Co-Occurrence of Recurrent Migrainous Headaches and Transient Global Amnesia Following Minor Head Trauma: A Case Report

A 32-year-old male, with a history of recurrent throbbing headaches, presented with three episodes of minor trauma to the head followed by throbbing headaches and blurred vision. In two of these episodes, he also had clinical features suggesting the occurrence of transient global amnesia (TGA) at the same time. Although migraines as well as TGAs are reported to occur following minor head trauma, the simultaneous occurrence of both is rather unusual and would support the fact that spreading depression is the main pathophysiological mechanism underlying TGAs as it is for migraines. We report an unusual case of migraine and TGA occurring simultaneously in a footballer after minor head traum

Clinical Presentation, Evaluation, And Management of Patients with Myasthenia Gravis at A Tertiary Care Center in Pakistan

Background and objectives: Little is known about the clinical profile and outcome of myasthenia gravis in Pakistan. The objective of this study is to review the clinical characteristics of patients with myasthenia gravis in Pakistan, and the outcome of investigations and treatment. Methods: The study comprised a retrospective review of charts of patients diagnosed with myasthenia gravis at Aga Khan University Hospital in Karachi, Pakistan, over a period of 16 years from 1987 to 2003. The following features were reviewed: (i) clinical presentation, (ii) investigations especially nerve conduction studies, acetylcholine receptor antibodies, and imaging studies of the thorax, (iii) treatments administered (including thymectomy). Data analysis was done using Excel sheets. Results:Of the 83 patients, 51(61.4%) were males, whereas 32 (38.6%) were females. The age range was from 12 to 81 years, mean age of 43.7 years (SD± 18.2). In the 60 years plus group, there were three times as many males as compared to females. Limb weakness was noted in 58 (69.9%), ocular symptoms in 57(68.7%), and oropharyngeal symptoms in 54(65.1%) patients. Three (3.6%) presented in a state of myasthenic crisis. Tensilon test was performed in 34 patients and was positive in 31(91.2%), repetitive nerve conduction studies (RNS) were performed in 37 patients and was positive in 26(70.3%), acetylcholine receptor antibodies were done in 60 patients, and were positive in 55(91.7%). Thymic enlargement was seen in 28 out of 43 patients who underwent CT-Scan/MRI studies of the thorax. Besides pyridostigmine, most patients received immunosuppressive therapy with either steroids or azathioprine or both. The thymectomy was performed in 44 patients. Conclusion:The general disease pattern of MG, as noted in our series, appears to follow a similar pattern as noted worldwide. However, this retrospective and hospital-based study has its limitations, and more prospective and epidemiological studies are needed

eP271 - Disease-causing variants in hereditary neuromuscular disorder genes in an ethnically diverse Pakistani population - Experience from an Academic Medical Centre

