Danny Bega

Randomized controlled trial of deutetrabenazine for tardive dyskinesia The ARM-TD study

Objective: To determine the efficacy and safety of deutetrabenazine as a treatment for tardive dyskinesia (TD). Methods: One hundred seventeen patients with moderate to severe TD received deutetrabenazine or placebo in this randomized, double-blind, multicenter trial. Eligibility criteria included an Abnormal Involuntary Movement Scale (AIMS) score of ≥6 assessed by blinded central video rating, stable psychiatric illness, and stable psychoactive medication treatment. Primary endpoint was the change in AIMS score from baseline to week 12. Secondary endpoints included treatment success at week 12 on the Clinical Global Impression of Change (CGIC) and Patient Global Impression of Change. Results: For the primary endpoint, deutetrabenazine significantly reduced AIMS scores from baseline to week 12 vs placebo (least-squares mean [standard error] −3.0 [0.45] vs −1.6 [0.46], p = 0.019). Treatment success on CGIC (48.2% vs 40.4%) favored deutetrabenazine but was not significant. Deutetrabenazine and placebo groups showed low rates of psychiatric adverse events: anxiety (3.4% vs 6.8%), depressed mood/depression (1.7% vs 1.7%), and suicidal ideation (0% vs 1.7%, respectively). In addition, no worsening in parkinsonism, as measured by the Unified Parkinsons Disease Rating Scale motor subscale, was noted from baseline to week 12 in either group. Conclusions: In patients with TD, deutetrabenazine was well tolerated and significantly reduced abnormal movements. Classification of evidence: This study provides Class I evidence that in patients with TD, deutetrabenazine reduces AIMS scores.

A Review of the Clinical Evidence for Complementary and Alternative Therapies in Parkinson’s Disease

Opinion statementNo conventional treatment has been convincingly demonstrated to slow or stop the progression of Parkinson’s disease (PD). Dopaminergic therapy is the gold standard for managing the motor disability associated with PD, but it falls short of managing all of the aspects of the disease that contribute to quality of life. Perhaps for this reason, an increasing number of patients are searching for a more holistic approach to healthcare. This is not to say that they are abandoning the standard and effective symptomatic therapies for PD, but rather are complementing them with healthy living, mind-body practices, and natural products that empower patients to be active participants in their healthcare and widen the net under which disease modification might one day be achieved. Despite high rates of utilization of complementary and alternative medicine (CAM) practices, data on efficacy is generally limited, restricting physicians in providing guidance to interested patients. Exercise is now well-established as integral in the management of PD, but mind-body interventions such as Tai Chi that incorporate relaxation and mindfulness with physical activity should be routinely encouraged as well. While no comment can be made about neuroplastic or disease-modifying effects of mind-body interventions, patients should be encouraged to be as active as possible and engage with others in enjoyable and challenging activities such as dance, music therapy, and yoga. Many PD patients also choose to try herbs, vitamins, and neutraceuticals as part of a healthy lifestyle, with the added expectation that these products may lower free radical damage and protect them against further cell death. Evidence for neuroprotection is limited, but patients can be encouraged to maintain a healthy diet rich in “high-power,” low-inflammatory foods, while at the same time receiving education that many promising natural products have produced disappointing results in clinical trials. It is vital that the science of holistic medicine reaches a point where all neutraceuticals are investigated with the same rigor as conventional drugs. A number of agents discussed here that have a proposed role in the treatment of neurodegenerative diseases (and PD in particular), including cannabis, mucuna pruriens, and Chinese herbals, deserve more attention from basic science researchers and clinical investigators before they can be either safely utilized or dismissed.

Complementary & Alternative Management of Parkinson’s Disease: An Evidence-Based Review of Eastern Influenced Practices

The prevalence of Parkinson’s disease (PD) appears to be lower in Asia compared to the Western world. It is unclear if this is related to the ubiquitous use of traditional medicine in Eastern healthcare, but the use of complementary and alternative medicine (CAM) modalities in countries like Korea may be as high as 76%. Among patients with PD, herbal medicines, health supplement foods, and acupuncture are interventions which are increasingly used throughout the world. Countries like Korea, China, India, and Japan have long embraced and incorporated traditional medicine into modern management of conditions such as PD, but research into various CAM modalities remains in its infancy limiting evidence-based recommendations for many treatments. We reviewed the literature on CAM treatments for PD, focusing on mind-body interventions and natural products. Based on evidence limited to randomized-controlled trials we found that mind-body interventions are generally effective forms of physical activity that are likely to foster good adherence and may reduce disability associated with PD. Based on the current data, modalities like Tai Chi and dance are safe and beneficial in PD, but better studies are needed to assess the effects of other frequently used modalities such as yoga and acupuncture. Furthermore, despite centuries of experience using medicinal herbs and plants in Eastern countries, and despite substantial preclinical data on the beneficial effects of nutritional antioxidants as neuroprotective agents in PD, there is insufficient clinical evidence that any vitamin, food additive, or supplement, can improve motor function or delay disease progression in PD.

