Ocular motor and vestibular dysfunction in central nervous system lymphoma.

BACKGROUND AND PURPOSE: Diagnosis of lymphoma involving the central nervous system (CNS) is challenging. This study aimed to explore the abnormal vestibular and ocular motor findings in CNS lymphoma. METHODS: A retrospective search of the medical records identified 30 patients with CNS lymphoma presenting ocular motor and vestibular abnormalities from four neurology clinics of university hospitals in South Korea (22 men, age range 14-81 years, mean 60.6 ± 15.2). The demographic and clinical features and the results of laboratory, radiological and pathological evaluation were analyzed. RESULTS: Patients presented with diplopia (13/30, 43%), vestibular symptoms (15/30, 50%) or both (2/30, 7%). In 15 patients with diplopia, abnormal ocular motor findings included ocular motor nerve palsy (n = 10, 67%), internuclear ophthalmoplegia (n = 2, 13%), external ophthalmoplegia (n = 2, 13%) and exophoria (n = 1, 7%). The vestibular abnormalities were isolated in 14 (82%) of 17 patients with vestibular symptoms and included combined unilateral peripheral and central vestibulopathy in three from lesions involving the vestibular nuclei. CNS lymphoma involved the brainstem (53%), cerebellum (33%), leptomeninges (30%), deep gray nuclei (23%) or cranial nerves (17%). Two patients showed the "double-panda" sign by involving the midbrain. CONCLUSIONS: This study expands the clinical and radiological spectra of CNS lymphoma. Neuro-ophthalmological and neuro-otological evaluation may guide the early diagnosis of CNS lymphoma.

Ocular Motor Findings Aid in Differentiation of Spinocerebellar Ataxia Type 17 from Huntington's Disease.

Differentiation of spinocerebellar ataxia type 17 (SCA17) from Huntington's disease (HD) is often challenging since they share the clinical features of chorea, parkinsonism, and dystonia. The ocular motor findings remain to be elucidated in SCA17, and may help differentiating SCA17 from HD. We retrospectively compared the ocular motor findings of 11 patients with SCA17 with those of 10 patients with HD. In SCA17, abnormal ocular motor findings included impaired smooth pursuit (9/11, 82%), dysmetric saccades (9/11, 82%), central positional nystagmus (CPN, 7/11, 64%), abnormal head-impulse tests (4/11, 36%), and horizontal gaze-evoked nystagmus (GEN, 3/11, 27%). Among these, CPN was more frequently observed in SCA17 than in HD (7/11 (64%) vs. 0/10 (0%), p = 0.004) while saccadic slowing was more frequently observed in HD than in SCA17 (8/10 (80%) vs. 2/11 (18%), p = 0.009). Of six patients with follow-up evaluation, five later developed bilateral saccadic hypermetria (n = 4), GEN (n = 1), CPN (n = 1), bilaterally abnormal smooth pursuit (n = 1), and hyperactive head-impulse responses (n = 1) along with a clinical decline. Ocular motor abnormalities can be utilized as a diagnostic marker for differentiation of SCA17 from HD as well as a surrogate marker for clinical decline in SCA17.

A Novel TFG Mutation in a Korean Family with α-Synucleinopathy and Amyotrophic Lateral Sclerosis.

