Movement Disorder in Wilson Disease: Correlation with MRI and Biomarkers of Cell Injury.

To report the phenomenology of movement disorder (MD) in neurological Wilson disease (NWD), and correlate these with MRI, and biomarkers of oxidative stress, excitotoxicity, and inflammation. Eighty-two patients were included, and their phenomenology of MD was categorized. The severity of dystonia was assessed using the Burke-Fahn-Marsden score, and chorea, athetosis, myoclonus, and tremor on a 0-4 scale. The MRI changes were noted. Serum glutamate, cytokines, and oxidative stress markers were measured. Movement disorders were noted in 78/82 (95.1%) patients and included dystonia in 69 (84.1%), chorea in 31 (37.8%), tremor in 24 (29.3%), parkinsonism in 19 (23.2%), athetosis in 13 (15.9%), and myoclonus in 9 (11.0%) patients. Dystonia was more frequently observed in the patients with thalamic (76.8 vs 23.2%), globus pallidus (72.0 vs 28.0%), putamen (69.5 vs 30.5%), caudate (68.3 vs 31.7%) and brainstem (61.0 vs 39.0%) involvement, and tremor with cerebellar involvement (37.5 vs 5.2%). The median age of onset of neurological symptoms was 12 (5-50) years. WD patients had higher levels of malondialdehyde (MDA), glutamate, and cytokines (IL-6, IL-8, IL-10, and TNFα) and lower levels of glutathione and total antioxidant capacity (TAC) compared with the controls. Serum glutamate, IL-6, IL-8, and plasma MDA levels were increased with increasing neurological severity, while glutathione and TAC levels decreased. The severity of dystonia related to the number of MRI lesions. MD is the commonest neurological symptoms in WD. Oxidative stress, glutamate, and cytokine levels are increased in WD and correlate with neurological severity.

Integrated Plasma and Neuroimaging Biomarkers Associated with Motor and Cognition Severity in Parkinson's Disease.

BACKGROUND/OBJECTIVE: Easily accessible biomarkers are crucial for disease-modifying clinical trials in patients with Parkinson's disease (PD). We investigated integrated plasma and neuroimaging biomarkers correlating with motor and cognitive severity in PD patients. METHODS: This cross-sectional study enrolled 170 participants (12 controls and 158 PD patients). Plasma α-synuclein and neurofilament light chain (NfL) level, and global and regional cortical thickness (CTh) on brain MRI were analyzed to predict advanced motor stage (Hoehn & Yahr stage ≥3), and PD dementia (PDD, MMSE score <26). RESULTS: Plasma α-synuclein and NfL levels were higher in PD patients than controls (both P < 0.0001 for α-synuclein and NfL). Plasma NfL levels were significantly elevated in patients with advanced motor stage (P = 0.008) or PDD; α-synuclein was elevated in the advanced motor stage group. Global CTh was thinner in patients with PDD than controls (2.33±0.19 mm vs 2.43±0.14 mm, P = 0.06). Among PD patients, higher α-synuclein was associated with thinner limbic CTh, whereas higher NfL was associated with thinner temporal CTh and insular CTh. The accuracy of predicting advanced motor stage using age and sex alone (area under the curve [AUC] 0.63) was significantly improved by the addition of plasma α-synuclein and NfL, and temporal and insula CTh (full model, AUC 0.77, P = 0.004). The accuracy of predicting PDD using age and sex alone (AUC 0.82) increased by incorporating plasma α-synuclein and NfL, and temporal and insula CTh as full model (AUC 0.87, P = 0.047). CONCLUSIONS: Integrated plasma and neuroimaging biomarkers reflect both motor and cognitive aspects of PD severity.

Measurement of serum cystatin C: A valuable tool for evaluating dyskinesia in Parkinson's disease.

