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.

Neurological Manifestations of Glutamic Acid Decarboxylase Autoimmunity in Indian Patients.

Objective: To study the neurological manifestations of glutamic acid decarboxylase (GAD 65) autoimmunity in Indian patients. Methods: Retrospective study conducted in a tertiary care referral hospital in South India. Patients who tested positive for GAD 65 antibodies from February 2013 to July 2019 were included. Results: We identified 922 patients who underwent GAD 65 testing, of which 81 tested positive (8.78%) [mean age 55.42 years (SD 17.39, range 9-86 years, median age 57 years)]. Males (n = 47) outnumbered the females (n = 34). All the GAD values measured were <5000 IU/ml. There were 34 cases (42%) of atypical parkinsonism (16/34, 47% fulfilled the diagnostic criteria for autoimmune atypical parkinsonism) in our series forming the most common group with GAD 65 positivity, followed by autoimmune encephalitis (8 cases, 9.88%). Men were more affected with atypical parkinsonism (22/34; 64.70%), stiff person syndrome (2/3; 66.66%), and neuropathy (4/7; 57.1%) while women were more with autoimmune encephalitis (6/8; 75%). Eighteen (22.6%) had underlying autoimmunity (three had type 1 diabetes mellitus). Six (7.4%) had underlying neoplasm. Thirty-three out of 43 patients responded to immunotherapy (76.74%). Five had spontaneous improvement. Conclusion: Glutamic acid decarboxylase65 antibody values were much lower in our study population. Male-dominant autoimmunity was seen unlike that in Western literature. The most striking was the high preponderance of atypical parkinsonism in GAD 65-positive patients. We also found that GAD 65 positivity is a useful marker for a positive response to immunotherapy in suspected autoimmune neurological syndromes irrespective of their titers.

Cerebrospinal fluid indices as predictors of treatment response in autoimmune encephalitis.

BACKGROUND: Cerebrospinal fluid (CSF) indices reflecting intrathecal antibody production and blood-brain barrier impairment are not routinely assessed in patients with autoimmune encephalitis (AE). We aimed to study CSF indices and their association with the prognosis of AE. METHODS: This retrospective cohort study conducted at Amrita Institute of Medical Sciences (AIMS), Kochi, India, included 60 patients aged more than 18 years with definite/probable/possible AE admitted to the Department of Neurology from August 2016 to November 2021. We introduced a classification of treatment response based on modified Rankin Scale change over time and treatment modalities. RESULTS: In our cohort of 60 patients (six [10%] seropositive cases), a good rapid treatment response was associated with CSF white blood cell count of more than 4 cells/mm3 (OR, 4.57; 95% CI 1.31-15.96; P = .02) and positive immunoglobulin G (IgG) Local Synthesis (OR, 7.27; 95% CI 1.56-33.86; P = .01). Albumin Index had association with a poor Glasgow Coma Scale score at the nadir of the disease (OR, 1.17; 95% CI 1.01-1.34; P = .04). Similar results were yielded in the seronegative cohort. IgG Local Synthesis appeared to be a strong predictor for good rapid treatment response in both univariate and multivariate (adjusted OR, 28.71; 95% CI 2.12-389.22; P= .01) analysis. Time to immunotherapy was reversely correlated with good response overall (in the cohort with outliers removed [N = 49]: unadjusted OR 0.97, 95% CI 0.95-0.99; P= .01; adjusted OR 0.97; 95% CI 0.95-0.99; P= .008). CONCLUSION: CSF indices reflecting intrathecal antibody production and blood-brain barrier impairment appear to be promising predictors of disease severity and therapeutic response in patients with autoimmune encephalitis.

The prevalence and clinical phenotype of dual seropositive neuromyelitis optica spectrum disorders at a national reference center in South Asia.