BACKGROUND: Tropomyosin-receptor kinase fused gene (TFG) functions as a regulator of intracellular protein packaging and trafficking at the endoplasmic reticulum exit sites. TFG has recently been proposed as a cause of multisystem proteinopathy. OBJECTIVES: Here, we describe a Korean family presenting with Parkinson's disease or amyotrophic lateral sclerosis caused by a novel variant of TFG (c.1148 G > A, p.Arg383His). METHODS: We collected clinical, genetic, dopamine transporter imaging, nerve conduction, and electromyography data from the seven subjects. To verify the pathogenicity of the R383H variant, we studied cell viability and the abnormal aggregation of α-synuclein and TAR DNA-binding protein 43 (TDP-43) in HeLa cells expressing R383H-TFG. RESULTS: The clinical phenotypes of the R383H-TFG mutation varied; of the five family members, one had Parkinson's disease, three had subclinical parkinsonism, and one (the proband) had amyotrophic lateral sclerosis. The individual with multiple system atrophy was the proband's paternal cousin, but the TFG genotype was not confirmed due to unavailability of samples. Our in vitro studies showed that R383H-TFG overexpression impaired cell viability. In cells co-expressing R383H-TFG and α-synuclein, insoluble α-synuclein aggregates increased in concentration and were secreted from the cells and co-localized with R383H-TFG. The levels of cytoplasmic insoluble aggregates of TDP-43 increased in HeLa cells expressing R383H-TFG and co-localized with R383H-TFG. CONCLUSIONS: Clinical and in vitro studies have supported the pathogenic role of the novel TFG mutation in α-synucleinopathy and TDP-43 proteinopathy. These findings expand the phenotypic spectrum of TFG and suggest a pivotal role of endoplasmic reticulum dysfunction during neurodegeneration. © 2021 International Parkinson and Movement Disorder Society.

A prospective multi-centre study of susceptibility map-weighted MRI for the diagnosis of neurodegenerative parkinsonism.

OBJECTIVES: This study aimed to compare susceptibility map-weighted imaging (SMwI) using various MRI machines (three vendors) with N-3-fluoropropyl-2-ß-carbomethoxy-3-ß-(4-iodophe nyl)nortropane (18F-FP-CIT) PET in the diagnosis of neurodegenerative parkinsonism in a multi-centre setting. METHODS: We prospectively recruited 257 subjects, including 157 patients with neurodegenerative parkinsonism, 54 patients with non-neurodegenerative parkinsonism, and 46 healthy subjects from 10 hospitals between November 2019 and October 2020. All participants underwent both SMwI and 18F-FP-CIT PET. SMwI was interpreted by two independent reviewers for the presence or absence of abnormalities in nigrosome 1, and discrepancies were resolved by consensus. 18F-FP-CIT PET was used as the reference standard. Inter-observer agreement was tested using Cohen's kappa coefficient. McNemar's test was used to test the agreement between the interpretations of SMwI and 18F-FP-CIT PET per participant and substantia nigra (SN). RESULTS: The inter-observer agreement was 0.924 and 0.942 per SN and participant, respectively. The diagnostic sensitivity of SMwI was 97.9% and 99.4% per SN and participant, respectively; its specificity was 95.9% and 95.2%, respectively, and its accuracy was 97.1% and 97.7%, respectively. There was no significant difference between the results of SMwI and 18F-FP-CIT PET (p > 0.05, for both SN and participant). CONCLUSIONS: This study demonstrated that the high diagnostic performance of SMwI was maintained in a multi-centre setting with various MRI scanners, suggesting the generalisability of SMwI for determining nigrostriatal degeneration in patients with parkinsonism. KEY POINTS: • Susceptibility map-weighted imaging helps clinicians to predict nigrostriatal degeneration. • The protocol for susceptibility map-weighted imaging can be standardised across MRI vendors. • Susceptibility map-weighted imaging showed diagnostic performance comparable to that of dopamine transporter PET in a multi-centre setting with various MRI scanners.

Longitudinal Changes in Isolated Rapid Eye Movement Sleep Behavior Disorder-Related Metabolic Pattern Expression.

