A recurrent rare intronic variant in CAPN3 alters mRNA splicing and causes autosomal recessive limb-girdle muscular dystrophy-1 in three Pakistani pedigrees.

Autosomal recessive limb-girdle muscular dystrophy-1 (LGMDR1) is an autosomal recessive disorder characterized by progressive weakness of the proximal limb and girdle muscles. Biallelic mutations in CAPN3 are reported frequently to cause LGMDR1. Here, we describe 11 individuals from three unrelated consanguineous families that present with typical features of LGMDR1 that include proximal muscle wasting, weakness of the upper and lower limbs, and elevated serum creatine kinase. Whole-exome sequencing identified a rare homozygous CAPN3 variant near the exon 2 splice donor site that segregates with disease in all three families. mRNA splicing studies showed partial retention of intronic sequence and subsequent introduction of a premature stop codon (NM_000070.3: c.379 + 3A>G; p.Asp128Glyfs*15). Furthermore, we observe reduced CAPN3 expression in primary dermal fibroblasts derived from an affected individual, suggesting instability and/or nonsense-mediated decay of mutation-bearing mRNA. Genome-wide homozygosity mapping and single-nucleotide polymorphism analysis identified a shared haplotype and supports a possible founder effect for the CAPN3 variant. Together, our data extend the mutational spectrum of LGMDR1 and have implications for improved diagnostics for individuals of Pakistani origin.

Poor sleep quality: A wake-up call for the elderly at a tertiary care centre in Islamabad, Pakistan.

OBJECTIVE: To assess the burden of sleep disorders in the elderly, and the effects of various co-morbidities linked with sleep disorders. METHODS: The longitudinal cross-sectional study was conducted in different outpatient departments at a tertiary care centre in Islamabad, Pakistan, from June 2014 to June 2015, and comprised patients of either gender aged 60 years or above. Pittsburgh sleep quality index and Epworth sleepiness scale were used to measure the quality and patterns of sleep and daytime sleepiness in the elderly. Data was analysed using SPSS 21. RESULTS: Of the 1000 subjects, 638(63.8%) were males, and 362(36.2%) were females. The overall mean age was 66.96±7.05 years. Epworth sleepiness scale >10 was found in 265(26.5%) subjects, while Pittsburgh sleep quality index score in 516(51.6%) was >5. Sleep quality score in 578(57.8%) women was statistically significant compared to 478(47.8%) males (p<0.05). CONCLUSIONS: There was a significant burden of sleep-related disorders in the subjects.

A rare case of Palizaeus Merzbacher Disease in a female patient diagnosed radiologically.

Pelizaeus Merzbacher's Disease is an inherited X-linked recessive trait. Males have the disease, while females are usually carriers. We report the case of a 6-years-old girl who had nystagmus since birth and later on developed head nodding. She started talking at one year and walking at 18 months. Then she developed regression of milestones, with speech impairment and inability to walk which progressively worsened. Before presenting she had a generalised seizure. Her parents were second cousins. Family history was unremarkable. On examination she was awake, alert, there was bilateral horizontal nystagmus. Cranial nerve examination was normal. There was spastic paraparesis with bilateral extensor plantar response. Magnetic resonance imaging of the brain showed classical features of diffuse hypomyelination characteristic of Pelizaeus Merzbacher's Disease for this age group.

Neurological disorders and disability in Pakistan: A cross-sectional multicenter study.

