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Objective To examine interactions between cortical areas and between cortical areas and muscles during sensory tricks in cervical dystonia (CD). Methods Thirteen CD patients and thirteen age-matched healthy controls performed forewarned reaction time tasks, sensory tricks, and two tasks replicating aspects of the tricks (moving necks/arms). Control subjects mimicked sensory tricks. Corticocortical and corticomuscular coherence values were calculated from surface electrodes placed over motor, premotor, and sensory cortical areas and dystonic muscles. Results During initial preparation (after the warning stimulus), the only between-task difference was found in the γ-band corticocortical coherence (higher during tricks than during voluntary neck movements). With movements (before/after the imperative stimulus), the γ-band coherence of CD patients significantly increased during tricks but decreased during voluntary movements, while opposite trends were observed in healthy subjects. Additionally, the α- and β-band coherence decreased in healthy subjects during movements. Between the two patient subgroups (typical vs. forcible tricks), only those with typical tricks showed significant decrease in corticomuscular coherence during tricks. Conclusions Observed changes in the corticocortical coherence suggest that sensory tricks improve cortical function, which reduces corticomuscular connectivity and the dystonia. Significance We demonstrated that sensory tricks fundamentally affect sensorimotor integration in CD, both in movement preparation and execution.

The neural substrates of working memory are spread across prefrontal, parietal and cingulate cortices and are thought to be coordinated through low frequency cortical oscillations in the theta (3 – 8 Hz) and alpha (8 – 12 Hz) frequency bands. While the functional role of many subregions have been elucidated using neuroimaging studies, the role of superior frontal gyrus (SFG) is not yet clear. Here, we combined electrocorticography and direct cortical stimulation in three patients implanted with subdural electrodes to assess if superior frontal gyrus is indeed involved in working memory. We found left SFG exhibited task-related modulation of oscillations in the theta and alpha frequency bands specifically during the encoding epoch. Stimulation at the frequency matched to the endogenous oscillations resulted in reduced reaction times in all three participants. Our results support the causal role of SFG in working memory and suggest that SFG may coordinate working memory through low-frequency oscillations thus bolstering the feasibility of targeting oscillations for restoring cognitive function.

Introduction Although sensory tricks are well known as the maneuvers that temporarily relieve dystonic symptoms in patients with cervical dystonia (CD), the underlying neurophysiological mechanisms remain unclear. We aimed to investigate brain potentials related to sensory tricks in patients with CD. Methods Thirteen patients with CD and 13 age-matched healthy volunteers participated. The experiment consisted of three conditions (moving the neck, moving an arm, and performing sensory tricks) presented in different blocks in random order in a contingent negative variation (CNV) paradigm. Warning and trigger stimuli (S1 and S2) were presented to the participants, who were instructed to prepare to perform the specific task for each condition after S1, and then to perform the task after S2. Early and late components of the CNV were measured. Results The late CNVs in patients with CD were significantly larger than those in healthy participants in Fz, FCz, Cz, and C3 electrodes. Only in patients with CD, the late CNVs were significantly greater for the ‘sensory tricks’ condition compared to the ‘move neck’ condition in Fz and C3 electrodes. Conclusion The late CNV is increased during sensory tricks in patients with CD, suggesting that sensory tricks may affect mechanisms related to the motor preparatory phase in the premotor and primary motor areas. Sensory tricks may normalize impaired motor preparation in dystonia, leading to improved dystonic symptoms.

Purpose The aim of this study was to investigate the association between autonomic dysfunction and striatal dopamine depletion or metabolic changes in de novo Parkinson disease (PD). Methods Based on the Composite Autonomic Severity Score (CASS), patients with de novo PD were classified into PD with (PD-AUT+) and without autonomic dysfunction (PD-AUT-) groups. We compared the dopamine transporter (DAT) availability in the striatum by quantitatively measuring F-FP-CIT PET between both groups. We also assessed the association between DAT availability and the CASS. In addition, we compared regional uptake in early-phase images of F-FP-CIT PET as well as cortical thickness between the PD-AUT+ and PD-AUT- groups. Results The PD-AUT+ group had significantly lower DAT availability in all striatal subregions than did the PD-AUT- group. The total CASS was significantly correlated with DAT availability in all striatal subregions. In addition, the subscores of the adrenergic component were correlated with DAT availability in all striatal subregions. The subscores of the cardiovagal component were negatively correlated with DAT availability in the caudate and ventral striatum. In early-phase F-FP-CIT PET, the PD-AUT+ group exhibited decreased regional perfusion in the parieto-occipital areas and increased regional perfusion in the pallidothalamic, pontocerebellar, inferior frontal, and primary motor areas compared with the PD-AUT- group. There were no regions of different cortical thickness between the PD groups. Conclusions The present study revealed that autonomic dysfunction is closely linked to striatal dopamine depletion and prominent PD-related perfusion patterns in de novo PD, suggesting a greater pathological burden in patients with dysautonomia.

Purpose Epilepsy surgery is the most successful method of treating medically unresponsive epilepsy, but carries a risk of morbidity. PET/MR is an emerging technique that increases detection of focal lesions whose resection may result in symptom remission. Methods Retrospective review of 74 focal epilepsy patients over a period of 3 years who had a PET/MR was performed following IRB permission and informed consent. 27 patients underwent surgery or RNS (responsive neurostimulator) placement. Results Hybrid PET-MR identified new anatomic or functional lesions in 10 patients not identified with standalone 3 T MR. Of the 27 patients who underwent focal surgery (19) or RNS placement (8), 24 showed improvement (Engel’s I-III), 2 did not (Engel’s IV), and one had an RNS explanted due to infection. MR and PET were read by 2 separate neuroradiologists and nuclear medicine physicians, respectively. Modalities were evaluated in terms of ability to detect the correct lobe and side for a focal lesion whose resection improved symptoms. Prior standalone MR exhibited 71–77% sensitivity and 0% specificity (as there were only 2 nonresponders), MR associated with PET/MR had 68–71% sensitivity and 0–50% specificity (depending on whether a lesion was seen on one of the nonresponders), and PET had 68–71% sensitivity and 25–33% specificity. Using either PET or MR to identify a focal lesion, PET/MR had sensitivity of 78–82% and specificity 0–50%. Conclusions PET-MR provides additional sensitivity when used as two combined modalities for detecting possible epileptic foci.

