Historical and More Common Nongenetic Movement Disorders From Asia

Nongenetic movement disorders are common throughout the world. The movement disorders encountered may vary depending on the prevalence of certain disorders across various geographical regions. In this paper, we review historical and more common nongenetic movement disorders in Asia. The underlying causes of these movement disorders are diverse and include, among others, nutritional deficiencies, toxic and metabolic causes, and cultural Latah syndrome, contributed by geographical, economic, and cultural differences across Asia. The industrial revolution in Japan and Korea has led to diseases related to environmental toxin poisoning, such as Minamata disease and β-fluoroethyl acetate-associated cerebellar degeneration, respectively, while religious dietary restriction in the Indian subcontinent has led to infantile tremor syndrome related to vitamin B12 deficiency. In this review, we identify the salient features and key contributing factors in the development of these disorders.

Nine Hereditary Movement Disorders First Described in Asia: Their History and Evolution

Clinical case studies and reporting are important to the discovery of new disorders and the advancement of medical sciences. Both clinicians and basic scientists play equally important roles leading to treatment discoveries for both cures and symptoms. In the field of movement disorders, exceptional observation of patients from clinicians is imperative, not just for phenomenology but also for the variable occurrences of these disorders, along with other signs and symptoms, throughout the day and the disease course. The Movement Disorders in Asia Task Force (TF) was formed to help enhance and promote collaboration and research on movement disorders within the region. As a start, the TF has reviewed the original studies of the movement disorders that were preliminarily described in the region. These include nine disorders that were first described in Asia: Segawa disease, PARK-Parkin, X-linked dystonia-parkinsonism, dentatorubral-pallidoluysian atrophy, Woodhouse-Sakati syndrome, benign adult familial myoclonic epilepsy, Kufor-Rakeb disease, tremulous dystonia associated with mutation of the calmodulin-binding transcription activator 2 gene, and paroxysmal kinesigenic dyskinesia. We hope that the information provided will honor the original researchers and help us learn and understand how earlier neurologists and basic scientists together discovered new disorders and made advances in the field, which impact us all to this day.

A KMT2B Frameshift Variant Causing Focal Dystonia Restricted to the Oromandibular Region After Long-Term Follow-up

KMT2B-linked dystonia (DYT-KMT2B) is a childhood-onset dystonia syndrome typically beginning in the lower limbs and progressing caudocranially to affect the upper limbs with eventual prominent craniocervical involvement. Despite its recent recognition, it now appears to be one of the more common monogenic causes of dystonia syndromes. Here, we present an atypical case of DYT-KMT2B with oromandibular dystonia as the presenting feature, which remained restricted to this region three decades after symptom onset. This appears to be the first reported case of DYT-KMT2B from Southeast Asia and provides further supporting evidence for the pathogenic impact of the KMT2B c.6210_6213delTGAG variant.

Fecal Calprotectin in Parkinson’s Disease and Multiple System Atrophy

Objective@#Converging evidence suggests that intestinal inflammation is involved in the pathogenesis of neurodegenerative diseases. Previous studies on fecal calprotectin in Parkinson’s disease (PD) were limited by small sample sizes, and literature regarding intestinal inflammation in multiple system atrophy (MSA) is very scarce. We investigated the levels of fecal calprotectin, a marker of intestinal inflammation, in PD and MSA. @*Methods@#We recruited 169 subjects (71 PD, 38 MSA, and 60 age-similar nonneurological controls). Clinico-demographic data were collected. PD and MSA were subtyped and the severity assessed using the MDS-UPDRS and UMSARS, respectively. Fecal calprotectin and blood immune markers were analyzed. @*Results@#Compared to controls (median: 35.7 [IQR: 114.2] μg/g), fecal calprotectin was significantly elevated in PD (median: 95.6 [IQR: 162.1] μg/g, p = 0.003) and even higher in MSA (median: 129.5 [IQR: 373.8] μg/g, p = 0.002). A significant interaction effect with age was observed; between-group differences were significant only in older subjects (i.e., ≥ 61 years) and became more apparent with increasing age. A total of 28.9% of MSA and 18.3% of PD patients had highly abnormal fecal calprotectin levels (≥ 250 μg/g); however, this difference was only significant for MSA compared to controls. Fecal calprotectin correlated moderately with selected blood immune markers in PD, but not with clinical features of PD or MSA. @*Conclusions@#Elevated fecal calprotectin suggests a role for intestinal inflammation in PD and MSA. A more complete understanding of gut immune alterations could open up new avenues of research and treatment for these debilitating diseases.