Introduction: Neuromuscular disorders (NMD) are a broad group of clinically heterogeneous disorders, largely classified as neuropathies, myopathies, muscular dystrophies and myasthenic syndromes. These sub-classes are further divided into several subtypes, depending on the involved causative gene and affected proteins encoded by these genes. This heterogeneous group of disorders may be inherited in autosomal recessive, autosomal dominant and X-linked fashion, with over 500 implicated genes. (Ankala et al., 2014; Chae et al., 2015) The most commonly seen disorders in the pediatric age group are Spinal Muscular Atrophy and Dystronipathies, testing for which is locally available. Other disorders, which require more specialized diagnostic testing such as Next Generation Sequencing (NGS) are harder to diagnose.Objective: To study the clinical and genetic profiles of patients presenting for evaluation of a hereditary neuromuscular disorder, excluding SMA and Dystrophinopathies.Methods: This is a retrospective chart review of patients seen in the Neurology Clinic and referred to the Genetics Clinic with a suspected hereditary neuromuscular disorder, between 2015 and 2020 at the Aga Khan University Hospital, Karachi. The genetic testing for these patients included NGS based single gene sequencing as part of a research collaboration, NGS based multi-gene panel and whole exome sequencing at multiple CAP and CLIA accredited commercial genetics laboratories.Result and Discussion: A total of 75 pediatric and adult patients evaluated in our Neurology and Genetics Clinic went ahead with genetic testing. 39 tested positive showing Pathogenic or Likely Pathogenic variant[s] in genes associated with NMDs, matching both the clinical phenotype and the inheritance pattern. 29 patients had one or multiple variants of uncertain significance (VUS) and seven had a negative test result. From the 29 results harboring VUSs, 23 results remained truly inconclusive. However, we believe that six of the VUSs are actually disease causing, showing variant segregation with disease phenotype in the family, and following the disease inheritance pattern. Based on this, we showed how the diagnostic yield improved, from a 52% positive results to 60% positive results, based on the clinical interpretation of results, with the help of deep phenotyping and familial segregation studies. The result distribution and yield are summarized in Table 1. The results showed a spectrum of 26 different genes with distinct phenotypes of NMDs in 45 patients. The result distribution across the genotype is summarized in Figure 1. The three commonly seen phenotypes were, Limb Girdle Muscular Dystrophy (LMGD) characterized in 12 patients, followed by Collagenopathies characterized in seven patients and GNE-associated Myopathy in six patients. Delving into the positive result findings genotypes, the most common genes include, GNE (13%), DYSF (11%), COL6A2 (9%), FKTN (9%) and SGCB (7%), accounting for 49% (n = 22) positive results. In all four unrelated Fukuyama muscular dystrophy patients, FKTN variant: NM_001079802, Exon 9 c.920G\u3eA, p.Arg307Gln was found in a homozygous state. We also observed, that out of the six unrelated GNE associated myopathy patients, only GNE variant: NM_001128227.2, Exon 12 c.2179G\u3eA, p.Val727Met, was present in four patients, one harbored a homozygous variant and three harbored heterozygous variant, present alongside another diseasecause variant in GNE, in compound heterozygous state. These two variants may represent possible founder mutations in the Pakistani population.Conclusion: This data from a clinical setting in an ethnically diverse Pakistani patient population shows the genetic heterogeneity and the spectrum of associated phenotypes found in NMDs. 80% of the positive patients (36/45) of the patients had a diagnosis of an autosomal recessive NMD. It was also observed that 21% of the reported VUSs identified were likely to be disease-causing based on clinical interpretation, warranting the need for larger NMD focused studies in our population. Variants unique to our population need to be validated by further functional studies, to clarify which ones are indeed pathogenic. As our understanding of the underlying genetic etiology of NMD improves, precision medicine initiatives for treating NMDs will accelerate

eP069: Possible founder variant and spectrum of phenotypic manifestation of Fukuyama muscular dystrophy reported in four unrelated Pakistani families

Background: Monogenic Neuromuscular disorders (NMDs) are clinically and genetically heterogeneous group of disorders with about 500 associated genes. NMDs may be inherited in autosomal recessive, autosomal dominant and X-linked fashion. In the context of highly consanguineous Pakistani population, we expect the autosomal recessive NMDs to have a higher prevalence, compared to that seen in the populations with European ancestry. However, we do not have contextual ethno-specific genomics data for NMDs in Pakistani population. Next Generation Sequencing (NGS) has revolutionized the diagnostic practice for NMDs, having the ability to simultaneously capture and sequence multiple genes with disease-specific gene panels, sequence the coding portion of the human genome with whole exome sequencing (WES) or the entire genome with whole genome sequencing (WGS). With this becoming a clinical practice to integrate genomic testing in offering diagnosis; the challenge of diagnostic odyssey is diminishing. From the broad spectrum of hereditary NMDs, dystroglycanopathies are heterogenous group of disorders that typically manifest as limb-girdle muscular weakness. About 18 genes are now known to be associated with dystroglycanopathies, these genes encode proteins that function as a modulator for the binding of α-dystroglycan to the extracellular matrix ligands by glycosylation alternation. As a result of which, the structural integrity of the myocytes is disrupted, subsequently leading to muscle degeneration. FKTN is one of the genes associate with dystroglycanopathies, it encodes for a glycosyltransferase.Case presentation: We report four unrelated families of FKTN associated autosomal recessive Fukuyama Muscular Dystrophy (MIM:613152), from a diverse Pakistani patient population seen at a Tertiary Healthcare Centre, in Karachi Pakistan. All four patients harbored homozygous, well-established pathogenic missense variant, FKTN, NM_001079802.1:c.920G\u3eA (p.Arg307Gln), (gnomAD MAF 0.001204%, rs119463992). This variant has been previously reported in multiple Turkish families in homozygous state, and one multi-ethnic (half Jewish and half Indian) family with another variant found in compound heterozygous state. At large, about half of the cases of FKTN associated muscular dystrophy are reported with severe brain involvement; clinically manifesting as intellectual disability and seizure disorder. Consistent with the genotype-phenotype correlation, the protein-truncating variants result in a more severe phenotype than missense variants. In our reported cases, the variant has showed a spectrum of phenotype with variable symptom onset age (between age of 2-16 years); in patients belonging to different regions of the country. However, it is not reported to be associated with intellectual disability and seizure disorder. In the previously reported cases for this variant, cardiac involved has not been mentioned. Additionally, three out of four patients from our center, presented with dilated cardiomyopathy which progressive reduction in the left-ventricular ejection fraction (LV EF), while for the fourth patient an echocardiogram was not present. The clinical details from four, unrelated families are described in Table 1.Conclusion: We report four unrelated Pakistani families from ethnically diverse backgrounds, harboring similar pathogenic variant in FKTN, which is likely to be a founder variant, in South Asian and Middle Eastern ethnic groups. In these cases, the age of first symptom manifestation was variable, however all began with motor delays or difficulties. The dilated cardiomyopathy was a saliant feature, observed in three patients, that can lead to initiating cardiac screening in patients harboring this variant, at a younger age. Consistent with previous work, the symptom severity in the reported missense variant was mild, compared with protein-truncating variants, which is accompanied with severe brain involvement. As NMDs are further characterized in Pakistani populations, our knowledge of ethno-specific FTKN variants and their genotype-phenotype correlations will be better elucidated