BACKGROUND/OBJECTIVE: The aim of this study is to identify frequencies of various neurological disorders (NDs) and associated disability in patients attending neurologic clinics in rural and urban centers in Pakistan. METHODS: This is an observational study conducted in 39 neurological centers in both rural and urban areas, public and private health sectors all over Pakistan. This study was conducted between august 2017 to December 2019. RESULTS: A total of 28,845 adults were enrolled. Mean age of the study participants was 46.2 ± 17.2 years, 15,252 (52.9%) were men and 13,593 (47.1%) were women. Most common comorbid medical condition was hypertension 7622(26.4%) followed by Diabetes 3409(11.8%). Among neurological diagnoses, vascular diseases (20%) were the most common followed by Headache disorders (18.6%), Epilepsy (12.5%), nerve and root diseases (12.4%), Psychiatric diseases (10%), Dementias (8%) and movement disorders (7.9%). Half of the patients 15,503(53.7%) had no neurological disability, while minor disability was present in 10,442(36.2%) of cases. Moderate to severe disability was present in 2876(10%) cases. Headache disorders, psychiatric diseases, muscle pain/muscle related disorders and demyelinating diseases were more common in women. Vascular diseases, movement disorders and Dementias were more common in 46 years and above age group whereas headache disorders, Epilepsy and Psychiatric disorders were more prevalent in <46 years age groups. CONCLUSION: Vascular diseases are the most common presentation of patients in neurology clinics followed by headache disorders and epilepsies. Minor disability was present in 36% while moderate to severe disability was present in 10% cases.

Electrophysiological Pattern and Predictors of Functional Outcome of Patients with Guillain Barre Syndrome at a Tertiary Care Hospital in Pakistan.

OBJECTIVE: To determine electrophysiological pattern and predictors of functional outcomes of patients with Gullain Barre Syndrome (GBS) at a tertiary care hospital. STUDY DESIGN: Observational study. PLACE AND DURATION OF STUDY: Shifa International Hospital, Islamabad, Pakistan from January 2016 to July 2020. METHODOLOGY: A total of 62 patients with GBS of all age groups, gender, locations and those with no other primary diagnosis such as poliomyelitis, botulism, hysterical paralysis, toxin neuropathy and diabetic neuropathy were included. Functional outcome using modified Rankin Scale (mRS) and HUGHES score were recorded at presentation, on discharge and 6-month follow-up. Results of this study were analyzed using SPSS version 20. RESULTS: There were 69% males with mean age of 31 ± 21years. The frequency of different GBS variants were 53% acute inflammatory demyelinating polyneuropathy (AIDP), 29% acute motor axonal neuropathy (AMAN), 11% acute motor and sensory axonal neuropathy (AMSAN) and pure sensory and atypical GBS were 2% each. The frequency of various antecedent events was recorded in 33 patients, including respiratory tract infection in 9 (14%) and diarrhea/vomiting in 13 (21%) patients. AIDP and AMSAN had a good prognosis where 31 (77%) patients out of the 40 fully recovered with HUGHES score 0-2 after 6 months. AMAN had poor prognosis as 2 (12%) patients died in the Hospital. Majority (n=32, 52%) of the patients were treated with plasmapheresis. CONCLUSION: In this study population, AIDP was the most common variant with good prognosis and AMAN variant had the worst prognosis. Key Words: Guillain Barre syndrome (GBS), Acute inflammatory demyelinating polyneuropathy (AIDP), Acute motor axonal neuropathy (AMAN), Peripheral neuropathy, Lower limb weakness, Acute motor and sensory axonal neuropathy (AMSAN), Sensory neuropathy, Autoimmune disease.

Stroke Outcome Prediction Using Admission Nihss In Anterior And Posterior Circulation Stroke.