Labrune’s Syndrome Presenting With Stereotypy-Like Movements and Psychosis: A Case Report and Review

Labrune’s syndrome, or leukoencephalopathy with brain calcifications and cysts (LCC), is a rare genetic syndrome with variable neurological presentations. Psychiatric manifestations and involuntary movements are uncommonly reported. We report the case of a 19-year-old female, initially diagnosed with Fahr’s syndrome, who presented to us with acute psychosis, abnormal behavior and involuntary movements. Her brain computed tomography showed extensive bilateral intracranial calcifications without cysts. Genetic testing detected two compound heterozygous variants, NR_033294.1 n.*9C>T and n.24C>T, in the SNORD118 gene, confirming the diagnosis of LCC. We discuss the expanding phenotypic spectrum of LCC and provide a literature review on the current diagnosis and management of this rare syndrome.

Management of Parkinson’s Disease in the COVID-19 Pandemic and Future Perspectives in the Era of Vaccination

The current coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2) has led to a serious global health crisis. Increasing evidence suggests that elderly individuals with underlying chronic diseases, including Parkinson’s disease (PD), are particularly vulnerable to this infection. Changes in the routine care of PD patients should be implemented carefully without affecting the quality provided. The utilization of telemedicine for clinical consultation, assessment and rehabilitation has also been widely recommended. Therefore, the aim of this review is to provide recommendations in the management of PD during the pandemic as well as in the early phase of vaccination programs to highlight the potential sequelae and future perspectives of vaccination and further research in PD. Even though a year has passed since COVID- 19 emerged, most of us are still facing great challenges in providing a continuum of care to patients with chronic neurological disorders. However, we should regard this health crisis as an opportunity to change our routine approach in managing PD patients and learn more about the impact of SARS-CoV-2. Hopefully, PD patients can be vaccinated promptly, and more detailed research related to PD in COVID-19 can still be carried out.

Management of Parkinson’s Disease in the COVID-19 Pandemic and Future Perspectives in the Era of Vaccination

The current coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2) has led to a serious global health crisis. Increasing evidence suggests that elderly individuals with underlying chronic diseases, including Parkinson’s disease (PD), are particularly vulnerable to this infection. Changes in the routine care of PD patients should be implemented carefully without affecting the quality provided. The utilization of telemedicine for clinical consultation, assessment and rehabilitation has also been widely recommended. Therefore, the aim of this review is to provide recommendations in the management of PD during the pandemic as well as in the early phase of vaccination programs to highlight the potential sequelae and future perspectives of vaccination and further research in PD. Even though a year has passed since COVID- 19 emerged, most of us are still facing great challenges in providing a continuum of care to patients with chronic neurological disorders. However, we should regard this health crisis as an opportunity to change our routine approach in managing PD patients and learn more about the impact of SARS-CoV-2. Hopefully, PD patients can be vaccinated promptly, and more detailed research related to PD in COVID-19 can still be carried out.

Differential expression of circulating miRNAs in Parkinson’s disease patients: Potential early biomarker?

@#Background & Objective: Circulating microRNAs (miRNAs) expressions have been suggested as potential biomarkers for Parkinson’s Disease (PD). Identification of early biomarkers for PD is important and crucial as PD symptoms occur at a late stage. Hence, these biomarkers could be used in molecular diagnosis for early detection. We therefore examined and compared the expression of circulating miRNAs between PD patients and controls. We also compared the miRNAs expression between early-onset PD (EOPD) and late-onset PD (LOPD). Methods: RNA was extracted from the plasma of EOPD (onset age <50 years; n=14), LOPD (onset age < 60 years; n=14) and healthy controls (n=11). The miRNAs expression was determined using the Affymetrix GeneChip microarray. Differential analysis was performed using the R software. Significantly differentiated miRNAs were subsequently analyzed for functional enrichment and biological pathway using the FunRich v1.3 software based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. The Omics.net was used to determine the predicted target mRNAs of these miRNAs, and their interactions, based on the five most differentially expressed miRNAs. Results: In total, 273 miRNAs were upregulated in PD patients compared to controls. The most significant miRNAs were hsa-miR-301a-3p, 100-5p, 140-5p, 486-3p, 143-3p (fold change ranging from 11.2 – 32.0). A total of 140 circulating miRNAs were differentially expressed in EOPD compared to LOPD. Five of these miRNAs (one upregulated miRNA (hsa-miR-29b-3p) and four downregulated miRNAs (hsa-miR-297, 4462, 1909-5p and 346) belonged exclusively to the EOPD patients. The predicted gene targets of these miRNAs involved in dopaminergic synapse regulation, crucial to the pathogenesis of PD. Conclusion: Circulating miRNAs differ between PD patients and controls, and between EOPD and LOPD patients. A validation study with a larger and more diverse multi-ethnic population should be conducted to confirm our results.