Factors associated with home delivery in rural Sindh, Pakistan: Results from the global network birth registry

Background: According to global estimates for 2017, nearly 295,000 maternal deaths occurred worldwide. Thus, approximately 810 women die every day due to pregnancy-related complications. This burden of maternal deaths in LMICs is primarily due to poor healthcare service utilization, as indicated by relatively low rates of institutional deliveries and skilled-birth attendance (SBA). We conducted this study with an aim to assess the factors associated with home delivery and its subsequent effect on the pregnancy outcome in rural Sindh, Pakistan. Methods: Data for this study were taken from The Global Network\u27s Maternal Newborn Health Registry (MNHR), which is a prospective, population-based observational cohort study. Registry data for 2018-2019 for District Thatta, Pakistan was retrieved for the analysis. Multivariable logistic regression models were used to determine the effect of each independent variable on the place of delivery by including all predictors and covariates. Results of the regression analyses are presented with crude odds ratios (OR) and adjusted odds ratios (aOR) with 95% confidence intervals (CIs). Results: A total of 4649 women were included in the study, of these, 1286 (27.7%) women had delivered at home. Of those who delivered at home, a larger proportion was illiterate (90%), had a BMI of less than 18.5 kg/m2 (26.0%), had parity of 3 or more (48.1%), and had a history of pregnancy loss as compared to women who had institutional delivery. In addition, two-thirds of women (63.4%) who had delivered at home had less than 4 ANC visits, whereas 15.6% did not receive any ANC. On multivariable logistic regression we found that home delivery was significantly associated with being illiterate (aOR = 1.60; [95% CI: 1.34, 2.04]), having high parity (aOR = 1.91; [95% CI: 1.58, 2.32]), and no ANC visit (aOR = 14.8; [95% CI: 10.2, 21.5]). Conclusions: More than a quarter of our study sample women delivered at home. These women were illiterate, multiparous, and did not receive antenatal care during pregnancy. It is essential to conduct extensive educational interventions for the women and their family members regarding the potential benefits of delivering in a safe and skilled environment. Moreover, the provision of comprehensive and quality antenatal care should be ensured as it improves the mothers\u27 health-seeking behavior and helps them make informed decisions about their health and well-being

Spectrum of EEG abnormalities in COVID-19 patients

Purpose: Neurologic involvement is commonly reported in coronavirus disease (COVID-19) patients. The published literature regarding the COVID-19-related neurophysiological findings, including the EEG findings, is still quite limited. The objective of this study was to evaluate the EEG findings in patients with a COVID-19 infection and look for a possible correlations and prognosis.Methods: This is an inpatient hospital-based retrospective observational study. All admitted COVID-19 patients undergoing an EEG study between January 1, 2020 and June 30, 2021 were included in this study. EEG was ordered by the primary intensive care physician or a neurologist taking part in the clinical care of patients.Results: Sixty-six EEG studies in 57 patients were included. Mean age was 62.2 ± 16.3 years with male predominance (65%). Encephalopathy (70%) was the most common indication for an EEG. Background EEG abnormalities were seen in most of the patients (92.4%) with severe abnormalities correlating with the prognosis of the patient. Epileptiform discharges were only seen in 7.5% of the EEGs, with majority of the discharges arising from the frontal region. Mortality reported was high (47%).Conclusions: Nonspecific diffuse background EEG abnormalities are commonly seen in COVID-19 patients. Epileptiform discharges are less common but mostly originate from frontal region. Most of these patients also had an abnormal neuroimaging. The significance of this peculiar finding needs further research.Significance: Nonspecific background EEG changes are common in COVID-19 patients. Among epileptiform discharges, focal epileptiform discharges arising from the frontal region were common, usually associated with an abnormal neuroimaging