Orthostatic Tremor is Responsive to Bilateral Thalamic Deep Brain Stimulation: Report of Two Cases Performed Asleep

Background: Orthostatic tremor (OT) is a hyperkinetic movement disorder characterized by rapid tremor in the lower extremities or trunk upon standing. Case Report: We report two patients presenting with OT, whose symptoms improved markedly following asleep bilateral thalamic deep brain stimulation (DBS) surgery. Discussion: Medically refractory OT can respond favorably to asleep bilateral DBS surgery similar to awake surgery, and may have the advantages of less psychological trauma to the patient, shorter procedure times, and less exposure to anesthesia

Efficacy and Safety of IncobotulinumtoxinA in Subjects Previously Treated with Botulinum Toxin versus Toxin-Naïve Subjects with Cervical Dystonia

Background: To determine whether botulinum toxin treatment history affected the outcomes of a study comparing the safety and efficacy of incobotulinumtoxinA with placebo in subjects with cervical dystonia (CD). Methods: This was a prospective, double‐blind, randomized, placebo‐controlled, multicenter trial in botulinum toxin‐treated or toxin‐naïve CD subjects. Subjects received a fixed dose of either 120 U or 240 U of incobotulinumtoxinA or placebo. The primary outcome measure was change from baseline to Week 4 in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total score. Treatment‐emergent adverse events (TEAEs) were also evaluated. This report represents a subgroup analysis of botulinum toxin‐treated or toxin‐naïve subjects. Results: Participants (N = 233; 38.6% toxin‐naïve) had a mean age of 52.8 years. IncobotulinumtoxinA significantly improved TWSTRS total scores from baseline to Week 4 in both dose groups versus placebo, and the improvement persisted through the end of the study (≤20 weeks). Both the previously toxin‐treated and toxin‐naïve subjects demonstrated significant improvements in TWSTRS total scores at Week 4 compared to baseline. The most frequent TEAEs in the incobotulinumtoxinA groups were dysphagia, neck pain, and muscular weakness, which were generally mild. TEAEs were more common in the 240 U group and toxin‐naïve subjects. Discussion: Overall, incobotulinumtoxinA was safe and effective in CD, regardless of toxin therapy history. A lower starting dose may be better tolerated among toxin‐naïve subjects without sacrificing efficacy

Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes.

Potassium channel mutations have been described in episodic neurological diseases. We report that K+ channel mutations cause disease phenotypes with neurodevelopmental and neurodegenerative features. In a Filipino adult-onset ataxia pedigree, the causative gene maps to 19q13, overlapping the SCA13 disease locus described in a French pedigree with childhood-onset ataxia and cognitive delay. This region contains KCNC3 (also known as Kv3.3), encoding a voltage-gated Shaw channel with enriched cerebellar expression. Sequencing revealed two missense mutations, both of which alter KCNC3 function in Xenopus laevis expression systems. KCNC3(R420H), located in the voltage-sensing domain, had no channel activity when expressed alone and had a dominant-negative effect when co-expressed with the wild-type channel. KCNC3(F448L) shifted the activation curve in the negative direction and slowed channel closing. Thus, KCNC3(R420H) and KCNC3(F448L) are expected to change the output characteristics of fast-spiking cerebellar neurons, in which KCNC channels confer capacity for high-frequency firing. Our results establish a role for KCNC3 in phenotypes ranging from developmental disorders to adult-onset neurodegeneration and suggest voltage-gated K+ channels as candidates for additional neurodegenerative diseases