Although cystatin C (Cys C) has been implicated in the pathophysiology of Parkinson's disease (PD), whether it can be used as a tool for evaluating dyskinesia is unknown. In the present study, the association of Cys C with dyskinesia in PD patients was investigated. Fasting serum Cys C levels were measured from 120 PD patients and 156 healthy controls. Demographic information was collected for all patients. In addition, levodopa (L-dopa)-equivalent dose, Unified Parkinson's Disease Rating Scale (UPDRS) score, Hoehn and Yahr (H&Y) stage, and dyskinesia were assessed in PD patients. Receiver operating characteristic (ROC) curves were adopted to assess the evaluating accuracy of Cys C levels for distinguishing dyskinesia in PD patients. Patients with PD exhibited significantly higher serum Cys C levels compared with heathy controls. Dyskinesia was observed in 32 patients (26.7%). Multiple logistic regression showed serum Cys C levels (odds ratio, OR 12.93; 95% confidence interval, CI 1.08-54.23; p = 0.043), duration of disease (OR 1.03, 95% CI 1.01-1.05, p = 0.001) and UPDRS II score (OR 1.07, 95% CI 1.01-1.14, p = 0.019) were independently associated with dyskinesia. The ROC curve for the Cys C levels yielded a valuable accuracy for distinguishing dyskinesia in PD patients. Serum Cys C levels were independently associated with dyskinesia and may be a valuable screening tool for differentiating dyskinesia in PD patients. Although the pathophysiological mechanism of PD is complicated, the results from our study provide a better understanding of the association between Cys C and dyskinesia in PD patients and may yield insights into the pathogenesis of PD.

Paediatric non-ketotic hyperglycaemic hemichorea-hemiballismus.

Non-ketotic hyperglycaemic hemichorea-hemiballismus (NHHH) is commonly seen among elderly Asian women with type 2 diabetes mellitus. Here, we present a case of a 16-year-old Filipina with type 1 diabetes mellitus who is poorly compliant to her medications and subsequently developed right hemichorea-hemiballismus (HH). She was initially admitted with hyperglycaemia but was negative for ketonuria or metabolic acidosis. Neuroimaging showed bilateral lentiform nuclei and left caudate hyperdensities on CT and T1-weighted hyperintensity on MRI. Blood glucose was controlled with insulin. Haloperidol and clonazepam were started for the HH with gradual resolution of symptoms in 6 weeks. This is the fifth reported case of NHHH seen among the paediatric age group. NHHH in the paediatric population is clinically and radiographically similar to NHHH seen among adults. Correction of hyperglycaemia results in clinical improvement and radiographic resolution of lesions but persistent cases may necessitate specific treatment targeted towards the abnormal movements.

Characterization of Paroxysmal Gluten-Sensitive Dyskinesia in Border Terriers Using Serological Markers.

BACKGROUND: Paroxysmal gluten-sensitive dyskinesia (PGSD) in border terriers (BTs) results from an immunologic response directed against transglutaminase (TG)2 and gliadin. Recent evidence suggests that PGSD is only one aspect of a range of possible manifestations of gluten sensitivity in the breed. HYPOTHESIS/OBJECTIVES: Gluten sensitivity in BTs is a heterogeneous disease process with a diverse clinical spectrum; to characterize the phenotype of PGSD using TG2 and gliadin autoantibodies as diagnostic markers. ANIMALS: One hundred twenty-eight client-owned BTs with various disorders. METHODS: Prospective study. BTs with paroxysmal episodes and a normal interictal examination were phenotyped using footage of a representative episode and assigned to 3 groups: idiopathic epilepsy (IE), paroxysmal dyskinesia (PD), or other. Owners of each dog completed a questionnaire to obtain information regarding clinical signs. Healthy BTs formed a control group. Serum antibodies against TG2 and AGA were measured in all dogs. RESULTS: One hundred twenty-eight BTs were enrolled; 45 with PD, 28 with IE, 35 with other conditions, and 20 controls. Three overlapping phenotypes were identified; PD, signs suggestive of gastrointestinal disease, and dermatopathy. AGA-IgG concentrations were increased in PD, compared with IE (P = 0.012), controls (P < 0.0001) and other (P = 0.018) conditions. Anti-canine TG2-IgA concentrations were increased in PD, compared with IE (P < 0.0001), controls (P < 0.0001) and other (P = 0.012) conditions. Serological markers are highly specific for PGSD but lack sensitivity. CONCLUSIONS: PGSD appears part of a syndrome of gluten intolerance consisting of episodes of transient dyskinesia, signs suggestive of gastrointestinal disease, and dermatological hypersensitivity.

