Tardive dyskinesia in Asia- current clinical practice and the role of neurologists in the care pathway.

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.

Whole exome sequencing and clinical investigation of young onset dystonia: What can we learn?

BACKGROUND: Dystonia is a heterogeneous movement disorder involving various genetic backgrounds, and the implication of whole exome sequencing (WES) has yet to be clearly elucidated. In this study, we performed WES in Korean patients with young-onset dystonia. METHODS: We recruited patients with young-onset dystonia based on the new MDS dystonia classification at Samsung Medical Centre from 2015 to 2019. We excluded subjects diagnosed by single gene tests (GCH1, TOR1A, PANK2, PRRT2, and SGCE) or levodopa trials and subjects with focal or possible secondary dystonia. We performed WES in all enrolled subjects and confirmed the results with Sanger sequencing. RESULTS: Of the 43 patients, we detected 11 disease-causing variants, classified as either pathogenic or likely pathogenic, in 9 patients (20.9%). Generalized dystonia, infancy-childhood-onset dystonia, and other combined neurologic manifestations were related with PV/LPV. When we retrospectively reviewed the patients with PV/LPV, brain imaging was diagnostic in 3 subjects (HTRA1, SCL20A, and WDR45), clinical characteristics of paroxysmal presentation were observed in 2 (ADCY5 and ATP1A3), and microcephaly was noted in 1 patient (KMT2B). CONCLUSION: Clinical exome sequencing is helpful for the diagnosis of dystonia, especially for that with infancy-childhood onset, and generalized dystonia with other neurologic manifestations. Additionally, careful evaluations and examinations could provide information for selecting candidates for genetic testing.

Subthalamic deep brain stimulation in Parkinson's disease with SNCA mutations: Based on the follow-up to 10 years.

BACKGROUNDS: Although the short-term efficacy of bilateral subthalamic deep brain stimulation (DBS) has been reported in a limited number of Parkinson's disease (PD) patients with SNCA mutations, there are no data for long-term outcome. METHODS: This multicenter retrospective study investigated previously reported PD patients with SNCA mutations, implanted with bilateral subthalamic DBS. We compared demographic and clinical data at baseline and last follow-up. Clinical data of motor and nonmotor symptoms and motor fluctuation were collected up to 10 years from DBS surgery. RESULTS: Among four subjects, three had SNCA duplication and one had c.158C.A (p.A53E) mutation. The mean post-implantation follow-up duration was 5.4 ± 3.7 years. All patients with SNCA duplication showed favorable outcome, although one died from breast cancer 1.5 years after DBS. The patient with the missense mutation became wheelchair-bound due to progressed axial, cognitive and psychiatric symptoms after 3.5 years from DBS despite the benefit on motor fluctuation. CONCLUSION: Based on findings in our small cohort, subthalamic DBS could be beneficial for motor fluctuation in PD patients with SNCA mutations, especially those with SNCA duplication, and cognitive and psychiatric symptoms are important for the long-term outcome of subthalamic DBS.

Extra-basal ganglia iron content and non-motor symptoms in drug-naïve, early Parkinson's disease.

BACKGROUND: Although iron dyshomeostasis is associated with Parkinson's disease (PD) pathogenesis, the relationship between iron deposition and non-motor involvement in PD is not fully understood. In this study, we investigated basal ganglia and extra-basal ganglia system iron contents and their correlation with non-motor symptoms in drug-naïve, early-stage PD patients. METHODS: We enrolled 14 drug-naïve, early-stage PD patients and 12 age/sex-matched normal controls. All participants underwent brain magnetic resonance imaging to obtain the effective transverse relaxation rate (R2*) and quantitative susceptibility mapping (QSM). Deep brain structures, including the nucleus accumbens, caudate nucleus, putamen, globus pallidus, thalamus, hippocampus, and amygdala, were delineated using the FSL-FIRST; the substantia nigra, red nucleus, and dentate nucleus were segmented manually. Inter-group differences in R2* and QSM values, as well as their association with clinical parameters of PD, were investigated. RESULTS: Substantia nigra and putamen R2* values were significantly higher in PD patients than in normal controls, despite no significant difference in QSM values. Regarding the non-motor symptom scales, PD sleep scale score negatively correlated with R2* values in the red nucleus and right amygdala, Scales for Outcomes in Parkinson's disease-Autonomic scores were positively correlated with R2* values in the right amygdala and left hippocampus, and cardiovascular sub-score of Non-Motor Symptoms Scale for PD was positively associated with the QSM value in the left hippocampus. CONCLUSION: In this study, iron content in the extra-basal ganglia system was significantly correlated with non-motor symptoms, especially sleep problems and dysautonomia, even in early-stage PD.

