Michael T. Hayes

A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor

BACKGROUND Uncontrolled pilot studies have suggested the efficacy of focused ultrasound thalamotomy with magnetic resonance imaging (MRI) guidance for the treatment of essential tremor. METHODS We enrolled patients with moderate-to-severe essential tremor that had not responded to at least two trials of medical therapy and randomly assigned them in a 3:1 ratio to undergo unilateral focused ultrasound thalamotomy or a sham procedure. The Clinical Rating Scale for Tremor and the Quality of Life in Essential Tremor Questionnaire were administered at baseline and at 1, 3, 6, and 12 months. Tremor assessments were videotaped and rated by an independent group of neurologists who were unaware of the treatment assignments. The primary outcome was the between-group difference in the change from baseline to 3 months in hand tremor, rated on a 32-point scale (with higher scores indicating more severe tremor). After 3 months, patients in the sham-procedure group could cross over to active treatment (the open-label extension cohort). RESULTS Seventy-six patients were included in the analysis. Hand-tremor scores improved more after focused ultrasound thalamotomy (from 18.1 points at baseline to 9.6 at 3 months) than after the sham procedure (from 16.0 to 15.8 points); the between-group difference in the mean change was 8.3 points (95% confidence interval [CI], 5.9 to 10.7; P<0.001). The improvement in the thalamotomy group was maintained at 12 months (change from baseline, 7.2 points; 95% CI, 6.1 to 8.3). Secondary outcome measures assessing disability and quality of life also improved with active treatment (the blinded thalamotomy cohort)as compared with the sham procedure (P<0.001 for both comparisons). Adverse events in the thalamotomy group included gait disturbance in 36% of patients and paresthesias or numbness in 38%; these adverse events persisted at 12 months in 9% and 14% of patients, respectively. CONCLUSIONS MRI-guided focused ultrasound thalamotomy reduced hand tremor in patients with essential tremor. Side effects included sensory and gait disturbances. (Funded by InSightec and others; ClinicalTrials.gov number, NCT01827904.).

Unrecognized vitamin D3 deficiency is common in Parkinson disease Harvard Biomarker Study

Objective: To conclusively test for a specific association between the biological marker 25-hydroxy-vitamin D3, a transcriptionally active hormone produced in human skin and liver, and the prevalence and severity of Parkinson disease (PD). Methods: We used liquid chromatography/tandem mass spectrometry to establish an association specifically between deficiency of 25-hydroxy-vitamin D3 and PD in a cross-sectional and longitudinal case-control study of 388 patients (mean Hoehn and Yahr stage of 2.1 ± 0.6) and 283 control subjects free of neurologic disease nested in the Harvard Biomarker Study. Results: Plasma levels of 25-hydroxy-vitamin D3 were associated with PD in both univariate and multivariate analyses with p values = 0.0034 and 0.047, respectively. Total 25-hydroxy-vitamin D levels, the traditional composite measure of endogenous and exogenous vitamin D, were deficient in 17.6% of patients with PD compared with 9.3% of controls. Low 25-hydroxy-vitamin D3 as well as total 25-hydroxy-vitamin D levels were correlated with higher total Unified Parkinson’s Disease Rating Scale scores at baseline and during follow-up. Conclusions: Our study reveals an association between 25-hydroxy-vitamin D3 and PD and suggests that thousands of patients with PD in North America alone may be vitamin D–deficient. This finding has immediate relevance for individual patients at risk of falls as well as public health, and warrants further investigation into the mechanism underlying this association.

Association between α-synuclein blood transcripts and early, neuroimaging-supported Parkinson’s disease

There are no cures for neurodegenerative diseases and this is partially due to the difficulty of monitoring pathogenic molecules in patients during life. The Parkinsons disease gene α-synuclein (SNCA) is selectively expressed in blood cells and neurons. Here we show that SNCA transcripts in circulating blood cells are paradoxically reduced in early stage, untreated and dopamine transporter neuroimaging-supported Parkinsons disease in three independent regional, national, and international populations representing 500 cases and 363 controls and on three analogue and digital platforms with P < 0.0001 in meta-analysis. Individuals with SNCA transcripts in the lowest quartile of counts had an odds ratio for Parkinsons disease of 2.45 compared to individuals in the highest quartile. Disease-relevant transcript isoforms were low even near disease onset. Importantly, low SNCA transcript abundance predicted cognitive decline in patients with Parkinsons disease during up to 5 years of longitudinal follow-up. This study reveals a consistent association of reduced SNCA transcripts in accessible peripheral blood and early-stage Parkinsons disease in 863 participants and suggests a clinical role as potential predictor of cognitive decline. Moreover, the three independent biobank cohorts provide a generally useful platform for rapidly validating any biological marker of this common disease.

Association of SNCA with Parkinson: replication in the Harvard NeuroDiscovery Center Biomarker Study

Mutations in the α‐synuclein gene (SNCA) cause autosomal dominant forms of Parkinsons disease, but the substantial risk conferred by this locus to the common sporadic disease has only recently emerged from genome‐wide association studies.

