Perverted Head-Shaking and Positional Downbeat Nystagmus in Essential Tremor.

Even though the pathophysiology is not completely understood, cerebellar dysfunction has been invoked in essential tremor (ET). We evaluated cerebellar dysfunction in ET with the presence of perverted head-shaking (pHSN) and positional downbeat nystagmus (pDBN) which are known to reflect cerebellar dysfunction. First, we reviewed the videooculography (VOG) of 185 patients with ET from March 2007 to April 2010. Seventeen of 28 patients with pHSN and pDBN were followed up for at least a 1.8-year interval from baseline to determine the clinical course. And then, we recruited 52 consecutive patients with ET and compared their ocular motor findings with 51 normal controls using VOG. Among the 185 patients with ET, 28 (15.1 %) showed pHSN (n = 23, 12.4 %) or pDBN (n = 8, 4.3 %). Seventeen of them who were followed up did not develop Parkinsonism or other neurologic deficits during the observation period. The subsequent case-control study showed a higher prevalence of pHSN or pDBN (11/52, 21.2 %, pHSN in nine and pDBN in five) in patients with ET than in the normal controls (2/51, 3.9 %, pHSN only, P = 0.015). The tremor rating scale or involved body sites did not differ between the patients with and without pHSN/pDBN. pHSN and pDBN were more common in patients with ET than in the normal controls. This result supports that cerebellar dysfunction is associated with ET.

Genetic variability of the retromer cargo recognition complex in parkinsonism.

BACKGROUND: A pathogenic mutation (VPS35 p.D620N) within the retromer complex has been shown to segregate with late-onset Parkinson's disease (PD). Several studies have subsequently detected the mutation in patients with PD and not in controls. METHODS: Mutation screening of the coding regions of the retromer cargo recognition complex genes (VPS26A/B, VPS29, and VPS35) was carried out in patients with PD (n = 396), atypical parkinsonism (n = 229), and in 368 controls. RESULTS: Overall, we identified five rare nonsynonymous mutations in VPS26A and one in VPS35; none were observed in VPS26B or VPS29. Three VPS26A variants (p.K93E, p.M112V, and p.K297X), identified in patients with atypical parkinsonism, were not observed in controls from this study (n = 368) or from publically available data sets (n = 4,426). CONCLUSION: Our results support the hypothesis that rare variants in the retromer complex genes may be involved in the development of parkinsonism, although further studies are warranted before any solid conclusions can be drawn.

Dysport and Botox at a ratio of 2.5:1 units in cervical dystonia: a double-blind, randomized study.

We aimed to compare Dysport (abobotulinumtoxinA, Ipsen Biopharm, Slough, UK) and Botox (onabotulinumtoxinA, Allergan, Irvine, CA, USA) at a 2.5:1 ratio in the treatment of cervical dystonia (CD). A Dysport/Botox ratio of lower than 3:1 was suggested as a more appropriate conversion ratio, considering its higher efficacy and more frequent incidence of adverse effects not only in the treatment of CD but also in other focal movement disorders. A randomized, double-blind, multicenter, non-inferiority, two-period crossover study was done in CD, with a duration of at least 18 months. Patients were randomly assigned to treatment for the first period with Dysport or Botox, and they were followed up for 16 weeks after the injection. After a 4-week washout period, they were switched to the other formulation and then followed up for 16 weeks. The primary outcome was the changes in the Tsui scale between the baseline value and that at 1 month after each injection. A total of 103 patients were enrolled, and 94 completed the study. Mean changes in the Tsui scale between baseline and 4 weeks after each injection tended to favor Botox; however, this was not statistically significant (4.0 ± 3.9 points for the Dysport treatment vs. 4.8 ± 4.1 points for Botox; 95% confidence interval, -0.1-1.7; P = 0.091). The mean change of the Toronto western spasmodic torticollis rating scale score, the proportion of improvement in clinical global impression and patient global impression, and the incidences of adverse events were not significantly different between the two treatments. With regard to safety and efficacy, Dysport was not inferior to Botox in patients with CD at a conversion factor of 2.5:1. [clinicaltrial.gov: NCT00950664]

Extrastriatal dopaminergic changes in Parkinson's disease patients with impulse control disorders.

