Clinical and radiological profile of neuromyelitis optica spectrum disorders in a Pakistani cohort.

BACKGROUND: The clinical and radiological characteristics of neuromyelitis optica spectrum disorder (NMOSD) from Pakistan is unknown. Our study aimed to describe the clinical and radiological features of NMOSD patients presenting to a Pakistani tertiary care center. MATERIALS AND METHODS: This retrospective, observational study was conducted at the Neurology Department, Pakistan Institute of Medical Sciences between January 2017 and September 2021 (56 months). The study included patients diagnosed with neuromyelitis optica spectrum disorder (NMOSD) according to the 2015 International Panel for NMO Diagnosis (IPND) criteria, with the exclusion of patients under 12 years of age and those who tested positive for Myelin oligodendrocyte glycoprotein (MOG) IgG antibody. The patients were divided into two groups based on clinical presentation and the presence of NMO-IgG antibodies: NMO-IgG positive NMO (Seropositive NMO) and NMO-IgG negative (Seronegative NMO). The clinical features of NMOSD were recorded, and data was analyzed using SPSS version 26.0. RESULTS: Among 204 patients with suspected demyelination, multiple sclerosis was diagnosed in 100 individuals (49.02%), while acute disseminated encephalomyelitis (ADEM), clinically isolated syndrome (CIS), and neuromyelitis optica (NMO) were found in 5 patients each (2.45%, 2.45%, and 17.65%, respectively). Out of 36 patients with NMO, 32 (88.89%) tested positive for NMO-Ab, while the remaining 4 (11.11%) were seronegative for both NMO and anti-MOG Abs. The mean age of NMO-positive patients who tested positive for NMO antibodies was 31.03±10.12 years, compared to 27.95±2.5 years for NMO-negative patients, though this difference was not statistically significant (p>0.05). Females were more commonly affected by NMO, accounting for 72.2% of the NMO-positive group, and there was a significant difference in clinical phenotypes between the two groups (p<0.05). The NMO-positive group predominantly had relapsing NMO presentation (75%), and 72.8% of these patients showed longitudinally extensive transverse myelitis on the MRI spine. Azathioprine was the most frequently administered treatment for positive NMO patients (69.44%), followed by rituximab and MMF. The follow-up period for the study participants lasted 24 months. CONCLUSION: This is the first study on NMOSD cases in Pakistan. According to the present study, NMOSD is most prevalent among women in their forties. Relapsing NMO was the most common form of presentation. 89% of patients had antibodies against AQP4. 72.8% of patients suffered from LETM during the course of their disease. There are some features of our NMOSD cases that appear comparable with those around the world, despite some limitations in testing and access to care. It is clear that the clinical and radiological spectrums of patients with NMO and NMOSD in this cohort are similar. It is reasonable to suspect NMO if demyelinating episodes are not characteristic of MS.

Injudicious use of cranio-spinal imaging in Guillain-Barré syndrome in a low resource country.

Background: Many patients being investigated for Guillain-Barré syndrome (GBS) undergo unnecessary neuroimaging. The objective of this study was to determine the proportion of patients with GBS undergoing neuroimaging investigation, and to investigate any association with different GBS variants using the Brighton criteria. Methods: This cross-sectional observational study was conducted in the leading tertiary care hospital in Pakistan; 148 patients being investigated for, and subsequently diagnosed with GBS between January 2017 and March 2020 were enrolled. Participants were asked if they had undergone neuroimaging of the craniospinal axis before or during hospital admission, and the purpose of any computed tomography (CT) scan was investigated. We enquired whether fundoscopy had been performed before lumbar puncture (LP) and determined the level of certainty based on the Brighton criteria. Results: The majority of participants were men (n = 107, 73%), with a mean age of 42.85 ± 18.40 years. The mean waiting time to their first interaction with a neurologist was 5.20 ± 4.01 days, and the demyelinating variant of GBS was more common than the axonal variant (1.6:1). Most patients were diagnosed with level I certainty using the Brighton criteria (n = 113, 76%). Brain and spine magnetic resonance imaging (MRI) were performed ahead of admission in 48 (32%) and 59 (39%) patients, respectively. Brain CT scan was performed in 121 (82%) patients before LP, while 27 (18%) only underwent fundoscopic examination before LP. Conclusion: Clinical examination is fundamental in the diagnosis of GBS. Neuroimaging may be inappropriate and unnecessary, and may detract attention from crucial peripheral neuropathy measures while misusing limited resources.