BACKGROUND: It remains unclear whether and how the isolated rapid eye movement (REM) sleep behavior disorder (iRBD)-related metabolic pattern (RBDRP) changes with disease progression in iRBD. OBJECTIVE: To examine longitudinal changes in RBDRP expression in iRBD patients and to explore trajectories of relative metabolic activities of individual brain regions constituting RBDRP. METHODS: In this cohort study, 25 iRBD patients (mean age [±standard deviation], 69.2 ± 5.3 years; 12 [48%] patients were men) and 24 age-matched healthy controls were included. The patients underwent at least two 18 F-fluorodeoxyglucose positron emission tomography scans at baseline and at the 2-year and/or 4-year follow-ups. We measured the RBDRP expression of the patients and controls which was validated by reproduction in a separate iRBD cohort (n = 13). RESULTS: At baseline, the RBDRP expression discriminated iRBD patients from healthy controls. However, the RBDRP expression z scores tended to decrease over time in the patients, especially with longer follow-ups, and this tendency was observed even in patients with high-risk of phenoconversion. Furthermore, the degree of RBDRP expression at baseline did not predict the disease conversion. The RBDRP breakdown was mainly provoked by the attenuation of relative hypermetabolism in the frontal cortex including premotor areas and relative hypometabolism in the occipital cortex. The putaminal metabolic activity increased steadily with the disease progression. CONCLUSIONS: The RBDRP expression in iRBD patients was altered significantly over time. Some of the brain metabolic changes seem to represent attempted functional compensation against ongoing neurodegeneration. The RBDRP expression measurement at one time point may not be a reliable biomarker for predicting disease conversion. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

An autopsy-proven case of Corticobasal degeneration heralded by Pontine infarction.

BACKGROUND: Neurodegenerative disorders are characterized by insidious progression with poorly-delineated long latent period. Antecedent clinical insult could rarely unmask latent neurodegenerative disorders. Here, we report an autopsy-proven case of corticobasal degeneration which was preceded by a lacunar infarction. CASE PRESENTATION: A 58-year-old man presented with acute ataxia associated with a lacunar infarction in the right paramedian pons. His ataxia persisted with additional progressive gait difficulty and left arm clumsiness. Six months later, a follow-up neurological examination showed asymmetrical bradykinesia, apraxia, dystonic posturing, postural instability, and mild ataxia of the left limbs. Cognitive examination revealed frontal executive dysfunction and visuospatial difficulties. Dopamine transporter imaging scan demonstrated bilateral reduced uptakes in mid-to-posterior putamen, more prominent on the right side. Levodopa-unresponsive parkinsonism, asymmetric limb dystonia, and ideomotor apraxia became more conspicuous, while limb ataxia gradually vanished. The patient became unable to walk without assistance after 1 year, and died 4 years after the symptom onset. Autopsy findings showed frontoparietal cortical atrophy, ballooned neurons, and phosphorylated tau-positive astrocytic plaques and neuropil threads with gliosis and neuronal loss, confirming the corticobasal degeneration. CONCLUSIONS: The case illustrates that precedent clinical events such as stroke might tip a patient with subclinical CBS into overt clinical manifestations.

Replication-Based Rearrangements Are a Common Mechanism for SNCA Duplication in Parkinson's Disease.

BACKGROUND: SNCA multiplication is a genomic cause of familial PD, showing dosage-dependent toxicity. Until now, nonallelic homologous recombination was suggested as the mechanism of SNCA duplication, based on various types of repetitive elements found in the spanning region of the breakpoints. However, the sequence at the breakpoint was analyzed only for 1 case. OBJECTIVES: We have analyzed the breakpoint sequences of 6 patients with PD who had duplicated SNCA using whole-genome sequencing data to elucidate the mechanism of SNCA duplication. METHODS: Six patient samples with SNCA duplication underwent whole-genome sequencing. The duplicated regions were defined with nucleotide-resolution breakpoints, which were confirmed by junction polymerase chain reaction and Sanger sequencing. The search for potential non-B DNA-forming sequences and stem-loop structure predictions was conducted. RESULTS: Duplicated regions ranged from the smallest region of 718.3 kb to the largest one of 4,162 kb. Repetitive elements were found at 8 of the 12 breakpoint sequences on each side of the junction, but none of the pairs shared overt homologies. Five of these six junctions had microhomologies (2-4 bp) at the breakpoint, and a short stretch of sequences was inserted in 3 cases. All except one junction were located within or next to stem-loop structures. CONCLUSION: Our study has determined that homologous recombination mechanisms involving repetitive elements are not the main cause of the duplication of SNCA. The presence of microhomology at the junctions and their position within stem-loop structures suggest that replication-based rearrangements may be a common mechanism for SNCA amplification. © 2020 International Parkinson and Movement Disorder Society.