OBJECTIVE: To investigate the extrastriatal dopaminergic neural changes in relation to the medication-related impulse control disorders (ICD) in Parkinson's disease (PD). METHOD: A total of 31 subjects (11 and 11 drug-treated PD patients with and without medication-related ICDs and 9 healthy controls) having no other co-morbid psychiatric disorders participated in this study. Each subject underwent dynamic N-(3-[(18)F]fluoropropyl)-2-carbomethoxy-3-(4-iodophenyl) nortropane (FP-CIT) positron emission tomography scans. Binding potentials (BP) at nucleus accumbens, amygdala, orbitofrontal and ventromedial prefrontal cortex (VMPFC), putamen and caudate nucleus were estimated, and whole brain parametric maps of [(18)F]-FP-CIT binding were analysed by original and putaminal normalised manners. RESULTS: Compared with the healthy controls, BPs at both VMPFCs were significantly high and the extrastriatal to putaminal BP ratios at all regions were approximately three times higher in both PD groups. The PD ICD patients showed significantly higher BPs at the right VMPFC and tendency to lower BPs at the left nucleus accumbens compared with those free of ICD. The ICD subjects also showed reduced uptakes at both ventral striatal regions in the original parametric analysis and higher uptakes at the left insular and right posterior cingulate cortex and lower uptakes at both ventral pallidums in the putaminal normalised parametric analysis compared with the non-ICD subjects. CONCLUSIONS: A great gap in extrastriatal versus striatal dopaminergic fibre degenerations is an intrinsic condition predisposing to ICD in PD. Distinct pattern of extrastriatal changes between the ICD and non-ICD patients could provide a further insight into a mechanism of ICD in PD.

Retinal nerve fiber layer thickness and visual hallucinations in Parkinson's Disease.

Defective visual information processing from both central and peripheral pathways is one of the suggested mechanisms of visual hallucination in Parkinson's disease (PD). To investigate the role of retinal thinning for visual hallucination in PD, we conducted a case-control study using spectral domain optical coherence tomography. We examined a representative sample of 61 patients with PD and 30 healthy controls who had no history of ophthalmic diseases. General ophthalmologic examinations and optical coherence tomography scans were performed in each participant. Total macular thickness and the thickness of each retinal layer on horizontal scans through the fovea were compared between the groups. In a comparison between patients with PD and healthy controls, there was significant parafoveal inner nuclear layer thinning, whereas other retinal layers, including the retinal nerve fiber layer, as well as total macular thicknesses were not different. In terms of visual hallucinations among the PD subgroups, only retinal nerve fiber layer thickness differed significantly, whereas total macular thickness and the thickness of other retinal layers did not differ. The retinal nerve fiber layer was thinnest in the group that had hallucinations without dementia, followed by the group that had hallucinations with dementia, and the group that had no hallucinations and no dementia. General ophthalmologic examinations did not reveal any significant correlation with hallucinations. There were no significant correlations between retinal thicknesses and duration or severity of PD and medication dosages. The results indicate that retinal nerve fiber layer thinning may be related to visual hallucination in nondemented patients with PD. Replication studies as well as further studies to elucidate the mechanism of thinning are warranted.

The prevalence of essential tremor in elderly Koreans.

Essential tremor (ET) is one of the most common movement disorders. The prevalence of ET varies substantially among studies. In Korea, there is no well-designed epidemiological study of the prevalence of ET. Thus, we investigated the prevalence of ET in a community in Korea. Standardized interviews and in-person neurological examinations were performed in a random sample of the elderly aged 65 yr or older. Next, movement specialists attempted to diagnose ET clinically. People who showed equivocal parkinsonian features underwent dopamine transporter imaging using [(123)I]-FP-CIT SPECT, to differentiate ET from parkinsonism. A total of 714 subjects participated in this population-based study. Twenty six of these subjects were diagnosed as having ET. The crude prevalence of ET was 3.64 per 100 persons. Age, gender, or education period were not different between the ET patients and the non-ET subjects. The prevalence of ET was slightly lower than those reported in previous studies. Further studies including more subjects are warranted.

Seven-Tesla magnetic resonance images of the substantia nigra in Parkinson disease.

