Clinical presentation, management, and outcome of suspected central nervous system infections in Indonesia: a prospective cohort study.

BACKGROUND: Little is known about the etiology, clinical presentation, management, and outcome of central nervous system (CNS) infections in Indonesia, a country with a high burden of infectious diseases and a rising prevalence of HIV. METHODS: We included adult patients with suspected CNS infections at two referral hospitals in a prospective cohort between April 2019 and December 2021. Clinical, laboratory, and radiological assessments were standardized. We recorded initial and final diagnoses, treatments, and outcomes during 6 months of follow-up. RESULTS: Of 1051 patients screened, 793 were diagnosed with a CNS infection. Patients (median age 33 years, 62% male, 38% HIV-infected) presented a median of 14 days (IQR 7-30) after symptom onset, often with altered consciousness (63%), motor deficits (73%), and seizures (21%). Among HIV-uninfected patients, CNS tuberculosis (TB) was most common (60%), while viral (8%) and bacterial (4%) disease were uncommon. Among HIV-infected patients, cerebral toxoplasmosis (41%) was most common, followed by CNS TB (19%), neurosyphilis (15%), and cryptococcal meningitis (10%). A microbiologically confirmed diagnosis was achieved in 25% of cases, and initial diagnoses were revised in 46% of cases. In-hospital mortality was 30%, and at six months, 45% of patients had died, and 12% suffered from severe disability. Six-month mortality was associated with older age, HIV, and severe clinical, radiological and CSF markers at presentation. CONCLUSION: CNS infections in Indonesia are characterized by late presentation, severe disease, frequent HIV coinfection, low microbiological confirmation and high mortality. These findings highlight the need for earlier disease recognition, faster and more accurate diagnosis, and optimized treatment, coupled with wider efforts to improve the uptake of HIV services.

Effectiveness of transcranial direct current stimulation (tDCS) as adjunctive treatment for chronic headache in adults with clinically stable systemic lupus erythematosus (SHADE): a randomised double-blind multiarm sham controlled clinical trial.

BACKGROUND: Chronic headache is a 'silent' neuropsychiatric systemic lupus erythematosus symptom with heterogeneous prevalence, potentially reaching 54.4%. It may reduce quality of life by increasing the likelihood of depression and sleep disturbance. While pharmacotherapy remains the first-line treatment, the current management is still challenging and needs other non-invasive modalities. An effective, tolerable and disease-specific treatment modality including transcranial direct current stimulation (tDCS) is considered to reduce the frequency of chronic headaches, including in SLE. Until recently, there was no standard protocol for tDCS in treating headaches. METHODS AND ANALYSIS: SHADE is a single-centre randomised double-blind multiarm sham-controlled trial for adults with clinically stable SLE, chronic headaches and without history of traumatic brain injury, brain infection, stroke or brain tumour. Random allocation is conducted to 88 subjects into 3 treatment groups (administration at primary motor, primary sensory and dorsolateral prefrontal cortex) and control group in 1:1:1:1 ratio. The primary endpoint is reduced number of headache days after adjunctive tDCS. The secondary endpoints are reduced headache intensity, increased quality of life, increased sleep quality, decreased depression and reduced analgesics use. The outcome is measured monthly until 3-month postintervention using headache diary, 36-Item Short Form Survey, Chronic Headache Quality of Life Questionnaire, Pittsburgh Sleep Quality Index and Mini International Neuropsychiatry Interview version 10 (MINI ICD 10). Intention-to-treat analysis will be performed to determine the best tDCS electrode placement. ETHICS AND DISSEMINATION: Ethical approval had been obtained from the local Institutional Review Board of Faculty of Medicine Universitas Indonesia. Results will be published through scientific relevant peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05613582.

Adjunctive Dexamethasone for Tuberculous Meningitis in HIV-Positive Adults.