Efficacy and Safety of Brivaracetam in Persons With Epilepsy in a Real-World Setting: A Prospective, Non-Interventional Study.

BACKGROUND AND AIM: Epilepsy stands out as one of the most prevalent neurological conditions. Brivaracetam (BRV) is a noteworthy antiseizure medication (ASM) distinguished by its pronounced and selective interaction with the synaptic vesicle protein 2A (SV2A) within the brain. Prior investigations, including regulatory trials, post-marketing assessments, and comparative meta-analyses, have consistently underscored BRV's equivalency in efficacy and superior tolerability when pitted against other antiseizure drugs. This study aimed to evaluate the effectiveness, safety, and acceptability of BRV in treating epileptic patients in the Pakistani population. METHODS: This prospective observational study, conducted in Pakistan from February to December 2022, employed a non-probability consecutive sampling technique. This study included 368 adult patients diagnosed with epilepsy, with a focus on those aged 18 and above experiencing focal seizures. Demographic data, clinical history, seizure types, and epilepsy profiles were recorded. Patients were administered BRV (Brivera; manufactured by Helix Pharma Pvt Ltd., Sindh, Pakistan) monotherapy therapy under physician guidance and followed up for three months. The study assessed changes in seizure frequency, side effects, and drug resistance at baseline, 14th day, and 90th day. Safety aspects were monitored, including documenting any adverse effects associated with BRV therapy. RESULTS: A total of 368 epileptic patients were included in this study, of which 287 (61.3%) were males and 181 (38.7%) were females. The mean age was 32.91±17.11 years. The mean number of seizures at the baseline visit was 5.74±6.21, at 14 days was 2.89±3.84 and at 90 days was 1.73±5.01 (p<0.001). Overall, a more than 50% reduction in seizure episodes was achieved in 178 (56.3%) patients at day 90, and less than 50% reduction in seizure episodes was achieved by 95 (26.8%) patients on Day 14, with a highly significant association between them (p<0.001). Among 316 patients, only 41 (4.4%) of all BRV-treated patients experienced adverse events; Of these 41 patients, 17 (41.7%) reported dizziness and 14(34.2%) reported behavioral issues. CONCLUSIONS: Epileptic patients receiving BRV demonstrated a substantial reduction of greater than 50% seizure episodes at the end of follow-up visits. Moreover, BRV exhibited fewer adverse effects in individuals with epilepsy.

A Case of Neuromyelitis Optica with Systemic Lupus Erythematosus.

Neuromyelitis Optica (NMO) is a rare idiopathic autoimmune demyelinating disease of the central nervous system (CNS) having a relapsing course. It consists of optic neuritis, longitudinally extensive transverse myelitis (LETM) which involves 3 or more neighbouring portions of the spine and positive serology for anti-NMO IgG antibodies. NMO is often misdiagnosed as multiple sclerosis (MS). Limited literature about NMO and its association with other systemic autoimmune diseases, such as systemic lupus erythematosus (SLE) is available so far. Here, we present a 21-year girl, previously diagnosed case of SLE seven years back, who suffered attacks of transverse myelitis. She had seropositivity for anti-aquaporin-4 (anti-AQP4) receptor antibody. An accurate clinical diagnosis is important to initiate timely immunosuppressive therapy to prevent disability. Key Words: Neuromyelitis Optica, Transverse myelitis, Systemic lupus erythematosus.

A Novel Missense Mutation in ERCC8 Co-Segregates with Cerebellar Ataxia in a Consanguineous Pakistani Family.

