A systematic review of the potential consequences of abnormal serum levels of vitamin B6 in people living with Parkinson's disease.

The prevalences of polyneuropathy and epilepsy are higher in people living with Parkinson's disease (PwPD) when compared to older adults. Vitamin B6 is widely available and affordable. PwPD are at higher risk of having abnormal serum levels of vitamin B6, which are associated with polyneuropathy and epilepsy that are potentially preventable and treatable. Potential contributors to abnormal B6 levels in PwPD include age, dietary habits, vitamin supplement misuse, gastrointestinal dysfunction and complex interactions with levodopa. The literature on the potential consequences of abnormal B6 levels in PwPD is limited by a small number of observational studies focused on polyneuropathy and epilepsy. Abnormal B6 levels have been reported in 60 of 145 PwPD (41.4% relative frequency). Low B6 levels were reported in 52 PwPD and high B6 levels were reported in 8 PwPD. There were 14 PwPD, polyneuropathy and low B6. There were 4 PwPD, polyneuropathy and high B6. There were 4 PwPD, epilepsy and low B6. Vitamin B6 level was low in 44.6% of PwPD receiving levodopa-carbidopa intestinal gel and in 30.1% of PwPD receiving oral levodopa-carbidopa. In almost all studies reporting low B6 in PwPD receiving oral levodopa-carbidopa, the dose of levodopa was ≥1000 mg/day. Rigorous epidemiological studies will clarify the prevalence, natural history and clinical relevance of abnormal serum levels of vitamin B6 in PwPD. These studies should account for diet, vitamin supplement use, gastrointestinal dysfunction, concurrent levels of vitamin B12, folate, homocysteine and methylmalonic acid, formulations and dosages of levodopa and other medications commonly used in PwPD.

Mendelian Randomisation Study of Smoking, Alcohol, and Coffee Drinking in Relation to Parkinson's Disease.

BACKGROUND: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson's disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. OBJECTIVE: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. METHODS: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). RESULTS: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60-0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. CONCLUSION: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.

The evidence for multidisciplinary care in Parkinson's disease.

INTRODUCTION: Parkinson's Disease (PD) is a chronic and slowly progressive neurodegenerative disease. Team-based care is required to address and manage the diverse array of motor and non-motor symptoms in PD and related conditions. As the evidence base for the efficacy of non-pharmacological treatment of PD is expanding, many different centers are implementing interdisciplinary models of care with allied health professionals trained in PD. AREAS COVERED: In this review, the authors outline these various models and review the evidence for multidisciplinary approaches to care in PD. They begin by defining the terms used to describe the spectrum of multidisciplinary and integrated care models, followed by synthesizing the evidence for these models in PD. The authors then highlight some representative models to illustrate the variety of multidisciplinary care interventions: a community network-based model, a day-hospital model, an academic clinic-based model, and an intensive inpatient rehabilitation model. The authors synthesize these results and suggest directions for team-based PD care for the future. EXPERT OPINION: The future of medicine is team-based care that is decentralized and integrated vertically and horizontally across health systems. Building an evidence base for these complex interventions will require alternative models of evaluation other than randomized controlled trials.

ADCK3-related Coenzyme Q10 Deficiency: A Potentially Treatable Genetic Disease.

BACKGROUND: Disorders related to dysfunction of coenzyme (CoQ10) metabolism, including AarF domain containing kinase 3 gene (ADCK3) mutations, have received attention due to the potential for response to CoQ10 supplementation. METHODS: We describe two new cases of neurological syndromes due to ADCK3 mutations that obtained striking benefit from CoQ10, and a third who did not. We also review 20 cases from the literature in which responses to CoQ10 were documented out of all 38 previously reported cases. RESULTS: Despite the remarkable responses in some cases with ataxia and movement disorders (myoclonus, dystonia, tremor), overall, we were not able to identify variables that predicted response to CoQ10 supplementation. CONCLUSIONS: Based on our experience and data from the literature, we recommend a minimum of 10 mg/kg/day of ubiquinone with titration up to 15 mg/kg/day, maintained at least for 6 months in order to obtain or exclude potential benefit from therapy.

