Correlation of electrode position and clinical outcomes in globus pallidus stimulation for dystonia.

BACKGROUND: The correlation between the electrode location and the clinical outcome for internal globus pallidus (GPi) deep brain stimulation (DBS) has not been fully elucidated. OBJECTIVE: The aim of this study was to determine the discrepancies between the theoretical target planned by magnetic resonance imaging (MRI) and the actual electrode location in postoperative MRI, as well as to find the correlation between the final electrode locations and the clinical outcome after GPi DBS. METHODS: Thirty-six patients who underwent GPi DBS for dystonia were included in this retrospective study. The X coordinate was defined as the lateral distance from the midline, the Y coordinate as the anterior distance from the midcommissural point, and the Z coordinate as the inferior distance from the intercommissural line. RESULTS: All coordinates showed a significant difference between theoretical and actual values for all electrode locations (p < 0.05). In particular, greater differences were exhibited for Y than for the X and Z coordinates. There was no significant difference in the accuracy of the localization of the left-side versus the right-side electrode for any coordinates. The patients whose electrodes were located within or near the posteroventral GPi showed better clinical outcomes. CONCLUSIONS: The actual electrode location was slightly more posterior to the theoretically planned target. Electrodes concentrated near the posteroventral GPi tended to yield favorable outcomes.

Pregnancy and Delivery in a Generalized Dystonia Patient Treated with Internal Globus Pallidal Deep Brain Stimulation: a Case Report.

Internal globus pallidus (GPi) deep brain stimulation (DBS) has been widely accepted as an effective treatment modality of medically refractory dystonia. However, there have been few studies regarding the safety issue of pregnancy and childbirth related with DBS. This report describes a female patient who was pregnant and delivered a baby after GPi DBS surgery. A 33-year-old female patient with acquired generalized dystonia underwent bilateral GPi DBS implantation. She obtained considerable improvement in both movement and disability after DBS implantation. Four years later, she was pregnant and the obstetricians consulted us about the safety of the delivery. At 38-weeks into pregnancy, a scheduled caesarian section was carried out under general anesthesia. After induction using thiopental and succinylcholine, intubation was done quickly, followed by DBS turn off. For hemostasis, only bipolar electrocautery was used. Before awakening from the anesthesia, DBS was turned on as the same parameters previously adjusted. After delivery, she could feed her baby by herself, because the dystonia of left upper extremity and hand was improved. Until now, she has been showing continual improvement and being good at housework, carrying for children, with no trouble in daily life. This observation indicates that the patients who underwent DBS could safely be pregnant and deliver a baby.

Vestibular Performance During High-Acceleration Stimuli Correlates with Clinical Decline in SCA6.

In spinocerebellar ataxia type 6 (SCA6), the vestibular dysfunction and its correlation with other clinical parameters require further exploration. We determined vestibular responses over a broad range of stimulus acceleration in 11 patients with SCA6 (six men, age range=33-72 years, mean age±SD=59±12 years) using bithermal caloric irrigations, rotary chair, and head impulse tests. Correlations were also pursued among disability scores, as measured using the International Cooperative Ataxia Rating Scale, disease duration, age at onset, cytosine-adenine-guanine (CAG) repeat length, and the gain of the vestibulo-ocular reflex (VOR). In response to relatively low-acceleration, low-frequency rotational and bithermal caloric stimuli, the VOR gains were normal or increased regardless of the severity of disease. On the other hand, with relatively high-acceleration, high-frequency head impulses, there was a relative increase in gain in the mildly affected patients and a decrease in gain in the more severely affected patients and gains were negatively correlated with the severity of disease (Spearman correlation, R=-0.927, p<0.001). Selective decrease of the vestibular responses during high-acceleration, high-frequency stimuli may be ascribed to degeneration of either the flocculus or vestibular nuclei. The performance of the VOR during high-acceleration, high-frequency head impulses may be a quantitative indicator of clinical decline in SCA6.

Rotigotine transdermal system as add-on to oral dopamine agonist in advanced Parkinson's disease: an open-label study.