Author(s): Hirsch, Lawrence J; Mirro, Emily A; Salanova, Vicenta; Witt, Thomas C; Drees, Cornelia N; Brown, Mesha-Gay; Lee, Ricky W; Sadler, Toni L; Felton, Elizabeth A; Rutecki, Paul; Shin, Hae Won; Hadar, Eldad; Hegde, Manu; Rao, Vikram R; Mnatsakanyan, Lilit; Madhavan, Deepak S; Zakaria, Tarek J; Liu, Anli A; Heck, Christianne N; Greenwood, Janet E; Bigelow, Jeffrey K; Nair, Dileep R; Alexopoulos, Andreas V; Mackow, Michael; Edwards, Jonathan C; Sotudeh, Nadia; Kuzniecky, Ruben I; Gwinn, Ryder P; Doherty, Michael J; Geller, Eric B; Morrell, Martha J | Abstract: ObjectiveTo describe seizure outcomes in patients with medically refractory epilepsy who had evidence of bilateral mesial temporal lobe (MTL) seizure onsets and underwent MTL resection based on chronic ambulatory intracranial EEG (ICEEG) data from a direct brain-responsive neurostimulatorn(RNS) system.MethodsWe retrospectively identified all patients at 17 epilepsy centers with MTL epilepsy who were treated with the RNS System using bilateral MTL leads, and in whom an MTL resection was subsequently performed. Presumed lateralization based on routine presurgical approaches was compared to lateralization determined by RNS System chronic ambulatory ICEEG recordings. The primary outcome was frequency of disabling seizures at last 3-month follow-up after MTL resection compared to seizure frequency 3nmonths before MTL resection.ResultsWe identified 157 patients treated with the RNS System with bilateral MTL leads due to presumed bitemporal epilepsy. Twenty-five patients (16%) subsequently had an MTL resection informed by chronic ambulatory ICEEG (meann=n42nmonths ICEEG); follow-up was available for 24 patients. After MTL resection, the median reduction in disabling seizures at last follow-up was 100% (mean: 94%; range: 50%-100%). Nine patients (38%) had exclusively unilateral electrographic seizures recorded by chronic ambulatory ICEEG and all were seizure-free at last follow-up after MTL resection; eight of nine continued RNS System treatment. Fifteen patients (62%) had bilateral MTL electrographic seizures, had an MTL resection on the more active side, continued RNS System treatment, and achieved a median clinical seizure reduction of 100% (mean: 90%; range: 50%-100%) at last follow-up, with eight of fifteen seizure-free. For those with more than 1nyear of follow-up (Nn=n21), 15 patients (71%) were seizure-free during the most recent year, including all eight patients with unilateral onsets and 7 of 13 patients (54%) with bilateral onsets.SignificanceChronic ambulatory ICEEG data provide information about lateralization of MTL seizures and can identify additional patients who may benefit from MTL resection.

Background Parkinson’s disease (PD) and drug-induced parkinsonism (DIP) are the major diseases of parkinsonism. To better understand parkinsonism, we aimed to assess the prevalence and incidence of PD and DIP in Korea from 2012 to 2015. Methods We used the Health Insurance Review and Assessment Service database, which covers the entire population in Korea. We used claims during 2011–2015 to assess epidemiology of PD and DIP during 2012–2015. Retrospective cross-sectional study design was employed to assess prevalence, whereas retrospective cohort study design was used to determine incidence. Patients with at least one claim with ICD-10 G20 and who received antiparkinsonian drugs for at least 60 days were classified as having PD. We excluded patients with antiparkinsonian drugs that can be used for indications other than PD. Patients with at least one claim with ICD-10 G211 or G251 during the prescription period of drugs that are frequently related with DIP were classified as having DIP. Incident cases had a disease-free period of 1 year before diagnosis. To evaluate the significance of changes in the prevalence or incidence over time, Poisson regression was used to determine p for trend. Results The prevalence of PD increased from 156.9 per 100,000 persons in 2012 to 181.3 per 100,000 persons in 2015 (p for trendp for trendp for trendp for trend Conclusions Our study suggests that the incidence of PD has gradually decreased whereas, the incidence of DIP increased from 2012 to 2015. Further studies are warranted to examine possible causes of increased DIP incidence in order to develop management strategy for parkinsonism.

The cerebellum has recently been highlighted as a key neural substrate responsible for dystonia. A 57-year-old female presented with isolated focal leg dystonia that developed 8 years after acute cerebellar infarction. Brain magnetic resonance imaging showed an old cerebellar infarct in the right anterior cerebellum. Low-frequency cerebellar repetitive transcranial magnetic stimulation on the right cerebellum partially improved dystonia in this patient. This case provides valuable evidence on cerebellar mechanisms related to the development of dystonia in a topographically specific manner. Cerebellar brain stimulation can be a potential therapeutic strategy for patients with dystonia.

Summary: Working memory is mediated by the coordinated activation of frontal and parietal cortices occurring in the theta and alpha frequency ranges. Here, we test whether electrically stimulating frontal and parietal regions at the frequency of interaction is effective in modulating working memory. We identify working memory nodes that are functionally connected in theta and alpha frequency bands and intracranially stimulate both nodes simultaneously in participants performing working memory tasks. We find that in-phase stimulation results in improvements in performance compared to sham stimulation. In addition, in-phase stimulation results in decreased phase lag between regions within working memory network, while anti-phase stimulation results in increased phase lag, suggesting that shorter phase lag in oscillatory connectivity may lead to better performance. The results support the idea that phase lag may play a key role in information transmission across brain regions. Thus, brain stimulation strategies to improve cognition may require targeting multiple nodes of brain networks. : Alagapan et al. use intracranial stimulation to simultaneously target multiple nodes of the working memory network. Functional connectivity within the network increases with stimulation, while task performance and phase lag between nodes in the network depend on the relative timing between stimulation. Keywords: cortical oscillations, intracranial eeg, human neuroscience, direct cortical stimulation, brain stimulation, working memory, phase lag