Glucocerebrosidase genetic variants in Malays with early and late-onset Parkinson’s disease

@#Background: Mutations in glucocerebrosidase (GBA) have been associated with the risk of developing Parkinson’s disease (PD) in different ethnic populations. The prevalence of GBA mutations among Malay PD patients is unknown. Thus, the aim of this study was to determine the frequency of GBA mutations among Malay PD patients, focusing on early (EOPD) and late-onset (LOPD) patients. Methods:EOPD (n = 50) and LOPD (n = 50) patients along with 50 ethnically and age-matched control wererecruited. The GBA exons of these patients were sequenced using the Ion Torrent PGMTM System. Results: Five heterozygous mutations exclusive to EOPD patients were identified; c.-203A>G,p.S146L, p.R159Q, p.L483P and p.L483R+c.-145G>A. In LOPD patients, c.543C>T(p.(F181=)), c.28-10C>A and p.R202Q were identified in which this p.R202Q was also present in a control subject. In addition, c.259C>A(p.(R87=)) and c.-145G>A were identified in two control subjects. In summary, we observed GBA mutations in 8% and 6% of Malay PD cases and control subject, respectively. The prevalence of GBA mutations was higher in EOPD (10%) than LOPD (6%). However, these differences were not statistically significant; [PD vs. controls: OR = 1.36, 95%CI 0.35-5.38, p = 0.752] and [EOPD vs. LOPD: OR = 1.74, 95%CI 0.39-7.71, p = 0.715]. Conclusion: We identified five exclusive heterozygous GBA mutations in EOPD patients which might predict the increase susceptibility of Malays to develop PD at young age. These findings could add knowledge into the existing evidences linking genetic alterations in GBA and PD.

Incidence and risk factors of delirium in patients with acute ischaemic stroke

@#Background & Objectives: The reported incidence of post-stroke delirium varies substantially in current medical literature. The impact of delirium on mortality and morbidity is significant and there is need for sustained research on the topic. We aimed to determine the incidence, risk factors and outcome of delirium in acute ischaemic stroke. Methods: We conducted a cross-sectional observational study on consecutive patients with ischaemic stroke. The Confusion Assessment Method was used to diagnose delirium within seven days of stroke onset. Results: Two hundred and eighty patients were recruited (mean age 63.6 years) and 36 (12.9%) developed delirium. After adjustments for covariates, age >65 years (odds ratio, OR 5.2; 95% confidence interval 1.6-17.5); pre-existing dementia (6.5; 1.1-38.2); TACI (7.2; 1.5-35); and a National Institute of Health Stroke Scale of ≥10 (6.8; 1.7-26.4), were independently associated with a risk of developing delirium. Lacunar infarcts were not associated with delirium (0.07; 0.03-0.16). The majority of patients with delirium were cared for in a dedicated stroke unit but this proportion was not significant compared to those without delirium (69.4% vs 58.2%, p=0.20). Delirious patients had significantly higher in-patient mortality (8.3% vs 0%, p=0.002) and longer length of hospital stay (6.94 vs 3.98 days, p< 0.001). Conclusions: One in 8 patients with ischaemic stroke in our centre developed delirium. Older age, pre-existing dementia and severe stroke were independent predictors of delirium. Patients with lacunar infarcts did not develop delirium as often as those with other stroke types. Delirium significantly increased in-patient mortality and length of hospital stay.

