Characteristics and outcomes of cerebral venous thrombosis associated with COVID-19.

INTRODUCTION: Previous reports and meta-analyses derived from small case series reported a mortality rate of up to 40% in patients with coronavirus disease 2019 associated cerebral venous thrombosis (COVID-CVT). We assessed the clinical characteristics and outcomes in an international cohort of patients with COVID-CVT. PATIENTS AND METHODS: This was a registry study of consecutive COVID-CVT patients diagnosed between March 2020 and March 2023. Data collected by the International Cerebral Venous Thrombosis Consortium from patients with CVT diagnosed between 2017 and 2018 served as a comparison. Outcome analyses were adjusted for age and sex. RESULTS: We included 70 patients with COVID-CVT from 23 hospitals in 15 countries and 206 controls from 14 hospitals in 13 countries. The proportion of women was smaller in the COVID-CVT group (50% vs 68%, p < 0.01). A higher proportion of COVID-CVT patients presented with altered mental state (44% vs 25%, p < 0.01), the median thrombus load was higher in COVID-CVT patients (3 [IQR 2-4] vs 2 [1-3], p < 0.01) and the length of hospital stay was longer compared to controls (11 days [IQR 7-20] vs 8 [4-15], p = 0.02). In-hospital mortality did not differ (5/67 [7%, 95% CI 3-16] vs 7/206 [3%, 2-7], aOR 2.6 [95% CI 0.7-9]), nor did the frequency of functional independence after 6 months (modified Rankin Scale 0-2; 45/58 [78%, 95% CI 65-86] vs 161/185 [87%, 81-91], aOR 0.5 [95% CI 0.2-1.02]). CONCLUSION: In contrast to previous studies, the in-hospital mortality rate and functional outcomes during follow-up did not differ between COVID-CVT patients and the pre-COVID-19 controls.

RE-OPEN: Randomised trial of biosimilar TNK versus TPA during endovascular therapy for acute ischaemic stroke due to large vessel occlusions.

Rationale: Rapid and timely treatment with intravenous thrombolysis and endovascular treatment (EVT) in patients with acute ischaemic stroke (AIS) and large vessel occlusion (LVO) significantly improves patient outcomes. Bridging therapy is the current standard of care in these patients. However, an incompletely answered question is whether one thrombolytic agent is better than another during bridging therapy. Aim: The current study aims to understand if one thrombolytic agent is superior to the other during bridging therapy in the treatment of AIS and LVO. Sample size estimates: Using 80% power and an alpha error of 5 %, presuming a 10% drop out rate, a total of 372 patients will be recruited for the study. Methods and design: This study is a prospective, randomised, multicentre, open-label trial with blinded outcome analysis design. Study outcomes: The primary outcomes include proportion of patients who will be independent at 3 months (modified Rankin score (mRS) ≤2 as good outcome) and proportion of patients who achieve recanalisation modified thrombolysis in cerebral infarction grade 2b/3 at first angiography run at the end of EVT. Secondary outcomes include proportion of patients with early neurological improvement, rate of symptomatic intracerebral haemorrhage (ICH), rate of any ICH, rate of any systemic major or minor bleeding and duration of hospital stay. Safety outcomes include any intracranial bleeding or symptomatic ICH. Discussion: This trial is envisioned to confirm the theoretical advantages and increase the strength and quality of evidence for use of tenecteplase (TNK) in practice. Also, it will help to generate data on the efficacy and safety of biosimilar TNK. Trial registration number: CTRI/2022/01/039473.

Opsoclonus myoclonus ataxia syndrome, ovarian teratoma and anti-NMDAR antibody: an 'unresolved' mystery.

Background: Opsoclonus-myoclonus-ataxia syndrome (OMAS) is characterised by the combination of opsoclonus and arrhythmic action myoclonus with axial ataxia and dysarthria. In adults, a majority are paraneoplastic secondary to solid organ tumours and could harbour antibodies against intracellular epitopes; however, certain proportions have detectable antibodies to various neuronal cell surface antigens. Anti-N-methyl-D-aspartate (NMDAR) antibodies and ovarian teratomas have been implicated in OMAS. Methods: Report of two cases and review of literature. Results: Two middle-aged women presented with subacute-onset, rapidly progressive OMAS and behavioural changes consistent with psychosis. The first patient had detectable antibodies to NMDAR in the cerebrospinal fluid (CSF) alone. Evaluation for ovarian teratoma was negative. The second patient had no detectable antibodies in serum or CSF; however, she had an underlying ovarian teratoma. Patient A was treated with pulse steroids, therapeutic plasma exchange (TPE) followed by bortezomib (BOR) and dexamethasone, while patient B was treated with steroids, TPE followed by surgical resection of ovarian teratoma. Both patients had favourable outcomes and were asymptomatic at the 6 monthly follow-up. Conclusions: With coexistent neuropsychiatric manifestations, OMAS can be considered a distinct entity of autoimmune encephalitis, pathogenesis being immune activation against known/unknown neuronal cell surface antigens. The observation of absence of anti-NMDAR antibody in patients with teratoma-associated OMAS and vice versa is intriguing. Further research on the potential role of ovarian teratoma in evoking neuronal autoimmunity and its targets is required. The management challenge in both cases including the potential use of BOR has been highlighted.