Major depressive disorder (MDD) occurs in a small proportion of patients with Parkinson's disease (PD) and reduces their quality of life. We performed a randomized sham-controlled study to evaluate the effect of high-frequency (HF) repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (DLPFC) on MDD in patients with PD. Ten patients participated to a real-rTMS group and eight patients to a sham-rTMS group. Evaluations were performed at baseline, 2 and 6 weeks after rTMS treatment. All participants underwent examinations of depression rating scales, including the Hamilton Rating Scale, the Montgomery-Asberg Depression Rating Scale (MADRS), and the Beck Depression Inventory (BDI) and the motor part of the Unified Parkinson Disease Rating Scale (UPDRS-III). The real-rTMS group had improved scores on HRS and the MADRS after 10 sessions, and these beneficial effects persisted for 6 weeks after the initial session. The BDI score did not change immediately after the sessions. The sham-rTMS group had no significant changes in any of the depression rating scales. The UPDRS-III did not change in either group. HF-rTMS of the left DLPFC is an effective treatment for MDD in patients with PD.

We investigated the prevalence and mechanisms of neurological deterioration after endovascular thrombectomy. Between January 2011 and October 2017, acute ischemic stroke patients treated by endovascular thrombectomy in a tertiary university hospital were included. Early neurological deterioration (END) was defined as an increase of 2 or more National Institute of Health Stroke Scale (NIHSS) compared to the best neurological status after stroke within 7 days. The END mechanism was categorized into ischemia progression, symptomatic hemorrhage, and brain edema. A total of 125 acute ischemic stroke patients received endovascular thrombectomy. Neurological deterioration was detected in 44 patients, and 38 cases (86.4% of END) occurred within 72 h. The END mechanism included 20 ischemia progression, 16 brain edema and 8 hemorrhagic transformation cases. Multivariable logistic regression analysis revealed that the patients who experienced END were more likely to have poor functional outcome defined as modified Rankin scale 3–6 at 90 days than neurologically stable patients (odds ratio (OR) = 4.06, confidence interval (CI) = 1.39–11.9). The risk factor of END due to ischemia progression was stroke subtype of large artery atherosclerosis (OR = 6.28, CI = 1.79–22.0). Successful recanalization (OR = 0.11, CI = 0.03–0.39) and NIHSS after endovascular thrombectomy (OR = 1.15 per one-point increase, CI = 1.06–1.24) were significantly associated with END due to hemorrhage or brain edema. Neurological deterioration frequently occurs after endovascular thrombectomy, and the risk factors of END differ according to the mechanism of END.

Objective Restless legs syndrome (RLS) has been associated with vascular diseases, including cerebrovascular and cardiovascular diseases. Among the various mechanisms in RLS, peripheral vascular endothelial dysfunction in patients with RLS has recently been proposed as a vascular pathophysiology of RLS. This study investigated arterial stiffness related to RLS in acute ischemic stroke patients and its influence on stroke outcome. Methods RLS in patients with acute ischemic stroke was assessed based on the four essential criteria of the International Restless Legs Syndrome Study Group described in 2003. The patients’ clinical and laboratory characteristics, arterial stiffness, small vessel disease occurrence, and burden on brain MRI were recorded. Stroke severity was determined using the National Institute of Health Stroke Scale (NIHSS), and clinical outcomes were determined using the modified Rankin Scale. Results Of 296 patients with acute ischemic stroke, 16 (5.4%) were diagnosed with restless legs syndrome. Logistic regression analysis showed that a 1 m/s increase in brachial arterial pulse wave velocity was associated with the diagnosis of RLS (odds ratio, 1.092; 95% confidence interval, 1.019–1.170, p = 0.012). Diagnosis of RLS in patients with acute ischemic stroke was associated with poor clinical outcome three months after stroke (modified Rankin Scale 3–6) (odds ratio, 4.263; 95% confidence interval, 1.229–14.792, p = 0.022) along with initial NIHSS score. Conclusion RLS in patients with acute ischemic stroke is associated with increased arterial stiffness and poor clinical outcomes.

Background and Purpose— The aim of this study was to determine the association between 25-hydroxyvitamin D (25(OH)D) and neuroimaging correlates of cerebral small vessel disease. Methods— We identified 759 consecutive patients with acute ischemic stroke or transient ischemic attack. Lacunes, white matter hyperintensity, and cerebral microbleed (CMB) were assessed using MR images. Deep CMB was defined as the presence of CMB in basal ganglia, thalamus, or brain stem. The association between 25(OH)D and small vessel disease was tested using linear and logistic regression analyses. Results— Mean age was 68 (±13) years. Mean level of 25(OH)D was 34.1±17.8 nmol/L. On bivariate analysis, a 25-nmol/L decrease in 25(OH)D was associated with lacunes (regression coefficient, 0.23; 95% confidence interval [CI], 0.02–0.45), severe white matter hyperintensity (odds ratio, 2.05; 95% CI, 1.41–3.08), and deep CMB (odds ratio, 1.28; 95% CI, 1.01–1.63). Also, 25(OH)D deficiency (≤25 nmol/L) was associated with lacunes (regression coefficient, 0.5; 95% CI, 0.04–0.95), severe white matter hyperintensity (odds ratio, 2.74; 95% CI, 1.31–6.45), and deep CMB (odds ratio, 1.68; 95% CI, 1.03–2.78). The association remained significant even after multivariable adjustment and in the subgroup of previously healthy patients. Conclusions— 25(OH)D is inversely associated with lacunes, white matter hyperintensity, and deep CMB. Our findings suggest that 25(OH)D is linked to small vessel disease, and in future trials it should be tested whether 25(OH)D supplementation can prevent small vessel disease.