Autosomal-recessive cerebellar ataxias (ARCAs) are heterogeneous rare disorders mainly affecting the cerebellum and manifest as movement disorders in children and young adults. To date, ARCA causing mutations have been identified in nearly 100 genes; however, they account for less than 50% of all cases. We studied a multiplex, consanguineous Pakistani family presenting with a slowly progressive gait ataxia, body imbalance, and dysarthria. Cerebellar atrophy was identified by magnetic resonance imaging of brain. Using whole exome sequencing, a novel homozygous missense mutation ERCC8:c.176T>C (p.M59T) was identified that co-segregated with the disease. Previous studies have identified homozygous mutations in ERCC8 as causal for Cockayne Syndrome type A (CSA), a UV light-sensitive syndrome, and several ARCAs. ERCC8 plays critical roles in the nucleotide excision repair complex. The p.M59T, a substitution mutation, is located in a highly conserved WD1 beta-transducin repeat motif. In silico modeling showed that the structure of this protein is significantly affected by the p.M59T mutation, likely impairing complex formation and protein-protein interactions. In cultured cells, the p.M59T mutation significantly lowered protein stability compared to wildtype ERCC8 protein. These findings expand the role of ERCC8 mutations in ARCAs and indicate that ERCC8-related mutations should be considered in the differential diagnosis of ARCAs.

Assessment Of Carpal Tunnel Syndrome With Ultrasonography.

BACKGROUND: Carpal tunnel syndrome (CTS) is the most common nerve entrapment neuropathy caused by compression of median nerve at wrist as it passes through Osseo fibrous canal known as carpal tunnel. Epidemiological statistics shows one in every ten people develops the disease at any stage of life. CTS mostly affect females than males with mean age of 50. Clinical features are considered to be enough for establishing the diagnosis of carpal tunnel syndrome. However, nerve conduction studies give quantitative information regarding median nerve function therefore good at predicting outcome of intervention. Ultrasound being easily available, cost effective and real time is a promising modality for diagnosis and grading carpal tunnel syndrome. METHODS: This correlational study was conducted in collaboration of Neurology and Radiology Department of Pakistan Institute of Medical Sciences, Islamabad from January 2018 to January 2019. Total 50 patients with 85 wrists involved were included in the study. All patients with positive nerve conduction study were included. Patient with history of wrist trauma were not included. Detailed history and clinical features were recorded. All patients with positive result on nerve conduction studies underwent ultrasound examinations. Fifty control wrists were also included to establish the normal median nerve cross sectional area value in our study population. Results were recorded. Data was analyzed and appropriate statistical tests were applied by using SPSS v20. RESULTS: Mean cross sectional area of median nerve for controls was 6.34±1.23. Mean cross sectional area of median nerve for mild CTS was 8.05±1.72, moderate CTS was 11.15±2.32, severe was 17.49±4.93. Strong correlation was found between (r=0.76, p-value <0.0001) between increased cross-sectional area on Ultrasonography and severity of CTS on NCS. Other finding on Ultrasonography included flattening in 4 and fluid in 10 affected wrists. CONCLUSIONS: Increased cross-sectional area on Ultrasonography and severity of carpal tunnel syndrome on nerve conduction studies are very strongly correlated.

Orbital mucormycosis - Post SARS-CoV-2 sequelae.

Multisystem involvement has not been uncommon in SARS-CoV-2 infection. There has been reports of devastating neurological complication both during and after the infection. Here we present a rare case of sino-orbital mucormycosis, diagnosis of which was confirmed on histopathology. Our patient presented with headache, 18 days after her recovery from SARS-CoV-2 infection and was extensively worked up for the cause. Initially she was treated as a severe sinusitis but failure to response to antibiotics treatment warranted for further investigations and imaging. Our patient had to undergo right eye enucleation plus debridement under general anesthesia. She is currently on anti-fungal treatment as advised by infectious disease department.

Neurological complications of SARS-CoV-2: A single-center case series authors.