Late-life falling and depressive symptoms associated with the risk of Parkinson's disease: a nationwide cohort data analysis.

BACKGROUND: This study aimed to evaluate the relationship between the history of late-life falling and the development of Parkinson's disease (PD) and investigate whether depressive symptoms interact with falling to increase PD risk. METHODS: We identified 1,223,726 subjects without PD who underwent the National Screening Program for Transitional Age at 66 years between 2009 and 2013 using the National Health Cohort database. In this program, every participant was assessed whether they experienced falling for the past six months. Depressive symptoms were evaluated with a three-item questionnaire extracted from the Geriatric Depression Scale. Incident PD was traced for a mean 4.23 ± 1.50 years. Cox proportional hazard regression models were used to assess the risk of PD by falling history with and without depressive symptoms after adjusting for other confounding variables. RESULTS: In this cohort, the PD incidence rate was 1.30 and 1.03 cases per 1000 person-years in groups with and without falling and 1.34 and 1.00 cases per 1000 person-years in groups with and without depressive symptoms. The predictive risk of PD was increased by either a history of falling (HR = 1.24; 95% CI 1.11-1.40) or the presence of depressive symptoms (HR = 1.31; 95% CI 1.21-1.42) after adjusting for possible confounding variables. For individuals with both falling and depressive symptoms, PD risk increased further (HR = 1.66; 95% CI 1.40-1.97), but with sex-differences. The two factors increased PD risk in a sub-additive manner in men, whereas synergistically in women. CONCLUSIONS: This national cohort database shows that late-life depressive symptoms accompanied by a falling event pose an increase in the risk of PD in older adults.

Alternating Hemiplegia of Childhood in Korea: a Case Report.

Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental disorder characterized by recurrent paroxysmal hemiplegic attacks that affect one or the other side of the body. Up to 74% of patients with AHC have a pathologic variant in the ATP1A3 gene. After the introduction of next-generation sequencing, intermediate cases and atypical cases have expanded the clinical spectrum of ATP1A3-related disorders. Herein, we report the first case of AHC in Korea. A 33-year-old man visited our hospital with recurrent hemiplegic and dystonic episode after his first birthday. He was completely normal between episodes and did not have any ataxia, but brain magnetic resonance imaging showed cerebellar atrophy. He also had pes planovalgus deformity. Whole exome sequencing revealed a heterozygous G947R variant in the ATP1A3 gene (c.2839G > C, rs398122887), which is a known pathologic variant. This atypical case of AHC demonstrates the importance of the clinical approach in diagnosing ATP1A3-related disorders.

Determinants of Functional Independence or Its Loss following Subthalamic Nucleus Stimulation in Parkinson's Disease.

OBJECTIVE: This study aimed to describe the change in functional status following bilateral subthalamic nucleus stimulation (STN-DBS) in Parkinson's disease (PD) and to identify predictors of postoperative functional dependence. METHODS: We included PD patients with bilateral STN-DBS who had complete Schwab & England Activities of Daily Living (S&E ADL) Scale data at baseline and 6 months after surgery from our prospective registry. Functional dependence was defined as an S&E ADL score of less than 80%. All data were collected from the on-medication state and on-stimulation state (after surgery). Logistic regression analyses were performed to determine the factors predictive of functional dependence after surgery. RESULTS: A total of 196 patients were included. At baseline, 41 patients were functionally dependent and the other 155 were functionally independent. Among the patients with preoperative dependence, 32 (78%) became functionally independent after surgery, and this conversion was associated with a lower baseline axial score (p = 0.012). Among the patients with preoperative independence, 21 (14%) developed postoperative dependence, and this conversion was associated with a higher baseline axial score (p = 0.013) and its smaller improvement (p < 0.001). Female sex (odds ratio [OR] 3.214; 95% confidence interval [CI] 1.210-8.542; p = 0.019) and a higher baseline axial score (OR 1.184; 95% CI 1.056-1.327; p = 0.004) significantly predicted the risk of postoperative functional dependence. CONCLUSIONS: We found that functional status following bilateral STN-DBS is closely related to preoperative axial symptoms. When loss of independence is a potential target for STN-DBS, clinicians should take into consideration the severity of axial impairment before surgery.