A validation study of the Bahasa Malaysia version of the National Institute of Health Stroke Scale

@#Background & Objectives: The National Institute of Health Stroke Scale (NIHSS) provides a valid and quick assessment of stroke severity in hyperacute stroke management. Stroke patients who are eligible for reperfusion therapy require prompt assessment. There is no validated Bahasa Malaysia (BM) version of the NIHSS that allows easier assessment by BM-speaking health professionals. This study aimed to translate and validate a BM version of the NIHSS. Methods: The English NIHSS was translated to BM, then back translated to ensure linguistic accuracy. We also adapted the language assessment of the NIHSS to be more culturally appropriate. Training and certification videos were downloaded from the NIH website and dubbed into BM. We determined intra-class correlation and unweighted kappa as the best measure of reliability. Median scores were used in the analysis for language items. Results: One hundred and one raters participated in the test-retest reliability study. Agreement between the original NIHSS and our translated version of the BM-NIHSS was good (ICC = 0.738, 95% CI: 0.611 to 0.823). Fair to moderate agreement was found on item-by-item analysis (unweighted κ=0.20-0.50) despite high observed agreement. Fifty patients participated in the language assessment arm. Scores were better in BM for reading, naming objects and repetition (Mdn = 100, p < 0.001). There was no difference in the median scores for the description component. Conclusions: The BM-NIHSS is a valid translation of the NIHSS, and may be used in clinical practice by BM-speaking healthcare professionals.

Validation study of the Malay version of the Myasthenia Gravis Quality of Life (MGQOL)15 and Myasthenia Gravis Activities of Daily Living (MGADL) questionnaires

Myasthenia gravis (MG) is an immune mediated neuromuscular disease causing fatiguability, which can influence quality of life (QOL). MG disease status can be established with Myasthenia Gravis Quality of Life (MGQOL) 15 and Myasthenia Gravis Activities of Daily Living (MGADL) questionnaires to measure patients’ perception of MG-related dysfunction. This study aims to validate the translated Malay versions of the MGQOL15 and MGADL for use in Malay-speaking MG patients. By using the cross cultural adaptation process, both questionnaires were translated into Malay language. Two sets of MGQOL15 Malay version and MGADL Malay version were distributed to MG patients during their routine follow-up to be filled up one week apart. A total of 38 patients were recruited during this study comprising predominantly females compared to males (71% vs 29%) and Malays compared to non-Malays (60% vs 40%). The mean age was 52.5 years; with most of the patients in the 60-69 years old category (37%).The Spearman’s correlation coefficient was 0.987 for MGQOL-15 Malay version and 0.976 for MGADL Malay version, while the internal consistency for MGQOL15 Malay version was 0.952-0.957, and 0.677-0.694 for MGADL Malay version. The MGQOL15 Malay version and MGADL Malay version are reliable and valid instruments for the measurement of quality of life in MG patients in the local setting.

Role of high resolution ultrasound in ulnar nerve neuropathy

SUMMARY Aim: This study was conducted to measure the cross sectional area (CSA) of the ulnar nerve (UN) in the cubital tunnel and to evaluate the role of high-resolution ultrasonography in the diagnosis of ulnar nerve neuropathy (UNN). Materials and Methods This was a cross sectional study with 64 arms from 32 patients (34 neuropathic, 30 nonneuropathic). Diagnosis was confirmed by nerve conduction study and electromyography. The ulnar nerves were evaluated with 15MHz small footprint linear array transducer. The ulnar nerve CSA was measured at three levels with arm extended: at medial epicondyle (ME), 5cm proximal and 5cm distal to ME. Results from the neuropathic and nonneuropathic arms were compared. Independent T-tests and Pearson correlation tests were used. P value of less than 0.05 was considered significant. Results: Mean CSA values for the UN at levels 5cm proximal to ME, ME and 5cm distal to ME were 0.055, 0.109, 0.045 cm2 respectively in the neuropathic group and 0.049, 0.075, 0.042 cm2 respectively in the non-neuropathic group. The CSA of the UN at the ME level was significantly larger in the neuropathic group, with p value of 0.005. However, there was no statistical difference between the groups at 5cm proximal and distal to the ME, with p values of 0.10 and 0.35 respectively. Conclusion: There is significant difference in CSA values of the UN at ME between the neuropathic and non-neuropathic groups with mean CSA value above the predetermined 0.10cm2 cut-off point. High-resolution ultrasonography is therefore useful to diagnose and follow up cases of elbow UNN.