Risk factors and prognosis of adult-onset post-pump chorea.

OBJECTIVES: Post-pump chorea (PPC), defined as the development of chorea after major cardiac surgery utilizing cardiopulmonary bypass (CPB), has been rarely reported in adults. METHODS: We compared 17 patients with adult-onset PPC to controls who did not develop chorea after cardiac surgery with CPB. Two patients were enrolled using hospital based data and 15 were collected by a systematic literature review. The controls without chorea after CPB (n = 4208) were collected using hospital based data. We described the clinical and surgical features of adult-onset PPC and compared them with those of the controls. RESULTS: Ten of 17 PPC patients were male, the mean age was 46.8 years, and the mean onset latency was 6.0 days. The adult-onset PPC patients were younger (46.8 ± 16.7 vs. 59.1 ± 15.0, p = 0.001), had a lower minimum body temperature (23.3 ± 5.5 vs. 29.7 ± 3.7, p < 0.001) and a longer total circulatory arrest time (63.7 ± 7.5 vs. 21.0 ± 14.6, p < 0.001) than controls. Forty-three percentage of patients with adult-onset PPC had persistent chorea on follow-up, and these patients showed a higher rate of abnormal initial brain MRI compared with the patients with good clinical outcomes (p = 0.041). CONCLUSIONS: The onset age, onset latency, underlying disease, treatment response, and surgical features were variable among PPC patients, while abnormal initial brain MRI was associated with persistent chorea. Pooling more cases through multicenter efforts will hopefully provide more knowledge on the underlying pathophysiology, prevention, and management of PPC.

Clinical characteristics of ataxia-telangiectasia presenting dystonia as a main manifestation.

INTRODUCTION: Besides cerebellar ataxia, various other movement disorders, including dystonia, could manifest as main clinical symptoms in ataxia-telangiectasia (A-T). However, the clinical characteristics of dystonic A-T patients are not clearly elucidated. METHODS: To investigate the characteristics of dystonic A-T, we screened previous reports with A-T patients presenting dystonia as a main manifestation, and included 38 dystonic A-T patients from 16 previous studies and our 2 cases. We reviewed clinical and demographic data of dystonic A-T patients. Additionally, to figure out clinical meaning of cerebellar involvement in dystonic A-T, we divided them into two groups based on the presence of cerebellar involvement, and compared clinical features between two groups. RESULTS: In the patients with dystonic A-T, dystonia tended to appear during childhood or adolescence and became generalized over time. Choreoathetosis and myoclonus accompanied more frequently than the typical clinical features, including cerebellar ataxia or atrophy, telangiectasia, or oculomotor apraxia. Additionally, alpha-fetoprotein level was also elevated in the patients with dystonic A-T. When we compared dystonic A-T with and without cerebellar involvement, the former was related with more chance for telangiectasia and oculomotor apraxia, while the latter with that for choreoathetosis and malignancy. CONCLUSION: Even without ataxia, telangiectasia, or oculomotor apraxia, A-T should be considered in undiagnosed dystonia, especially generalized dystonia which started from childhood or adolescence period, and alpha-fetoprotein level can be a useful screening tool. In addition, cerebellar involvement is important considering different phenotype in dystonic A-T patients with and without cerebellar sign.

Anti-CV2/CRMP5 Paraneoplastic Chorea Effectively Managed with Intravenous Amantadine.

Background: Paraneoplastic chorea is typically a subacute progressive hyperkinetic movement disorder. The mainstay of treatment is managing the underlying neoplasm. However, the clinical course may be variable, and effective symptomatic management can precede the start of cancer treatment. Case report: A 63-year-old man presented with insidious onset, slowly progressive generalized chorea for 1 year, later diagnosed as anti-CV2/CRMP5 autoantibody positive paraneoplastic chorea. His chorea was markedly improved with intravenous amantadine. Discussion: In patients with anti-CV2/CRMP5 autoantibody-related chorea, sequential follow-up of brain magnetic resonance imaging reveals progression from active inflammation to atrophy. Our report highlights the efficacy of intravenous amantadine in paraneoplastic chorea.