Various Motor and Non-Motor Symptoms in Early Multiple System Atrophy.

BACKGROUND: Multiple system atrophy (MSA) patients pre-sent a variety of symptoms other than autonomic dysfunctions, parkinsonism, and cerebellar ataxia. The aim of this study was to evaluate the frequency of various motor and non-motor symptoms including so-called "red flags" in patients with early MSA and to determine whether the frequency of these symptoms was different between the parkinsonian (MSA-P) and cerebellar (MSA-C) subtypes. METHODS: Sixty-one probable or possible MSA patients with disease duration of 3 years or less were included. Patients were classified into MSA-P, MSA-C, and MSA-PC. The frequency of 13 features including various motor and non-motor symptoms that commonly occur in MSA was assessed. RESULTS: Dysarthria was the most prevalent feature (98.4%) followed by sexual dysfunction (95.1%). Probable REM sleep behavior disorder was present in 90.2%. The frequency of constipation (82.0%), dysphagia (68.9%), and snoring (70.5%) was also high. Stridor was present in 42.6% and more common in MSA-C than in MSA-P. CONCLUSIONS: Increasing awareness of various motor and non-motor symptoms may assist clinicians to make an early, accurate diagnosis and to improve management of patients with MSA. We suggest that the diagnostic accuracy can be improved if these features are appropriately reflected in the new diagnostic criteria for MSA.

Survey of the Knowledge, Attitudes, and Practices of Neurologists Regarding Exercise in Parkinson's Disease.

BACKGROUND AND PURPOSE: Exercise and physiotherapy can exert potentially beneficial effects on the motor and nonmotor features of Parkinson's disease (PD). We conducted an e-mail survey to assess the knowledge, attitudes, and practices of neurologists regarding exercise among patients with PD. METHODS: A total of 222 neurologists from the Korean Movement Disorder Society and the Korean Society of Neurologists completed the survey and were classified into 4 clusters using the k-means clustering algorithm based on their institute types, the proportions of PD patients in their clinics, and the number of years working as neurologists. RESULTS: Specialists working at referral hospitals (Clusters 1 and 2) were more confident than general neurologists (Clusters 3 and 4) about exercise improving the general motor features of PD. Specialists recommended more-frequent intense exercise compared with physicians not working at referral hospitals. The specialists in Cluster 1, representing >50% of PD patients in the clinics at referral hospitals, recommended exercise regardless of the disease stage, whereas the general neurologists in Clusters 3 and 4 recommended low-intensity exercise at an early stage of disease. Although most of the respondents agreed with the need for PD patients to exercise, less than half had prescribed rehabilitation or physiotherapy. More than 90% of the respondents answered that developing an exercise/physiotherapy protocol for PD would be helpful. CONCLUSIONS: Specialists were more confident than general neurologists about the effect of exercise and recommended more-intense activities regardless of the disease stage. These results highlight the need to develop clinical practice guidelines and PD-specialized exercise protocols to provide optimal care for PD patients.

Trends in Physiotherapy Interventions and Medical Costs for Parkinson's Disease in South Korea, 2011-2020.