BACKGROUND: Neuromyelitis Optica Spectrum Disorders (NMOSD) is an autoimmune syndrome that is frequently positive for Aquaporin 4 (AQP4) IgG or Myelin Oligodendrocyte Glycoproteins (MOG) IgG. However, dual positivity to both is rare. OBJECTIVE: To assess the prevalence of dual-positive NMOSD and outline its clinical phenotype. DESIGN/METHODS: This is a retrospective cross-sectional study conducted at a tertiary healthcare center in South Asia between August 2018 and November 2021. The serum and/or CSF samples of suspected cases of NMOSD were tested for both AQP4-IgG and MOG-IgG using an Indirect immunofluorescence test on transfected cells. RESULTS: During the study period, 1935 cases of NMOSD were tested for both antibodies- 65 patients (3.35%; 57 females and 8 males) tested positive for AQP4-IgG, 217 patients (11.21%; 122 females and 95 males) tested positive for MOG-IgG and 3 patients (0.15%; 2 females and 1 male) showed dual positivity. There was a strong female preponderance in all three groups (87.69%, 56.22%, and 66.66% respectively). This study identified 3 patients with dual positivity. The first patient (42 years, Male) presented with area postrema syndrome initially and subsequently relapsed by developing right-sided numbness of the temporal area and limbs during which he tested dual positive. The second patient (27 years, Female) presented with bilateral optic neuritis (left>right) initially and subsequently relapsed following an episode of a seizure with left-sided hemiplegia. The third patient (25 years, Female) initially presented with acute bilateral optic neuritis and later developed left-sided hemiplegia post-recovery at which point she tested dual positive. Management using methylprednisolone was ineffective for all three patients, however, plasmapheresis and/or periodic rituximab injections produced an excellent response. CONCLUSIONS: Our study reports that the prevalence of dual-positive NMOSD is 0.15% and its clinical phenotype is more similar to NMO rather than MOG- associated disease.

Ayurvedic Treatment in the Rehabilitation of Ischemic Stroke Patients in India: A Randomized Controlled Trial Study Protocol.

In patients with ischemic stroke, motor and sensory impairments are common and are associated with functional disability. Conventional physiotherapy (CP) is the primary modality of rehabilitation for post-stroke sensorimotor dysfunction. Ayurveda is a commonly practiced alternative system of medicine that offers unique rehabilitative measures for post-stroke recovery. We hypothesize that Ayurvedic rehabilitative treatment (ART) is superior to similar duration CP in improving the sensorimotor recovery of patients with ischemic stroke at 90 days after enrollment. AyuRvedic TrEatment in the Rehabilitation of Ischemic STrOke Patients in India: A Randomized controllEd trial (RESTORE) is an investigator-initiated, multicenter, prospective, randomized, controlled, parallel-arm, blinded outcome assessment trial being conducted under the Indian Stroke Clinical Trial (INSTRuCT) Network across the four comprehensive stroke centers in India. Consecutive hemodynamically stable adult patients with their first acute ischemic stroke between 1 and 3 months from stroke onset are being randomized (1:1) into two treatment groups to receive either 1 month of ART or 1 month of CP. The primary outcome measure is the Fugl Meyer Assessment-upper extremity for physical performance at 90 days. The secondary outcomes are the modified Rankin Scale, Barthel Index, Berg Balance, and SF-36 at 90 days. The safety outcomes include a composite of irreversible morbidity and mortality. A sample size of 140 (70 in each group) patients with ischemic stroke will allow us to detect a minimal clinical important difference of 9.4 (standard deviation) with superiority margin of 5, an attrition rate of 10%, alpha of 5%, and power of 80%. This randomized trial will systematically assess the efficacy and safety of traditional ART compared to CP. The trial has been registered in the Clinical Trial Registry India (CTRI/2018/04/013379).

High Prevalence of Plasminogen Activator Inhibitor-1 4G/5G Polymorphism among Patients with Venous Thromboembolism in Kerala, India.