OBJECTIVE: To investigate anatomical changes in the substantia nigra (SN) of Parkinson disease (PD) patients with age-matched controls by using ultra-high field magnetic resonance imaging (MRI). METHODS: We performed 7T MRI in 10 PD and 10 age-matched control subjects. Magnetic resonance images of the SN were obtained from a 3-dimensional (3D) T(2)*-weighted gradient echo sequence. Region of interest-based 3D shape analysis was performed to quantitatively compare images from the 2 groups. RESULTS: The boundary between the SN and crus cerebri was not smooth in PD subjects. Undulation in the lateral surface of the SN appeared more intense in the side contralateral to that with the more severe symptoms, and more prominent at the rostral level of the SN than at the intermediate or caudal levels. In addition to the lateral surface, there was a striking difference in the dorsomedial aspects of the SN between PD and control subjects. In control subjects, a brighter signal region was observed along the dorsomedial surface of the lateral portion of SN, whereas in PD subjects, this region was observed as a dark region containing a hypointense signal in T(2)*-weighted images. The measurement of SN volumes, normalized to the intracranial volumes, showed higher values in PD subjects than in control subjects. INTERPRETATION: This study demonstrates that 3D 7T MRI can definitively visualize anatomical alterations occurring in the SN of PD subjects. Further pathological studies are required to elucidate the nature of these anatomical alterations.

Population-specific frequencies for LRRK2 susceptibility variants in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) Consortium.

BACKGROUND: Variants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine-rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late-onset sporadic disorders like Parkinson's disease. METHODS: The Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine-rich repeat kinase 2 gene across 23 different sites in 15 countries. RESULTS: Herein, we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K-R1398H-K1423K) nominated in the original publication. Simple population allele frequencies not only can provide insight into the clinical relevance of specific variants but also can help genetically define patient groups. CONCLUSIONS: Establishing individual patient-based genomic susceptibility profiles that incorporate both risk factors and protective factors will determine future diagnostic and treatment strategies.

Musculoskeletal problems in Parkinson's disease.

Musculoskeletal problems are very common and are an important contributor to poor quality of life in Parkinson's disease. However, they are under-appreciated, under-evaluated, and under-treated. This paper will address the prevalence of musculoskeletal problems in Parkinson's disease, and review the clinical characteristics of selected musculoskeletal conditions, such as shoulder problems, low back pain, arthritis, deformity, osteoporosis and fracture. Finally, a variety of treatment modalities for musculoskeletal problems will be reviewed.

Unusual epileptic deterioration and extensive white matter lesion during treatment in Wilson's disease.

BACKGROUND: Wilson's disease (WD) is a genetic disorder which can be controlled fairly well with decupuration therapy. However, symptoms, on rare occasions, can worsen even when WD is being treated. Herein, we report a case involving unusual neurological deterioration during decupuration therapy for WD. CASE PRESENTATION: A 28-year-old man was diagnosed with WD 13 years prior to his clinical visit; however, his drug compliance has been poor over the years. He was treated with trientine because tremors and dysarthria have presented in recent years. However, dysarthria and dystonia developed in his limbs, which were worse on the right side and had been aggravated for several weeks despite good drug compliance. His symptoms were fluctuating. It was initially misdiagnosed as dystonia; although, it turned out to be a seizure due to cortical degeneration. These symptoms were completely resolved with antiepileptic drugs. Moreover, the cortical enhancement of bifrontal degeneration has disappeared on the MRI. CONCLUSION: This case showed unusual epileptic neurologic deterioration due to cortical degeneration during decupuration therapy. Seizures in WD can easily be mistaken as part of dystonia. However, the fluctuating symptoms suggest a seizure.

Comparison of once-daily versus twice-daily combination of ropinirole prolonged release in Parkinson's disease.

BACKGROUND: Ropinirole prolonged release (RPR) is a once-daily formulation. However, there may be individual pharmacokinetic differences so that multiple dosing may be preferred in some individuals. This study compares once-daily and twice-daily RPR in patients with Parkinson's disease. METHODS: This study was an open-label crossover study. We enrolled Parkinson's disease patients on dopamine agonist therapy with unsatisfactory control such as motor fluctuation, dyskinesia and sleep-related problems. Agonists were switched into equivalent dose of RPR. Subjects were consecutively enrolled into either once-daily first or twice-daily first groups, and received the same amount of RPR in a single and two divided dosing for 8 weeks respectively in a crossover manner without a washout period.The primary outcome was a questionnaire of the preference completed by patients in the last visit. The secondary outcome measures included the Unified Parkinson's Disease Rating Scale part 3 (mUPDRS), Hoehn and Yahr stage (H&Y); sleep questionnaire including overall quality of sleep, nocturnal off symptoms and early morning symptoms; Epworth Sleep Scale (ESS); compliances and patient global impression (PGI). RESULTS: A total of 82 patients were enrolled and 61 completed the study. 31 patients preferred twice-daily regimen, 17 preferred the once-daily regimen, and 13 had no preference. Their mean mUPDRS, H&Y, ESS, sleep quality, compliance and adverse events were not statistically different in both regimens. PGI-improvement on wearing off defined was better in twice-daily dosing regimen. CONCLUSIONS: RPR is a once-daily formulation, but multiple dosing was preferred in many patients. Multiple dosing of RPR might be a therapeutic option if once-daily dosing is unsatisfactory.