Subthalamic nucleus-deep brain stimulation for early motor complications in Parkinson's disease-the EARLYSTIM trial: early is not always better.

Subthalamic nucleus deep brain stimulation (STN-DBS) has revolutionized the management of disabling motor complications in Parkinson's disease. The EARLYSTIM trial applied this treatment to patients who had been experiencing motor complications for less than three years. STN-DBS significantly improved all primary and secondary outcome measures while best medical therapy failed to provide any improvement at the two-year follow-up time point. On face value these results strongly favor the application of STN-DBS far earlier than is currently applied, when patients are just beginning to experience problems with motor complications. Here we review the application of early DBS and the EARLYSTIM trial from the perspectives of clinical issues, health economics and study design and patient expectation of benefit. We conclude that the most relevant issue is not when to operate but on whom and that early is not always better. © 2014 International Parkinson and Movement Disorder Society.

Trial designs used to study neuroprotective therapy in Parkinson's disease.

There have been numerous trials conducted to evaluate putative disease-modifying or neuroprotective treatments in Parkinson's disease. These trials have used several different study designs and outcome measures. Each of these has its own strengths and weaknesses. Confounding all studies is the potential symptomatic benefit that the treatment might have on the features of Parkinson's disease. In addition, patient-related factors such as age of onset and the nature of the dominant symptoms may have important impacts that are often not addressed. Here we provide an overview of the various trial designs that have been used and emphasize the challenges faced in attempting to study neuroprotection in Parkinson's disease and the advances needed before this goal can be successfully achieved.

Unilateral subdural motor cortex stimulation improves essential tremor but not Parkinson's disease.

Epidural motor cortex stimulation has been reported to be effective in treating some movement disorders. Nevertheless, clinical results have been variable and no double-blinded evaluations have been reported. The aim of this study was to investigate efficacy and safety of unilateral subdural motor cortex stimulation in patients with essential tremor and Parkinson's disease. Six patients with essential tremor and five parkinsonian patients were selected. Craniotomy was performed under local anaesthesia with conscious sedation. A four contact electrode (Resume II model 3587, Medtronic, Inc) was positioned on the motor cortex, after identification of the area with direct monopolar cortical stimulation. Soon after surgery, a variety of different settings of stimulation were assessed using standard rating scales to select the optimal stimulation parameters. The effects of chronic stimulation were evaluated in both groups of patients after 3 months (double-blinded fashion) and 1 year (open fashion). In essential tremor, contralateral hand tremor scores significantly improved (P = 0.04) with stimulation during the double-blinded study, whereas in Parkinson's disease, there were no changes in the OFF medication/on stimulation motor scores compared with off stimulation. At 1 year, tremor was improved by stimulation in two out of three patients with essential tremor available at follow-up, whereas no improvement was observed in the five parkinsonian patients. One parkinsonian patient had a cortical venous infarct. Three other patients had self-limiting seizures with aggressive trials of stimulation in the period of dosage selection. These findings suggest that unilateral subdural motor cortex stimulation may be useful for contralateral hand tremor in selected patients with essential tremor but was not effective in improving parkinsonian signs in our series.

Thalamic neuronal and EMG activity in psychogenic dystonia compared with organic dystonia.