Drug-induced parkinsonism (DIP) is the common cause of parkinsonism. It is difficult to make a differentiation between DIP and Parkinson's disease (PD) because there are no notable differences in the clinical characteristics between the two entities. In this study, we examined the relationship between the characteristics of [(18)F] fluorinated-N-3-fluoropropyl-2-β-carboxymethoxy-3-β-(4-iodophenyl)nortropane (FP-CIT) positron emission tomography (PET) images and clinical features in DIP patients. We retrospectively studied 76 patients with DIP who underwent [(18)F] FP-CIT PET. We also enrolled 16 healthy controls who underwent it. We compared the clinical characteristics between the DIP patients with normal [(18)F] FP-CIT PET scans and those with abnormal ones. Symmetric parkinsonism was more frequent in the patients with normal [(18)F] FP-CIT PET scans as compared with those with abnormal ones. Interval from drug intake to onset of parkinsonism was longer in the patients with abnormal [(18)F] FP-CIT PET scans as compared with those with normal ones. A semi-quantitative analysis showed that specific to non-specific binding ratios in the putamen was lower in the patients with abnormal [(18)F] FP-CIT PET scans as compared with those with normal ones and the age-matched control group. Our results suggest that symmetric parkinsonism was more prevalent, and the duration of drug exposure before the onset of parkinsonism was shorter in the patients with normal [(18)F] FP-CIT PET scans as compared with those with abnormal ones.

Purpose Patients with intracerebral hemorrhage (ICH) are often initiated on antiepileptic drugs without a clear indication. We compared the percentage of patients with spontaneous ICH who had seizures at onset or during hospitalization, and examined empiric use of antiepileptic drugs (AEDs) in these patients in 2 cohorts 10 years apart. Methods Using a clinical data registry at a tertiary care adult hospital, we retrospectively selected admissions for spontaneous ICH between 1/1/99–12/31/00 (Cohort A, n =30) and 1/1/09–12/31/10 (Cohort B, n =108). Clinical, neurophysiological and radiological data were collected in both cohorts. Results In Cohorts A and B respectively, AEDs were started in 53.3% and 50.0%, and continued on discharge in 50.0% and 20.4% of patients; 86.6% and 59.1% of patients discharged on AEDs did not have a clinical/electrographic seizure or epileptiform EEG findings. Seizures occurred in 6.6% and 13.0% in Cohorts A and B respectively. The presence of a seizure at presentation ( p =0.01) and during hospitalization ( p =0.02) were predictors for continuing AED on discharge. Conclusion In both cohorts, a significant number of patients were discharged on AEDs without a clear indication, though there is a change in practice between the two cohorts.

Aside from the glucocerebrosidase gene, the genetic risk factors for cognitive decline in Parkinson's disease (PD) are controversial. We investigated whether the G2385R polymorphism in leucine-rich repeat kinase 2 gene (LRRK2), a risk variant for the development of PD in East Asians, is associated with cognitive dysfunction in PD. We recruited 299 PD patients, consisting of 23 carriers and 276 non-carriers of LRRK2 G2385R, from 14 centers. Global cognitive function was assessed using the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MoCA). PD with cognitive dysfunction was defined as an MMSE Z score that, adjusting for age at study entry and years of education, was below -1.0 standard deviations. In multivariate analysis, PD duration, age at study entry and depression were significant risk factors for cognitive dysfunction as assessed by MMSE performance or the MoCA. In linear regression analysis of the association between MMSE Z scores and PD duration, there was no significant difference associated with the LRRK2 G2385R genotype. The interaction terms between PD duration and the LRRK2 G2385R genotype were not significant for the MMSE Z score but were significant for the MoCA. In conclusion, the LRRK2 G2385R genotype may not be associated with cognitive dysfunction in PD.

To investigate whether surround inhibition (SI) in the motor system is altered in professional musicians, we performed a transcranial magnetic stimulation (TMS) study in 10 professional musicians and 15 age-matched healthy non-musicians. TMS was set to be triggered by self-initiated flexion of the index finger at different intervals ranging from 3 to 1,000 ms. Average motor evoked potential (MEP) amplitudes obtained from self-triggered TMS were normalized to average MEPs of the control TMS at rest and expressed as a percentage. Normalized MEP amplitudes of the abductor digiti minimi (ADM) muscles were compared between the musicians and non-musicians with the primary analysis being the intervals between 3 and 80 ms (during the movement). A mixed-design ANOVA revealed a significant difference in normalized ADM MEPs during the index finger flexion between groups, with less SI in the musicians. This study demonstrated that the functional operation of SI is less strong in musicians than non-musicians, perhaps due to practice of movement synergies involving both muscles. Reduced SI, however, could lead susceptible musicians to be prone to develop task-specific dystonia.

Cholesterol in brain membranes may modulate the conformational state and accumulation of α-synuclein in α-synucleinopathies.We examined the association between serum cholesterol and the risk of multiple system atrophy (MSA), one of the α-synucleinopathies. We enrolled 142 patients with probable MSA from two tertiary referral hospitals and 155 age- and gender-matched healthy people with no neurological disease. The levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were significantly lower in MSA patients than in controls (total cholesterol: 172.7 vs. 196.3 mg/dL, P < 0.001; LDL-C: 104.0 vs. 115.3 mg/dL, P = 0.001; HDL-C: 47.3 vs. 54.2 mg/dL, P < 0.001). After adjusting for age, gender, use of cholesterol-lowering drugs, and histories of hypertension, diabetes mellitus, and smoking, the odds ratios was 5.9 (95% CI = 2.3–11.5, P < 0.001) for MSA patients in the lowest quartile of total cholesterol and 2.6 (95% CI = 1.2–5.5, P = 0.016) for those in the lowest quartile of HDL-C, compared with the highest quartiles. Levels of serum cholesterol did not significantly correlate with disease duration or severity. Our data suggest that lower levels of total cholesterol and HDL may be associated with an increased risk of MSA. © 2009 Movement Disorder Society

The aim was to evaluate the correlates of existential well-being (EWB) and investigate the relationship between EWB and health-related quality of life (HRQOL) according to the McGill Quality of Life Questionnaire (MQOL) in breast cancer survivors (BCS) and in the general population. BCS (N = 1,933) recruited from five large hospitals completed a mailed survey, which included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30), Quality of Life Questionnaire Breast Cancer Module (QLQ-BR23) and the MQOL. Reference data were derived from a representative sample of the Korean adult population composed of 500 women selected by a nationwide random route technique. Multiple logistic regression analysis showed that members of the general population with a lower educational status were more likely to report poor EWB. However, among BCS, correlates that were associated with poor EWB included lower monthly income, lower educational status, unemployment and comorbidities. Almost all factors listed on the HRQOL questionnaire were correlated with EWB in BCS as well as in the general population (P < 0.001). Factors listed on the QLQ-C30 that were correlated to a clinically meaningful extent with EWB in the general population included physical functioning, nausea and vomiting, and appetite loss, whereas among BCS, insomnia and distress over hair loss were meaningfully correlated with EWB. Compared with general population, BCS showed different EWB correlates and distinct associations with HRQOL findings. Our data suggest that socio-economic status and comorbidities influence on their EWB.