A Phase Ib Randomized Controlled Study to Evaluate the Effectiveness of a Single-Dose of the NR2B Selective N-Methyl-D-Aspartate Antagonist MK-0657 on Levodopa-Induced Dyskinesias and Motor Symptoms in Patients With Parkinson Disease.

OBJECTIVES: Blockade of N-methyl-D-aspartate receptors containing the NR2B subunit has been shown to be therapeutic in animal models of Parkinson disease (PD). However, findings with investigational NR2B receptor antagonists in PD patients have been mixed. The objective of this study was to evaluate the effects of the NR2B selective N-methyl-D-aspartate receptor antagonist MK-0657 on levodopa-induced dyskinesias and motor symptoms in PD patients. METHODS: A randomized, double-blind, single-dose, 2-period crossover study was conducted in 22 patients with PD and levodopa-induced peak-dose dyskinesias. Patients received oral MK-0657 (7 mg) or placebo, in randomized order, on each of 2 test days. On both days, levodopa was administered as a 2-hour intravenous infusion at greater than or equal to 1 mg/kg per hour with frequent assessments of dyskinesia, motor function, and pharmacokinetics. RESULTS: MK-0657 7 mg had no significant effect on dyskinesias (difference versus placebo in modified Abnormal Involuntary Movement Scale mean change from baseline area under the curve over 5 hours, -2.3; 95% confidence interval, -5.1 to 0.4) or motor function (difference versus placebo in Unified Parkinson's Disease Rating Scale Part III mean change from baseline area under the curve over 5 hours, 13.9; 95% confidence interval, -1.7 to 29.5). MK-0657 7 mg achieved the target mean maximum plasma concentration of 400 nM. CONCLUSIONS: These data suggest that a single dose of MK-0657 7 mg is not effective in improving levodopa-induced dyskinesias and motor symptoms in PD patients. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov NCT00505843.

Benign Neonatal Shudders, Shivers, Jitteriness, or Tremors: Early Signs of Vitamin D Deficiency.

Jitteriness and tremors in the newborn period typically precipitate an extensive, invasive, and expensive search for the etiology. Vitamin D deficiency has not been historically included in the differential of tremors. We report a shivering, jittery newborn who was subjected to a battery of testing, with the only biochemical abnormality being vitamin D deficiency. A second case had chin tremors and vitamin D deficiency. Review of our patients suggests that shudders, shivers, jitteriness, or tremors may be the earliest sign of vitamin D deficiency in the newborn. Neonates who present with these signs should be investigated for vitamin D deficiency.

Anti-Yo, chorea and hemiballismus: A case report.

68-year-old female presented with involuntary movements. MRI was normal. Cerebrospinal fluid analysis was normal. whole body CT and biopsy confirmed diagnosis of metastatic adenocarnimoa. The autoimmune panel was positive for anti-Yo antibodies.

Serum sodium and chloride are inversely associated with dyskinesia in Parkinson's disease patients.

Objective: We aim to report and evaluate the associations between serum sodium and chloride and dyskinesia in patients with Parkinson's disease. One hundred and two patients with Parkinson's disease were enrolled in this study. Methods: Patients' serum electrolytes including sodium, calcium, potassium, magnesium, and chloride were measured. Other demographic information was collected, and Unified Parkinson's disease rating scale and Hoehn and Yahr stage scale were also performed. Results: Patients with dyskinesia tended to have longer duration of disease, higher daily levodopa-equivalent dose, and Hoehn-Yahr stage, with lower serum sodium than those without dyskinesia. Spearman correlation analyses showed that serum sodium inversely correlated with duration of disease (r = -.218, p = .028), and positively correlated with serum chloride levels (r = .565, p < .001). Univariate logistic regression analysis found that duration of disease, daily levodopa-equivalent dose, serum sodium, and serum chloride were associated with dyskinesia in Parkinson's disease patients (p < .05 for all). After adjusting for age, sex, age at onset of Parkinson's disease, medical history, and other covariates, serum sodium and chloride were still associated with dyskinesia, with corresponding Odd ratios 0.783 (95% confidence intervals, 0.642-0.955) and 0.796 (95% confidence intervals, 0.652-0.972), respectively. Conclusion: Our findings indicated that serum sodium and chloride levels were inversely associated with dyskinesia in patients with Parkinson's disease. Further studies with large samples and range of serum sodium and chloride are needed.