Bilateral subthalamic deep brain stimulation is an effective and safe treatment option for the older patients with Parkinson's disease.

OBJECTIVES: We aimed to provide evidence that subthalamic nucleus (STN) deep brain stimulation (DBS) is an effective and safe treatment option for older patients with Parkinson's disease (PD). PATIENTS AND METHODS: Bilateral STN DBS was performed in 55 patients with PD from 2012 to 2016 at Samsung Medical Center. We divided them into two groups based on the age at DBS: younger group (<65 years, n = 38) and older group (≥65 years, n = 17). For evaluating effectiveness, we compared pre- and post-DBS Unified Parkinson's Disease Rating Scale (UPDRS) part 3 and 4 scores and levodopa equivalent daily dose (LEDD) between the two groups. Additionally, surgery-related complications in each group were assessed. RESULTS: The mean age of the younger group was 56.7 ± 5.7 and that of the older group was 68.5 ± 2.9. More female patients underwent STN DBS in the younger group, but there were no differences in baseline characteristics. In terms of effectiveness, UPDRS part 3 and 4 scores and LEDD significantly improved 6 months after DBS in both groups. In terms of safety, 1 complication was observed in the younger group (2.6%), while 2 complications, including 1 subject with intracerebral hemorrhage, were observed in the older group (11.8%, p = 0.225). CONCLUSION: Based on our results, STN DBS can be applied in well-selected older patients with PD as well as in younger patients. However, despite the lack of statistical significance, more attention should be paid on surgical complications in the older group.

Severe Hemifacial Spasm is a Predictor of Severe Indentation and Facial Palsy after Microdecompression Surgery.

BACKGROUND AND PURPOSE: Hemifacial spasm (HFS) is mostly caused by the compression of the facial nerve by cerebral vessels, but the significance of spasm severity remains unclear. We investigated the clinical significance of spasm severity in patients with HFS who underwent microvascular decompression (MVD). METHODS: We enrolled 636 patients with HFS who underwent MVD between May 2010 and December 2013 at Samsung Medical Center (SMC), Seoul, Korea. Subjects were divided into two groups based on spasm severity: severe (SMC grade 3 or 4) and mild (SMC grade 1 or 2). We compared demographic, clinical, and surgical data between these two groups. RESULTS: The severe-spasm group was older and had a longer disease duration at the time of MVD compared to the mild-spasm group. Additionally, hypertension and diabetes mellitus were more common in the severe-spasm group than in the mild-spasm group. Regarding surgical findings, there were more patients with multiple offending vessels and more-severe indentations in the severe-spasm group than in the mild-spasm group. Even though the surgical outcomes did not differ, the incidence of delayed facial palsy after MVD was higher in the severe-spasm group than in the mild-spasm group. Logistic regression analysis showed that severe-spasm was correlated with longer disease duration, hypertension, severe indentation, multiple offending vessels, and delayed facial palsy after MVD. CONCLUSIONS: Spasm severity does not predict surgical outcomes, but it can be used as a marker of pathologic compression in MVD for HFS, and be considered as a predictor of delayed facial palsy after MVD.

Outcome of gamma knife thalamotomy in patients with an intractable tremor.

OBJECTIVE: Tremor is a common movement disorder that interferes with daily living. Since the medication for tremor has some limitations, surgical intervention is needed in many patients. In certain patients who cannot undergo aggressive surgical intervention, Gamma Knife thalamotomy (GKT) is a safe and effective alternative. METHODS: From June 2012 to August 2013, 7 patients with an intractable tremor underwent GKT. Four of these 7 patients had medical comorbidities, and 3 patients refused to undergo traditional surgery. Each patient was evaluated with the modified Fahn-Tolosa-Marin tremor rating scale (TRS) along with analysis of handwriting samples. All of the patients underwent GKT with a maximal dose of 130 Gy to the left ventralis intermedius (VIM) nucleus of the thalamus. Follow-up brain MRI was performed after 3 to 8 months of GKT, and evaluation with the TRS was also performed. RESULTS: Six patients showed objective improvement in the TRS score. Excluding one patient who demonstrated tremor progression, there was 28.9% improvement in the TRS score. However, five patients showed subjective improvement in their symptoms. On comparing the TRS scores between follow-up periods of more and less than 4 months, the follow-up TRS score at more than 4 months of GKT was significantly improved compared to that at less than 4 months of GKT. Follow-up MRI showed radiosurgical changes in 5 patients. CONCLUSION: GKT with a maximal dose of 130 Gy to the VIM is a safe procedure that can replace other surgical procedures.