BACKGROUND: Stroke is a worldwide disease with high morbidity. Various scales are used to measure the severity and outcome of stroke. National Institute of Health Stroke Scale (NIHSS) is a quantifiable scale used to assess stroke severity. However, it is biased towards anterior circulation stroke as compared to posterior circulation stroke, giving higher values in the former. Therefore, it is imperative to know the mean values of NIHSS in each group to predict the functional outcome. The main aim of the study is to compare the mean NIHSS at the time of admission for determining favourable and unfavourable functional outcome in anterior and posterior circulation ischemic stroke. METHODS: It is a descriptive case study of six months' duration done in a Tertiary Care Hospital. All patients of 18 years and above with ischemic stroke involving single arterial territory presented in hospital within 72 hours were included. With the help of the WHO sample size calculator, a target population of 100 patients was determined with a confidence level of 95%. For mean difference we applied independent t test and t score with mean differences for NIHSS at admission and location of stroke has been calculated. Patients with haemorrhagic stroke, venous stroke secondary to Dural Sinus thrombosis, with concomitant disability because of any reason including previous stroke, stroke involving watershed areas and concomitant Acute Coronary Syndrome were excluded. A favourable outcome was defined as Modified Ranking scale score of ≤3 at 1-month post stroke. RESULTS: In anterior circulation, mean baseline NIHSS was 11.3 [SD 7.4], while in posterior circulation, mean NIHSS was 7.30 [SD 7.6]. Comparing the means for functional outcome in anterior circulation using independent t test score, a lower baseline NIHSS score was independently predictive of a favourable outcome for patients with AC (OR 1.268, 95% CI 1.76 -1.358) and PC (OR 1.534, 95% CI 1.321-1.891) stroke. CONCLUSIONS: The mean NIHSS of good functional outcome group is much lower for posterior circulation stroke as compared to anterior circulation stroke which highlights the need for basing the decision of acute stroke emergency management on full neurological examination, rather than a single scale, especially if the posterior circulation stroke is in question.

Usefulness of neutrophil-to-lymphocyte ratio as a predictor of functional outcome in patients with acute ischemic stroke after thrombolysis therapy.

In stroke patients, a high neutrophil-to-lymphocyte ratio (NLR) has been associated with poor functional outcome at 3 months, higher mortality, and a higher hemorrhagic transformation. We assessed the role of NLR in patients with acute ischemic stroke who received thrombolysis. The charts of 98 patients treated between 2015 and 2019 were retrospectively reviewed. The mean NLR was compared using an independent Student's t test. At 3 months, a good functional outcome was seen in 31 patients (32%) and a poor functional outcome was seen in 67 patients (68%). Patients with NLR >2.39 had a poor functional outcome (odds ratio 2.7; 95% confidence interval 1.11-6.39; P < 0.02). Our study revealed that patients who present with acute ischemic stroke and have an increased NLR at the time of administration of thrombolysis have a poor functional outcome at 3 months.

Exome sequencing identifies novel and known mutations in families with intellectual disability.

BACKGROUND: Intellectual disability (ID) is a phenotypically and genetically heterogeneous disorder. METHODS: In this study, genome wide SNP microarray and whole exome sequencing are used for the variant identification in eight Pakistani families with ID. Beside ID, most of the affected individuals had speech delay, facial dysmorphism and impaired cognitive abilities. Repetitive behavior was observed in MRID143, while seizures were reported in affected individuals belonging to MRID137 and MRID175. RESULTS: In two families (MRID137b and MRID175), we identified variants in the genes CCS and ELFN1, which have not previously been reported to cause ID. In four families, variants were identified in ARX, C5orf42, GNE and METTL4. A copy number variation (CNV) was identified in IL1RAPL1 gene in MRID165. CONCLUSION: These findings expand the existing knowledge of variants and genes implicated in autosomal recessive and X linked ID.

Frequency of non convulsive status epilepticus in patients with impaired level of consciousness.

OBJECTIVE: To determine the frequency of Non Convulsive Status Epilepticus in patients admitted with impaired consciousness. METHODS: All EEG's in patients with impaired level of consciousness over four years from 2002- 2006 were reviewed. All EEG's showing continuous epileptiform discharges were included. Findings of all these EEG's were divided into five groups; generalized spikes and wave, generalized sharp and wave, focal spike and wave, focal sharp and wave and periodic lateralized epileptiform discharges. RESULTS: There were 785 EEG's recorded in patients with impaired level of consciousness. Only 12 (1.5%) patients were identified with NCSE on EEG. The commonest EEG findings in our patients with NCSE were: Continuous focal spike and wave seen in 4(33%), Continuous generalized spike and wave 3 (25%), Continuous generalized sharp and wave 3 (25%), Continuous focal sharp and wave 1 (8.3) and Continuous periodic lateralized epileptiform discharges (PLEDs) in 1 (8.3%) patient. CONCLUSION: NCSE is an important treatable entity which can be easily recognized by doing an EEG.