The neurological manifestations of SARS-CoV-2 are wide-ranging from simple headache to severe demyelinating brain disease. This is a review of collected case reports of patients with SARS-CoV-2 with neurological manifestations presenting to the Pakistan Institute of Medical Sciences (PIMS). Neurological manifestations associated with SARS-CoV-2 such as encephalitis, acute cerebrovascular disease, encephalitis with chorea, post-COVID myositis and Guillain-Barré Syndrome (GBS) are of great concern but are often overlooked in the presence of life-threatening abnormal vital signs in severely ill SARS-CoV-2 patients. There is a need to diagnose these manifestations at the earliest opportunity to limit long-term consequences and complications. Much research is needed to explore the role of SARS-CoV-2 in causing these neurological manifestations by isolating it either from the cerebrospinal fluid (CSF) or the brain tissue of the deceased on autopsy. We also recommend exploring the risk factors that lead to the development of these neurological manifestations.

Ocular surface: A route for SARS CoV-2 transmission- a case report.

SARS-CoV-2 infections are transmitted through droplets or through direct contact with secretions from an infected person. The transmission of the virus through tears and other body secretions remains controversial. PCR detection of Covid-19 in the samples/swabs taken from nasopharynx, CSF fluid, and tears, clarifies that the virus may be transmitted through the modes other than aerosol droplets or direct contact. In order to control and prevent this infectious disease, cutting-off the route of transmission will be one of the most important steps. SARS-CoV-2 RNA has been detected in tears and conjunctival samples of patients. The ocular tropism of Covid-19 is still uncertain but contentious.

Cerebral venous sinus thrombosis sequel of COVID encephalitis; a rare presentation.

The SARS Covid-19 pneumonia became a pandemic in 2019 affecting millions worldwide and carried a significant high mortality rate. The common presentation of this novel virus is upper and lower respiratory tract infection. However, its popularity as neuropathogen has increased dramatically. Patient presents a wide range of symptoms. We report a case of Covid-19 encephalitis which was incidentally found to have cerebral venous sinus thrombosis, presented with acute delirium and then developed new onset seizures.

SARS-CoV-2 infection with pneumonia and stroke.

BACKGROUND: Covid-19 pandemic has been manifested mainly as respiratory and constitutional symptoms. Though, it may demonstrate the involvement of other systems i.e. cardiovascular system (CVS), central nervous system (CNS) or gastrointestinal system (GI). DISCUSSION: Systemic manifestation of Covid-19 requires further research. Recent surveys revealed a few alarming facts about Covid-19, that, when it hits the brain, can cause some serious complications like; psychosis, stroke and dementia. CASE PRESENTATION: Here, the case is about two patients, having PCR confirmed Covid-19 and radiographic evidence of stroke, who eventually died during hospital stay. Data collection was done after informed consent and in retrospective manner.

SARS-CoV-2 infection with pneumonia and encephalitis.

The pandemic of severe acute respiratory virus (SARS-CoV-2) is characterized by respiratory symptoms with serious consequences, mainly associated with pneumonia and extreme ARDS. There is a lack of data about specific neurological manifestations of covid-19 infections literature. Epidemiological trials in fewer than 30% of a population reported symptoms of headache and delirium (Helms et al., 2020). Covid-19's neurotropism is still debatable, uncertain and in the present case study patient with Covid-19 is identified. He suffered with extreme respiratory complications during hospitalization and eventually died.

Putative second hit rare genetic variants in families with seemingly GBA-associated Parkinson's disease.

Rare variants in the beta-glucocerebrosidase gene (GBA1) are common genetic risk factors for alpha synucleinopathy, which often manifests clinically as GBA-associated Parkinson's disease (GBA-PD). Clinically, GBA-PD closely mimics idiopathic PD, but it may present at a younger age and often aggregates in families. Most carriers of GBA variants are, however, asymptomatic. Moreover, symptomatic PD patients without GBA variant have been reported in families with seemingly GBA-PD. These observations obscure the link between GBA variants and PD pathogenesis and point towards a role for unidentified additional genetic and/or environmental risk factors or second hits in GBA-PD. In this study, we explored whether rare genetic variants may be additional risk factors for PD in two families segregating the PD-associated GBA1 variants c.115+1G>A (ClinVar ID: 93445) and p.L444P (ClinVar ID: 4288). Our analysis identified rare genetic variants of the HSP70 co-chaperone DnaJ homolog subfamily B member 6 (DNAJB6) and lysosomal protein prosaposin (PSAP) as additional factors possibly influencing PD risk in the two families. In comparison to the wild-type proteins, variant DNAJB6 and PSAP proteins show altered functions in the context of cellular alpha-synuclein homeostasis when expressed in reporter cells. Furthermore, the segregation pattern of the rare variants in the genes encoding DNAJB6 and PSAP indicated a possible association with PD in the respective families. The occurrence of second hits or additional PD cosegregating rare variants has important implications for genetic counseling in PD families with GBA1 variant carriers and for the selection of PD patients for GBA targeted treatments.