Pallidal deep brain stimulation for dystonia: a case series.

OBJECT Pallidal deep brain stimulation (DBS) is a treatment option for those with early-onset dystonia. However, there are limited data on long-term outcome and treatment complications. The authors report on the short- and long-term effects of pallidal DBS in a cohort of patients with early-onset dystonia. METHODS Fourteen consecutive pediatric patients with early-onset dystonia were systematically evaluated and treated. The duration of follow-up ranged from 16 to 84 months. RESULTS There were no immediate postoperative complications. At last follow-up, 12 of the 14 patients displayed a significant decline in the Burke-Fahn-Marsden Dystonia Rating Scale motor subscale score, with an average decrease of 62% ± 8.4%. The most common hardware complication was lead fracture (14.3%). CONCLUSIONS These data provide further evidence that DBS is a safe and effective treatment for those with earlyonset dystonia.

Acute brachial diplegia due to Lyme disease.

ObjectiveTo describe acute brachial diplegia as the initial manifestation of Lyme disease. BackgroundBilateral, predominantly motor, cervical radiculoplexus neuropathy, the “dangling arm syndrome,” has not been reported as a complication of acute Lyme infection. MethodsRetrospective series of 5 patients from 2 tertiary neuromuscular centers. ResultsThere were 4 men and 1 woman with an average age of 69 years. One recalled a tick bite, and preceding constitutional symptoms included headache (2) and fever, arthralgias, and fatigue in 1 patient each. Proximal arm weakness and acute pain developed within 3 weeks from onset; pain was bilateral in 3 patients and unilateral in 2 patients, and was described as severe throbbing. Arm weakness was bilateral at onset in 3 patients, and right sided in 2 patients followed by spread to the left arm within days. All the patients had weakness in the deltoid and biceps that was 3/5 or less (Medical Research Council scale), with variable weakness of the triceps and wrist extensors; 1 patient had a flail right arm and moderate (4/5) weakness of the proximal left arm muscles. Light touch was normal in the regions of weakness, and 1 patient had mildly reduced pin sensation over the forearm. Serum IgM Lyme titers were elevated in all the patients and were detected in the cerebrospinal fluid in 4 tested patients. The cerebrospinal fluid protein ranged between 135 and 176 mg/dL with lymphocytic pleocytosis (range, 42 to 270 cells). Electrodiagnostic studies showed normal median and ulnar motor potentials with asymmetrically reduced sensory amplitudes in the median (4), ulnar (3), and radial, and lateral antebrachial cutaneous potentials in 1 patient each. Two patients had acute denervation in the cervical or proximal arm muscles. There was full recovery after antibiotic therapy in 4 patients and considerable improvement in 1 patient after 2 months. ConclusionAcute brachial diplegia is a rare manifestation of acute Lyme infection and responds promptly to antibiotic therapy.

Neuromodulation for neurodegenerative conditions.

Pharmacological therapy has had limited success in the treatment of most major neurological diseases. This has motivated the development of a number of novel surgical approaches designed to ameliorate drug-induced side effects or pharmacoresistant symptoms. Deep brain stimulation (DBS) has been quite successful in controlling both the cardinal motor manifestation of Parkinsons disease and the side effects of prolonged levodopa therapy. This has encouraged the application of DBS technology to treat a number of other neurodegenerative conditions, including secondary dystonia associated with pantothenate kinase-associated neurodegeneration (PKAN, formerly Hallervorden-Spatz syndrome), chorea associated with Huntingtons disease, and most recently, cognitive decline associated with Alzheimers type dementia. We review the rationale, indications and outcomes of neuromodulation for selected neurodegenerative conditions. In addition to DBS, we discuss select small molecule and gene-based neuromodulatory approaches. Ongoing study of basic pathophysiological mechanisms may eventually allow directed primary prevention of some of these diseases, but until then, invasive neuromoduation will likely continue to play an ever-increasing role in the delivery of the most advanced care for patients with these debilitating conditions.

Evolution of Movement Disorders Surgery Leading to Contemporary Focused Ultrasound Therapy for Tremor

Progressively less invasive neurosurgical approaches for the treatment of movement disorders have evolved, beginning with open craniotomy for placement of lesions within pyramidal structures followed by refined stereotactic ablation of extrapyramidal targets that encouraged nondestructive electrode stimulation of deep brain structures. A noninvasive approach using transcranial high-energy focused ultrasound has emerged for the treatment of intractable tremor. The ability to target discreet intracranial sites millimeters in size through the intact skull using focused acoustic energy marks an important milestone in movement disorders surgery. This article describes the evolution of magnetic resonance-guided focused ultrasound for ventrolateral thalamotomy for tremor.

Treating patients with movement disorders using MRI-guided focused ultrasound: recent developments and challenges

License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Research and Reports in Focused Ultrasound 2015:3 5–9 Research and Reports in Focused Ultrasound Dovepress