Obstructive Sleep Apnoea in Pakistan: A Single Tertiary Care Center Experience.

INTRODUCTION: Considerable interest has been shown in the field of sleep medicine in recent decades. Obstructive sleep apnoea (OSA) is a common condition that remains neglected in most parts of the world. Data are scarce, if any, when it comes to developing countries. We sought to describe the patient population in a single private tertiary care center from such a country. MATERIALS AND METHODS: A cross-sectional study that included a total of 203 patients over a five-year period was conducted. Polysomnographic studies were conducted in a dedicated sleep laboratory, under the supervision of sleep physicians. Data were described and analyzed based on clinical and self-reported outcomes, as well as polysomnographic characteristics, and compared them between genders and severity. RESULTS: With the participants having an average age of 50.84 years and a BMI of 34.7 kg/m2, the study found that the increase in age and BMI was significantly correlated with an increase in the severity of obstructive sleep apnea in the Pakistani population. There was a significant difference in sleep latency (20.6 min in women vs. 10.8 min in men; p-value = 0.001) and efficiency (63.7% in women vs. 69.8 in men; p-value = 0.02) between the two genders. Decreases in nadir saturation, total sleep time, and sleep latency were also associated with an increase in the level of severity. CONCLUSION: There is a dire need for Pakistani, and in extension Asian, medical professionals to ramp up their pace to meet the needs of their population with regard to sleep medicine.

Salvage decompressive craniectomy in malignant MCA infarcts--results of local experience at Shifa International Hospital, Islamabad, Pakistan.

Malignant infarctions of the middle cerebral artery (MCA) have high mortality. Recent studies showed decreased mortality with good functional outcome in young people with decompressive surgery. We report prospective, non-randomized case series of live patients in whom successful life saving decompressive craniectomy was performed. All five were males. Mean age was 59.2 +/- 13 years. Four had right MCA infarction while I had left MCA infarction. Ipsilateral temporoparietal craniectomy with duraplasty was performed in mean time of 76 +/- 27 hours after onset of symptoms. Four (80%) patients were discharged to home in awake, alert, conversant, hemiparetic state. One patient developed status epilepticus, and was transferred to another facility in intubated. sedated state. Three month follow-up on three patients showed moderate improvement in neurological status. Early craniectomy was life saving in all of our patients. Neurosurgical intervention should be considered early in large MCA infarcts, especially in young patients.

Factors delaying hospital arrival of patients with acute stroke.

INTRODUCTION: To determine the proportion of patients with acute stroke presenting late to hospital and to identify the factors that delay hospital arrival of patients with acute stroke. METHODS: A cross sectional study was carried out between Sept 2006 to Feb 2007 in the department of Neurology, Liaquat National Hospital Karachi. All patients of both genders, ago >18 years with symptoms of stroke and neuro- imaging (CT scan/MRI brain) findings consistent with stroke were included. RESULTS: Atotal of 165 patients attending the Emergency department were included. There were 86 (52%) males and 79 (47.9%) females. The mean age was 60.04+/-13.98 years, (males 58.2 years and females 61.9 years). The median delay from onset of symptoms to hospital arrival was six hours. Only 28.5% of the patients came within three hours while 71.5% after three hours. Attendants of 47 patients had a low throat perception, 53 (32%) of the patients did not know a single symptom of stroke and 63% (104) patients first contacted their General Practitioner who referred them to hospital. Similarly 60.6% of patients wore first taken to a local hospital not equipped to handle major emergencies. CONCLUSION: Time elapsed from onset of symptoms to hospital arrival is influenced by lack of knowledge of stroke symptoms, contact with a local doctor, low threat perception and non availability of ambulance services.

Association of Anemia with Stroke Severity in Acute Ischemic Stroke Patients.