Pulmonary tuberculosis and diabetes mellitus: Clinical profile and outcomes.

Background: India is endemic for Tuberculosis (TB), contributing to the world's highest number of active cases. Diabetes (DM), with its increasing burden in India, could contribute to adverse outcomes among patients with TB. Methods: Consecutive patients with sputum smear positive pulmonary tuberculosis were included in the study. We defined cases as those patients with diabetes at recruitment. Controls were non diabetics (NDM). Sputum samples for AFB smears, AFB culture and Xpert PCR along with blood samples for glycosylated Haemoglobin and glucose levels were collected at recruitment and at 6 months from patients with sputum positive pulmonary TB. Blood glucose levels and sputum smears were repeated at 2 months and monthly till they tested negative. The primary outcome studied was mortality at 6 month follow-up. The secondary outcomes included the time to conversion of sputum smears and cure rates between cases and controls. Results: We recruited 124 patients of which 68 were cases. Mortality after therapy was 15% in cases and 7% in controls, however, the difference was not statistically significant. Equal proportions in each group (Diabetics: 9% vs. NDM 9%) had persistent smear positivity at 2 months. There was no association between delayed sputum conversion and uncontrolled diabetes. Only about 57% of cases and 50% of controls were documented to have completed treatment or been cured. A significant reduction in HbA1c after 6 months of Antituberculous therapy was noted among the cases. [Mean difference - 1.76, P-value - 0.001, 95% CI of difference - (1.01 - 2.52)]. Conclusions: Diabetes did not have adverse outcomes in the form of increased mortality or delayed sputum conversion rates. The high proportion of loss to follow-up seems to be a trend of concern, which should be addressed emergently.

Utility of positron emission tomography-computed tomography in the evaluation of fever of unknown origin in a resource-limited tropical nation.

Positron emission tomography-computed tomography (PET-CT) has been used as an imaging modality in workup of fever of unknown origin (FUO). The aim of our study is to evaluate the diagnostic utility of PET-CT in FUO workup in a resource-limited setting. We also looked at laboratory parameters as predictors of contributory PET-CT scans and propose an algorithm for evaluation of FUO in resource-limited tropical regions. This retrospective observational study included patients admitted for FUO workup under general medicine in a teaching hospital in South India from June 2013 to May 2016. PET-CT was done when the patient remained undiagnosed after a detailed clinical assessment and first- and second-tier investigations. Among 43 patients included in our study, a definite diagnosis was established in 74% (32). Noninfectious inflammatory diseases, infections, malignancies, and miscellaneous diseases were diagnosed in 37.2% (16/43), 23.3% (10/43), 9.3% (4/43), and 4.7% (2/43), respectively. Tuberculosis was the single most common disease seen in 20.9% (9/43). PET-CT scans were contributory toward establishment of final diagnosis in 90.7% (39/43). High C-reactive protein (CRP) and aspartate aminotransferase (AST) levels were associated with contributory PET-CT scans (P = 0.006 and 0.011, respectively). PET-CT delineating organ/tissue for diagnostic biopsy was associated with final diagnosis of infectious disease (P = 0.001). Sensitivity, specificity, and positive and negative predictive value of PET-CT scans were 76.9% (20/26), 33.3% (2/6), 83% (20/24), and 25% (2/8), respectively. High CRP and AST were predictors of contributory PET-CT scans. PET-CT scans have high sensitivity and positive predictive value when used in evaluation of FUO. Although it is a useful tool in FUO workup, especially in the diagnosis of tropical infections, PET-CT should be done after a comprehensive clinical assessment and basic investigations.

Infection-Associated Peripheral Nerve Hyperexcitability: An Under-Recognized Entity.