BACKGROUND: Achieving optimal symptom control with minimal side effects is a major goal in clinical practice. Dual-agent dopamine receptor agonist (DA) therapy in Parkinson's disease (PD) may represent a promising approach to treatment, as the combination of different pharmacokinetic/pharmacological profiles may result in a lesser need for high dosages and, accordingly, may be well tolerated. The objective of the current study was to investigate safety and efficacy of rotigotine transdermal system as add-on to oral DA in patients with advanced PD inadequately controlled with levodopa and low-dose oral DA. METHODS: PD0015 was an open-label, multinational study in patients with advanced-PD and sleep disturbance or early-morning motor impairment. Patients were titrated to optimal dose rotigotine (≤8 mg/24 h) over 1-4 weeks and maintained for 4-7 weeks (8-week treatment). Dosage of levodopa and oral DA (pramipexole ≤1.5 mg/day, ropinirole ≤6.0 mg/day) was stable. Primary variable was Clinical Global Impressions (CGI) item 4: side effects, assessing safety. Other variables included adverse events (AEs), Patient Global Impressions of Change (PGIC), Unified Parkinson's Disease Rating Scale (UPDRS) II and III, Parkinson's Disease Sleep Scale (PDSS-2), Pittsburgh Sleep Quality Index (PSQI), and "off" time. RESULTS: Of 90 patients who received rotigotine, 79 (88%) completed the study; 5 (6%) withdrew due to AEs. Most (83/89; 93%) had a CGI-4 score <3 indicating that rotigotine add-on therapy did not interfere with functioning; 6 (7%) experienced drug-related AEs that interfered with functioning (score ≥3). AEs occurring in ≥5% were application site pruritus (13%), dizziness (10%), orthostatic hypotension (10%), nausea (8%), dyskinesia (8%), and nasopharyngitis (6%). Numerical improvements in motor function (UPDRS III), activities of daily living (UPDRS II), sleep disturbances (PDSS-2, PSQI), and reduction in "off" time were observed. The majority (71/88; 81%) improved on PGIC. CONCLUSIONS: Addition of rotigotine transdermal system to low-dose oral DA in patients with advanced-PD was feasible and may be associated with clinical benefit. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01723904 . Trial registration date: November 6, 2012.

Preserved high-centrality hubs but efficient network reorganization during eyes-open state compared with eyes-closed resting state: an MEG study.

A question to be addressed in the present study is how different the eyes-closed (EC) and eyes-open (EO) resting states are across frequency bands in terms of efficiency and centrality of the brain functional network. We investigated both the global and nodal efficiency and betweenness centrality in the EC and EO resting states from 39 volunteers. Mutual information was used to obtain the functional connectivity for each of the four frequency bands (theta, alpha, beta, and gamma). We showed that the cortical hubs with high betweenness centrality were maintained in the EC and EO resting states. We further showed that these hubs were associated with more than three frequency bands, suggesting that these hubs play an important role in the brain functional network at multiple temporal scales in the resting states. Enhanced global efficiency values were found in the theta and alpha bands in the EO state compared with those in the EC state. Moreover, it turned out that in the EO state the functional network was reorganized to enhance nodal efficiency at the nodes related to both the default mode and the dorsal attention networks and sensory-related resting-state networks. This result suggests that in the EO state the brain functional network was efficiently reorganized, facilitating the adaptation of the brain network to the change in state, which could help in understanding brain disorders that have a disturbance in communication with external environments by using the adaptation ability of brain functional networks.

Alpha-synuclein repeat variants and survival in Parkinson's disease.

OBJECTIVES: To determine whether α-synuclein dinucleotide repeat (REP1) genotypes are associated with survival in Parkinson's disease (PD). METHODS: Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium provided REP1 genotypes and baseline and follow-up clinical data for cases. The primary outcome was time to death. Cox proportional hazards regression models were used to assess the association of REP1 genotypes with survival. RESULTS: Twenty-one sites contributed data for 6,154 cases. There was no significant association between α-synuclein REP1 genotypes and survival in PD. However, there was a significant association between REP1 genotypes and age at onset of PD (hazard ratio: 1.06; 95% confidence interval: 1.01-1.10; P value = 0.01). CONCLUSIONS: In our large consortium study, α-synuclein REP1 genotypes were not associated with survival in PD. Further studies of α-synuclein's role in disease progression and long-term outcomes are needed.

Clinical spectrum of dopa-responsive dystonia and related disorders.