Tocilizumab and Cytokine Release Syndrome in COVID-19 Pneumonia: Experience From a Single Center in Pakistan.

Background Tocilizumab (TCZ), an interleukin-6 (IL-6) receptor blocker, emerged as a treatment for cytokine release syndrome (CRS) in patients with severe COVID-19 pneumonia. The main objective of the study is to discuss the treatment response of TCZ in severe and critically ill patients with COVID-19 pneumonia. Patient demographics, laboratory parameters before and after TCZ therapy, and clinical outcomes in 20 patients in a single center were prospectively reviewed. Results Out of 120 patients, 96 (80%) were males and 24 (20%) were females. Only eight (10%) patients did not have any previously known comorbidity. There were 78 (65%) patients with severe disease, while 42 (35%) have critically severe disease. Of the 120 patients, only 36 required a second dose of TCZ in our study based on clinical background. Neutrophils and C-reactive protein (CRP) levels were observed to be raised in all patients, while lymphopenia was observed in 114/120, and D-dimer levels were elevated in 102 (85%) patients. After the second dose of tocilizumab, 102 (85%) patients reduced oxygen requirement within four days, and 14 patients were removed on the second dose of tocilizumab on clinical grounds. Of these 120 patients, in two weeks, 30 (25%) were discharged. Within three weeks, 60 of them were discharged, while 12 were discharged after three weeks, and 18 patients died in our study despite treatment. Conclusion TCZ appeared to be a good treatment option in patients with CRS and severe and critical pneumonia, and for patients with raised IL-6 levels despite single TCZ therapy, a repeat dose is recommended.

Segregation and potential functional impact of a rare stop-gain PABPC4L variant in familial atypical Parkinsonism.

Atypical parkinsonian disorders (APDs) comprise a group of neurodegenerative diseases with heterogeneous clinical and pathological features. Most APDs are sporadic, but rare familial forms have also been reported. Epidemiological and post-mortem studies associated APDs with oxidative stress and cellular protein aggregates. Identifying molecular mechanisms that translate stress into toxic protein aggregation and neurodegeneration in APDs is an active area of research. Recently, ribonucleic acid (RNA) stress granule (SG) pathways were discussed to be pathogenically relevant in several neurodegenerative disorders including APDs. Using whole genome sequencing, mRNA expression analysis, transfection assays and cell imaging, we investigated the genetic and molecular basis of a familial neurodegenerative atypical parkinsonian disorder. We investigated a family with six living members in two generations exhibiting clinical symptoms consistent with atypical parkinsonism. Two affected family members suffered from parkinsonism that was associated with ataxia. Magnetic resonance imaging (MRI) of these patients showed brainstem and cerebellar atrophy. Whole genome sequencing identified a heterozygous stop-gain variant (c.C811T; p.R271X) in the Poly(A) binding protein, cytoplasmic 4-like (PABPC4L) gene, which co-segregated with the disease in the family. In situ hybridization showed that the murine pabpc4l is expressed in several brain regions and in particular in the cerebellum and brainstem. To determine the functional impact of the stop-gain variant in the PABPC4L gene, we investigated the subcellular localization of PABPC4L in heterologous cells. Wild-type PABPC4L protein localized predominantly to the cell nucleus, in contrast to the truncated protein encoded by the stop-gain variant p.R271X, which was found homogeneously throughout the cell. Interestingly, the wild-type, but not the truncated protein localized to RasGAP SH3 domain Binding Protein (G3BP)-labeled cytoplasmic granules in response to oxidative stress induction. This suggests that the PABPC4L variant alters intracellular distribution and possibly the stress granule associated function of the protein, which may underlie APD in this family. In conclusion, we present genetic and molecular evidence supporting the role of a stop-gain PABPC4L variant in a rare familial APD. Our data shows that the variant results in cellular mislocalization and inability of the protein to associate with stress granules.