Short and long term outcome of bilateral pallidal stimulation in chorea-acanthocytosis.

BACKGROUND: Chorea-acanthocytosis (ChAc) is a neuroacanthocytosis syndrome presenting with severe movement disorders poorly responsive to drug therapy. Case reports suggest that bilateral deep brain stimulation (DBS) of the ventro-postero-lateral internal globus pallidus (GPi) may benefit these patients. To explore this issue, the present multicentre (n=12) retrospective study collected the short and long term outcome of 15 patients who underwent DBS. METHODS: Data were collected in a standardized way 2-6 months preoperatively, 1-5 months (early) and 6 months or more (late) after surgery at the last follow-up visit (mean follow-up: 29.5 months). RESULTS: Motor severity, assessed by the Unified Huntington's Disease Rating Scale-Motor Score, UHDRS-MS), was significantly reduced at both early and late post-surgery time points (mean improvement 54.3% and 44.1%, respectively). Functional capacity (UHDRS-Functional Capacity Score) was also significantly improved at both post-surgery time points (mean 75.5% and 73.3%, respectively), whereas incapacity (UHDRS-Independence Score) improvement reached significance at early post-surgery only (mean 37.3%). Long term significant improvement of motor symptom severity (≥ 20 % from baseline) was observed in 61.5 % of the patients. Chorea and dystonia improved, whereas effects on dysarthria and swallowing were variable. Parkinsonism did not improve. Linear regression analysis showed that preoperative motor severity predicted motor improvement at both post-surgery time points. The most serious adverse event was device infection and cerebral abscess, and one patient died suddenly of unclear cause, 4 years after surgery. CONCLUSION: This study shows that bilateral DBS of the GPi effectively reduces the severity of drug-resistant hyperkinetic movement disorders such as present in ChAc.

Safety and effectiveness of microvascular decompression for the treatment of hemifacial spasm in the elderly.

BACKGROUND: Hemifacial spasm (HFS) is a common disorder and has a significant impact on the quality of life. Microvascular decompression (MVD) is an effective and safe treatment option for patients with HFS, however the effectiveness and safety of MVD in elderly patients with HFS is not clear. METHODS: We enrolled 699 HFS patients who underwent MVD from February 2008 to December 2011 at the Samsung Medical Center in Seoul, Korea. Subjects were divided into two groups: an elderly group (patients who were 60 years old or older) and a younger group. We compared demographic and clinical data, surgical outcome and complications after MVD between the groups. RESULTS: The elderly group had more severe spasms and higher grade indentation than the younger group. Multiple offending vessels were more commonly detected in the elderly group. Although the improvement was similar 6 months after MVD between the groups, complications were more common in the elderly group even after controlling for possible confounding factors. In particular, ear problems including hearing loss were more common in the elderly group. CONCLUSION: MVD is an effective treatment option in elderly patients with HFS. However, surgeons should be pay attention to potential complications in elderly patients with HFS.

Characteristics of neurological Wilson's disease without Kayser-Fleischer ring.

BACKGROUND: Although Kayser-Fleischer ring has been regarded as a key diagnostic feature of neurologic Wilson's disease, there have been previous reports of neurologic Wilson's disease patients without Kayser-Fleischer ring. We assessed the characteristics of neurologic Wilson's disease patients without Kayser-Fleischer ring. METHODS: We enrolled neurologic Wilson's disease patients from 4 university hospitals by review of medical records in this study. Patients with neurologic Wilson's disease were diagnosed based on the neurologic symptoms and international scoring system for the diagnosis of Wilson's disease. All subjects were divided into two groups according to the presence of a Kayser-Fleischer ring. We compared demographic data, laboratory findings and imaging findings of the liver and brain between the two groups. RESULTS: There were 12 (26.7%) patients without Kayser-Fleischer ring out of a total of 45 neurologic Wilson's disease patients. The Wilson's disease patients without Kayser-Fleischer ring demonstrated a higher ceruloplasmin concentration and serum copper level than those with Kayser-Fleischer ring. In addition, liver cirrhosis and typical signal changes in brain magnetic resonance imaging were less common in neurologic Wilson's disease patients without Kayser-Fleischer ring. CONCLUSION: Based on our results, the absence of Kayser-Fleischer ring can be regarded as a form of neurologic Wilson's disease with less copper involvement. In addition, it is important to understand these features and to perform further investigations if patients without Kayser-Fleischer ring are suspected of having neurologic Wilson's disease.