Bis-choline tetrathiomolybdate in patients with Wilson's disease: an open-label, multicentre, phase 2 study

BACKGROUND Wilsons disease is a genetic disorder in which copper accumulates in the liver, brain, and other tissues. Therapies are limited by efficacy, safety concerns, and multiple daily dosing. Bis-choline tetrathiomolybdate (WTX101) is an oral first-in-class copper-protein-binding molecule that targets hepatic intracellular copper and reduces plasma non-ceruloplasmin-bound copper (NCC) by forming tripartite complexes with albumin and increasing biliary copper excretion. We aimed to assess the efficacy and safety of WTX101 in the initial or early treatment of patients with Wilsons disease. METHODS We did this open-label, phase 2 study at 11 hospitals in the USA and Europe. We enrolled patients (≥18 years) with Wilsons disease who were untreated or had received no more than 24 months of treatment with chelators or zinc, had a Leipzig score of 4 or more, and had NCC concentrations above the lower limit of the normal reference range (≥0·8 μmol/L). Eligible patients received WTX101 monotherapy at a starting dose of 15-60 mg/day on the basis of baseline NCC concentrations for the first 4-8 weeks, with response-guided individualised dosing for the remaining weeks up to week 24. Investigators, other hospital personnel, and patients were aware of the identity of the treatment. The primary endpoint was change in baseline NCC concentrations corrected for copper in tetrathiomolybdate-copper-albumin complexes (NCCcorrected) at 24 weeks, with treatment success defined as achievement or maintenance of normalised NCCcorrected (≤2·3 μmol/L [upper limit of normal]) or achievement of at least a 25% reduction in NCCcorrected from baseline at 24 weeks. This study is registered with ClinicalTrials.gov, number NCT02273596. FINDINGS Between Nov 24, 2014, and April 27, 2016, 28 patients were enrolled and received WTX101; 22 (79%) patients completed the study up to week 24. At 24 weeks, 20 (71%, 95% CI 51·3-86·8; p<0·0001) of 28 patients met the criteria for treatment success: 16 (57%) treated with WTX101 either achieved or maintained normalised NCCcorrected concentrations and 4 (14%) had at least a 25% reduction from baseline NCCcorrected. Mean NCCcorrected was reduced by 72% from baseline to week 24 (least squares mean difference -2·4 μmol/L [SE 0·4], 95% CI -3·2 to -1·6; p<0·0001). No cases of paradoxical drug-related neurological worsening were recorded. Liver function was stable in all patients, although reversible increased concentrations of asymptomatic alanine or aspartate aminotransferase, or γ-glutamyltransferase, without increased bilirubin, occurred in 11 (39%) of 28 patients who received at least 30 mg/day. 11 serious adverse events were reported in seven (25%) patients and included psychiatric disorders (six events in four patients), gait disturbance (one event), elevated liver aminotransferases (two events in two patients, one with agranulocytosis), and decline in neurological functioning (one event, likely due to natural disease progression although causality could not be ruled out). The seven serious adverse events categorised as psychiatric disorders and as gait disturbance were assessed as unlikely to be related to the study drug, whereas the remaining four events were possibly or probably related. INTERPRETATION Our findings indicate that WTX101 might be a promising new therapeutic approach for Wilsons disease, with a unique mode of action. In view of its once-daily dose and favourable safety profile, WTX101 could improve the treatment of patients with this debilitating condition. FUNDING Wilson Therapeutics AB.

Fatal Hyperammonemic Brain Injury from Valproic Acid Exposure

Background: Hyperammonemia is known to cause neuronal injury, and can result from valproic acid exposure. Prompt reduction of elevated ammonia levels may prevent permanent neurological injury. We report a case of fatal hyperammonemic brain injury in a woman exposed to valproic acid. Case: A 38-year-old woman with schizoaffective disorder and recent increase in valproic acid dosage presented with somnolence and confusion and rapidly progressed to obtundation. Brain MRI showed diffuse bilateral restricted diffusion in nearly the entire cerebral cortex. She had normal liver function tests but serum ammonia level was severely elevated at 288 µmol/l. Genetic testing showed no mutation in urea cycle enzymes. Despite successful elimination of ammonia with hemodialysis she developed fatal cerebral edema. Conclusion: Cerebral edema secondary to hyperammonemia is potentially reversible if recognized early. Ammonia excretion can be facilitated by initiation of hemodialysis and administration of scavenging agents (sodium phenylacetate and sodium benzoate). Severe hyperammonemia can result from valproic acid exposure even in the absence of hepatotoxicity or inborn errors of metabolism. It is important to check serum ammonia in any patient with encephalopathy who has had recent valproic acid exposure.