BACKGROUND: This is a retrospective analysis of thalamic neuronal and electromyogram activities between subjects with organic dystonia and a subject with psychogenic dystonia in whom a thalamotomy was carried out before the diagnosis of psychogenic dystonia was made. RESULTS: The signal-to-noise ratio in the lowest frequency band (dystonia frequency < 0.76 Hz) in the electromyogram was not significantly different by diagnosis or muscle. The coherence at dystonia frequency for wrist flexors X biceps electromyograms was significantly higher in organic dystonia, whereas the phase was not apparently different from zero for either diagnosis. In a thalamic pallidal relay nucleus (ventral oral posterior), neuronal firing rates were not apparently different between psychogenic and organic dystonia. The neuronal signal-to-noise ratio in ventral oral posterior was significantly higher in organic dystonia than in psychogenic dystonia, whereas both were greater than in controls with chronic pain. Spike X electromyogram coherence apparently was not different between psychogenic and organic dystonia. The proportion of thalamic cells responding to joint movements was higher in the cerebellar relay nucleus (ventral intermediate) of psychogenic dystonia than in organic dystonia. CONCLUSIONS: These results suggest that some features, such as firing rates and thalamic reorganization, are similar in psychogenic and organic dystonia. Other features differ, such as the coherence between the electromyograms from different muscles and the thalamic neuronal signal-to-noise ratio, which may reflect pathophysiological factors in organic dystonia. © 2011 Movement Disorder Society.

Involvement of the cerebellothalamocortical pathway in Parkinson disease.

OBJECTIVE: Lesioning or stimulation of the cerebellar thalamus is an established treatment for rest and postural tremors in Parkinson disease (PD). The cerebellothalamocortical (CTC) pathway can be assessed by transcranial magnetic stimulation (TMS) of the cerebellum, which suppresses the contralateral primary motor cortex (M1), a phenomenon termed cerebellar inhibition (CBI). Tremor reset can be used to assess whether the stimulated brain area is involved in the generation or transmission of tremor. We tested whether M1 or cerebellar stimulation can reset PD tremor, and investigated the excitability of the CTC pathway in PD. METHODS: Ten mild to moderate PD patients in the OFF medication state and 10 healthy controls were studied. Tremor reset was tested with TMS delivered to the cerebellum or M1. CBI was assessed by cerebellar stimulation followed by M1 stimulation at interstimulus intervals of 3 to 8 milliseconds. Subjects were tested both at rest and during arm extension. RESULTS: Rest tremor in PD was reset by M1 stimulation but not by cerebellar stimulation. Postural tremor was reset by both types of stimulation. At rest, CBI was reduced in PD patients compared to controls. Arm extension decreased CBI in controls and turned the inhibition into facilitation in patients. CBI correlated with the degree of tremor reset caused by the cerebellar stimulation. INTERPRETATION: The excitability of CTC pathway is decreased in PD. Rest and postural tremors in PD are mediated by different neuronal pathways, and the CTC pathway is involved in the generation or transmission of postural tremor.

Pathological gambling in Parkinson's disease improves on chronic subthalamic nucleus stimulation.

Pathological gambling (PG) related to dopaminergic treatment in Parkinson's disease (PD) is part of a spectrum of behavioral disorders called the dopamine dysregulation syndrome (DDS). We describe a series of PD patients with preoperative active PG due to dopaminergic treatment from a total of 598 patients who have undergone surgery for subthalamic nucleus stimulation for disabling motor fluctuations. The patients had systematic open assessment of behavioral symptoms and standardized assessments of motor symptoms, mood, and apathy. Seven patients (6 men, 1 woman; age, 54 +/- 9 years; levodopa equivalent dose, 1,390 +/- 350 mg/day) had preoperative PG over a mean of 7 years, intolerant to reduction in medication. Six had nonmotor fluctuations and four had other behavioral symptoms consistent with a diagnosis of the DDS. After surgery, motor symptoms improved, allowing for 74% reduction of dopaminergic treatment, below the dosage of gambling onset. In all patients, PG resolved postoperatively after 18 months on average (range, 0-48), although transient worsening occurred in two. Improvement paralleled the time course and degree of reduction in dopaminergic treatment. Nonmotor fluctuations, off period dysphoria, and other symptoms of the DDS improved. Two patients developed persistent apathy. In conclusion, PG and other symptoms of the DDS-associated dopaminergic treatment improved in our patients following surgery. Dopaminergic dysregulation commonly attributed to pulsatile overstimulation of the limbic dopaminergic system may be subject to desensitization on chronic subthalamic stimulation, which has a relative motor selectivity and allows for decrease in dopaminergic treatment.