Objective: Physiotherapy (PT), an effective strategy for managing Parkinson's disease (PD), can influence healthcare utilization. We analyzed trends in healthcare utilization, PT interventions, and medical costs among patients with PD. Methods: Using data from the Korean National Health Insurance Service from 2011 to 2020, we analyzed the number of patients with PD and their healthcare utilization and assessed the odds ratio (OR) for receiving regular PTs. Results: Over 10 years, 169,613 patients with PD were present. The number of patients with PD increased annually from 49,417 in 2011 to 91,841 in 2020. Patients with PD receiving PT increased from 4,847 (9.81%) in 2011 to 13,163 (14.33%) in 2020, and PT prescriptions increased from 81,220 in 2011 to 377,651 in 2019. Medical costs per patient with PD have increased from 1,686 United States Dollars (USD) in 2011 to 3,201 USD in 2020. Medical expenses for each patient with PD receiving PT increased from 6,581 USD in 2011 to 13,476 USD in 2020. Moreover, Regular PTs were administered to 31,782 patients (18.74%) and conducted only through hospitalization. Those in their 50s with disabilities demonstrated a high OR for regular PTs, while those aged 80 years or older and residing outside Seoul had a low OR. Conclusions: The PD burden increased in South Korea between 2011 and 2020, including an increase in healthcare utilization and medical costs. The significant rise in medical expenses can be associated with increased PD prevalence and PT interventions. Regular PT applications remain restricted and have barriers to access.

Impaired cognitive flexibility and disrupted cognitive cerebellum in degenerative cerebellar ataxias.

There is a clinically unmet need for a neuropsychological tool that reflects the pathophysiology of cognitive dysfunction in cerebellar degeneration. We investigated cognitive flexibility in degenerative cerebellar ataxia patients and aim to identify the pathophysiological correlates of cognitive dysfunction in relation to cerebellar cognitive circuits. We prospectively enrolled degenerative cerebellar ataxia patients with age-matched healthy controls who underwent 3 T 3D and resting-state functional MRI. All 56 participants were evaluated with the Scale for Assessment and Rating of Ataxia and neuropsychological tests including the Wisconsin Card Sorting Test, Trail Making Test, Montreal Cognitive Assessment and Mini-Mental State Examination. From MRI scans, we analysed the correlation of whole-brain volume and cortico-cerebellar functional connectivity with the Wisconsin Card Sorting Test performances. A total of 52 participants (29 ataxia patients and 23 healthy controls) were enrolled in this study. The Wisconsin Card Sorting Test scores (total error percentage, perseverative error percentage, non-perseverative error percentage and categories completed), Trail Making Test A and Montreal Cognitive Assessment were significantly impaired in ataxia patients (P < 0.05) compared to age-matched healthy controls. The Wisconsin Card Sorting Test error scores showed a significant correlation with the ataxia score (P < 0.05) controlling for age and sex. In volumetric analysis, the cerebellar right crus I, II, VIIb and VIII atrophy correlated with non-perseverative error percentage in the ataxia group. In functional connectivity analysis, the connectivity between crus I, II and VIIb of the cerebellum and bilateral superior parietal and superior temporal gyrus was significantly altered in ataxia patients. The functional connectivity between left crus II and VIIb of the cerebellum and dorsolateral prefrontal and superior frontal/parietal cortices showed a positive correlation with perseverative error percentage. The connectivity between left crus VIIb and pontine nucleus/middle cerebellar peduncle showed a significant negative correlation with non-perseverative error percentage in the ataxia group. The impaired cognitive flexibility represented by the Wisconsin Card Sorting Test was significantly impaired in degenerative cerebellar ataxia patients and correlated with disease severity. The Wisconsin Card Sorting Test performance reflects hypoactivity of the cognitive cerebellum and disrupted cortico-cerebellar connectivity in non-demented patients with degenerative cerebellar ataxia.

Profiling Analysis of Tryptophan Metabolites in the Urine of Patients with Parkinson's Disease Using LC-MS/MS.