Dopa-responsive dystonia (DRD) has a classic presentation of childhood or adolescent-onset dystonia, mild parkinsonism, marked diurnal fluctuations, improvement with sleep or rest, and a dramatic and sustained response to low doses of L-dopa without motor fluctuations or dyskinesias. However, there have been many papers on patients with a wide range of features, which report them as DRD mainly because they had dystonic syndromes with L-dopa responsiveness. Many mutations in the dopaminergic system have been found as molecular genetic defects. Therefore, the clinical and genetic spectra of DRD are unclear, which lead to difficulties in diagnostic work-ups and planning treatments. We propose the concept of DRD and DRD-plus to clarify the confusion in this area and to help understand the pathophysiology and clinical features, which will help in guiding diagnostic investigations and planning treatments. We critically reviewed the literature on atypical cases and discussed the limitations of the gene study.

Influence of propofol and fentanyl on deep brain stimulation of the subthalamic nucleus.

We investigated the effect of propofol and fentanyl on microelectrode recording (MER) and its clinical applicability during subthalamic nucleus (STN) deep brain stimulation (DBS) surgery. We analyzed 8 patients with Parkinson's disease, underwent bilateral STN DBS with MER. Their left sides were done under awake and then their right sides were done with a continuous infusion of propofol and fentanyl under local anesthesia. The electrode position was evaluated by preoperative MRI and postoperative CT. The clinical outcomes were assessed at six months after surgery. We isolated single unit activities from the left and the right side MERs. There was no significant difference in the mean firing rate between the left side MERs (38.7 ± 16.8 spikes/sec, n=78) and the right side MERs (35.5 ± 17.2 spikes/sec, n=66). The bursting pattern of spikes was more frequently observed in the right STN than in the left STN. All the electrode positions were within the STNs on both sides and the off-time Unified Parkinson's Disease Rating Scale part III scores at six months after surgery decreased by 67% of the preoperative level. In this study, a continuous infusion of propofol and fentanyl did not significantly interfere with the MER signals from the STN. The results of this study suggest that propofol and fentanyl can be used for STN DBS in patients with advanced Parkinson's disease improving the overall experience of the patients.

Phenotypic differences in Dyt1 between ethnic groups.

A DYT1 mutation is the most common genetic cause of early-onset primary torsion dystonia. Herein we present the phenotypes of 25 Korean dystonia patients with DYT1 mutations. We further compare the clinical features of the Asian patients with those of the Western DYT 1 mutation patients. In Korean patients, upper extremity was the most common site of symptom onset while there were a few patients with axial-onset dystonia. Generalized dystonia was the most common subtype followed by segmental dystonia. A few patients from the same families had their symptoms at the same age. The clinical features of Korean patients were similar to those of other Asian patients. The Asian patients were differentiated from Western patients by more frequent axial onset, no cranial involvement at onset, and more common segmental dystonia. The variable clinical manifestation in different ethnic groups may suggest that ethnicity is a significant modifier of DYT1 dystonia.

Electrode position and the clinical outcome after bilateral subthalamic nucleus stimulation.

We compared the surgical outcome with electrode positions after bilateral subthalamic nucleus (STN) stimulation surgery for Parkinson's disease. Fifty-seven patients treated with bilateral STN stimulations were included in this study. Electrode positions were determined in the fused images of preoperative MRI and postoperative CT taken at six months after surgery. The patients were divided into three groups: group I, both electrodes in the STN; group II, only one electrode in the STN; group III, neither electrode in the STN. Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr stage, and activities of daily living scores significantly improved at 6 and 12 months after STN stimulation in both group I and II. The off-time UPDRS III speech subscore significantly improved (1.6 ± 0.7 at baseline vs 1.3 ± 0.8 at 6 and 12 months, P < 0.01) with least L-dopa equivalent daily dose (LEDD) (844.6 ± 364.1 mg/day at baseline; 279.4 ± 274.6 mg/day at 6 months; and 276.0 ± 301.6 mg/day at 12 months, P < 0.001) at 6 and 12 months after STN deep brain stimulation (DBS) in the group I. Our findings suggest that the better symptom relief including speech with a reduced LEDD is expected in the patients whose electrodes are accurately positioned in both STN.

Erratum: Validation Study of the Official Korean Version of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale.

This corrects the article on p. 633 in vol. 16, PMID: 33029970.

The effect of amantadine on corneal endothelium in subjects with Parkinson's disease.

