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Paraneoplastic autoimmune movement disorders

Lim TT

Parkinsonism Relat Disord, 2017 Nov;44:106-109.
PMID: 29097081 DOI: 10.1016/j.parkreldis.2017.08.017

PURPOSE OF REVIEW: To provide an overview of paraneoplastic autoimmune disorders presenting with various movement disorders.
RECENT FINDINGS: The spectrum of paraneoplastic autoimmune disorders has been expanding with the discovery of new antibodies against cell surface and intracellular antigens. Many of these paraneoplastic autoimmune disorders manifest as a form of movement disorder. With the discovery of new neuronal antibodies, an increasing number of idiopathic or neurodegenerative movement disorders are now being reclassified as immune-mediated movement disorders. These include anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis which may present with orolingual facial dyskinesia and stereotyped movements, CRMP-5 IgG presenting with chorea, anti-Yo paraneoplastic cerebellar degeneration presenting with ataxia, anti-VGKC complex (Caspr2 antibodies) neuromyotonia, opsoclonus-myoclonus-ataxia syndrome, and muscle rigidity and episodic spasms (amphiphysin, glutamic acid decarboxylase, glycine receptor, GABA(A)-receptor associated protein antibodies) in stiff-person syndrome.
SUMMARY: Movement disorders may be a presentation for paraneoplastic autoimmune disorders. Recognition of these disorders and their common phenomenology is important because it may lead to the discovery of an occult malignancy.
Fulltext Adult-Onset Satoyoshi Syndrome and Axial Spondyloarthritis

Chee YC, Lim TT, Ong BH

J Clin Neurol, 2021 Oct;17(4):593-595.
PMID: 34595874 DOI: 10.3988/jcn.2021.17.4.593
Editorial: Inclusion, equity, diversity and social justice in movement disorders research

Miyasaki JM, Lim TT, Bhidayasiri R

Parkinsonism Relat Disord, 2021 04;85:114-116.
PMID: 33840573 DOI: 10.1016/j.parkreldis.2021.03.022
Exploring bedside clinical features of parkinsonism: A focus on differential diagnosis

Bhidayasiri R, Rattanachaisit W, Phokaewvarangkul O, Lim TT, Fernandez HH

Parkinsonism Relat Disord, 2019 Feb;59:74-81.
PMID: 30502095 DOI: 10.1016/j.parkreldis.2018.11.005

The proper diagnosis of parkinsonian disorders usually involves three steps: identifying core features of parkinsonism; excluding other causes; and collating supportive evidence based on clinical signs or investigations. While the recognition of cardinal parkinsonian features is usually straightforward, the appreciation of clinical features suggestive of specific parkinsonian disorders can be challenging, and often requires greater experience and skills. In this review, we outline the clinical features that are relevant to the differential diagnosis of common neurodegenerative parkinsonian disorders, including Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration. We aim to make this process relatable to clinicians-in-practice, therefore, have categorised the list of clinical features into groups according to the typical sequence on how clinicians would elicit them during the examination, starting with observation of facial expression and clinical signs of the face, spotting eye movement abnormalities, examination of tremors and jerky limb movements, and finally, examination of posture and gait dysfunction. This review is not intended to be comprehensive. Rather, we have focused on the most common clinical signs that are potentially key to making the correct diagnosis and those that do not require special skills or training for interpretation. Evidence is also provided, where available, such as diagnostic criteria, consensus statements, clinicopathological studies or large multi-centre registries. Pitfalls are also discussed when relevant to the diagnosis. While no clinical signs are pathognomonic for certain parkinsonian disorders, certain clinical clues may assist in narrowing a differential diagnosis and tailoring focused investigations for the individual patient.
Fulltext Genotypic and phenotypic variation of CADASIL among Chinese, Indians and Rungus in Malaysia

Toh, Tsun-Haw, Lim, Kheng-Seang, Ng, Ching-Ching, Imran Idris, Sherrini Bazir Ahmad, Lim, Thien-Thien, et al.

Neuroscience Research Notes, 2019;2(3):1-11.
MyJurnal

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary disease of small cerebral arteries. This case series aims to describe the mutations in NOTCH3and their phenotypes in Malaysia. We includedpatients who were genetically confirmed to have CADASIL, diagnosed at the University of Malaya Medical Centre, Malaysia. Family members who fulfilled clinical or imaging criteria, and patients from two previous published Malaysian families were also included. Six families (eleven cases) were included in this series. Genetic testing revealed NOTCH3 mutations in c.328C>T (p.Arg110Cys, R110C), c.553T>G (p.Cys185Gly, C185G), c.1630C>T (p.Arg544Cys, R544C) and c.160C>T (p.Arg54Cys, R54C). Two out of four Chinese families had R544C mutation in exon 11, with a later age of onset, absence of migraine and lack of anterior temporal pole involvement on MRI. One family with mixed Indian and Chinese ancestry had a mutation in exon 3 with R110C and another Indian family exon 4 with C185G mutation. This case series highlights the genotypic and phenotypic variability of CADASIL in a multi-ethniccountry. The finding of p.Arg544Cys mutation among the older Chinese families, similar to those reported in Jeju Island and Taiwan, suggest the need to screen the older Chinese stroke patients with typical MRI changes.
A South East Asian perspective of neuropsychiatric startle syndromes of latah