Botulinum Toxin Therapy for Cervical Dystonia: The Science of Dosing

The first‐line treatment for cervical dystonia (CD) is botulinum toxin type A (BoNT‐A), which has been established as a highly effective and well‐tolerated therapy. However, this treatment is also complex and challenging to apply in clinical practice. Approximately 20% of patients discontinue therapy due to treatment failure, adverse effects, and other reasons. In addition, expert consensus recommendations are lacking to guide physicians in the optimal use of BoNT‐A for CD. Among the issues still to be clarified is the optimal dosing frequency. The generally accepted standard for intervals between BoNT‐A injections is ≥12 weeks; however, this standard is based primarily on the methodology of pivotal trials for the BoNT‐A products, rather than on evidence that it is optimal in comparison to other intervals. While some retrospective, observational studies of BoNT‐A used in clinical practice appear to support the use of ≥12‐week dosing intervals, it is often unclear in these studies how the need for reinjection was determined. In contrast, a prospective dose‐ranging trial in which patients were allowed to request reinjection as early as 8 weeks showed that about half of patients receiving abobotulinumtoxinA, at the currently recommended initial dose of 500 U, requested reinjection at 8 weeks. Moreover, results from an open‐label, 68‐week extension phase of the pivotal trial of incobotulinumtoxinA showed that 47.1% of patients had received reinjection at ≤12 weeks. Ongoing studies, such as the Cervical Dystonia Patient Registry for Observation of BOTOX® Efficacy (CD PROBE), may help clarify this question of optimal dosing intervals for BoNT‐A in CD

Comparing Cerebral White Matter Lesion Burdens between Parkinson’s Disease with and without Dementia

Cerebral white matter lesions (CWMLs) have been suggested to be associated with an increased risk of dementia, disability, and death. CWMLs are more common in individuals with Alzheimer’s disease (AD) than in normal elderly individuals of comparable age. Only a few studies have been done to determine whether CWMLs may influence cognitive decline in Parkinson’s disease (PD). Fully developed PD with concurrent AD was reported to likely cause impaired cognition in spite of accumulating evidence suggesting that PD with dementia (PDD) is more closely associated with Lewy body (LB) pathology. Currently, contradictory data on the neuropathology of dementia in PD require further prospective clinicopathological studies in larger cohorts to elucidate the impact of AD and α-synuclein (SCNA) pathologies on the cognitive status in these disorders. Previous reports did not suggest CWMLs to be associated with an increased risk of PDD. After adjusting for age at death, age at onset of PD, and duration of PD, our recent study investigating CWMLs in PDD via autopsy has shown a positive correlation between the burden of CWMLs and PDD. The frequent co-existence of both LB and AD lesions suggests that both pathologies independently or synergistically contribute to both movement disorders and cognitive impairment. The individual and cumulative burden of CWMLs, LB lesions, and AD lesions may synergistically contribute to cognitive decline in LB disorders such as PDD

Cerebellar Ataxia from Multiple Potential Causes: Hypothyroidism, Hashimoto's Thyroiditis, Thalamic Stimulation, and Essential Tremor

Background: Both hypothyroidism and Hashimoto's thyroiditis (HT) can rarely be associated with cerebellar ataxia. Severe essential tremor (ET) as well as bilateral thalamic deep brain stimulation (DBS) may lead to subtle cerebellar signs. Case Report: We report a 74-year-old male with hypothyroidism and a 20-year history of ET who developed cerebellar ataxia after bilateral thalamic DBS. Extensive workup revealed elevated thyroid stimulating hormone and thyroperoxidase antibody titers confirming the diagnosis of HT. Discussion: Our case demonstrates multiple possible causes of cerebellar ataxia in a patient, including hypothyroidism, HT, chronic ET, and bilateral thalamic DBS. Counseling of patients may be appropriate when multiple risk factors for cerebellar ataxia coexist in one individual.</div

A randomized, double-blind study of repeated incobotulinumtoxinA (Xeomin\u3csup\u3e®\u3c/sup\u3e) in cervical dystonia