Venous thromboembolism (VTE) is a multifactorial clotting disorder in which inherited and environmental factors synergistically contribute to its pathogenesis. The aim of this case-control study was to analyze the prevalence of hereditary thrombophilic risk factors, provoking and non-provoking environmental risk factors in patients with VTE from Kerala, India. We have observed a low prevalence of factor V Leiden (7%), prothrombin G20210A (2%), and prothrombin G20030A (2%) mutations and a high prevalence of plasminogen activator inhibitor-1 (PAI-1) 4G/5G (52%), PAI-1 4G/4G (24%) genotypes in the VTE patients (n = 147). Deficiency of anticoagulants, antithrombin (3.4%), and protein C (4.1%) was relatively low. None of the risk factors were observed in 17% of the patients. Majority of VTE patients were younger than 50 years with a median age of 43 years. In conclusion, our results indicate a high prevalence of PAI-1 4G/5G polymorphism among the VTE patients which is in concordance with previous studies in the Asian population. The PAI-1 4G/5G polymorphism could be a potential biomarker for assessing VTE risk, particularly among the Indian population.

Fluoxetine or Venlafaxine for Early Post Stroke Depression.

Context: Post stroke depression (PSD) is an under diagnosed morbidity of stroke and can negatively affect the prognosis of the patient. Aims: We intended to study the prevalence of PSD and the commonly used anti-depressants and their outcome in patients with PSD. Settings and Design: A prospective observational study was conducted in the patients admitted to the stroke unit of a tertiary care centre. Methods and Materials: Diagnosis of post stroke depression was made by the Hamilton Depression Rating Scale (HDRS) during the two-week period after stroke or in the clinic follow up. A comparison of clinical outcome and adverse events of the two anti-depressants used, i.e. venlafaxine and fluoxetine were done by a follow up of up to 6 months. Statistical Analysis Used: Independent sample test was used for statistical purposes in the study. Results: Out of the 326 stroke patients admitted in the department, 73 had PSD and 60 patients out of this were assigned into the study. Forty patients were males, and the mean age of the sample population was found to be 62.13 ± 11.14. Major risk factors identified were hypertension, diabetes mellitus, and dyslipidemia. Venlafaxine showed better outcome and less adverse events compared to fluoxetine. Major adverse events observed were hyponatremia, headache, insomnia, and anxiety. Conclusions: PSD in the early phase affects a substantial number of the stroke patients. Venlafaxine has got a better outcome and adverse event profile compared to fluoxetine in this group of patients. However, larger multicenter studies will provide more helpful data in this area.

One-year mortality after acute stroke: a prospective cohort study from a comprehensive stroke care centre, Kerala, India.

OBJECTIVES: The primary objective was to report the 1-year all-cause mortality among patients with stroke. The secondary objectives were (1) to report the mortality stratified by type of stroke and sex and (2) to report predictors of 1-year mortality among patients with stroke. DESIGN: A prospective cohort study. SETTING: Institutional-stroke care unit of a tertiary care hospital PARTICIPANTS: Patients who were treated in the study institution during 2016-2020 for acute stroke and were followed up for a period of 1 year after stroke in the same institution. MAIN OUTCOME MEASURES: The main outcome measures were the mortality proportion of any stroke and first ever stroke cohorts at select time points, including in-hospital stay, along with 2 weeks, 2 months, 6 months and 1 year after index stroke. The secondary outcomes were (1) mortality proportions stratified by sex and type of stroke and (2) predictors of 1-year mortality for any stroke and first ever stroke. RESULTS: We recruited a total of 1336 patients. The mean age of participants was 61.6 years (13.5 years). The mortality figures for 2 weeks, 2 months, 6 months and 12 months after discharge were 79 (5.9%), 88 (6.7%), 101 (7.6%) and 114 (8.5%), respectively, in the full cohort. The in-hospital mortality was 45 (3.4%). The adjusted analysis revealed 3 predictors for 1-year mortality after first ever stroke-age, pre-treatment National Institutes of Health Stroke Scale (NIHSS) score and Modified Rankin Scale (mRS) score at baseline. The same for the full cohort had only two predictors-age and pre-treatment NIHSS score. CONCLUSION: Mortality of stroke at 1-year follow-up in the study population is low in comparison to several studies published earlier. The predictors of 1-year mortality after stroke included age, NIHSS score at baseline and mRS score at baseline.

