stiffness, MRC grade (children aged >5 years) and hydrocephalus were also associated with the combined endpoint of death or disability. CONCLUSIONS: Tuberculous meningitis in Vietnamese children has significant mortality and morbidity. There is significant delay in diagnosis; interventions that increase the speed of diagnosis and treatment initiation are likely to improve outcomes.

HIV-associated opportunistic CNS infections: pathophysiology, diagnosis and treatment.

Nearly 30 years after the advent of antiretroviral therapy (ART), CNS opportunistic infections remain a major cause of morbidity and mortality in HIV-positive individuals. Unknown HIV-positive disease status, antiretroviral drug resistance, poor drug compliance, and recreational drug abuse are factors that continue to influence the morbidity and mortality of infections. The clinical and radiographic pattern of CNS opportunistic infections is unique in the setting of HIV infection: opportunistic infections in HIV-positive patients often have characteristic clinical and radiological presentations that can differ from the presentation of opportunistic infections in immunocompetent patients and are often sufficient to establish the diagnosis. ART in the setting of these opportunistic infections can lead to a paradoxical worsening caused by an immune reconstitution inflammatory syndrome (IRIS). In this Review, we discuss several of the most common CNS opportunistic infections: cerebral toxoplasmosis, progressive multifocal leukoencephalopathy (PML), tuberculous meningitis, cryptococcal meningitis and cytomegalovirus infection, with an emphasis on clinical pearls, pathological findings, MRI findings and treatment. Moreover, we discuss the risk factors, pathophysiology and management of IRIS. We also summarize the challenges that remain in management of CNS opportunistic infections, which includes the lack of phase II and III clinical trials, absence of antimicrobials for infections such as PML, and controversy regarding the use of corticosteroids for treatment of IRIS.

Epidemiology of meningitis in an HIV-infected Ugandan cohort.

There is limited understanding of the epidemiology of meningitis among human immunodeficiency virus (HIV)-infected populations in sub-Saharan Africa. We conducted a prospective cohort study of HIV-infected adults with suspected meningitis in Uganda, to comprehensively evaluate the etiologies of meningitis. Intensive cerebrospiral fluid (CSF) testing was performed to evaluate for bacterial, viral, fungal, and mycobacterial etiologies, including neurosyphilis,16s ribosomal DNA (rDNA) polymerase chain reaction (PCR) for bacteria, Plex-ID broad viral assay, quantitative-PCR for HSV-1/2, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and Toxoplasma gondii; reverse transcription-PCR (RT-PCR) for Enteroviruses and arboviruses, and Xpert MTB/RIF assay. Cryptococcal meningitis accounted for 60% (188 of 314) of all causes of meningitis. Of 117 samples sent for viral PCR, 36% were EBV positive. Among cryptococcal antigen negative patients, the yield of Xpert MTB/RIF assay was 22% (8 of 36). After exclusion of cryptococcosis and bacterial meningitis, 61% (43 of 71) with an abnormal CSF profile had no definitive diagnosis. Exploration of new TB diagnostics and diagnostic algorithms for evaluation of meningitis in resource-limited settings remains needed, and implementation of cryptococcal diagnostics is critical.

Tuberculous meningitis: more questions, still too few answers.

Tuberculous meningitis is especially common in young children and people with untreated HIV infection, and it kills or disables roughly half of everyone affected. Childhood disease can be prevented by vaccination and by giving prophylactic isoniazid to children exposed to infectious adults, although improvements in worldwide tuberculosis control would lead to more effective prevention. Diagnosis is difficult because clinical features are non-specific and laboratory tests are insensitive, and treatment delay is the strongest risk factor for death. Large doses of rifampicin and fluoroquinolones might improve outcome, and the beneficial effect of adjunctive corticosteroids on survival might be augmented by aspirin and could be predicted by screening for a polymorphism in LTA4H, which encodes an enzyme involved in eicosanoid synthesis. However, these advances are insufficient in the face of drug-resistant tuberculosis and HIV co-infection. Many questions remain about the best approaches to prevent, diagnose, and treat tuberculous meningitis, and there are still too few answers.

Frequency, severity, and prediction of tuberculous meningitis immune reconstitution inflammatory syndrome.

BACKGROUND: Tuberculosis immune reconstitution inflammatory syndrome (IRIS) is a common cause of deterioration in human immunodeficiency virus (HIV)-infected patients receiving tuberculosis treatment after starting antiretroviral therapy (ART). Potentially life-threatening neurological involvement occurs frequently and has been suggested as a reason to defer ART. METHODS: We conducted a prospective study of HIV-infected, ART-naive patients with tuberculous meningitis (TBM). At presentation, patients started tuberculosis treatment and prednisone; ART was initiated 2 weeks later. Clinical and laboratory findings were compared between patients who developed TBM-IRIS (TBM-IRIS patients) and those who did not (non-TBM-IRIS patients). A logistic regression model was developed to predict TBM-IRIS. RESULTS: Forty-seven percent (16/34) of TBM patients developed TBM-IRIS, which manifested with severe features of inflammation. At TBM diagnosis, TBM-IRIS patients had higher cerebrospinal fluid (CSF) neutrophil counts compared with non-TBM-IRIS patients (median, 50 vs 3 cells ×10(6)/L, P = .02). Mycobacterium tuberculosis was cultured from CSF of 15 TBM-IRIS patients (94%) compared with 6 non-TBM-IRIS patients (33%) at time of TBM diagnosis; relative risk of developing TBM-IRIS if CSF was Mycobacterium tuberculosis culture positive = 9.3 (95% confidence interval [CI], 1.4-62.2). The combination of high CSF tumor necrosis factor (TNF)-α and low interferon (IFN)-γ at TBM diagnosis predicted TBM-IRIS (area under the curve = 0.91 [95% CI, .53-.99]). CONCLUSIONS: TBM-IRIS is a frequent, severe complication of ART in HIV-associated TBM and is characterized by high CSF neutrophil counts and Mycobacterium tuberculosis culture positivity at TBM presentation. The combination of CSF IFN-γ and TNF-α concentrations may predict TBM-IRIS and thereby be a means to individualize patients to early or deferred ART.

Seasonal variation in the incidence rate of tuberculous meningitis is associated with sunshine hours.

Tuberculous meningitis (TBM) is a severe complication of tuberculosis and occurs mainly during early childhood. The incidence rate of TBM varies with season, and serum vitamin D levels, which are dependent on sunlight, might play a role. We studied the association between TBM incidence rate and hours of sunshine in Cape Town, South Africa and found a significant association between the incidence rate of TBM and hours of sunshine 3 months earlier (incidence rate ratio per 100 sunshine hours 0·69, 95% confidence interval 0·54-0·88, P = 0·002). The association supports the hypothesis that vitamin D might play a role in the pathophysiology of TBM. Further prospective studies in which vitamin D status is measured are necessary to determine causality.