BACKGROUND: Peripheral nerve hyperexcitability (PNH) and neuromyotonia have been mainly attributed to antibodies against voltage-gated potassium channels (VGKC). Concurrent autoimmune disorders, malignancies, and heavy metal toxicity have also been implicated. There is scarce mention about infection as a triggering factor for PNH. There are no reports of methicillin-resistant Staphylococcus aureus (MRSA) infection being a possible precipitating factor for development of PNH. METHODS: Case series and literature review. RESULTS: Four subjects were diagnosed to have features of PNH based on clinical and electrophysiological assessment. All the subjects had concurrent evidence of cutaneous abscesses requiring surgical intervention and antibiotic therapy. The cultures in all of them revealed growth of Staphylococcus aureus with three of them being MRSA isolates. Two subjects tested positive for anti-VGKC antibodies. There was remarkable resolution in neuromyotonia after antibiotics in three subjects. One subject succumbed to fulminant MRSA septicemia. CONCLUSION: There appears to be a definitive link between staphylococcal infection (MRSA in particular) and development of PNH. The temporal evolution of PNH associated with the infection and resolution following treatment of the infection does support a causal association. The enterotoxins produced by staphylococci act as superantigens and could trigger an inflammatory cascade along with development of cross reacting antibodies against VGKC in peripheral nerves. Future studies with animal models could provide more directions in this regard.

Emergence of Meropenem Resistance Among Cefotaxime Non-susceptible Streptococcus pneumoniae: Evidence and Challenges.

The principal causative agent of acute bacterial meningitis (ABM) in children and the elderly is Streptococcus pneumoniae, with a widespread increase in penicillin resistance. Resistance is due to non-synonymous single-nucleotide polymorphisms (nsSNPs) that alter the penicillin-binding proteins (PBPs), the targets for all ß-lactam drugs. Hence, resistance against one ß-lactam antibiotic may positively select another. Since meropenem is an alternative to cefotaxime in meningeal infections, we aim to identify whether nsSNPs in the PBPs causing penicillin and cefotaxime resistance can decrease the pneumococcal susceptibility to meropenem. Comparison of the nsSNPs in the PBPs between the cefotaxime-resistant Indian (n = 33) and global isolates (n = 28) revealed that nsSNPs in PBP1A alone elevated meropenem minimal inhibitory concentrations (MICs) to 0.12 µg/ml, and nsSNPs in both PBP2X and 2B combined with PBP1A increases MIC to ≥ 0.25 µg/ml. Molecular docking confirmed the decrease in the PBP drug binding affinity due to the nsSNPs, thereby increasing the inhibition potential and the MIC values, leading to resistance. Structural dynamics and thermodynamic stability pattern in PBPs as a result of mutations further depicted that the accumulation of certain nsSNPs in the functional domains reduced the drug affinity without majorly affecting the overall stability of the proteins. Restricting meropenem usage and promoting combination therapy with antibiotics having non-PBPs as targets to treat cefotaxime non-susceptible S. pneumoniae meningitis can prevent the selection of ß-lactam resistance.

Role of cerebrospinal fluid C-reactive protein in tuberculous meningitis.

Background: Tuberculosis (TB) is still a significant health problem worldwide. Central nervous system TB amounts to 10% of all cases of TB. Despite advances in the pharmacological management of TB, the overall outcomes remain poor with significant mortality and morbidity. There are no predictors for neurological outcomes in tuberculosis meningitis (TBM). In this study, we aimed to evaluate the role of cerebrospinal fluid (CSF) C-reactive protein (CRP) in predicting mortality and neurological outcome in TBM. Method: In this observational study, all patients with TBM were recruited prospectively over a 12-month duration. Baseline demographic data, laboratory parameters, and Imaging findings were collected. CSF CRP was obtained on the CSF sample collected at the time of diagnosis. Patients were followed up at 3 months to assess neurological status and mortality. Results: Seventy-one patients with TBM were recruited in this study. The overall mortality in this study was 22.5% of patients. The primary composite outcome of mortality and adverse neurological outcome occurred in 40.8%. The CSF CRP levels ranged between 0.1 and 4.8 mg/dl, and the mean CSF CRP level was 1.11 mg/dl. The Relative risk for a patient with high CSF CRP to develop adverse outcome was 1.84 (P = 0.038). CSF CRP was a good predictor of mortality with a relative risk of 2.92 (P = 0.027). Stroke in TBM had a high incidence of 47.9% and a relative risk of 3.42 for an adverse neurological outcome. CSF CRP did not predict the occurrence of stroke. Hydrocephalus and elevated intracranial pressure were good predictors of stroke. Conclusion: TBM is a disease with significant mortality and morbidity. CRP level in the CSF can be measured, but a highly sensitive scale may be needed as the mean values were much lower compared to the serum values. CSF CRP Levels showed significant associations with adverse outcomes and mortality.

Clinical Profile and Outcome of Patients with Cerebral Venous Thrombosis Secondary to Bacterial Infections.