BACKGROUND: Adjunctive glucocorticoids are widely used to treat human immunodeficiency virus (HIV)-associated tuberculous meningitis despite limited data supporting their safety and efficacy. METHODS: We conducted a double-blind, randomized, placebo-controlled trial involving HIV-positive adults (≥18 years of age) with tuberculous meningitis in Vietnam and Indonesia. Participants were randomly assigned to receive a 6-to-8-week tapering course of either dexamethasone or placebo in addition to 12 months of antituberculosis chemotherapy. The primary end point was death from any cause during the 12 months after randomization. RESULTS: A total of 520 adults were randomly assigned to receive either dexamethasone (263 participants) or placebo (257 participants). The median age was 36 years; 255 of 520 participants (49.0%) had never received antiretroviral therapy, and 251 of 484 participants (51.9%) with available data had a baseline CD4 count of 50 cells per cubic millimeter or less. Six participants withdrew from the trial, and five were lost to follow-up. During the 12 months of follow-up, death occurred in 116 of 263 participants (44.1%) in the dexamethasone group and in 126 of 257 participants (49.0%) in the placebo group (hazard ratio, 0.85; 95% confidence interval, 0.66 to 1.10; P = 0.22). Prespecified analyses did not reveal a subgroup that clearly benefited from dexamethasone. The incidence of secondary end-point events, including cases of immune reconstitution inflammatory syndrome during the first 6 months, was similar in the two trial groups. The numbers of participants with at least one serious adverse event were similar in the dexamethasone group (192 of 263 participants [73.0%]) and the placebo group (194 of 257 participants [75.5%]) (P = 0.52). CONCLUSIONS: Among HIV-positive adults with tuberculous meningitis, adjunctive dexamethasone, as compared with placebo, did not confer a benefit with respect to survival or any secondary end point. (Funded by the Wellcome Trust; ACT HIV ClinicalTrials.gov number, NCT03092817.).

Prognostic identifier of cerebrovascular complications in tuberculous meningitis: Meta-analysis.

INTRODUCTION: Cerebrovascular complications could occur in 15-57 % of patients with tuberculous meningitis (TBM). It is crucial to rapidly identify TBM patients who are at risk for stroke. This study aimed to find predictors of stroke in patients with TBM. METHODS: This systematic review and meta-analysis were done using literature searches through online databases up to April 30th, 2022. Three independent authors performed literature screening, data extraction, and critical appraisal of the studies. Eight studies involving 1535 samples were included. RESULTS: We analyzed data regarding demographic, comorbidity, clinical presentation, radiologic, and laboratory parameters. Overall, clinical presentation that showed outcome difference was found in patients with findings of vomiting (OR = 2.71, 95 % CI: 1.30-5.63), cranial nerve deficit (OR = 4.10, 95 % CI: 1.83-9.21), focal deficit (OR = 5.56, 95 % CI: 2.24-13.79), and altered consciousness (OR = 1.90, 95 % CI: 1.24-2.92). Some comorbidities showed significant differences such as diabetes mellitus (OR = 2.58, 95 % CI: 1.51-4.41), hypertension (OR = 5.73, 95 % CI: 3.36-9.77), ischemic heart disease (OR = 2.18, 95 % CI: 1.02-4.63), and smoking (OR = 2.65, 95 % CI: 1.22-5.77). Two radiological changes shown to have significantly higher proportions are hydrocephalus (OR = 2.50, 95 % CI: 1.74-3.58) and meningeal enhancements (OR = 3.99, 95 % CI: 1.73-9.20). CONCLUSION: Our analysis indicated that clinical presentations of vomiting, cranial nerve deficit, focal deficit, altered consciousness; comorbidity of diabetes mellitus, hypertension, smoking history, ischemic heart disease; and radiological findings of meningeal enhancement and hydrocephalus showed significant association with stroke incidence in tuberculous meningitis.

Tryptophan metabolism determines outcome in tuberculous meningitis: a targeted metabolomic analysis.