Translation of nondopaminergic treatments for levodopa-induced dyskinesia from MPTP-lesioned nonhuman primates to phase IIa clinical studies: keys to success and roads to failure.

Studies in MPTP-lesioned nonhuman primates have demonstrated the potential of nondopaminergic drugs in reducing the problems of levodopa-induced dyskinesia (LID). Here we review the process of translating findings from the monkey to man. Agents targeting glutamate, adensosine, noradrenaline, 5-hydroxytryptamine, cannabinoid, and opioid transmitter systems have been assessed for antidyskinetic potential in human studies. Eleven nondopaminergic drugs with antidyskinetic efficacy in the MPTP primate have been advanced to proof-of-concept phase IIa trials in PD patients (amantadine, istradefylline, idazoxan, fipamezole, sarizotan, quetiapine, clozapine, nabilone, rimonabant, naloxone, and naltrexone). For all six nondopaminergic transmitter systems reviewed, the MPTP-lesioned primate correctly predicted phase II efficacy of at least one drug. Of the 11 specific molecules tested in both monkeys and humans, 8 showed clear antidyskinetic properties in both human and monkey. In the instances where the primate studies did not, or did not consistently, predict the outcome of the human studies, the discrepancy may reflect limitations in the validity of the model or limitations in the design of either the clinical or the preclinical studies. We find that the major determinant of success in predicting efficacy is to ensure that primate studies are conducted in a statistically rigorous way and incorporate designs and outcome measures with clinical applicability. On the other hand, phase IIa trials should strive to replicate the preclinical study, especially in terms of protocol, drug dose equivalence, and outcome measure, so as to test the same hypothesis. Failure to meet these criteria carries the risk of false negative conclusions in phase IIa trials.

Psychiatric symptoms following surgery for Parkinson's disease with an emphasis on subthalamic stimulation.

Bilateral subthalamic stimulation is a very effective neurosurgical treatment for advanced Parkinson's disease. Despite the range and frequency of psychiatric symptoms occurring in the postoperative state, most of these symptoms are transient and manageable. In clinical practice, preoperative psychiatric vulnerability, as with that of preoperative cognitive status, takes on an important role. Psychiatric assessment and active preoperative and postoperative intervention can potentially modify psychiatric outcomes. These psychiatric and psychological issues will take on greater importance, particularly with the rapid expansion of the number of neurosurgical sites and the need for adequate assessment and optimal management of patients. The paucity of the literature underscores the need for well-designed studies on psychiatric issues investigating both pathophysiology and clinical outcomes.

Involvement of human thalamus in the preparation of self-paced movement.

Cortical areas participating in the preparation of voluntary movements have been studied extensively. There is emerging evidence that subcortical structures, particularly the basal ganglia, also contribute to movement preparation. The thalamus is connected to both the basal ganglia and the cerebellar pathways, but its role in movement preparation has not been studied extensively in humans. We studied seven patients who underwent deep brain stimulation (DBS) electrode implantation in the thalamus for treatment of tremor (six patients) and myoclonus-dystonia (one patient). We recorded from the DBS contacts and scalp simultaneously, while patients performed self-paced wrist extension movements. Post-surgical MRI was used for precise localization of the DBS contacts in six patients. Back-averaging of the scalp recordings showed a slow negative movement-related potential (MRP) in all patients (onset 1846 +/- 189 ms prior to electromyography onset), whereas DBS electrode recordings showed pre-movement MRP in five out of seven patients. The thalamic MRP preceded both contralateral and ipsilateral wrist movements. There was no significant difference between the onset time of thalamic MRP (-2116 +/- 607 ms) and cortical MRP. Neither the scalp nor the thalamus showed pre-movement potentials with passive wrist extensions in two patients. In four patients with postoperative MRI who had thalamic MRP, the maximum amplitude or phase reversal occurred at contacts located in the ventral lateral nucleus. Frequency analysis was performed in the five patients with thalamic MRP. The medial frontocentral scalp contacts and the thalamic contacts with maximum MRP amplitude showed two discrete frequency bands in the alpha (mean peak 9 Hz) and beta (mean peak 17 Hz) range. Both frequency bands showed pre-movement event-related desynchronization (ERD). In the grand average, alpha and beta ERD in the scalp and beta ERD in the thalamus began 2.5-2.8 s prior to the onset of movement. However, the thalamic alpha ERD began considerably later, at 1.2 s before EMG onset. The beta band showed cortico-thalamic coherence from the beginning of the baseline period until approximately 0.5 s before the onset of movement. There was no cortico-thalamic coherence in the alpha band. Our findings suggest that the cerebellar thalamus is involved early in the process of movement preparation. Different cortico-subcortical circuits may mediate alpha and beta oscillations. During movement preparation, the motor thalamus and the supplementary motor area predominantly interact in the beta band.