[Antibodies to native and denatured DNA in the serum of patients with schizophrenia depending on the clinical features of the disease].

OBJECTIVE: To study the correlations between the level of antibodies to native and denatured DNA and psychopathological symptoms and illness duration in patients with schizophrenia. MATERIAL AND METHODS: The level of antibodies to native (double-stranded) DNA and denatured (single-stranded) DNA was studied in the serum of 50 patients with schizophrenia, including 12 patients with tardive dyskinesia (TD). The control group consisted of 30 people. RESULTS: A significant twofold increase in antibodies to native DNA was detected in patients with TD. There was no correlation of the amount of antibodies to double-stranded DNA with the duration of disease and leading symptoms both between the groups of patients as well as in comparison with controls. A significant decrease in antibody levels to the denatured (single-stranded) DNA was found in schizophrenic patients compared to the control group (p=0.009). A significant decrease in the concentration of antibodies to single-stranded DNA in patients with increasing duration of the disease, as well as in patients with leading negative symptoms was revealed. CONCLUSION: The results suggest that anti-DNAantibodies may not play a major role in the pathogenesis of schizophrenia.

The Clinical and Serological Effect of a Gluten-Free Diet in Border Terriers with Epileptoid Cramping Syndrome.

BACKGROUND: Canine epileptoid cramping syndrome (CECS) is a paroxysmal movement disorder of Border Terriers (BTs). These dogs might respond to a gluten-free diet. OBJECTIVES: The objective of this study was to examine the clinical and serological effect of a gluten-free diet in BTs with CECS. ANIMALS: Six client-owned BTs with clinically confirmed CECS. METHODS: Dogs were prospectively recruited that had at least a 6-month history of CECS based on the observed phenomenology (using video) and had exhibited at least 2 separate episodes on different days. Dogs were tested for anti-transglutaminase 2 (TG2 IgA) and anti-gliadin (AGA IgG) antibodies in the serum at presentation, and 3, 6, and 9 months after the introduction of a gluten-free diet. Duodenal biopsies were performed in 1 dog. RESULTS: Serum TG2 IgA titers were increased in 6/6 BTs (P = .006) and AGA IgG titers were increased in 5/6 BTs at presentation compared to those of controls (P = .018). After 9 months, there was clinical and serological improvement in all BTs with CECS strictly adhering to a gluten-free diet (5/5). One dog had persistently increased antibody titers. This dog scavenged horse manure. On the strict introduction of a gluten-free diet this dog also had an improved clinical and serological response. The diet-associated improvement was reversible in 2 dogs on completion of the study, both of which suffered a relapse of CECS on the re-introduction of gluten. CONCLUSIONS: Canine epileptoid cramping syndrome in BTs is a gluten-sensitive movement disorder triggered and perpetuated by gluten and thus responsive to a gluten-free diet.

Caspr2 antibodies in limbic encephalitis with cerebellar ataxia, dyskinesias and myoclonus.

Here we report on a case of contactin-associated protein-2 (Caspr2) antibody positive but voltage gated potassium channel (VGKC) antibody negative limbic encephalitis associated with cerebellar ataxia, myoclonus and dyskinesias with favorable response to immunotherapy. This case underlines the importance of Caspr2-specific antibody testing and demonstrates that Caspr2 antibodies are associated with a broader clinical spectrum than hitherto described.

L-745,870 reduces L-DOPA-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson's disease.