Lim TT, Tan K, Eow GB, Bhidayasiri R

Parkinsonism Relat Disord, 2022 Jan 26.
PMID: 35120841 DOI: 10.1016/j.parkreldis.2022.01.013

Latah is a culture-specific syndrome characterized by exaggerated startle response, echolalia, palilalia, echopraxia, coprolalia, forced obedience and involuntary vocalization in response to startle. Latah is stimulus-induced and is associated with behavior and psychiatric features. The aim of this review is to provide a comprehensive description on latah from a regional perspective based on previous literature and clinical experiences and highlight the clinical characteristics of latah from a movement disorders perspective. The pathophysiology of latah is complex and poorly understood although psychological stressors have been implicated. In view of the distressing psychosocial impact of latah, this neuropsychiatric startle syndrome warrants further studies to understand the pathophysiology and identify the appropriate treatments.
Fulltext A Paradoxical Phenomenon: Hemichorea-Hemiballismus Resolution After Stroke in Moyamoya Disease

Por CY, Lim TT, Chee YC, Raymond AA

J Clin Neurol, 2023 Jul;19(4):410-412.
PMID: 37417437 DOI: 10.3988/jcn.2023.0009
Suprasellar lymphoma masquerading as tuberculosis of the central nervous system

Dang YL, Hor JY, Chia YK, Lim TT, Eow GB

Acta Neurol Belg, 2014 Sep;114(3):239-41.
PMID: 23757110 DOI: 10.1007/s13760-013-0217-3
Treatment of startle and related disorders

Lim TT, Por CY, Beh YY, Schee JP, Tan AH

Clin Park Relat Disord, 2023;9:100218.
PMID: 37808566 DOI: 10.1016/j.prdoa.2023.100218
Fulltext Tardive dyskinesia in Asia- current clinical practice and the role of neurologists in the care pathway

Bhidayasiri R, Phokaewvarangkul O, Shang HF, Lim TT, Cho JW, Pal PK, et al.

Front Neurol, 2024;15:1356761.
PMID: 38419696 DOI: 10.3389/fneur.2024.1356761

Tardive dyskinesia (TD) is a movement disorder that can arise as a side effect of treatment with dopamine receptor-blocking agents (DRBAs), including antipsychotic drugs (APDs) used to manage psychotic illnesses. Second-generation APDs (SGAs) are often preferred to first-generation drugs due to their lower propensity to cause TD, however many SGAs-treated patients still develop the condition. Although TD is a global health concern, evidence regarding the occurrence of TD and how it is managed in Asian countries is currently limited. This article reports the results of a systematic review of the published literature on TD focusing on its prevalence, types of patients, knowledge of the condition, causative factors, and usual treatment pathways in clinical practice in Asian countries. Epidemiological data suggest that the prevalence of TD is increasing globally due to an overall rise in APD use, contributing factors being polypharmacy with multiple APDs, the use of higher than necessary doses, and off-label use for non-psychotic indications. Although exact prevalence figures for TD in Asian countries are difficult to define, there is a similar pattern of rising APD use which will result in increasing numbers of TD patients in this region. These issues need to be addressed and strategies developed to minimize TD risk and manage this disabling condition which impacts patients' quality of life and daily functioning. To date, both research into TD has been predominantly psychiatry focused and the perspectives from neurologists regarding the clinical management of this challenging condition are scarce. However, neurologists have an essential role in managing the movement disorders manifestations that characterize TD. Optimum management of TD, therefore, should ideally involve collaboration between psychiatrists and neurologists in joint care pathways, wherever practical. Collaborative pathways are proposed in this article, and the challenges that will need to be addressed in Asian countries to improve the care of people with TD are highlighted, with a focus on the neurologist's viewpoint and the implications for the management of TD globally.
Fulltext Neurological perspectives should be integrated into the management of tardive dyskinesia - expert opinion and proposed educational initiatives in Asia

Bhidayasiri R, Phokaewvarangkul O, Lim TT, Pal PK, Watanabe H, Cho JW, et al.

J Mov Disord, 2024 Apr 11.
PMID: 38600683 DOI: 10.14802/jmd.24068
A previously misdiagnosed cohort of aquaporin 4 antibody-positive neuromyelitis optica spectrum disorder with disease duration of >10 years in multi-ethnic Penang, Malaysia: Clinical features and disease course

Hor JY, Lim TT, Chow HB, Tan K, Cheah CF, Ching YM, et al.