Alternative treatment of restless legs syndrome: an overview of the evidence for mind–body interventions, lifestyle interventions, and neutraceuticals

Conventional pharmacologic treatment of restless legs syndrome (RLS) may be limited in some people. Up to 65% of patients with RLS regularly use alternative practices for symptom relief. We reviewed the current clinical evidence, and we proposed physiologic basis for various alternative practices for RLS including mind-body interventions (conventional exercise, yoga, and acupuncture), non-pharmacologic lifestyle interventions (pneumatic compression devices [PCDs], light therapy, and cognitive-behavioral therapy [CBT]), and neutraceuticals (vitamins, valerian, and Chinese herbs). Based on the available evidence, regular physical activity should be recommended for the treatment of RLS symptoms. Oral iron supplementation should be considered for people with RLS who have low ferritin levels, although criteria to identify probable responders, and optimal formulations and durations of treatment are needed. Supplementation for low levels of vitamins E, C, and D could be considered, although evidence specifically in RLS is limited, and it is unclear if levels should routinely be checked in patients with RLS. Insufficient evidence exists for yoga, acupuncture, PCDs, near-infrared light therapy, CBT, valerian, or Chinese herbs, but preliminary studies on each of these suggest that high-quality randomized controlled trials may be warranted to support and verify the data presented.

Recognition and Treatment of Depressive Symptoms in Parkinson's Disease: The NPF Dataset

Depression is a major determinant of Health Related Quality of Life in PD, but there is limited data on physician recognition of depression and treatment efficacy. We used data obtained from the QII dataset of the National Parkinsons Foundation database to determine whether there was an association between depressive symptoms and utilization of antidepressants and/or mental health services (MHS) in a large cohort of PD patients. We found that prevalence of depressive symptoms remained high in the PD population despite improved physician recognition and treatment initiation.

Long-term Clinical Outcomes After Fetal Cell Transplantation in Parkinson Disease: Implications for the Future of Cell Therapy

JAMA Neurology Long-term Clinical Outcome of Fetal Cell Transplantation for Parkinson Disease: Two Case Reports Zinovia Kefalopoulou, MD, PhD; Marios Politis, MD, PhD; Paola Piccini, MD, PhD, FRCP; Niccolo Mencacci, MD; Kailash Bhatia, MD, PhD; Marjan Jahanshahi, PhD; Hakan Widner, MD, PhD; Stig Rehncrona, MD, PhD; Patrik Brundin, MD, PhD; Anders Bjorklund, PhD; Olle Lindvall, MD, PhD; Patricia Limousin, MD, PhD; Niall Quinn, MD; Thomas Foltynie, MRCP, PhD Importance: Recent advances in stem cell technologies have rekindled an interest in the use of cell replacement strategies for patients with Parkinson disease. This study reports the very long-term clinical outcomes of fetal cell transplantation in 2 patients with Parkinson disease. Such long-term follow-up data can usefully inform on the potential efficacy of this approach, as well as the design of trials for its further evaluation. Observations: Two patients received intrastriatal grafts of human fetal ventral mesencephalic tissue, rich in dopaminergic neuroblasts, as restorative treatment for their Parkinson disease. To evaluate the very long-term efficacy of the grafts, clinical assessments were performed 18 and 15 years posttransplantation. Motor improvements gained gradually over the first postoperative years were sustained up to 18 years posttransplantation, while both patients have discontinued, and remained free of any, pharmacological dopaminergic therapy. Conclusions and Relevance: The results from these 2 cases indicate that dopaminergic cell transplantation can offer very long-term symptomatic relief in patients with Parkinson disease and provide proof-of-concept support for future clinical trials using fetal or stem cell therapies.

Is There a Role for DAT-SPECT Imaging in a Specialty Movement Disorders Practice?

Objective: Analyze indications for ordering DAT-SPECT scans and the clinical impact of scan results on patients evaluated in a movement disorders practice. Background: DAT-SPECT is FDA approved to evaluate cases of suspected presynaptic dopaminergic deficiency. Little data is available on clinical use and impact of these scans among movement disorders neurologists. Methods: DAT-SPECT scans ordered at the Northwestern University Parkinsons disease (PD) and movement disorders center from 2011-2013 were reviewed. Clinic notes were reviewed for information regarding the indication for ordering each scan, and to assess for any changes in clinical impression or management choices that followed the scan. Results: 83 scans were ordered by four specialists. Scans were commonly ordered to differentiate PD from Essential Tremor (21.7%, n = 18) or from drug-induced parkinsonism (21.7%, n = 18). In 59% (n = 49) of cases, a change in clinical diagnosis or medication regimen occurred within one visit after the scan. The strongest impact was seen for the indication of ET vs. PD in which 72.2% (n = 13) had a change in diagnosis, management, or both. Conclusions: Diagnostic uncertainty in cases of parkinsonism exists even in a tertiary referral center. DAT-SPECT has significant impact on clinical diagnosis and management even in the hands of movement disorders specialists.

Reversible Palinacousis From Intracranial Metastases

Palinacousis is an auditory illusion consisting of perseveration or echoing of an external auditory stimulus after it has ceased. This rare clinical symptom has been reported in ictal (seizure), postictal, and nonictal states, and causative lesions have been most consistently found in or near the temporal lobes. It is distinct from the auditory hallucinations seen in psychiatric illness. We report the case of a 61-year-old man who experienced several days of palinacousis while undergoing treatment for newly diagnosed metastatic lung adenocarcinoma. Palinacousis was presumed to be triggered by intracranial metastases near the auditory cortex. An electroencephalogram showed bilateral theta slowing over the left greater than right temporal lobes without epileptiform activity. Palinacousis remitted with corticosteroid and whole brain radiation therapy.