L-DOPA-induced dyskinesia remains an unmet challenge in the treatment of Parkinson's disease (PD). Here, we investigate the potential antidyskinetic efficacy of 3-([4-(4-chlorophenyl)piperazin-1-yl]methyl)-1H-pyrrolo[2,3-b]pyridine (L-745,870), a potent and selective dopamine D(4) receptor antagonist with a good toxicology profile and an excellent safety and tolerability record in phase I/II clinical studies, for non-PD indications. Six macaques were rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration. After induction of stable and marked dyskinesia, animals were administered acute challenges of L-745,870 in combination with L-DOPA. To guarantee D(4) selectivity at the doses used in the study, we determined the plasma, cerebrospinal fluid, and brain levels of L-745,870. Coadministration of L-745,870 (1 mg/kg) and L-DOPA significantly reduced the severity of dyskinesia, by up to 59%, in comparison with L-DOPA alone (P < 0.01). L-745,870 had no effect on the duration of antiparkinsonian benefit (ON-time) (P > 0.05). However, L-745,870 (1 mg/kg) significantly increased the duration of ON-time without disabling dyskinesia (+204%; P < 0.001) and decreased duration of ON-time with disabling dyskinesia compared with L-DOPA alone (-56%; P < 0.01). Brain levels of L-745,870 (∼600 ng/g) were within the range at which L-745,870 provides selective D(4) receptor antagonism. Plasma levels were comparable with those demonstrated to be well tolerated in human studies. These data suggest that selective D(4) receptor antagonists represent a potential therapeutic approach for L-DOPA-induced dyskinesia. It is noteworthy that L-745,870 has already undergone significant clinical development, has an excellent profile for a therapeutic candidate, and could be advanced rapidly to phase IIa clinical studies for dyskinesia in PD.

Use of memantine (akatinol) for the correction of cognitive impairments in Parkinson's disease complicated by dementia.

This study addresses the effects of 52 weeks of treatment with the NMDA glutamate receptor antagonist memantine on motor, cognitive, and mental disorders in patients with Parkinson's disease complicated by dementia, as compared with a control group of patients not treated with memantine. Patients of the experimental group (32 subjects) received memantine (20 mg/day), while patients in the control group continued on antiparkinsonism treatment alone. Cognitive, psychiatric, and motor symptoms were assessed before the study and then at the ends of weeks 12, 24, and 52, using clinical assessment, rating scales, and neuropsychological tests. Plasma homocysteine levels were measured by HPLC. Patients treated with memantine had better measures on the MMSE (p < 0.05), ADAS-cog (p < 0.05), clock drawing test (p < 0.05), and FAB (p < 0.01) as compared with the control group by the end of study week 24. Members of the group of patients with high homocysteine levels mounted significantly better responses with memantine treatment, as compared with patients of the control group with high homocysteine levels but not receiving memantine, at the ends of study weeks 24 and 52, in terms of all rating scales (UPDRS, MMSE, ADAS-cog, D-KEFS Verbal Fluency Test, FAB. NPI, and DAD, p < 0.05). By the end of week 52, significant changes in points scores on the NPI-12 scale from baseline were in favor of patients receiving memantine, this applying to the disinhibition (p = 0.006), irritability (p = 0.04), anxiety (p = 0.04), and hallucinations (p = 0.048) subscales. The presence of hyperhomocysteinemia may indicate faster progression of both motor and cognitive impairments in Parkinson's disease. Prolonged memantine treatment of patients with Parkinson's disease complicated by dementia leads to improvements in cognitive functions, stabilization of motor impairments, and decreases in the severity of mental disorders, especially in patients with hyperhomocysteinemia.

Trace elements and flapping tremors in patients with liver cirrhosis. Is there a relationship?