Mult Scler Relat Disord, 2016 Jan;5:89-90.
PMID: 26856950 DOI: 10.1016/j.msard.2015.11.008
Eleven episodes of recurrent optic neuritis of the same eye for 22 years eventually diagnosed as neuromyelitis optica spectrum disorder

Yew YC, Hor JY, Lim TT, Kanesalingam R, Ching YM, Arip M, et al.

Mult Scler Relat Disord, 2016 Nov;10:22-25.
PMID: 27919493 DOI: 10.1016/j.msard.2016.08.009

It is difficult to predict whether a particular attack of neuromyelitis optica spectrum disorder (NMOSD) will affect the optic nerve [optic neuritis (ON): unilateral or bilateral], spinal cord (myelitis), brain or brainstem, or a combination of the above. We report an interesting case of recurrent ON of the same eye for a total of 11 episodes in a Chinese woman. Over a period of 22 years, the attacks only involved the left eye, and never the right eye and also no myelitis. For a prolonged duration, she was diagnosed as recurrent idiopathic ON. Only until she was tested positive for aquaporin 4 antibody that her diagnosis was revised to NMOSD. Optical coherence tomography revealed thinning of the retinal nerve fibre layer (RNFL) for the affected left eye, while the RNFL thickness was within normal range for the unaffected right eye. The disability accrual in NMOSD is generally considered to be attack-related - without a clinical attack of ON, there shall be no visual impairment, and no significant subclinical thinning of RNFL. Our case is in agreement with this notion. This is in contrast to multiple sclerosis where subclinical RNFL thinning does occur. This case highlights the importance of revisiting and questioning a diagnosis of recurrent idiopathic ON particularly when new diagnostic tools are available.
From parasomnia to agrypnia excitata - An illustrative case on diagnostic approach

Fong SL, Dy Closas AMF, Lim TT, Lean PL, Loh EC, Lim SY, et al.

Parkinsonism Relat Disord, 2023 Apr;109:105332.
PMID: 36948111 DOI: 10.1016/j.parkreldis.2023.105332

The diagnostic approach to sleep-related movements disorders is seldom discussed. We report a case of fatal familial insomnia who initially presented with persistent limb movements in sleep, which later progressed to a state of agrypnia excitata. Here, the evaluation of abnormal movements in sleep is discussed using a step-by-step diagnostic approach. Although no cure is available for fatal familial insomnia, prompt recognition of this condition is important to facilitate proper management, including the involvement of interdisciplinary neuropalliative care.
Thymoma-associated myasthenia gravis and LGI1-encephalitis, with nephrotic syndrome post-thymectomy

Hor JY, Lim TT, Cheng MC, Chia YK, Wong CK, Lim SM, et al.

J Neuroimmunol, 2018 04 15;317:100-102.
PMID: 29395322 DOI: 10.1016/j.jneuroim.2018.01.011

Thymoma is associated with a wide spectrum of autoimmune paraneoplastic syndromes, though it is uncommon for multiple paraneoplastic syndromes to be present in a single individual. We report a rare case of an elderly gentleman who was found to have thymoma-associated myasthenia gravis and LGI1-encephalitis with myokymia, who presented with nephrotic syndrome (minimal change glomerulopathy) after thymectomy. The latter two paraneoplastic syndromes had manifested when prednisolone was tapered down to low dose. This case serves to remind neurologists that apart from paraneoplastic neurological manifestations, thymoma may also be associated with renal disease. Nephropathy in myasthenia patients with thymoma should be properly evaluated, as it is treatable with immunotherapy, and it may even occur post-thymectomy.
Prevalence of neuromyelitis optica spectrum disorder in the multi-ethnic Penang Island, Malaysia, and a review of worldwide prevalence

Hor JY, Lim TT, Chia YK, Ching YM, Cheah CF, Tan K, et al.

Mult Scler Relat Disord, 2018 Jan;19:20-24.
PMID: 29100047 DOI: 10.1016/j.msard.2017.10.015