A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants.

BACKGROUND: Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive. METHODS AND RESULTS: We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort. CONCLUSIONS: Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.

Acute brain reaction to DBS electrodes after deep brain stimulation: chronological observation.

BACKGROUND: As increasing numbers of deep brain stimulation (DBS) procedures are performed, rare abnormal findings on postoperative images that are not attributable to well-known complications are reported. Between 2005 and 2012, we encountered several symptomatic patients with transient abnormal low-attenuation lesions on postoperative computed tomography (CT) scans. The aim of this study was to clarify this rare phenomenon using chronological observations and to suggest a feasible mechanism. RESULTS: In this period, seven (3.2 %) patients displayed transient increased low-attenuation signals, circumferentially surrounding the DBS electrodes and extending into the subcortical white matter. All these patients suffered from unexpected but transient neurological symptoms during the postoperative period. The abnormal low-attenuation lesions only disappeared completely a considerable time after the clinical symptoms had disappeared, without treatment in most patients. CONCLUSIONS: We report here our chronological observations of acute brain reactions after DBS procedures, which we believe are neither infectious nor vascular, but are possibly caused by the mechanical breakdown of the blood-brain barrier by microelectrode recordings or by anchored DBS electrodes. These lesions are thought to constitute a self-limiting disorder requiring no further treatment.

Striatal dopaminergic functioning in patients with sporadic and hereditary spastic paraplegias with parkinsonism.

Sporadic spastic paraplegia (SSP) and hereditary spastic paraplegia (HSP) belong to a clinical and genetically heterogeneous group of disorders characterized by progressive spasticity and weakness in the lower extremities. The symptoms are associated with pyramidal tract dysfunction and degeneration of the corticospinal tracts. Parkinsonism is uncommon in SSP/HSP patients. However, both disorders are associated with damage to the nigrostriatal dopaminergic system. In the present study, the clinical features of patients with SSP/HSP were investigated, and nigrostriatal dopaminergic binding potential was assessed using dopamine transporter (DAT) single-photon emission computer tomography (SPECT). Nine patients with spastic paraplegia participated in the present study. The subjects underwent DAT SPECT using the agent [2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3,2,1]oct-2-yl]methyl](2-mercaptoethyl)amino]ethyl]amino]ethanethiolato (3-)-N2,N20,S2,S20]oxo-[IR-(exo-exo)])-[(99)mTc]technetium ([(99)mTc]TRODAT-1). The [(99)mTc]TRODAT-1 SPECT images of five patients appeared normal, whereas the images of four patients revealed reduced striatal ligand uptake. Among the four patients with reduced uptake, two had parkinsonism, and one exhibited periodic limb movements and restless leg syndrome. Our DAT SPECT imaging study shows that reduced DAT density may be observed in patients with parkinsonism. The results of the present study offer an explanation for the spectrum of spastic paraplegia symptoms and the progression of the disorder.

Meningitis by Toxocara canis after ingestion of raw ostrich liver.

Recently reports on toxocariasis are increasing by serodiagnosis in Korea. A previously healthy 17-yr-old boy complained of headache, fever, dyspnea, and anorexia. He showed symptoms and signs of eosinophilic meningitis with involvement of the lungs and liver. Specific IgG antibody to Toxocara canis larval antigen was positive in serum and cerebrospinal fluid by ELISA. He took raw ostrich liver with his parents 4 weeks before the symptom onset. His parents were seropositive for T. canis antigen but had no symptoms or signs suggesting toxocariasis. This is the first report of toxocariasis in a family due to ingestion of raw ostrich liver in Korea.

SNPs in axon guidance pathway genes and susceptibility for Parkinson's disease in the Korean population.