Autoimmune parkinsonism with faciobrachiocrural dystonic seizures: a new phenotype of leucine-rich glioma-inactivated 1 (LGI1) autoimmunity.

Extrapyramidal symptoms are seen in patients with leucine-rich glioma-inactivated 1 (LGI1) antibody-positive patients infrequently and this can be successfully treated with immunotherapy. This is a retrospective hospital-based study from 2013 to 2021 at a tertiary care referral hospital in South India. LGI1 antibody-positive cases with Faciobrachio-crural dystonic seizures [FBCDS] were identified by reviewing electronic medical records and Neuroimmunology laboratory register. Clinical and laboratory details and treatment outcomes were analysed. There was a total of 23 patients who were positive for LGI1 antibody. Of these, three cases had FBCDS (2 males, age range 30-76 years). Upon reviewing the records they had additional asymmetric parkinsonian features. All had similar presentations with progressive slowness of activities and gait and later went on to have paroxysmal events of sudden falls with vocalization. Prolonged VEEG monitoring captured the habitual event, which were confirmed to be FBCDS. MRI did not show significant structural abnormalities, CSF showed elevated proteins and normal cell in two and lymphocytic pleocytosis in one, PET scans ruled out malignancy. Of the three patients, two were completely relieved of FBCDS with immunosuppression and there was complete resolution of extrapyramidal features in all. Thus, the patients in our series of FBCDS showed additional features of parkinsonism which responded well to immunotherapy. Involvement of basal ganglia can explain all the manifestations of this phenotype. This series reveals a unique phenotype of the LGI1 antibody.

Acute Ischemic Stroke in Children - Should We Thrombolyze?

Ischemic stroke is a major cause of acute neurological symptoms in children with significant long-term neurological sequelae. Unlike in the adult population, the clinical presentation of strokes in children may not be stereotyped. Hence, many other differential diagnostic possibilities might have to be considered in the emergency setting. Due to this heterogeneous presentation and the resultant clinical dilemma in the early detection, acute thrombolysis even now remains as a very rarely tried therapeutic option in children. Many case reports over these years have shown consistently good results of acute intravenous thrombolysis in children with tissue plasminogen activator (tPA) administered within the time frame. There are also some recent reports of endovascular interventions. However, unlike in the adult population, class 1 clinical studies and good Randomized controlled trials (RCT) are yet to emerge in children. The absence of age-appropriate safety and outcome data for the commonly used thrombolytic agents in children is another major roadblock for developing clinical guidelines and recommendations for this age group. The ambitious Thrombolysis in Pediatric Stroke (TIPS) trial had to be terminated prematurely due to poor patient enrolment. This review critically looks at the current status of the acute management of ischemic strokes in children with a specific emphasis on thrombolytic therapy. Until we have better evidence-based guidelines for this age group, it will be prudent to develop robust institutional pathways to provide this important intervention for all eligible children with acute strokes.

Clinical profile and outcome of non-COVID strokes during pandemic and the pre pandemic period: COVID-Stroke Study Group (CSSG) India.