OBJECTIVE: To investigate the association of anemia with stroke severity in acute ischemic stroke patients. MATERIAL & METHODS: We enrolled 96 patients (mean age: 60.25 ± 11.92 years old) who were admitted to the stroke unit of Shifa International Hospital between 1st March 2015 and 31st August 2015. Each patient presented within 72 hours of onset of symptoms, underwent computed tomography (CT) of the head and blood tests, including hemoglobin concentration, on the first day of hospitalization. Stroke severity was assessed on admission using the National Institute of Health Stroke Scale. Anemia was evaluated according to the World Health Organization (WHO) criteria (men, <13 g/dL; women, <12 g/dL). We examined the frequency of anemia in patients with different severities of acute ischemic stroke. RESULTS: World Health Organization defined anemia was positive in 38 (39.6%) and negative in 58 (60.4%) patients. Among the patients who were positive for anemia, seven (18.4%) had a minor stroke, 10 (26.3%) had a moderately severe stroke, and 21 (55.3%) had a severe stroke. There was a significant association between anemia and stroke severity (P-value 0.000). CONCLUSION: Our data indicated that anemia was a frequent finding in acute ischemic stroke patients, with increasing frequency corresponding to stroke severity.

Facebook as a Learning Tool: Perception of Stroke Unit Nurses in a Tertiary Care Hospital in Islamabad.

Objective To obtain the perception of nurses on the use of Facebook as a learning tool. Materials & methods We conducted a pilot observational study in which data were collected through a detailed course evaluation and feedback survey questionnaire. Twelve stroke care nurses were enrolled in a stroke course specifically designed to provide participants with information and knowledge about stroke unit nursing care. Firstly, a closed Facebook group consisting of the participants and facilitators was created. An activity in accordance with the course content was posted in the group daily. Before the start of the course, a pre-course test was conducted. The four-week course culminated in a graded written examination. Its results were compared with the pre-course test. A detailed feedback questionnaire was given to the participants at the end of the course, which was specifically designed to elicit perceptions of nurses about the use of Facebook as a learning tool. Results Of the 12 enrolled nurses, 10 completed the certification and the post-course feedback evaluation. Facebook was used by all participants as a platform to view and study the course contents. The timing of the course activities was rated "very good" by three and 'good' by six of 10 participants. However, one of the major issues faced by five participants was problematic internet access. The overall rating of the course was "very good" by five participants, "good" by three, and "satisfactory" by two of 10 participants. The post-course test showed that nine of 10 candidates passed with scores >70% compared to only two candidates getting scores >50% in the pre-course test. Conclusion Facebook use enabled participants to study the material when their schedule permitted them. The online teaching and facilitation were ideal for our full-time stroke unit nurses as reflected by their improved post-course test results.

Pattern of stroke in type 2 diabetic subjects versus non diabetic subjects.

BACKGROUND: Diabetes mellitus is a well-recognized risk factor for ischaemic stroke. Stroke in diabetic patients is different from stroke in non-diabetics from several perspectives. There is no local study on this topic. This is the first study from Pakistan, in which pattern of stroke in diabetics have been described and compared with non-diabetics. The object of this study was to compare pattern of stroke in diabetic subjects with non-diabetics. METHODS: This is a prospective comparative cross sectional study, carried out at Liaquat national hospital, Karachi, neurology department from October to March 2006. Fifty patients were enrolled in diabetic group and 50 in non-diabetic. Clinical features, risk factors and stroke patterns were identified. RESULTS: Mean age was 59.5 (+/- 11.82) in diabetics and 60.4 (+/- 14.8) in non diabetics. There was slight preponderance of male patients in non diabetic group. Out of 50 diabetic patients, 44 (88.0%) had ischaemic stroke and 6 (12.0%) had intracerebral haemorrhage. In non-diabetics, 29 (58.0%) had ischaemic stroke while 21 (42.0%) had intracerebral haemorrhage. On further analysis of ischaemic stroke, cortical infarcts (CI) was found in 22, sub cortical infarcts (SCI) in 14, brainstem in 5 and cerebellar in 2 diabetic patients. CI was also the commonest subtype of ischaemic stroke in nondiabetics. CONCLUSION: Patterns of stroke in diabetics are different from non-diabetics. Ischaemic stroke is more prevalent than hemorrhagic strokein diabetics. Sub cortical infarcts are more common in diabetics than non diabetics (p = 0.04).