Histological analysis of the location of effective thalamic stimulation for tremor. Case report.

Chronic electrical stimulation of the thalamus is an effective treatment for essential and parkinsonian tremor. Although the preferred surgical target is generally accepted to lie within the ventral intermediate nucleus (Vim), the relationship between the surgically defined target and the true histologically defined target is addressed in only a few reports, due in large measure to the need for advanced cytoarchitectonic techniques to define the borders of the thalamic nuclei. The authors report on a patient who underwent effective thalamic deep brain stimulation (DBS) for tremor. By defining the boundaries of the thalamic nuclei, they were able to relate effective DBS to electrode location within the anterior region of the ventral posterior lateral nucleus--the proprioceptive shell of the sensory nucleus--and the posteroventral region of the ventral lateral nucleus, which are equivalent to the Vim defined by Hassler, et al.

Primary dystonia is more responsive than secondary dystonia to pallidal interventions: outcome after pallidotomy or pallidal deep brain stimulation.

OBJECTIVE: The response of patients with dystonia to pallidal procedures is not well understood. In this study, we assessed the postoperative outcome of patients with primary and secondary dystonia undergoing pallidotomy or pallidal deep brain stimulation. METHODS: Fifteen patients with dystonia had pallidal surgery (lesions or deep brain stimulation). These included nine patients with primary dystonia (generalized and cervical dystonias) and six with secondary dystonia (generalized, segmental, and hemidystonias). There were nine male patients and six female patients. The mean age at onset was 21 years for primary dystonia and 18 years for secondary dystonia. The primary outcome measure was a Global Outcome Scale score for dystonia at 6 months after surgery. Other outcome measures were the Burke-Fahn-Marsden Dystonia Rating Scale and Toronto Western Spasmodic Torticollis Rating Scale scores. RESULTS: The mean Global Outcome Scale score at 6 months for patients with primary dystonia was 3 (improvement in both movement disorder and function). In contrast, patients with secondary dystonia had a mean score of 0.83 (mild or no improvement in movement disorder with no functional improvement). All patients with primary dystonia had normal brains by magnetic resonance imaging, whereas five of six patients with secondary dystonia had basal ganglia abnormalities on their magnetic resonance imaging scans. CONCLUSION: This study indicates that primary dystonia responds much better than secondary dystonia to pallidal procedures. We could not distinguish a difference in efficacy between pallidotomy and pallidal deep brain stimulation. The presence of basal ganglia abnormalities on the preoperative magnetic resonance imaging scan is an indicator of a lesser response to pallidal interventions for dystonia.

Long-term follow-up of thalamic deep brain stimulation for essential and parkinsonian tremor.

Thirteen consecutive patients with thalamic deep brain stimulation (DBS) were examined serially for 3 to 5 years. Initially, all demonstrated at least 50% improvement in contralateral tremor. At last follow-up, three of eight patients with Parkinson disease no longer used DBS because tremor had markedly improved, and for two, motor fluctuations and levodopa-induced dyskinesias became the major disability, with tremor less troublesome. Two of five patients with essential tremor had contralateral tremor improvement after ongoing stimulation for 2 years; two developed marked tolerance to DBS.

Deep brain stimulation for Parkinson's disease dissociates mood and motor circuits: a functional MRI case study.