Mutations in five PARK genes (SNCA, PARKIN, DJ-1, PINK1, and LRRK2) are well-established genetic causes of Parkinson disease (PD). Recently, G2385R substitution in LRRK2 has been determined as a susceptibility allele in Asian PD. The objective of this study is to determine the frequency of mutations in these PARK genes in a Korean early-onset Parkinson disease (EOPD) cohort. The authors sequenced 35 exons in SNCA, PARKIN, DJ-1, PINK1, and LRRK2 in 72 unrelated EOPD (age-at-onsetor=50) recruited from ten movement disorders clinics in South Korea. Gene dosage change of the aforementioned genes was studied using multiple ligation-dependent probe amplification. We found four patients with PARKIN mutations, which were homozygous deletion of exon 4, compound heterozygous deletion of exon 2 and exon 4, heterozygous deletion of exon 4, and heterozygous nonsense mutation (Q40X). Four patients had PINK1 mutations; a compound heterozygous mutation (N367S and K520RfsX522) and three heterozygous mutations (G32R, R279H, and F385L). A missense mutation of SNCA (A53T) was found in a familial PD with autosomal dominant inheritance. Nine patients (12.5%) had heterozygous G2385R polymorphism of LRRK2, whereas none had G2019S mutation. However, no mutations were detected in DJ-1 and UCHL1 in our series. We identified genetic variants in PARKIN, PINK1, LRRK2, and SNCA as a cause or genetic risk factors for PD in 25% of Korean EOPD, and mutation of PARKIN was the most common genetic cause.

Background We investigated the incidence and risk factors of early neurological worsening according to ischemia progression among acute cerebral infarction patients after intravenous thrombolysis. Methods The medical records of consecutive cerebral infarction patients treated with intravenous thrombolysis from 2 university hospitals were reviewed. Early neurological deterioration (END) was defined as 2 or more National Institutes of Health Stroke Scale aggravations within 24 hours after thrombolysis, and its etiologies were categorized by follow-up imaging into 3 groups: ischemia progression, symptomatic hemorrhage, and brain edema. We compared clinical variables between the group of patients with ischemia progression and the patients without neurological deterioration to derive etiology-specific risk factors. Results A total of 210 patients were included in this study, with 57 (26.2%) patients experiencing neurological deterioration. The prevalence of patients with END due to ischemia progression (27 patients, 12.9%) outnumbered the prevalence of patients with neurological deterioration due to symptomatic hemorrhage (n = 13) or brain edema (n = 15). Compared to the group of patients without END, the patients with ischemia progression were more likely to have a stroke subtype of large-artery atherosclerosis, to be current smokers, and to have less severe initial neurological deficits. Multivariate logistic regression analysis revealed that large-artery atherosclerosis was an independent predictor of END due to ischemia progression (odds ratio = 3.8, confidence interval = 1.6-9.3). Conclusions A major contributor to END within 24 hours after intravenous thrombolysis was ischemia progression, and the stroke subtype of large-artery atherosclerosis predicted ischemia progression.

Viral meningitis is the most common cause of aseptic meningitis. Use of the polymerase chain reaction (PCR) has increased the ability to determine the etiology of viral meningitis. This study used PCR analysis to evaluate the etiology of aseptic meningitis in 177 previously healthy adults over a 5-year period, as well as analyzing the clinical characteristics, cerebrospinal fluid (CSF) findings, and prognosis according to each etiology. The most frequent cause of aseptic meningitis was enterovirus (EV), followed by varicella zoster virus (VZV). Patients with EV meningitis were significantly younger than those with VZV meningitis. The percentage of lymphocytes in white blood cell counts and protein concentrations in the CSF differed significantly among patients with EV, VZV and meningitis of undetermined etiology. Younger age and lower percentage of lymphocyte and protein level in CSF analysis may be suggestive of EV meningitis. Further prospective studies are warranted to identify the correlations between the clinical characteristics and the etiologies of meningitis.

Ophthalmopathy related to thyroid disease is due mainly to diffuse periorbital or eye muscle inflammation. It is more common in Grave's hyperthyroidism and rare in Hashimoto's hypothyroidism. Here we report a case of recurrent oculomotor nerve palsy associated with autoimmune hypothyroidism. Brain MRI revealed enhancement of the oculomotor nerves. Despite thyroid hormone replacement therapy, oculomotor nerve palsy recurred at the side contralateral to the initially involved nerve and the autoimmune antibody titer remained high. The symptom was responsive to high-dose steroid therapy.

Background and purpose The prognostic value of contrast accumulation from non-contrast brain computed tomography taken immediately after endovascular reperfusion treatment in acute ischaemic stroke patients to predict symptomatic hemorrhage was studied. Methods Between July 2007 and August 2014, acute anterior circulation ischaemic stroke patients who were treated by intra-arterial thrombolysis or thrombectomy were included. Contrast accumulation was defined as a high attenuation area from non-contrast brain computed tomography immediately taken after endovascular reperfusion treatment, and patients were categorized into three groups according to the presence and location of contrast: (i) negative, (ii) cortical involvement and (iii) non-cortical involvement. The rates of symptomatic hemorrhage after 24 h and functional outcome at discharge were compared between patients with and without cortical involvement. Results Of 64 patients who were treated by endovascular intervention, contrast accumulation was detected in 56, including 33 patients with cortical involvement and 23 patients without cortical involvement. The cortical involvement pattern was more frequently associated with symptomatic hemorrhage (13 vs. 1 patient, P = 0.003) and with grave outcome at discharge with modified Rankin Scale 5 or 6 (14 vs. 4, P = 0.048) than the non-cortical involvement group. Multivariate logistic regression analysis including initial collateral status and occlusion site disclosed that cortical involvement pattern independently predicted symptomatic hemorrhage after endovascular treatment (odds ratio 19.0, confidence interval 1.6–227.6, P = 0.020). Conclusion Our study provides evidence that the cortical involvement of contrast accumulation is associated with symptomatic hemorrhage after endovascular reperfusion treatment.