Prevalence of Obesity in Carpal Tunnel Syndrome Patients: A Cross-Sectional Survey.

Carpal tunnel syndrome (CTS) is the most common compressive entrapment neuropathy caused by the compression of the median nerve at the wrist space known as the carpal tunnel. The epidemiologic factors related to CTS include genetic, medical, social, vocational, and demographic factors. The common symptoms experienced include pain, paresthesia, and numbness in the median nerve distribution. If left untreated, it can lead to irreversible median nerve damage, causing a loss of hand function. Body mass index (BMI) has been attributed as a risk factor for the development of CTS. We planned to determine the frequency of obesity among CTS patients in the neurophysiology department of a tertiary care center in Islamabad, Pakistan. The survey was designed as a cross-sectional descriptive study from March 2016 to August 2016 using a consecutive nonprobability sampling technique. A total of 112 patients with a mean age of 54 ± 5 years were included in the study. In the study population, 39 patients (35 percent) were males and 73 were females (65 percent). Based on BMI, 74 patients (66 percent) had a normal weight and 38 (34 percent) were obese. The frequency of obesity in our study was 34 percent, excluding the other comorbid conditions, which is quite high. Targeted therapy in those with CTS should also include weight reduction measures because obesity poses a cause-and-effect relationship for both the severity and the pathogenesis of CTS.

Functional Outcome After Decompressive Craniectomy in Patients with Dominant or Non-Dominant Malignant Middle Cerebral Infarcts.

BACKGROUND:  The use of decompressive craniectomy (DC) has been studied in the setting of different conditions, including traumatic brain injury, subarachnoid hemorrhage, and malignant middle cerebral artery (MCA) infarction. The rationale of this study is to determine the functional outcome after DC in patients with malignant MCA infarcts. METHODS:  A longitudinal cohort study was performed based on patients diagnosed with malignant MCA territory infarction admitted to the Neurosurgery Department of a tertiary care hospital in Islamabad, Pakistan between July 2015 and November 2016. All patients had a clinical diagnosis of stroke according to the World Health Organization (WHO) stroke criteria. RESULTS:  A total of 34 patients participated in this study, out of which 20/31 (64.5%) were males while 11/31 (35.5%) were females with a mean age of 51.61 ± 13.96 years. The mean time from diagnosis to surgery was 60.61 ± 49.83 hours. Out of 31 patients, 18 (58.1%) had a right middle cerebral artery infarct (RMCAI) and 13 (41.9%) had a left middle cerebral artery infarct (LCAI). Logistic regression was applied to assess the association between the type of MCA infarct with the National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), modified Barthel Index (mBI) scores, and upper and lower limb motor power. However, the logistic regression model was not statistically significant χ2 (4) = 3.896, p = 0.866. There was a statistically significant mild improvement of neurological scores and upper and lower motor power over a course of six months, but the overall functional outcome was poor with mBI < 60 and mRS > 4 (p < 0.001) with total mortality of 8.7%. CONCLUSION:  Decompressive craniectomy is a life-saving surgery that appears to benefit patients with malignant MCA infarcts of either the dominant or non-dominant cerebral hemisphere. Decompressive craniectomy results in mild improvements in neurological scores but still poor functional outcome after six months.

A rare case of medullary carcinoma thyroid metastasizing to bilateral breast parenchyma.

Medullary carcinoma of the thyroid (MTC) commonly spreads through the lymphatics to distant sites such as lung, liver and bone. Spread to the breast is rare. We report a case of metastatic MTC which progressed to develop nodal metastases to cer-vical and mediastinal regions, visceral metastases to the liver, lung and ultimately to bilateral breasts. Clinically it is important to distinguish metastatic breast lesions from primary breast cancer as each is managed differently. Both cytological and radio-logical investigations were done followed by excision biopsy. Histopathological examination of post excision breast specimen revealed metastatic medullary carcinoma, with positive immunohistochemical staining for calcitonin. A brief review of literature and differential diagnosis is also presented.