BACKGROUND: As the health systems around the world struggled to meet the challenges of COVID-19 pandemic, care of many non-COVID emergencies was affected. AIMS: The present study examined differences in the diagnosis, evaluation and management of stroke patients during a defined period in the ongoing pandemic in 2020 when compared to a similar epoch in year 2019. METHODS: The COVID stroke study group (CSSG) India, included 18 stroke centres spread across the country. Data was collected prospectively between February and July 2020 and retrospectively for the same period in 2019. Details of demographics, stroke evaluation, treatment, in-hospital and three months outcomes were collected and compared between these two time points. RESULTS: A total of 2549 patients were seen in both study periods; 1237 patients (48.53%) in 2019 and 1312 (51.47%) in 2020. Although the overall number of stroke patients and rates of thrombolysis were comparable, a significant decline was observed in the month of April 2020, during the initial period of the pandemic and lockdown. Endovascular treatment reduced significantly and longer door to needle and CT to needle times were observed in 2020. Although mortality was higher in 2020, proportion of patients with good outcome were similar in both the study periods. CONCLUSIONS: Although stroke admissions and rates of thrombolysis were comparable, some work flow metrics were delayed, endovascular stroke treatment rates declined and mortality was higher during the pandemic study period. Reorganization of stroke treatment pathways during the pandemic has likely improved the stroke care delivery across the globe.

INSTRuCT: Protocol, Infrastructure, and Governance.

Background and Purpose: Very few large scale multicentric stroke clinical trials have been done in India. The Indian Council of Medical Research funded INSTRuCT (Indian Stroke Clinical Trial Network) as a task force project with the objectives to establish a state-of-the-art stroke clinical trial network and to conduct pharmacological and nonpharmacological stroke clinical trials relevant to the nation and globally. The purpose of the article is to enumerate the structure of multicentric stroke network, with emphasis on its scope, challenges and expectations in India. Methods: Multiple expert group meetings were conducted by Indian Council of Medical Research to understand the scope of network to perform stroke clinical trials in the country. Established stroke centers with annual volume of 200 patients with stroke with prior experience of conducting clinical trials were included. Central coordinating center, standard operating procedures, data and safety monitoring board were formed. Discussion: In first phase, 2 trials were initiated namely, SPRINT (Secondary Prevention by Structured Semi-Interactive Stroke Prevention Package in India) and Ayurveda treatment in the rehabilitation of patients with ischemic stroke in India (RESTORE [Rehabilitation of Ischemic stroke Patients in India: A Randomized controlled trial]). In second phase, 4 trials have been approved. SPRINT trial was the first to be initiated. SPRINT trial randomized first patient on April 28, 2018; recruited 3048 patients with an average of 128.5 per month so far. The first follow-up was completed on May 27, 2019. RESTORE trial randomized first patient on May 22, 2019; recruited 49 patients with an average of 3.7 per month so far. The first follow-up was completed on August 30, 2019. Conclusions: In next 5 years, INSTRuCT will be able to complete high-quality large scale stroke trials which are relevant globally. REGISTRATION: URL: http://www.ctri.nic.in/; Unique Identifier: CTRI/2017/05/008507.

Clinical Features and Outcome of Stroke with COVID-19. COVID-19 Stroke Study Group (CSSG), India.

BACKGROUND AND PURPOSE: Occurrence of stroke has been reported among patients with COVID-19. The present study compares clinical features and outcomes of stroke patients with and without COVID-19. METHODS: The COVID-19 Stroke Study Group (CSSG) is a multicentric study in 18 sites across India to observe and compare the clinical characteristics of patients with stroke admitted during the current pandemic period and a similar epoch in 2019. The present study reports patients of stroke with and without COVID-19 (CoVS and non-CoVS, respectively) seen between February 2020 and July 2020. Demographic, clinical, treatment, and outcome details of patients were collected. RESULTS: The mean age and gender were comparable between the two groups. CoVS patients had higher stroke severity and extent of cerebral involvement on imaging. In-hospital complications and death were higher among CoVS patients (53.06% vs. 17.51%; P < 0.001) and (42.31% vs. 7.6%; P < 0.001), respectively. At 3 months, higher mortality was observed among CoVS patients (67.65% vs. 13.43%; P < 0.001) and good outcome (modified Rankin score [mRS]: 0-2) was seen more often in non-CoVS patients (68.86% vs. 33.33%; P < 0.001). The presence of COVID-19 and baseline stroke severity were independent predictors of mortality. CONCLUSIONS: CoVS is associated with higher severity, poor outcome, and increased mortality. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and baseline stroke severity are independent predictors of mortality.

