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.

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.

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.

LRRK2 N551K and R1398H variants are protective in Malays and Chinese in Malaysia: A case-control association study for Parkinson's disease.

BACKGROUND: The LRRK2 gene is associated with Parkinson's disease (PD) as a number of mutations within the gene have been shown to be susceptibility factors. Studies on various global populations have determined that mutations such as G2019S, G2385R, and R1628P in LRRK2 increase the risk of developing PD while the N551K-R1398H haplotype is associated with conferring protection against developing PD. Here we report a study looking at the N551K and R1398H variants for the first time in the Malaysian population. METHODS: Cases (523) which conformed to the United Kingdom PD Brain Bank Criteria for PD were recruited through trained neurologists and age- and ethnically matched controls (491) were individuals free of any neurological disorder. The N551K and R1398H mutations were genotyped using the Taqman SNP genotyping assay. RESULTS: A significant protective association for N551K was found in those of Malay ancestry, with a protective trend seen for R1398H. A meta-analysis of Chinese individuals in this cohort with other published cohorts of Chinese ancestry indicated a significant protective role for N551K and R1398H. CONCLUSION: This study reports that the N551K-R1398H haplotype is also relevant to the Malaysian population, with a significant protective effect found in those of Malay and Chinese ancestries.

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.

PARK16 is associated with PD in the Malaysian population.

PARK16 was identified as a risk factor for Parkinson's disease in a Japanese cohort; however, subsequent studies in the other populations including the Chinese, European, Caucasian, and Chilean have shown a protective role instead. To investigate this locus in our Malaysian cohort, 1,144 individuals were screened for five SNPs in the PARK16 locus and logistic regression analysis showed that the A allele of the rs947211 SNP reduced the risk of developing PD via a recessive model (Odds ratio 0.57, P-value 0.0003). Pooled analysis with other Asian studies showed that A allele of the rs947211 SNP decreased the risk of developing PD via a recessive model (Odds ratio 0.71, P-value 0.0001). In addition, when meta-analysis was performed with other Asian population, three SNPs (rs823128, rs823156, and rs11240572) reduced risk of developing PD via a dominant model. © 2016 Wiley Periodicals, Inc.

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.

Stroke thrombolysis at 5.5 hours based on computed tomography perfusion.

A young man was admitted with sudden onset of right-sided weakness. He was assessed in the emergency department, and an immediate computed tomography (CT) perfusion study of the brain was arranged, which showed a left middle cerebral artery territory infarct with occlusion of the M1 segment. There was a significant penumbra measuring approximately 50% of the arterial territory. By the time his assessment was completed, it was 5.5 hours from the onset of symptoms. He was nonetheless administered intravenous recombinant tissue plasminogen activator (rtPA) based on the significant penumbra. He was discharged from the hospital after one week with significant residual deficit. At 2 months clinic follow-up, he showed almost complete recovery with a Modified Rankin Score of 1. We hope to demonstrate that a significant penumbra is an important determinant for good neurological recovery and outcome following stroke thrombolysis, even when patients present outside the 4.5 hours onset-to-treatment time window.

Nonmotor symptoms in a malaysian Parkinson's disease population.

Background. The nonmotor symptoms are important determinants of health and quality of life in Parkinson's disease but are not well recognized and addressed in clinical practice. This study was conducted to determine the prevalence of nonmotor symptoms and their impact on quality of life in patients with Parkinson's disease. Methods. This was a cross-sectional study among patients with idiopathic Parkinson's disease. Exclusion criteria were a Mini Mental State Examination score of <21/30. Prevalence of nonmotor symptoms was determined using the NMSQuest. The severity of nonmotor symptoms and the quality of life were assessed using validated disease-specific questionnaires (PDQ-39 and NMSS). Results. A total of 113 patients consisting of 60 males and 53 females were recruited. The median duration of illness was 5.0 (2.0-8.0) years. The prevalence rate of nonmotor symptoms in our cohort was 97.3%. The most common reported nonmotor symptom in our cohort was gastrointestinal (76.1%). We found that the severity of the nonmotor symptoms was associated with poorer quality of life scores (r s : 0.727, P < 0.001). Conclusions. Nonmotor symptoms were highly prevalent in our patients with Parkinson's disease and adversely affected the quality of life of our patients. In contrast to western studies, the most common nonmotor symptom is gastrointestinal. The possibility of an Asian diet playing a role in this observation requires further study.

Review of emotion recognition in stroke patients.

OBJECTIVE: Patients suffering from stroke have a diminished ability to recognize emotions. This paper presents a review of neuropsychological studies that investigated the basic emotion processing deficits involved in individuals with interhemispheric brain (right, left) damage and normal controls, including processing mode (perception) and communication channels (facial, prosodic-intonational, lexical-verbal). METHODS: An electronic search was conducted using specific keywords for studies investigating emotion recognition in brain damage patients. The PubMed database was searched until March 2012 as well as citations and reference lists. 92 potential articles were identified. RESULTS: The findings showed that deficits in emotion perception were more frequently observed in individuals with right brain damage than those with left brain damage when processing facial, prosodic and lexical emotional stimuli. CONCLUSION: These findings suggest that the right hemisphere has a unique contribution in emotional processing and provide support for the right hemisphere emotion hypothesis. SIGNIFICANCE: This robust deficit in emotion recognition has clinical significance. The extent of emotion recognition deficit in brain damage patients appears to be correlated with a variety of interpersonal difficulties such as complaints of frustration in social relations, feelings of social discomfort, desire to connect with others, feelings of social disconnection and use of controlling behaviors.