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) occurs worldwide in all ethnicities. Recently, population-based studies have shown that NMOSD is more common among non-White populations. There is scarce data about NMOSD prevalence in South East Asian populations.
METHODS: (1) A population-based study was undertaken to estimate NMOSD prevalence in the multi-ethnic Penang Island, Malaysia, comprising Chinese, Malays, and Indians. Medical records of NMOSD patients followed up at the Penang General Hospital (the neurology referral centre in Penang Island) were reviewed. The 2015 diagnostic criteria of the International Panel for NMO Diagnosis were used for case ascertainment. (2) A review of population-based prevalence studies of NMOSD worldwide was carried out. PubMed and conference proceedings were searched for such studies.
RESULTS: Of the 28 NMOSD patients, 14 were residents of Penang Island on prevalence day [13 (93%) Chinese and one (7%) Malay]. All 14 patients were females and aquaporin 4 seropositive. The prevalence of NMOSD in Penang Island was 1.99/100,000 population; according to ethnicities, the prevalence in Chinese was significantly higher than in Malays (3.31/100,000 vs 0.43/100,000, respectively, p = 0.0195).
CONCLUSION: Based on our and other population-based studies, among Asians, East Asian origin populations (Chinese and Japanese) appear to have higher NMOSD prevalence than other Asian ethnic groups. Worldwide, Blacks seem to have the highest NMOSD prevalence. More studies in different geographical regions and ethnic groups will be useful to further inform about potential factors in NMOSD pathogenesis.
Fulltext LRRK2 G2385R and R1628P mutations are associated with an increased risk of Parkinson's disease in the Malaysian population

Gopalai AA, Lim SY, Chua JY, Tey S, Lim TT, Mohamed Ibrahim N, et al.

Biomed Res Int, 2014;2014:867321.
PMID: 25243190 DOI: 10.1155/2014/867321

The LRRK2 gene has been associated with both familial and sporadic forms of Parkinson's disease (PD). The G2019S variant is commonly found in North African Arab and Caucasian PD patients, but this locus is monomorphic in Asians. The G2385R and R1628P variants are associated with a higher risk of developing PD in certain Asian populations but have not been studied in the Malaysian population. Therefore, we screened the G2385R and R1628P variants in 1,202 Malaysian subjects consisting of 695 cases and 507 controls. The G2385R and R1628P variants were associated with a 2.2-fold (P = 0.019) and 1.2-fold (P = 0.054) increased risk of PD, respectively. Our data concur with other reported findings in Chinese, Taiwanese, Singaporean, and Korean studies.
Lack of association between the LRRK2 A419V variant and Asian Parkinson's disease

Gopalai AA, Lim SY, Aziz ZA, Lim SK, Tan LP, Chong YB, et al.

Ann Acad Med Singap, 2013 May;42(5):237-40.
PMID: 23771111

INTRODUCTION: The G2385R and R1628P LRRK2 gene variants have been associated with an increased risk of Parkinson's disease (PD) in the Asian population. Recently, a new LRRK2 gene variant, A419V, was reported to be a third risk variant for PD in Asian patients. Our objective was to investigate this finding in our cohort of Asian subjects.
MATERIALS AND METHODS: Eight hundred and twenty-eight subjects (404 PD patients, and 424 age and gender-matched control subjects without neurological disorders) were recruited. Genotyping was done by Taqman® allelic discrimination assay on an Applied Biosystems 7500 Fast Real-Time PCR machine.
RESULTS: The heterozygous A419V genotype was found in only 1 patient with PD, compared to 3 in the control group (0.4% vs 1.3%), giving an odds ratio of 0.35 (95% confidence interval (CI), 0.01 to 3.79; P = 0.624).
CONCLUSION: A419V is not an important LRRK2 risk variant in our Asian cohort of patients with PD. Our data are further supported by a literature review which showed that 4 out of 6 published studies reported a negative association of this variant in PD.
Glucocerebrosidase (GBA) gene variants in a multi-ethnic Asian cohort with Parkinson's disease: mutational spectrum and clinical features

Lim JL, Lohmann K, Tan AH, Tay YW, Ibrahim KA, Abdul Aziz Z, et al.

J Neural Transm (Vienna), 2022 Jan;129(1):37-48.
PMID: 34779914 DOI: 10.1007/s00702-021-02421-0

GBA variants are associated with increased risk and earlier onset of Parkinson's disease (PD), and more rapid disease progression especially with "severe" variants typified by p.L483P. GBA mutation screening studies from South-East Asia, with > 650 million inhabitants of diverse ancestries, are very limited. We investigated the spectrum of GBA variants, and associated clinico-demographic features, in a multi-ethnic PD cohort in Malaysia. Patients (n = 496) were recruited from seven centres, primarily of Chinese (45%), Malay (37%), and Indian (13%) ethnicities. All GBA coding exons were screened using a next-generation sequencing-based PD gene panel and verified with Sanger sequencing. We identified 14 heterozygous GBA alleles consisting of altogether 17 missense variants (8 classified as pathogenic or likely pathogenic for PD) in 25 (5.0%) patients, with a substantially higher yield among early (
Fulltext LRRK2 N551K and R1398H variants are protective in Malays and Chinese in Malaysia: A case-control association study for Parkinson's disease

Gopalai AA, Lim JL, Li HH, Zhao Y, Lim TT, Eow GB, et al.

Mol Genet Genomic Med, 2019 Nov;7(11):e604.
PMID: 31487119 DOI: 10.1002/mgg3.604

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.

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