BACKGROUND: Cerebral venous thrombosis (CVT) secondary to infectious aetiology has become rare in the antibiotic era, but is still encountered in clinical practice occasionally. In this study, we describe the clinical profile, diagnosis, and management of patients with CVT secondary to an infectious aetiology. METHODS: This retrospective study included all adult patients over 15 years (1 January 2002 to 1 January 2017). Adult patients with a diagnosis of infective CVT secondary to bacterial infections were included in the study. RESULTS: Totally, 22 patients were identified with CVT complicating bacterial infections. The focus of infection in 12 (54.54%) patients was pyogenic meningitis, 9 (40.9%) patients had a parameningeal focus and one patient developed CVT secondary to bacterial sepsis from a remote focus. Fever was the most common symptom seen in 77.3% followed by headache and depressed sensorium in 72.7% and 63.6%, respectively. The most common organism in the meningitis group was Streptococcus species, and in the parameningeal group was Staphylococcus aureus. At presentation MRI identified CVT in all 7 patients as compared to CT brain with contrast in 2/3 (66.6%). Transverse sinus was the most commonly involved sinus in meningitis. All patients were treated with appropriate antibiotics and anticoagulation was used in 50% of the patients. The in hospital, mortaility was 9%. CONCLUSION: Septic CVT, though rare can be a complication of bacterial meningitis and facial infections. Clinical symptoms that suggest a co-existing CVT should be identified and diagnosed at the earliest. The mainstay of treatment is antibiotics; the role of anticoagulation is controversial.

Septicemic listeriosis: An emerging food-borne illness in India?

Listeriosis is a food borne illness of significant public health concern, caused by consumption of food contaminated by gram negative bacilli, Listeria monocytogenes. Clinical listeriosis is relatively rare and it has varying spectrum of presentation, ranging from severe sepsis in immune-compromised individuals, febrile gastroenteritis and meningo-encephalitis in infants and adults. This disease is under reported in developing nations due to the lack of awareness and inadequate laboratory facilities to promptly isolate and identify the organism. We report a case of sporadic food-borne listeriosis, in an otherwise healthy individual presenting with meningo-encephalitis. Prompt identification and appropriate antibiotic therapy led to a favorable outcome.

Abiotrophia defectiva endarteritis with infective spondylodiscitis in an adult patient with patent ductus arteriosus.

Endarteritis is a major complication in patients with patent ductus arteriosus, causing significant morbidity and mortality. We report an adult patient with asymptomatic patent ductus arteriosus and endarteritis involving the main pulmonary artery and secondary infective spondylodiscitis at the L5-S1 intervertebral disc caused by Abiotrophia defectivaA. defectiva, commonly referred to as nutritionally variant streptococci, cannot be identified easily by conventional blood culture techniques from clinical specimens. Its isolation was confirmed by 16S ribosomal RNA sequencing. The patient was successfully managed with a combination of penicillin G and gentamicin, pending surgical repair of the patent ductus arteriosus.

A prospective study from south India to compare the severity of malaria caused by Plasmodium vivax, P. falciparum and dual infection.

BACKGROUND & OBJECTIVES: Traditionally, Plasmodium falciparum has been attributed to cause severe malaria, whereas P. vivax is considered to cause "benign" tertian malaria. Recently, there has been an increasing body of evidence challenging this conviction. However, the spectrum and degree of severity of the disease caused by P. vivax, as per World Health Organization (2012) remains unclear. Thus, in this prospective study, we aimed at comparing the severity of malaria caused by P. vivax, P. falciparum and dual infection. METHODS: Adult patients presenting to Christian Medical College, Vellore from October 2012 to September 2013 with microscopically confirmed malaria were included in the study. Their clinical and laboratory parameters were recorded and analyzed. Paired t-test and chi-square with 95% CI and post-hoc analyses using the Scheffι post-hoc criterion were used to assess the statistical significance at the level of α <0.05. RESULTS: In total, 131 cases of malaria were identified during the study period, comprising 83 cases of P. vivax, 35 cases of P. falciparum and 13 cases of mixed vivax and falciparum infections. The spectrum and degree of hematological, hepatic, renal, metabolic, central nervous system complications of vivax malaria was not different from that of falciparum group. Thrombocytopenia and hyperbilirubinemia were the most common laboratory abnormalities identified in all the groups. INTERPRETATION & CONCLUSION: This cross-sectional comparative study clearly demonstrates that clinical features, complications and case-fatality rates in vivax malaria can be as severe as in falciparum malaria. Hence, vivax malaria could not be considered benign; and appropriate preventive strategies along with antimalarial therapies should be adopted for control and elimination of this disease.