IncobotulinumtoxinA (Xeomin®, NT 201), a preparation without accessory (complexing) proteins, has shown comparable efficacy and safety to onabotulinumtoxinA in treating cervical dystonia (CD). This study evaluated the efficacy and safety of repeated incobotulinumtoxinA injections in subjects with CD. Following a ≤20-week placebo-controlled, randomized, double-blind, single-dose main period, subjects could enter a ≤68-week prospective, randomized, double-blind, repeated-dose, flexible-interval (minimum 6 weeks) extension period with 240 U or 120 U of incobotulinumtoxinA (≤5 injections). Outcome measures included the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and adverse events (AEs). Of 219 subjects completing the main period, 214 were randomized in the extension period to receive incobotulinumtoxinA 240 U (n = 111) or 120 U (n = 103); 169 subjects completed the extension period, with 90 receiving five injection sessions. Both doses of incobotulinumtoxinA provided statistically significant and clinically relevant improvements in mean TWSTRS-Total, -Severity, -Disability, and -Pain scores, from each injection session to respective 4-week follow-up visits. The most frequently reported AE was dysphagia (240 U: 23.4 %; 120 U: 12.6 %), which did not result in any study withdrawals. There was no impact of injection interval on the incidence of AEs (post hoc analysis). A major limitation of this study was the fixed dose design requested by regulatory authorities, which does not reflect clinical practice. However, repeated incobotulinumtoxinA injections (240 or 120 U; flexible intervals) provided sustained efficacy and were well tolerated, with no unexpected safety risks following repeated injections. The incidence of AEs was similar in subjects requiring repeated injections at shorter intervals (≤12 weeks) compared with those treated using longer intervals (\u3e12 weeks). © 2013 The Author(s)

Neuropathological findings of PSP in the elderly without clinical PSP: Possible incidental PSP?

Aims: We aimed to describe cases with incidental neuropathological findings of progressive supranuclear palsy (PSP) from the Banner Sun Health Research Institute Brain and Body Donation Program. Methods: We performed a retrospective review of 277 subjects with longitudinal motor and neuropsychological assessments who came to autopsy. The mean Gallyas-positive PSP features grading for subjects with possible incidental neuropathological PSP was compared to those of subjects with clinically manifest disease. Results: There were 5 cases with histopathological findings suggestive of PSP, but no parkinsonism, dementia or movement disorder during life. Cognitive evaluation revealed 4 of the 5 cases to be cognitively normal; one case had amnestic mild cognitive impairment (MCI) in her last year of life. The mean age at death of the 5 cases was 88.9 years (range 80-94). All 5 individuals had histopathologic microscopic findings suggestive of PSP. Mean Gallyas-positive PSP features grading was significantly lower in subjects with possible incidental neuropathological PSP than subjects with clinical PSP, particularly in the subthalamic nucleus. Conclusions: We present 5 patients with histopathological findings suggestive of PSP, without clinical PSP, dementia or parkinsonism during life. These incidental neuropathological PSP findings may represent the early or pre-symptomatic stage of PSP. The mean Gallyas-positive PSP features grading was significantly lower in possible incidental PSP than in clinical PSP, thus suggesting that a threshold of pathological burden needs to be reached within the typically affected areas in PSP before clinical signs and symptoms appear. © 2011 Elsevier Ltd

Defining mild cognitive impairment in Parkinson\u27s disease

Our purpose was to characterize a state of mild cognitive impairment (MCI) in Parkinson\u27s disease (PD) (PD-MCI) that would be analogous to the MCI that is posited as a precursor of Alzheimer\u27s disease (AD). We categorized 86 PD subjects in a brain bank population as either cognitively normal (PD-CogNL), PD-MCI using criteria that included a 1.5 standard deviation or greater deficit upon neuropsychological testing consistently across at least one cognitive domain without dementia, and PD dementia (PD-D) using DSM-IV criteria. Twenty-one percent of our PD sample met criteria for PD-MCI, 62% were PD-CogNL, and 17% had PD-D. The mean duration of PD and MMSE scores of the PD-MCI group were intermediate and significantly different from both PD-CogNL and PD-D. The cognitive domain most frequently abnormal in PD-MCI was frontal/executive dysfunction followed by amnestic deficit. Single domain PD-MCI was more common than PD-MCI involving multiple domains. We conclude that a stage of clinical cognitive impairment in PD exists between PD-CogNL and PD-D, and it may be defined by applying criteria similar to the MCI that is posited as a precursor of AD. Defining PD-MCI offers an opportunity for further study of cognitive impairment in PD and targets for earlier therapeutic intervention. © 2007 Movement Disorder Society