A Korean Parkinson's disease family with the LRRK2 p.Tyr1699Cys mutation showing clinical heterogeneity.

BACKGROUND: Although leucine-rich repeat kinase 2 (LRRK2) is the gene most commonly linked to autosomal dominant inherited Parkinson's disease (PD), there have been few reports in Asia, probably because of population-specific differences in allele frequencies. METHODS: We identified a large Korean PD family with the p.Tyr1699Cys mutation in LRRK2 and analyzed genealogical, clinical, and genetic data from the family. RESULTS: Although the clinical findings of these patients were indistinguishable from those of patients with sporadic PD, the patients with the p.Tyr1699Cys mutation demonstrated clinical heterogeneity including differences in age at onset, rate of disease progression, clinical phenotype, and prognosis. CONCLUSIONS: This is the first report describing an Asian PD family with the p.Tyr1699Cys mutation in LRRK2. The affected members of this family showed clinical heterogeneity.

Association between parkinsonism and participation in agriculture in Korea.

BACKGROUND AND PURPOSE: Environmental factors might influence the pathogenesis of Parkinson's disease (PD) or multiple-system atrophy (MSA), and previous examinations of pesticide exposure, well-water drinking, and farming have produced inconclusive results. Because agriculture has been of considerable importance to Korean society, and hence the risk of exposure to pesticides was high in Korea, this study investigated whether such exposure is associated with elevated risks of developing PD and MSA. METHODS: Two hundred and thirty-five PD patients, 133 MSA patients, and 77 normal control subjects were examined. Data concerning environmental factors were collected by face-to-face interviews using a structured questionnaire. Odds ratios (ORs) were calculated by binary logistic regression. RESULTS: ORs for environmental risk factors for developing PD were 1.06 [95% confidence interval (CI) = 1.02-1.10] for age and 2.37 (95% CI = 1.32-4.27) for rural well-water drinking for >10 years. Smoking >10 pack-years (OR = 0.31; 95% CI = 0.11-0.64) was a preventable factor for developing PD in this study. However, no significant risk factors were identified for MSA. CONCLUSIONS: These results suggest that exposure to certain environmental risk factors plays a role in the development of PD. However, the development of MSA appears to be independent of environmental risk factors in Korean patients.

A patient with proximal myotonic myopathy and parkinsonism.

INTRODUCTION: There are two case reports of patients who had proximal myotonic myopathy (PROMM)/myotonic dystrophy (DM) Type 1 and parkinsonism. The combination of myotonic myopathy and parkinsonism is so rare that it may appear to be just a coincidence. However, previous neuropathological examinations of patients who had myotonic dystrophy showed that there were intracytoplasmic inclusion bodies in the nigra and striatum, which raises the possibility that myotonic myopathy may be associated with parkinsonism. In this report we describe a patient with PROMM and a clinically definite parkinsonism to highlight this possibility. CASE REPORT: A 65-year-old man developed proximal muscle weakness, myotonia and atrophy around the age of 55 and was diagnosed as having PROMM at the age of 62. Needle electromyography and muscle biopsy supported the diagnosis. A gene study of the DM Type 1 showed a normal CTG repeat length. At age 63, he developed rest tremor, bradykinesia, hypomimia, stooped posture, and gait disturbance. The postural instability worsened rapidly. The tremor and rigidity were much worse in his right side, where myotonia was more severe. Levodopa therapy was only partially effective. CONCLUSION: This is a case report of a patient with PROMM that shows an association with a rapidly progressive form of parkinsonism. We suggest that this may be a novel form of a neurodegenerative disorder, which we name 'Parkinsonism-Myotonic Myopathy-Complex'.