OBJECTIVE: To evaluate the effect of amantadine on corneal endothelial cells in subjects with Parkinson's disease. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 169 subjects (169 eyes) taking amantadine orally for Parkinson's disease and the same number of age- and gender-matched controls. METHODS: Endothelial indices were compared between the amantadine-treated and age-matched control groups. The amantadine-treated group was divided into 3 subgroups according to the cumulative dose and duration of treatment. Endothelial changes were compared between the amantadine group and the normal control group, and among subgroups. MAIN OUTCOME MEASURES: Slit-lamp biomicroscopy, central corneal thickness (CCT), endothelial cell density (ECD), coefficient of variation, and hexagonality. RESULTS: The amantadine group had significantly lower ECD (mean +/- standard error; 2662.47+/-29.06 vs. 2784.72+/-25.89, P = 0.002), lower hexagonality (56.94+/-1.07 vs. 60.97+/-0.87, P = 0.004), and greater coefficient of variation (35.59+/-0.57 vs. 32.66+/-0.52, P = 0.000) compared with the age-matched control group. Longer duration and higher cumulative dose amantadine therapy led to a greater reduction in ECD (P<0.05) compared with the normal age-matched control group. CONCLUSIONS: Amantadine is more likely to have an effect on corneal endothelial cells in a dose-dependent manner when used long-term.

Data management system in a movement disorder center: technical report.

OBJECTIVE: We designed a specialized monitoring unit and data management system with systematic storage and easy access for a deep brain stimulation program of patients with movement disorders. METHODS: All patients were monitored and evaluated in a specialized 24-hour monitoring system whenever it was needed, postoperatively as well as preoperatively. We digitized all the data and developed a data management system that allowed for systematic storage and easy access to the data on demand by users in the offices and outpatient clinics. CONCLUSION: We describe our data management system and how it provides benefit to patients in order that others may use it as a template for designing their own data management system.

Comparison of electrode location between immediate postoperative day and 6 months after bilateral subthalamic nucleus deep brain stimulation.

OBJECTIVE: We compared the electrode positions of subthalamic nucleus (STN) deep brain stimulation (DBS) estimated at the immediate postoperative period with those estimated 6 months after surgery. METHODS: Brain CT scans were taken immediately and 6 months after bilateral STN DBS in 53 patients with Parkinson's disease. The two images were fused using the mutual information technique. The discrepancies of electrode positions in three coordinates were measured in the fused images, and the relationship with the pneumocephalus was evaluated. RESULTS: The average discrepancy of x- and y-coordinates of electrode positions at the level of STN (3.5 mm below the anterior commissure-posterior commissure line) were 0.6 ± 0.5 mm (range, 0~2.1 mm) and 1.0 ± 0.8 mm (range, 0~5.2 mm), respectively. The average discrepancy of z-coordinates of the electrode tips of the fused images was 1.0 ± 0.8 mm (range, 0.1~4.0 mm). The volume of pneumocephalus (range, 0~76 ml) was correlated with the y-coordinate discrepancies (p < 0.005). CONCLUSION: The electrode positions in the immediate postoperative CT might have significant discrepancies with those in the CT taken at a stable period after STN DBS especially when there is a large amount of pneumocephalus.

Is MRI a reliable tool to locate the electrode after deep brain stimulation surgery? Comparison study of CT and MRI for the localization of electrodes after DBS.

PURPOSE: MRI has been utilized to localize the electrode after deep brain stimulation, but its accuracy has been questioned due to image distortion. Under the hypothesis that MRI is not adequate for evaluation of electrode position after deep brain stimulation, this study is aimed at validating the accuracy of MRI in electrode localization in comparison with CT scan. METHODS: Sixty one patients who had undergone STN DBS were enrolled for the analysis. Using mutual information technique, CT and MRI taken at 6 months after the operation were fused. The x and y coordinates of the centers of electrodes shown of CT and MRI were compared in the fused images to calculate average difference at five different levels. The difference of the tips of the electrodes, designated as the z coordinate, was also calculated. RESULTS: The average of the distance between the centers of the electrodes in the five levels estimated in the fused image of brain CT and MRI taken at least 6 months after STN DBS was 1.33 mm (0.1-5.8 mm). The average discrepancy of x coordinates for all five levels between MRI and CT was 0.56 ± 0.54 mm (0-5.7 mm), the discrepancy of y coordinates was 1.06 ± 0.59 mm (0-3.5 mm), and for the z coordinate, it was 0.98 ± 0.52 mm (0-3.1 mm) (all p values < 0.001). Notably, the average discrepancy of x coordinates at 3.5 mm below AC-PC level, i.e., at the STN level between MRI and CT, was 0.59 ± 0.42 mm (0-2.4 mm); the discrepancy of y coordinates was 0.81 ± 0.47 mm (0-2.9 mm) (p values < 0.001). CONCLUSIONS: The results suggest that there was significant discrepancy between the centers of electrodes estimated by CT and MRI after STN DBS surgery.