A prospective study on the effects of Ayurvedic massage in post-stroke patients.

BACKGROUND: Few stroke patients have reported improvements after Ayurvedic massage. Unfortunately, there is a dearth of indexed literature to support the use of this in rehabilitation. OBJECTIVES: To objectively measure the differences between patients with stroke who received Ayurvedic massage in addition to standard Physiotherapy (PT) versus those who received only standard PT. MATERIALS AND METHODS: The study was a prospective case control study, retrospectively analysed. The setting was a tertiary level hospital with neuro-rehabilitation unit. Fifty-two patients undergoing acute inpatient rehabilitation were prospectively followed post stroke. They were self-selected one month from the event for Ayurvedic massage with regular PT or PT alone. Twenty five received Ayurvedic massage with PT and twenty seven received only PT. All participants completed treatment. Information related to age, gender, National Institute of Health Stroke Scale result, number of co-morbidities, and whether cases were deemed simple or complex were taken at baseline. All patients received 6 hours of physical therapy averaged over a week. Massage was delivered daily for a total of 10 sessions followed by steam application. RESULTS: Patients were categorized as simple or complicated stroke based on events prior to rehabilitation. Both simple and complicated patients who received Ayurvedic massage had lower MAS and need for antispastic drugs, achieved standing with minimal assistance sooner, and had better locomotion at discharge. All these differences were significant. CONCLUSION: Utilizing Ayurvedic massage in post stroke patients with flaccidity can promote faster standing with minimal assistance and lead to less need for antispastic drugs at discharge.

Expanding spectrum of contactin-associated protein 2 (CASPR2) autoimmunity-syndrome of parkinsonism and ataxia.

Contactin-associated protein 2 (CASPR2) antibodies are originally associated with Morvan's syndrome and peripheral nerve hyper excitability. Our objective was to study retrospectively the clinical spectrum of CASPR2 antibody-positive patients in our hospital. This is a retrospective observational study. Patients treated at the Amrita Institute of Medical Sciences from May 2013 to April 2016, who were tested positive for CASPR2 antibodies, were included. A total of 1584 samples were tested in the neuroimmunology laboratory during the study period for voltage-gated potassium channel (VGKC) complex antibodies-leucine-rich glioma-inactivated protein 1 (LGI1) and CASPR2 antibodies. Thirty-four were positive for LGI1, 13 were positive for CASPR2, and 7 were for both (total 54-3.4% positivity). Of these 54 cases, 11 were treated in our hospital. Seven were positive for LGI1, three for CASPR2, and one for both. The patient who had both CASPR2 and LGI1 antibody positive had Morvan's syndrome. One patient with CASPR2 had neuromyotonia. The other patient was admitted with status epilepticus with a syndrome of parkinsonism and ataxia. The third patient had encephalopathy and myoclonus with a syndrome of parkinsonism and ataxia. Two of them underwent siddha treatment for other ailments prior to the onset of the disease for other ailments. Our short series shows the expanding spectrum of CASPR2 autoimmunity. Syndrome of parkinsonism and ataxia is an important manifestation of CASPR2 autoimmunity where we can offer a definitive treatment.

"Missing clot" during mechanical thrombectomy in acute stroke using Solitaire stent retrieval system.

Stent retrieval system is an established treatment modality in acute ischemic stroke with large vessel occlusion. Here, we describe a complication which occurred during mechanical thrombectomy in three cases where the clot dislodged during retrieval. There was a possibility of the clot getting reinjected into the artery with possible dire consequences.