High prevalence of diabetes in stroke patients and its association with lacunar infarction

Background & Objectives: The burden of stroke is increasing, in part due to increasing prevalence of diabetes mellitus. Given the high prevalence of diabetes in the Malaysian population (22.6%), we aimed to determine the prevalence of diabetes in our stroke population. We also aimed to study the stroke subtype associated with diabetes. We hypothesized that lacunar infarction would be more prevalent in diabetics. Methods: We retrospectively reviewed data of consecutive patients with acute ischaemic stroke admitted from October 2004 to December 2010 from our stroke registry. Demographic data, risk factors profile and stroke subtypes were reviewed and analyzed. Results: Eight hundred and fifty eight patients were identified from the registry. As high as 59.3% (n=509) of our patients were diabetics, of which 49.2% (n=422) had pre-existing diabetes and 10.1% (n=87) were newly diagnosed. Lacunar infarction was the commonest stroke subtype, comprising 60.6% (n=519) of all strokes. Diabetes was significantly associated with lacunar infarction (OR 1.5, CI 95% 1.16-2.01, p=0.003), particularly in those aged ≤ 55 years (OR 2.29, 95% CI 1.12-4.67) and HbA1C ≥ 6.5% (χ²=8.77, p=0.003). Conclusions: The prevalence of diabetes in our stroke patients is amongst the highest reported. Diabetes mellitus, particularly those with poor glycaemic control is strongly associated with lacunar infarction.

Evaluation of time-dependent pathways in an acute ischemic stroke protocol that incorporates CT perfusion: A tertiary referral center experience

Background and Objective: Intravenous thrombolysis service for stroke was introduced at the Universiti Kebangsaan Malaysia Medical Centre (UKMMC) in 2009, based on the recommendations of a multidisciplinary team of clinicians. We report the experience at our center in establishing a stroke protocol incorporating computed tomography perfusion (CTP) of the brain, to assess the feasibility of incorporating CTP in the stroke protocol. Methods: A retrospective review of all patients who had a CTP between January 2010 and December 2011 was performed. Results: Of 272 patients who were admitted with acute ischemic stroke, 44 (16.2%) arrived within 4.5 hours from symptom onset and had a CTP performed with the intention to treat. The median time for symptom-to-door, symptom-to-scan and door-to-scan was 90.0 minutes (62.5 – 146.3), 211.0 minutes (165.5 – 273.5) and 85.0 minutes (48.0 – 144.8) respectively. Eight patients (2.9%) were thrombolysed of whom five received IV thrombolysis and three underwent mechanical thrombolysis. The median symptom-to-needle and door-to-needle times were 290.5 minutes (261.3 – 405.0) and 225.0 minutes (172.5 – 316.8) respectively. Four patients were thrombolysed despite being outside the window of treatment based on the CTP findings. Six of the thrombolysed patients had a Modified Rankin Score (MRS) of 1-2 at 5 months post procedure. Conclusions: CTP provides a benefit to management decisions and subsequent patient outcome. It is feasible to incorporate CTP as a standard imaging modality in a stroke protocol. The delays in the time-dependent pathways are due to our work flow and organisational process rather than performing the CTP per se.

Prevalence of Helicobacter pylori infection in epilepsy patients in a teaching hospital in Malaysia

Background & Objective: Helicobacter pylori infection has been associated with extradigestive diseases including epilepsy. The main aim of the study was to determine the prevalence of Helicobacter pylori using 13C urea breath test (UBT) in epilepsy patients in a teaching hospital in Malaysia and compared to control. Methods: The study subjects were epilepsy patients from the neurology clinic in a teaching hospital. The study was conducted from August 2010 to February 2011. The control consisted of healthy individuals matched for age and gender, not on any acid suppression medications and antibiotics. All subjects underwent UBT as per protocol. Variables such as age, race, household income, types of epilepsy, duration of epilepsy, number of antiepileptic drugs, prognosis were analysed. Good prognosis was defi ned as seizure free for 3 years. Results: Forty eight epilepsy patients and 47 control subjects were studied. Prevalence of H. pylori infection in the epilepsy patients was 37.5% (n=18) and was 36.2% (n=17) in control. There were signifi cantly more subjects in the epilepsy group with lower income. There were also more smokers in the epilepsy group but there was no association between smoking and positive UBT. Epilepsy patients with poor prognosis have a higher UBT positive rate compared to the good prognosis group (64.3% vs 35.7 %). However the difference was not statistically signifi cant. Conclusion: The prevalence of H. pylori infection in epilepsy patients is similar to that of the control in this study involving Malaysian subjects.