Single-nucleotide polymorphisms (SNPs) in genes of the axon guidance pathway have been reported to be a possible susceptibility factor for Parkinson's disease (PD). This study investigated whether the genetic variability in the axon guidance pathway is a susceptibility factor in PD patients in the Korean population. A total of 373 patients and 384 healthy subjects were included. A set of 22 SNPs was analyzed, and the risk of PD was evaluated using odds ratios in an unconditional and conditional logistic regression models of age- and gender-matched subsets. A multidimensionality reduction (MDR) analysis was performed to explore potential gene-gene interactions. SNPs in the DCC, CHP, RRAS2 and EPHB1 genes of the axon guidance pathway showed significant associations with PD. The DCC rs17468382 and EPHB1 rs2030737 SNPs may be associated with increased PD risk, and the CHP rs6492998 and RRAS2 rs2970332 SNPs may be associated with reduced PD risk. However, no significant interactions for PD risk were found in the MDR analysis and logistic regression analysis using SNP interaction terms. This study supports that only four of the selected 22 SNPs are regulating factors associated with PD in the Korean population. However, no interactions were found among the SNPs, suggesting that the effect for the pathway as a whole is not greater than that for single genes in the Korean population. Further investigations involving populations of various ethnicities and other genetic markers and models are warranted.

Differential genetic susceptibility in diphasic and peak-dose dyskinesias in Parkinson's disease.

To examine whether there is a differential genetic susceptibility in the diphasic and peak-dose forms of levodopa-induced dyskinesias (LID) in patients with Parkinson's disease (PD). The study cohort comprised 503 unrelated Korean PD patients who were treated with levodopa and had a disease duration of at least 5 years. The presence of LID was identified during a routine follow-up and special care was taken to separate the two distinct forms of LID into diphasic and peak-dose dyskinesias (PDSK). Genotyping was performed in the 503 patients and in 559 healthy controls to search for polymorphisms of DRD3 p.S9G, DRD2 Taq1A, GRIN2B c.2664C>T, c.366C>G, c.-200T>G, and the promoter region of SLC6A4. A total of 229 patients expressed LID (peak-dose in 205, diphasic in 57, and both in 33). The presence of diphasic dyskinesia (DDSK) was exclusively associated with the DRD3 p.S9G variant after adjusting for gender, age at PD onset, Hoehn & Yahr stage, and duration of levodopa treatment. Carrying the AA genotype was likely to shorten the onset of DDSK according to the duration of levodopa therapy (P = 0.02). The presence of PDSK was not significantly associated with any of the six genetic variants studied. There may be a genetic susceptibility in the development of DDSK in PD patients on chronic levodopa therapy, and its underlying pathophysiological mechanism might be distinct from that of PDSK.

Survival of Korean patients with multiple system atrophy.

METHODS: We conducted a retrospective medical record review to determine the survival of 455 Korean multiple system atrophy (MSA) patients and examined the effect of clinical factors that could possibly influence survival. The patients comprised 222 men and 233 women. RESULTS: Age at onset was 60.1 ± 8.8 years (mean ± SD) and did not differ between the sexes. Parkinsonism was the most prevalent initial symptom, followed by cerebellar dysfunction and dysautonomia. Age at onset was significantly older in patients with predominant parkinsonism at the last visit (MSA-P) than in the other patients. At the time of data collection, 107 patients had died. Median survival time was 10 years. The survival rate of women was slightly better than that of men, especially in MSA-P patients. CONCLUSIONS: Survival was not affected by age at onset, initial symptom, or predominant symptom at the last visit or by the presence of autonomic symptoms or multiple symptoms at disease onset.

Direct visualization of Parkinson's disease by in vivo human brain imaging using 7.0T magnetic resonance imaging.

Parkinson's disease (PD) is a neurodegenerative disorder resulting from progressive loss of dopaminergic neurons in the substantia nigra (SN) pars compacta. Therefore, imaging of the SN has been regarded to hold greatest potential for use in the diagnosis of PD. At the 7.0T magnetic resonance imaging (MRI), it is now possible to delineate clearly the shapes and boundaries of the SN. We scanned eight early and two advanced PD patients, along with nine age-matched control subjects, using a 7.0T MRI in an attempt to directly visualize the SN and quantify the differences in shape and boundaries of SN between PD subjects in comparison with the normal control subjects. In the normal controls, the boundaries between the SN and crus cerebri appear smooth, and clean "arch" shapes that stretch ventrally from posterior to anterior. In contrast, these smooth and clean arch-like boundaries were lost in PD subjects. The measured correlation analyses show that, in PD patients, there is age-dependent correlation and substantially stronger UPDRS motor score-dependent correlation. These results suggest that, by using 7.0T MRI, it appears possible to use these visible and distinctive changes in morphology as a diagnostic marker of PD.