White matter hyperintensity (WMH) is commonly detected in patients with Alzheimer's disease (AD), but its role in cortical impairment is unclear. This study investigated the effects of WMH on gray matter (GM) volume in patients with AD. We consecutively enrolled 84 patients with AD and 35 normal controls, who underwent brain MRI and were then classified according to WMH grade, based on a combination of deep white matter hyperintensity (DWMH) and periventricular white matter hyperintensity (PVWMH). The volume changes in GM were observed using voxel-based morphometry. It was found that global GM volume decreased with increasing WMH. Regional atrophies were in the dorsolateral frontal lobes, orbitofrontal gyri and insula (false discovery rate [FDR], p0.01). After controlling for PVWMH, DWMH affected cortical atrophy in the frontal lobe, insula and precuneus (FDR, p0.05), but PVWMH did not. Thus, WMH in AD is associated with GM volume reduction, especially in the frontal lobe, and DWMH is independently related to cortical atrophy.

To evaluate the interhemispheric interaction of paired associative stimulation (PAS)-induced plasticity, we performed a transcranial magnetic stimulation study on nine healthy volunteers after PAS, motor evoked potentials were significantly enhanced in both the nonstimulated and stimulated primary motor cortex (M1). Short-interval intracortical inhibition and intracortical facilitation were not changed in the nonstimulated M1, but interhemispheric inhibition was significantly reduced after PAS. Motor evoked potential enhancement in the nonstimulated M1 was significantly correlated to that in the stimulated M1 and tended to correlate with the degree of pre-PAS interhemispheric inhibition. These results show that PAS-induced plasticity in the dominant M1 can transfer to contralateral M1 depending on the amount of plastic change induced in the stimulated M1 and, also probably, on the amount of transcallosal connection.

Although restless legs syndrome (RLS) and akathisia have similar clinical manifestations and seem to share a common pathophysiology, they are regarded as distinct clinical syndromes. We present three patients with acute pontine infarction and RLS or akathisia as clinical manifestations. They presented with abrupt onset of restlessness of various body parts, as well as other neurological signs including dysarthria or weakness of the legs. Brain MRI of all three patients showed acute pontine infarction. The clinical syndrome in two of the patients was compatible with RLS and one with akathisia. Their symptoms improved after a brief period. Our finding of secondary RLS and akathisia as manifestations of acute pontine infarction provides information that assists in understanding the common anatomical and pathophysiological basis of RLS and akathisia.

Levosulpiride is a substituted benzamide that is widely used for the management of dyspepsia and emesis. However, little is known about levosulpiride-induced movement disorders (LIM). The aim of this study was to investigate the clinical characteristics of patients with LIM. Among 132 consecutive patients who were diagnosed with drug-induced movement disorders between January 2002 and March 2008, 91 patients with LIM were identified and their medical records reviewed. Seventy-eight (85.7%) patients were aged more than 60 years. The most common LIM was parkinsonism (LIP) (n = 85, 93.4%), followed by tardive dyskinesia (n = 9, 9.9%) and isolated tremor (n = 3, 3.3%). Twenty-one (24.7%) of the 85 patients with LIP were rated as Hoehn and Yahr stage III-V. The oro-lingual area was the only body part that was involved by tardive dyskinesia. LIM persisted after withdrawal of levosulpiride in 48.1% of patients with LIP, 66.7% with dyskinesia, and none with isolated tremor. None of clinical and MRI features predicted the reversibility of LIP. Levosulpiride frequently causes drug-induced movement disorders, presenting mainly with LIP followed by lower face dyskinesia. The symptoms are often severe, and irreversible even after the withdrawal of levosulpiride. Physicians should be cautious in using levosulpiride, especially in elderly patients.

Objective Paroxysmal kinesigenic dyskinesia (PKD) is characterized by recurrent attacks of dyskinesia, in which movement of one body part produces involuntary movements of other body parts. Surround inhibition (SI), a mechanism for suppression of unwanted movements, could be deficient in these patients. To test this idea, we performed a transcranial magnetic stimulation (TMS) study in drug-naive patients with PKD. Methods TMS was set to be triggered by self-initiated flexion of the index finger at different intervals. Average motor evoked potential (MEP) amplitudes obtained from self-triggered TMS were normalized to average MEPs of the control TMS at rest. Normalized MEP amplitudes of the patients’ self-triggered TMS sessions at different intervals were compared to those of the controls. Results During index finger flexion, MEP amplitudes from the little finger muscle were unchanged in both the patients and normal subjects, however, post-movement MEP enhancement observed in the normal subjects was absent in patients with PKD. These results suggest that the functional operation of SI is itself preserved, but that post-movement excitation of surrounding muscles is deficient in PKD. Conclusions This finding may represent that the operation of SI is extended to the post-movement period, perhaps as a compensatory mechanism for preventing unwanted movement in surrounding muscles. Significance While many types of impaired inhibition have been described previously in PKD, this is the first possible example of increased inhibition.

Rapid eye movement sleep behavior disorder (RBD) is commonly accompanied in Parkinson disease (PD). However, the underlying mechanism linking RBD to PD remains unclear. We interviewed and examined 447 consecutive patients with PD to investigate factors associated with the presence of RBD in PD patients. Using the minimal diagnostic criteria for parasomnias provided in the International Classification of Sleep Disorders-Revised (ICSD-R), 164 patients (36.5%) were diagnosed with clinically probable RBD (cpRBD). PD patients with cpRBD were older, had a longer duration of PD, a more severe level of disability, a longer duration of antiparkinsonian medication, and a lower proportion of their Unified Parkinson Disease Rating Scale (UPDRS) scores accounted for by tremor than those without RBD. Multivariate and univariate logistic regression analyses revealed that patient age, PD symptom duration (and, accordingly, more severe motor disability), tremor score, and proportion of the UPDRS score accounted for by tremor were significant factors associated with the presence of RBD in PD patients. The results of the present study support previous observations that PD with RBD may result from a different underlying pattern of neurodegeneration than PD without RBD.