Background: Cellular metabolism is critical for the host immune function against pathogens, and metabolomic analysis may help understand the characteristic immunopathology of tuberculosis. We performed targeted metabolomic analyses in a large cohort of patients with tuberculous meningitis (TBM), the most severe manifestation of tuberculosis, focusing on tryptophan metabolism. Methods: We studied 1069 Indonesian and Vietnamese adults with TBM (26.6% HIV-positive), 54 non-infectious controls, 50 with bacterial meningitis, and 60 with cryptococcal meningitis. Tryptophan and downstream metabolites were measured in cerebrospinal fluid (CSF) and plasma using targeted liquid chromatography-mass spectrometry. Individual metabolite levels were associated with survival, clinical parameters, CSF bacterial load and 92 CSF inflammatory proteins. Results: CSF tryptophan was associated with 60-day mortality from TBM (hazard ratio [HR] = 1.16, 95% confidence interval [CI] = 1.10-1.24, for each doubling in CSF tryptophan) both in HIV-negative and -positive patients. CSF tryptophan concentrations did not correlate with CSF bacterial load nor CSF inflammation but were negatively correlated with CSF interferon-gamma concentrations. Unlike tryptophan, CSF concentrations of an intercorrelating cluster of downstream kynurenine metabolites did not predict mortality. These CSF kynurenine metabolites did however correlate with CSF inflammation and markers of blood-CSF leakage, and plasma kynurenine predicted death (HR 1.54, 95% CI = 1.22-1.93). These findings were mostly specific for TBM, although high CSF tryptophan was also associated with mortality from cryptococcal meningitis. Conclusions: TBM patients with a high baseline CSF tryptophan or high systemic (plasma) kynurenine are at increased risk of death. These findings may reveal new targets for host-directed therapy. Funding: This study was supported by National Institutes of Health (R01AI145781) and the Wellcome Trust (110179/Z/15/Z and 206724/Z/17/Z).

Encephalomyelitis associated with coronavirus disease 2019: a case report.

BACKGROUND: Despite a considerable number of articles regarding neurological manifestations associated with severe acute respiratory syndrome coronavirus 2 infection, reports on transverse myelitis and encephalitis are scarce. CASE PRESENTATION: We report a 35-year-old Asian Arab female presenting with longitudinally extensive transverse myelitis within 3 weeks after being diagnosed with mild coronavirus disease 2019 infection. Administration of high-dose methylprednisolone led to significant clinical improvement. However, 2 days after discharge, the patient was readmitted with encephalitis manifestations, consisting of fever and loss of consciousness, along with deterioration in myelitis symptoms. Severe acute respiratory syndrome coronavirus 2 antibody was detected in cerebrospinal fluid, but DNA of severe acute respiratory syndrome coronavirus 2 was not found. Clinical recovery was achieved after the administration of intravenous immunoglobulin. CONCLUSION: Longitudinally extensive transverse myelitis can be a neurological manifestation of coronavirus disease 2019 and can be followed by encephalomyelitis episodes. High-dose steroids and intravenous immunoglobulin as an immunomodulator are possible effective treatment options.

Intractable singultus as an initial symptom of medulla oblongata tuberculoma: A rare case report.

Tuberculoma of medulla oblongata is a rare manifestation of central nervous system tuberculosis (CNS TB), which may manifest as intractable singultus as the initial symptom. It is almost impossible to obtain definite diagnosis through biopsy consider its location. Immediate thorough diagnostic workup is needed, and empirical treatment should be started. We report a case of medulla oblongata tuberculoma in an HIV-negative 38-year-old man with intractable singultus as one of the early symptoms. He was treated empirically with anti-tuberculosis therapy and his symptoms subsided within 2 weeks.

Presentation, etiology, and outcome of brain infections in an Indonesian hospital: A cohort study.

BACKGROUND: Little detailed knowledge is available regarding the etiology and outcome of CNS infection, particularly in HIV-infected individuals, in low-resource settings. METHODS: From January 2015 to April 2016, we prospectively included all adults with suspected CNS infection in a referral hospital in Jakarta, Indonesia. Systematic screening included HIV testing, CSF examination, and neuroimaging. RESULTS: A total of 274 patients with suspected CNS infection (median age 26 years) presented after a median of 14 days with headache (77%), fever (78%), seizures (27%), or loss of consciousness (71%). HIV coinfection was common (54%), mostly newly diagnosed (30%) and advanced (median CD4 cell count 30/µL). Diagnosis was established in 167 participants (65%), including definite tuberculous meningitis (TBM) (n = 44), probable TBM (n = 48), cerebral toxoplasmosis (n = 48), cryptococcal meningitis (n = 14), herpes simplex virus/varicella-zoster virus/cytomegalovirus encephalitis (n = 10), cerebral lymphoma (n = 1), neurosyphilis (n = 1), and mucormycosis (n = 1). In-hospital mortality was 32%; 6-month mortality was 57%. The remaining survivors had either moderate or severe disability (36%) according to Glasgow Outcome Scale. CONCLUSION: In this setting, patients with CNS infections present late with severe disease and often associated with advanced HIV infection. Tuberculosis, toxoplasmosis, and cryptococcosis are common. High mortality and long-term morbidity underline the need for service improvements and further study.