OBJECTIVE: To investigate the possible correlation between hepatic flapping tremors and serum manganese Mn, iron Fe, zinc Zn, and copper Cu. METHODS: This case control study was carried out in Assiut University Hospital, Assiut, Egypt from June 2006 to June 2007. It included 100 patients with liver cirrhosis, 78 had flapping tremor, and 22 had not, and 60 healthy controls. All patients were subjected to assessment of serum Mn, total Fe, total iron binding capacity (TIBC), Zn, and Cu. Assessment of hepatic encephalopathy was carried out using a battery of cognitive function tests. All patients had electroencephalography and MRI of the brain. RESULTS: Compared to healthy controls, patients showed increase in Mn (p<0.0001), Cu (p<0.05) and decrease in TIBC (p<0.000), Zn (p<0.05). Eighty-two percent of patients had minimal hepatic encephalopathy (mHE). In 85%, MRI-brain showed bilateral hyperintense substantia nigra and globus pallidus on T1-weighted images. A significant positive correlation was present between tremors and severity of liver dysfunction, mHE and serum Cu, and negative correlation with total Fe, TIBC, and Zn. CONCLUSION: Altered homeostasis of Mn and other minerals could be responsible for the pathophysiology of cognitive deficits associated with liver cirrhosis, but not with flapping tremors. The exact pathogenic role and possibilities for therapeutic implications need further study.

Elevated plasma homocysteine levels in L-dopa-treated Parkinson's disease patients with dyskinesias.

BACKGROUND: Elevated plasma homocysteine (Hcy) concentrations are associated with increased risk of systemic vascular diseases, Alzheimer's disease and vascular dementia. Several cross-sectional reports and two prospective clinical studies have recently reported elevated plasma Hcy levels in L-dopa-treated Parkinson's disease (PD) patients and Hcy has been proposed as a possible mediator for the development of long-term L-dopa motor complications (such as wearing off and on-off phenomena, and dyskinesias). The aim of the study was to elucidate a possible role of L-dopa-related hyperhomocysteinemia in the development of dyskinesias. METHODS: In this cross-sectional study we compared Hcy, B(12) and folate levels in 53 PD patients treated with L-dopa (29 with dyskinesias, 24 without dyskinesias). RESULTS: Mean plasma Hcy levels were higher in the group of PD patients with dyskinesias (19 vs. 15.4 micromol/L; T: 2.12; p=0.04). After taking into account potential confounding factors, analysis of the data revealed that the occurrence of dyskinesias progressively increased with plasma Hcy levels (relative risk 1.2, 95% CI 1.015-1.4; p=0.03). CONCLUSIONS: Our results raise the possibility that Hcy plays a role in the development of dyskinesias, through its toxic effects on both dopaminergic neurons and non-substantia nigra, non-dopaminergic neurons.

Tardive dyskinesia in schizophrenia is associated with prolactin-related sexual disturbances.

Tardive dyskinesia (TD) may occur in never-medicated patients with psychotic illness, indicating the existence of non-medication, possibly disease-related, causes. We tested the hypothesis that, independent of the antipsychotic-induced rise in prolactin, the incidence of TD would be associated with the incidence of prolactin-related sexual disturbances (PRSD), which would be suggestive of a common pathology involving multiple dopamine tracts. Simple, global measures of TD and PRSD (loss of libido, amenorrhea, gynaecomastia, impotence, and galactorrhea) were rated in a prospective, observational European Health Outcomes Study (SOHO). New onset of TD and new onset of PRSD at 3, 6, and 12 months was analyzed in a risk set of 4263 patients using a Cox proportional hazard model yielding adjusted hazard ratios (aHR). Incidence of TD was significantly and linearly comorbid with the incidence of PRSD in both men and women. Compared to those with no PRSD, the risk for TD was 2.0 (95% CI: 1.1, 3.7) with one PRSD, 2.4 (95% CI: 1.3, 4.5) with two PRSD, and 3.6 (95% CI: 1.1, 11.8) with three PRSD. Associations were stronger in those who only had received prolactin-sparing medications (aHR per unit PRSD increase=2.0, 95% CI: 1.2, 3.3) than in those who only had received prolactin-raising medications (aHR=1.3, 95% CI: 0.9, 1.9). In people with schizophrenia, TD and PRSD show comorbidities that are independent of antipsychotic-induced alterations in plasma prolactin. This may suggest a shared, pandopaminergic pathological mechanism associated with schizophrenia itself, rather than only a medication effect.