Effect of botulinum toxin A & task-specific training on upper limb function in post-stroke focal dystonia.

OBJECTIVE: To determine the effect of botulinum toxin A and task-specific training on upper limb function in post-stroke focal dystonia patients. METHODS: A randomised control trial was conducted at hospitals in Rawalpindi and Islamabad, Pakistan, from October 2015 to September 2016. The subjects were recruited using non-probability purposive sampling and were divided equally into control and experimental groups by sealed envelope method. The experimental group received botulinum toxin A followed by task-specific training, while the control group received only task-specific training for 8 weeks. Data was collected at baseline, after 4 weeks and 8 weeks by using upper extremity items of Motor Assessment Scale and Fugl-Meyer Assessment scale of upper limb. RESULTS: There were 43 subjects divided into two equal groups of 23(50%) each. In the experimental group, mean age of patients was 43.57±10.94 years while in the control group it was 48.75±10.75 years (p=0.135). There were 15(71.4%) male and 6(28.6%) female patients in the experimental group and 9(45%) were male and 11(55%) were female in the control group. Both groups showed significant improvements on the Motor Assessment Scale and Fugl-Meyer Assessment scale (p<0.01), but no significant differences were observed between the groups at baseline, after 4 and 8 weeks of intervention (p>0.05). CONCLUSIONS: Eight weeks of task-specific training improved upper limb function in post-stroke focal dystonia patients.

Absence of SNCA polymorphisms in Pakistani Parkinsons disease patients.

OBJECTIVE: To elucidate the genetic risk and role of alpha-synuclein gene in the pathogenesis of Parkinson's disease in Pakistani population. METHODS: This case-control study was conducted at Institute of Biomedical and Genetic Engineering (IBGE), Islamabad from May 2013 to May 2016, and comprised patients with Parkinson's disease and their ethnically-matched healthy controls. Allele-specific polymerase chain reaction was used for screening of three pathogenic single nucleotide polymorphisms in alpha-synuclein gene. Moreover, 20% samples were randomly selected for bidirectional Sanger sequencing to confirm the results. SPSS 13 was used for data analysis. RESULTS: Of the 374 participants, 174(46.5%) were patients and 200(53.5%) were controls. The mean age for the onset of the disease was 55±13 years. No polymorphism was observed for rs104893875(G>A), rs104893877(G>A) and rs104893878(C>G) in alpha-synuclein gene in samples of patients and controls. CONCLUSIONS: Alpha-synuclein gene mutations might not be relevant to all the populations in causing Parkinson's disease.

Review of acute ischaemic stroke in Pakistan: progress in management and future perspectives.

Ischaemic stroke is a major cause of neurological morbidity and mortality. The objective of this review article is to summarise facts pertaining to acute ischaemic stroke and its various aspects in a developing country like Pakistan, where resources are limited and the healthcare system is underdeveloped. No large-scale epidemiological studies are available to determine the true incidence of stroke in Pakistan. We reviewed the available literature on stroke from Pakistan and through this article we primarily aim to present the current acute ischaemic stroke management in Pakistan in juxtaposition to that of the developed world. We also intend to highlight areas for future development and improvement in management. The routine practice in Pakistan is that of using stat dose of aspirin in emergency (ER) at large with only a handful of centres offering thrombolytic therapy with recombinant tissue plasminogen activator for acute ischaemic stroke. This too is faced with the problem of long window periods before the patient reaches a proper stroke care centre. The facilities of interventional therapies like arterial thrombolysis and endovascular surgery are non-existent and rehabilitation facilities limited. The opportunities for training physicians in acute stroke are also scarce. Stroke in children is underdiagnosed and that in women not availing facilities at stroke care centres. While basic research has gained pace regarding local demographic data, advanced research and genetic studies are extremely limited. The field of stroke neurology needs to grow at a substantial pace in Pakistan to be at par with the developed world.