Objective: Surround inhibition (SI) in the motor system is an essential mechanism for the selective execution of desired movements. To investigate the relationship between the efficiency of SI operation in the motor system and handedness, we performed a transcranial magnetic stimulation (TMS) study in 10 healthy, right-handed volunteers. Methods: TMS was set to be triggered by self-initiated flexion of the index finger at different intervals ranging from 3 to 1000 ms. Average motor evoked potential (MEP) amplitudes obtained from self-triggered TMS were normalized to average MEPs of the control TMS at rest and expressed as a percentage. Normalized MEP amplitudes of the adductor digiti minimi (ADM) and the flexor digitorum superficialis (FDS) muscles were compared between the dominant and non-dominant hands. Results: During index finger flexion, MEP amplitudes of the ADM in the dominant hand were suppressed but not in the non-dominant hand, while MEP amplitudes of the FDS were comparably enhanced in both hands. F-wave amplitudes of ADM were comparably enhanced during index finger flexion in both hands. Conclusion: These results suggest that the functional operation of SI in the motor system is more efficient in the dominant hand than the non-dominant hand. More efficient SI in the dominant hand could lead to greater dexterity in the dominant hand. Significance: Hemispheric asymmetry of SI might be able to serve as a neurophysiological proxy for handedness.

Although restless legs syndrome (RLS) commonly accompanies Parkinson disease (PD), the mechanism of RLS development in PD is still unclear. We investigated the prevalence of RLS in Korean patients with PD, and the possible contributing factors to the development of RLS in those patients. Four hundred forty-seven consecutive patients with PD were interviewed and examined. Among them, 73 patients (16.3%) were diagnosed with RLS. PD patients with RLS had a longer duration of PD symptoms, more severe PD disability, a greater degree of cognitive decline, and a longer duration of antiparkinson therapy than those without RLS. Multivariate logistic regression analysis revealed that the duration of antiparkinson therapy was the most significant factor contributing to the development of RLS in patients with PD. The present results support a higher prevalence of RLS in patients with PD and suggest that long-term antiparkinson therapy, rather than PD itself, may contribute to the development of RLS.

Objective Surround inhibition in the motor system is an essential mechanism for selective execution of desired movements. To evaluate the functional operation of surround inhibition in Parkinson disease, we performed a transcranial magnetic stimulation (TMS) study in the asymptomatic hands of hemiparkinsonism patients. Methods TMS was set to be triggered by self-initiated flexion of the index finger at different intervals from 3 to 2000 ms. Average motor evoked potential (MEP) amplitudes obtained from self-triggered TMS were normalized to average MEPs of control TMS at rest. Normalized MEP amplitudes of the patients’ self-triggered TMS sessions at different intervals were compared to those of the controls. Results During index finger flexion, MEP amplitudes from the little finger muscle were unchanged in normal subjects. However, they were enhanced in Parkinson patients, despite the absence of any motor disturbance. Conclusions These results suggest that the functional operation of surround inhibition is impaired in Parkinson disease. This disturbance may precede motor disturbance in Parkinson disease. Significance Impaired surround inhibition can be useful to detect preclinical parkinsonism.

Increasing evidence suggests an association between elevated serum aminotransferase level and the metabolic syndrome. However, the significance of relatively low levels of aminotransferase in relation to the metabolic syndrome has not been fully investigated in the general population. We investigated the association between serum amiontransferase level and the metabolic syndrome using data from a nationwide survey in Korea. We measured serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and metabolic conditions among 9771 participants aged 20 or more in the 1998 and 2001 Korean National Health and Nutrition Examination Surveys. Metabolic syndrome was defined according to NCEP-ATP III criteria with a modified waist circumference cutoff (men > 90 cm; women > 80 cm). Serum aminotransferase level, even within normal range, was associated with the metabolic syndrome independent of age, body mass index, waist circumference, smoking, and alcohol intake. Compared with the lowest level (< 20 IU/L), the adjusted odds ratios (95% CI) for an AST level of 20-29, 30-39, 40-49 and ≥ 50 IU/L were 1.10 (0.85-1.42), 1.37 (1.02-1.83), 1.62 (1.08-2.43), and 2.25 (1.47-3.44) in men, and 1.18 (0.99-1.41), 1.43 (1.29-1.83), 1.71 (1.09-2.68), and 2.14 (1.20-3.80) in women, respectively. Corresponding odds ratios for ALT levels were 1.27 (0.99-1.63), 1.69 (1.28-2.23), 2.17 (1.58-2.99), and 2.65 (1.96-3.58) in men, and 1.44 (1.22-1.70), 1.65 (1.26-2.15), 2.94 (1.93-4.47), and 2.25 (1.54-3.30) in women, respectively. In conclusion, elevated serum aminotransferase levels, even in the normal to near normal range, are associated with features of the metabolic syndrome.

Purpose Ulnar neuropathy at the cubital tunnel (UCT) is diagnosed on the basis of history, physical examination, and nerve conduction studies (NCSs); however, the wide spectrum of findings often makes the diagnosis difficult. The purpose of this study was to document the ultrasonographic differences in ulnar nerve size between patients with UCT and control subjects, and to correlate those differences with clinical examination findings and NCS abnormalities, thereby testing the validity of ultrasound (US) as an additional adjunct diagnostic modality for UCT. Methods Fifteen elbows in 14 patients with symptoms, clinical examination, and NCS findings consistent with UCT had US of the ulnar nerve. Patients were excluded if they had a history of polyneuropathy, acute trauma involving the upper extremity, previous trauma in the region of the elbow (including previous surgery), or brachial plexus injury. The control group consisted of 60 elbows from 30 normal volunteers that also had US. Maximal cross-sectional areas (CSAs) were measured and compared for the 2 groups and a correlation analysis was performed between nerve size and NCS findings. Results The average CSA of the ulnar nerve was 0.065 cm 2 in the control group, whereas in the UCT group it was 0.19 cm 2 , indicating a significant statistical difference in ulnar nerve size between the 2 groups. The Pearson correlation coefficient between motor nerve conduction velocity of the ulnar nerve and the CSA was 0.80. Conclusions High-resolution US is a noninvasive, safe, and reliable modality for imaging the ulnar nerve at the elbow and it may provide a valuable adjunct to NCS in the diagnosis of UCT. Type of study/level of evidence Diagnostic III.