Although Parkinson's disease (PD) is a representative neurodegenerative disorder and shows characteristic motor impediments, the pathophysiological mechanisms and treatment targets for PD have not yet been clearly identified. Since several tryptophan metabolites produced by gut microbiota could pass the blood-brain barrier and, furthermore, might influence the central nervous system, tryptophan metabolites within the indole, kynurenine, and serotonin metabolic pathways might be the most potent targets for PD development. Furthermore, most metabolites are circulated via the blood, play roles in and/or are metabolized via the host organs, and finally are excreted into the urine. Therefore, profiling the overall tryptophan metabolic pathways in urine samples of patients with PD is important to understanding the pathological mechanisms, finding biomarkers, and discovering therapeutic targets for PD. However, the development of profiling analysis based on tryptophan metabolism pathways in human urine samples is still challenging due to the wide physiological ranges, the varied signal response, and the structural diversity of tryptophan metabolites in complicated urine matrices. In this study, an LC-MS/MS method was developed to profile 21 tryptophan metabolites within the indole, kynurenine, and serotonin metabolic pathways in human urine samples using ion-pairing chromatography and multiple reaction monitoring determination. The developed method was successfully applied to urine samples of PD patients (n = 41) and controls (n = 20). Further, we investigated aberrant metabolites to find biomarkers for PD development and therapeutic targets based on the quantitative results. Unfortunately, most tryptophan metabolites in the urine samples did not present significant differences between control and PD patients, except for indole-3-acetic acid. Nonetheless, indole-3-acetic acid was reported for the first time for its aberrant urinary levels in PD patients and tentatively selected as a potential biomarker for PD. This study provides accurate quantitative results for 21 tryptophan metabolites in biological samples and will be helpful in revealing the pathological mechanisms of PD development, discovering biomarkers for PD, and further providing therapeutic targets for various PD symptoms. In the near future, to further investigate the relationship between gut microbial metabolites and PD, we will employ studies on microbial metabolites using plasma and stool samples from control and PD patients.

Lambert-Eaton myasthenic syndrome (LEMS) in a patient with lung cancer under treatment with pembrolizumab: a case study.

Pembrolizumab is an immune checkpoint inhibitor (ICI) against the programmed death-1 receptor. Herein, we introduce a rare adverse effect during using pembrolizumab. We present the case of an 80-year-old man with biopsy-proven unresectable double primary squamous cell carcinoma and large cell neuroendocrine carcinoma of the lung. After using pembrolizumab for 10 months, he complained of muscle weakness of both upper and lower extremities. In a nerve conduction study, the repetitive nerve stimulation test in the abductor digiti minimi was diagnostic of Lambert-Eaton myasthenic syndrome (LEMS): low in the amplitude of compound muscle action potential (1.4 mV), 28.6% decrement in the 5-Hz stimulation, and 579% increment in the 50-Hz stimulation. The disease did not progress after the discontinuation of pembrolizumab, even without any anti-cancer treatment for 12 months. We believe our clinical experience of this rare and unexpected adverse effect should be shared.

Parainfectious Anti-Glial Fibrillary Acidic Protein-Associated Meningoencephalitis.

Movement disorders associated with glial fibrillary acidic protein (GFAP) autoantibodies have rarely been reported as ataxia or tremors. A 32-year-old man with headache and fever, initially diagnosed with viral meningoencephalitis, showed gradual improvement with empirical treatment. Two weeks after the illness, he suddenly developed orofacial, tongue, and neck dyskinesia accompanied by oculomotor abnormalities, which developed into severe generalized choreoballism. Brain magnetic resonance imaging (fluid-attenuated inversion recovery) showed signal hyperintensities in the bilateral globus pallidus interna. The clinical picture suggested an acute inflammatory trigger of secondary autoimmune encephalitis. The autoimmune antibody test was positive for GFAP, with the strongest reactivity in the cerebrospinal fluid (CSF) before treatment and decreased reactivity in serial CSF examinations during immunotherapy. Dyskinesia gradually improved to the extent that it could be controlled with only oral medications. This patient presented with parainfectious GFAP meningoencephalitis with distinctive clinical features and imaging findings.