Validation Study of the Official Korean Version of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale.

BACKGROUND AND PURPOSE: The Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is widely used for estimating the symptoms of Parkinson's disease. Translation and validation of the MDS-UPDRS is necessary for non-English speaking countries and regions. The aim of this study was to validate the Korean version of the MDS-UPDRS. METHODS: Altogether, 362 patients in 19 centers were recruited for this study. We translated the MDS-UPDRS to Korean using the translation-back translation method and cognitive pretesting. We performed both confirmatory and exploratory factor analyses to validate the scale. We calculated the comparative fit index (CFI) for confirmatory factor analysis, and used unweighted least squares for exploratory factor analysis. RESULTS: The CFI was higher than 0.90 for all parts of the scale. Exploratory factor analysis also showed that the Korean MDS-UPDRS has the same number of factors in each part as the English version. CONCLUSIONS: The Korean MDS-UPDRS has the same overall structure as the English MDS-UPDRS. Our translated scale can be designated as the official Korean MDS-UPDRS.

The G2019S LRRK2 mutation is rare in Korean patients with Parkinson's disease.

BACKGROUND: A number of causative mutations such as alpha-synuclein, parkin, UCHL1, Pink-1, DJ-1 have been identified in Parkinson's disease (PD). They are usually found in the familial cases. One mutation of great interest is the G2019S mutation in the LRRK2 gene, which has been reported in both familial and sporadic PD. Its prevalence has been reported to vary markedly among different races. We examined the prevalence of the G2019S mutation in the Korean PD population for genetic study planning. METHODS: We conducted a genetic analysis of the G2019S mutation by standard PCR and restriction digestion method. 453 PD patients were studied, 34% of whom had an age at onset of < 50 years and 3.8% had a positive family history. RESULTS: None of the 453 study subjects carried the G2019S mutation. CONCLUSIONS: Our result confirms previous reports that the G2019S mutation is rare among PD patients in the Asian population. This result supports the notion that the prevalence of this LRRK2 mutation is population specific, and that there may be a founder effect within western populations.

Clinical Heterogeneity of Atypical Pantothenate Kinase-Associated Neurodegeneration in Koreans.

OBJECTIVE: Neurodegeneration with brain iron accumulation (NBIA) represents a group of inherited movement disorders characterized by iron accumulation in the basal ganglia. Recent advances have included the identification of new causative genes and highlighted the wide phenotypic variation between and within the specific NBIA subtypes. This study aimed to investigate the current status of NBIA in Korea. METHODS: We collected genetically confirmed NBIA patients from twelve nationwide referral hospitals and from a review of the literature. We conducted a study to describe the phenotypic and genotypic characteristics of Korean adults with atypical pantothenate kinase-associated neurodegeneration (PKAN). RESULTS: Four subtypes of NBIA including PKAN (n = 30), PLA2G6-related neurodegeneration (n = 2), beta-propeller protein-associated neurodegeneration (n = 1), and aceruloplasminemia (n = 1) have been identified in the Korean population. The clinical features of fifteen adults with atypical PKAN included early focal limb dystonia, parkinsonism-predominant feature, oromandibular dystonia, and isolated freezing of gait (FOG). Patients with a higher age of onset tended to present with parkinsonism and FOG. The p.R440P and p.D378G mutations are two major mutations that represent approximately 50% of the mutated alleles. Although there were no specific genotype-phenotype correlations, most patients carrying the p.D378G mutation had a late-onset, atypical form of PKAN. CONCLUSIONS: We found considerable phenotypic heterogeneity in Korean adults with atypical PKAN. The age of onset may influence the presentation of extrapyramidal symptoms.