Behavioral disturbances have been reported with subthalamic (STN) deep brain stimulation (DBS) treatment in Parkinson's disease (PD). We report correlative functional imaging (fMRI) of mood and motor responses induced by successive right and left DBS. A 36-year-old woman with medically refractory PD and a history of clinically remitted depression underwent uncomplicated implantation of bilateral STN DBS. High-frequency stimulation of the left electrode improved motor symptoms. Unexpectedly, right DBS alone elicited several reproducible episodes of acute depressive dysphoria. Structural and functional magnetic resonance imaging (fMRI) imaging was carried out with sequential individual electrode stimulation. The electrode on the left was within the inferior STN, whereas the right electrode was marginally superior and lateral to the intended STN target within the Fields of Forel/zona incerta. fMRI image analysis (Analysis of Functional NeuroImages, AFNI) contrasting OFF versus ON stimulation identified significant lateralized blood oxygen level-dependent (BOLD) signal changes with DBS (P < 0.001). Left DBS primarily showed changes in motor regions: increases in premotor and motor cortex, ventrolateral thalamus, putamen, and cerebellum as well as decreases in sensorimotor/supplementary motor cortex. Right DBS showed similar but less extensive change in motor regions. More prominent were the unique increases in superior prefrontal cortex, anterior cingulate (Brodmann's area [BA] 24), anterior thalamus, caudate, and brainstem, and marked widespread decreases in medial prefrontal cortex (BA 9/10). The mood disturbance resolved spontaneously in 4 weeks despite identical stimulation parameters. Transient depressive mood induced by subcortical DBS stimulation was correlated with changes in mesolimbic cortical structures. This case provides new evidence supporting cortical segregation of motor and nonmotor cortico-basal ganglionic systems that may converge in close proximity at the level of the STN and the adjacent white matter tracts (Fields of Forel/zona incerta).

Motor cortical stimulation for parkinsonism in multiple system atrophy.

BACKGROUND: Functional neuroimaging studies have demonstrated disturbances in the activity of premotor and motor cortices in Parkinson disease and in animal models of parkinsonism that improve in response to effective basal ganglia surgical therapy. Techniques that directly alter the function of these cortical areas, such as transcranial magnetic stimulation, have been applied in patients with Parkinson disease, with transient improvement in their bradykinesia and gait dysfunction. Recently, a patient with refractory Parkinson disease was claimed to have obtained a marked bilateral clinical benefit from extradural unilateral motor cortical stimulation. We hypothesized that direct cortical stimulation could alleviate the disability of the treatment-refractory parkinsonian symptoms commonly present in MSA. OBJECTIVE: To evaluate the efficacy of motor cortical stimulation in patients with refractory parkinsonism due to multiple system atrophy (MSA). METHODS: Five patients with a diagnosis of MSA with predominant parkinsonism underwent surgery for subdural motor cortical stimulation. MAIN OUTCOME MEASURES: Changes in activities of daily living and motor subscores on the Unified Parkinson's Disease Rating Scale 12 hours after medication withdrawal. Scores at baseline and 3 to 6 months following surgery were compared. RESULTS: All patients had a decline in motor scores at the follow-up evaluations despite the application of a variety of adjustments. The activities of daily living score mildly worsened by 9.7% (95% confidence interval, 32.3 to-13.0; P =.37) and the motor score worsened by 25.6% (95% confidence interval, 58.7 to -7.5; P =.06). Despite objective worsening over time and no deterioration when stimulation was immediately turned off, 3 patients still claimed subjective benefit and requested continued stimulation. No patients suffered adverse effects from the surgery or long-term stimulation, although 1 patient had a stimulation-induced seizure during the initial programming. The range of settings for 4 patients with bipolar configuration and 1 patient with monopolar configuration were as follows: amplitude, 3 to 3.6 V; pulse width, 40 to 90 milliseconds; and pulse rate, 145 to 185 Hz. CONCLUSIONS: Our data suggest that motor cortical stimulation using these parameters fails to improve the motor disability in MSA. Worsening of motor scores was likely a function of disease progression.