AIM: To evaluate the association between the severity of liver steatosis and metabolic syndrome in apparently healthy Korean adults. METHODS: We examined 1 022 men and women, aged 30-79 years, who participated in a health screening test. A standard interview, anthropometrics, biochemical studies, and abdominal ultrasonography were conducted for each participant. Metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III, with a modification for the waist circumference cut-off level. The severity of liver steatosis was evaluated using liver ultrasonography, and serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyl transferase (γ-GT) levels were determined. RESULTS: Ultrasonographic liver steatosis was strongly associated with metabolic syndrome and common metabolic abnormalities. Compared with people without steatosis, people with mild, moderate, and severe steatosis had adjusted odds ratios for metabolic syndrome of 1.72 (95%CI, 1.01-2.94), 2.89 (1.75-4.76) and 3.53 (1.25-9.98) in men, and 2.86 (1.64-5.01), 3.19 (1.80-5.65) and 3.70 (0.82-16.73) in women, respectively. The serum AST level was not associated with metabolic syndrome. The serum ALT and γ-GT levels were significantly associated with metabolic syndrome in men but not in women. CONCLUSION: The occurrence of metabolic syndrome shows a stronger association with the severity of ultrasonographic steatosis than with the serum liver enzyme levels. The degree of fatty infiltration detected on ultrasonography can be used as an indicator of liver dysfunction attributable to metabolic abnormalities.

Various sensory symptoms and disturbed sensory perception are often observed in patients with idiopathic Parkinson's disease (PD). The basis of sensory disturbance in PD is unknown but possibly reflects a role for the basal ganglia in sensory processing. To investigate the relationship between the sensory dysfunction and dopaminergic deficiency in PD, we measured spatial discrimination using the Grating Orientation Task in 21 drug-naive patients with PD, before and after long-term antiparkinson therapy, and 25 age-matched healthy controls. The grating orientation threshold was significantly higher in patients (3.03 +/- 0.84) than controls (2.03 +/- 0.79). After 3 to 10 months of antiparkinson therapy, the grating orientation threshold was significantly lowered (2.66 +/- 0.84), although it was still higher than that in controls. Improvement in the patients' sensory function was significantly correlated with motor improvement (r = 0.44). These results suggest that sensory dysfunction in Parkinson's disease is related at least in part to the dopaminergic deficit.

Enteroviral CNS infection is common and its clinical course is usually benign. In immunocompromised patients, however, it can cause meningoencephalitis, presenting with altered mentality and seizure. We describe a previously healthy female patient with enteroviral meningoencephalitis who showed rapidly progressive aphasia. Examination of her cerebrospinal fluid (CSF) showed pleocytosis with lymphocyte dominance, elevated protein, and normal glucose, findings compatible with viral encephalitis. Fluid-attenuated inversion recovery (FLAIR) brain MRI showed hyperintensity in the left frontal and parietal cortices. Enterovirus in the CSF was confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) of the CSF. Although her neurological deficits had progressed to global aphasia, conservative management resulted in complete improvement within 3 months. This case provides unusual clinical manifestations and imaging findings in enteroviral encephalitis.

Purpose To investigate the influence of 2 phases of short interval intracortical inhibition (SICI) on the cortical silent period (SP). Materials and Methods Single- and paired-pulse transcranial magnetic stimulations (TMSs) at 1 and 2.5 ms interstimulus intervals (ISIs) were applied to the left motor cortex in 12 healthy subjects while their right hand muscles were moderately activated. Conditioning stimulation intensity was 90% of the active motor threshold (AMT). Test stimulation intensities were 120, 140, 160, 180, 200, 220, 240, 260% of the AMT and at 100% of the maximal stimulator output, the order of which was arranged randomly. The rectified electromyography area of motor evoked potential (MEP) and duration of the SP were measured off-line using a computerized program. Results At high-test stimulation intensities, MEP areas were saturated in both single- and paired-pulse stimulations, except that saturated MEPs were smaller for the paired-pulse TMS at 1 ms ISI than for the other conditions. As the test stimulation intensity increased, SP was progressively prolonged in both single- and paired-pulse stimulations but was shorter in paired-pulse than single-pulse TMS. Overall, the ratio of SP duration/MEP area was comparable between single- and paired-pulse TMS except for the paired-pulse TMS at 1 ms ISI with a test stimulation intensity at 140 - 180% of the AMT, in which the ratio was significantly higher than in the single pulse TMS. Conclusion These results suggest that 2 phases of SICI modulate MEP saturation and SP duration differently and provide additional evidence supporting the view that 2 phases of SICI are mediated by different inhibitory mechanisms.

Background: Three main genes are described as causative genes for early-onset Alzheimer dementia (EOAD): APP, PSEN1 and PSEN2. We describe a woman with EOAD had a novel PSEN1 mutation. Case presentation: A 54-year-old right-handed woman presented 12-year history of progressive memory decline. She was clinically diagnosed as familial Alzheimer's disease due to a PSEN1 mutation. One of two daughters also has the same mutation, G209A in the TM-IV of PS1 protein. Her mother had unspecified dementia that began at the age of 40s. PolyPhen2 and SIFT prediction suggested that G209A might be a damaging variant with high scores. 3D modeling revealed that G209A exchange could result significant changes in the PS1 protein. Conclusion: We report a case of EOAD having probable novel PSEN1 (G209A) mutation verified with structural prediction.