Aparna Wagle Shukla

Worsening essential tremor following deep brain stimulation: disease progression versus tolerance

A major concern regarding ventralis intermedius nucleus deep brain stimulation for essential tremor has been the loss of surgical efficacy over time in a minority of patients. Some experts have ascribed the worsening tremor to tolerance, while other evidence has suggested that disease progression may play a role. Suboptimal lead placement has also been reported to be a factor in worsening tremor following deep-brain stimulation; however, most authors consider this phenomenon to manifest within a few months of the actual surgery. We aimed to dissect the tolerance versus disease progression issue by analysing preoperative versus long-term post-surgical Fahn-Tolosa-Marin Tremor Rating Scale scores both on and off stimulation among 28 patients who underwent ventralis intermedius nucleus deep brain stimulation and 21 age-matched controls. Of the 28 patients in the treatment arm of the cohort, seven (25%) demonstrated evidence of tremor progression, and had a 34% increase in the tremor score off stimulation at the 36 month follow-up compared with a 32% increase among controls (P = 0.67). In one of the seven patients there was evidence of suboptimal lead placement given the lateral position of the lead, and the motor side effects during threshold testing. This patient demonstrated a loss of stimulation benefit between 24 and 36 months, which may have been more indicative of tolerance. The other six subjects (86%) maintained stimulation benefit throughout the follow-up period, despite worsening tremor off stimulation (at a comparable rate to that of controls), making disease progression the most likely explanation. The data suggest that deep brain stimulation tolerance may be over-reported in the literature, and that a tolerance versus disease progression work-up should include: examining the trend in off stimulation scores, accounting for image based lead locations, and during programming sessions checking for thresholds which may elicit clinical benefits and side effects.

Micrographia and related deficits in Parkinson's disease: a cross-sectional study.

Objectives To determine the prevalence and clinical features associated with micrographia in Parkinsons Disease (PD). Setting This study was conducted at a Movement Disorders clinic located in a Veteran Administration Hospital. Participants PD subjects were included only if they satisfied UK Parkinsons Disease Society criteria for diagnosis. Subjects with history of severe tremors, dystonia, dyskinesia, strokes, peripheral neuropathy and dementia were excluded. Design This was a case–control study where PD subjects were prospectively enrolled and their demographics, Hoehn & Yahr stage, Unified Parkinsons Disease Rating Scale and Mini Mental Status examination (MMSE) scores were recorded. All subjects were specifically asked for micrographia on history and the handwritings were quantitatively documented. Bradykinesia was determined by history and quantified by a finger tap, Purdue pegboard and a timed walk test. Similarly, hypophonia was determined by history and the volume of speech quantified using a decibel meter. Controls were enrolled for validation of handwriting test scores and decibel meter recordings. Primary outcome measures Prevalence of micrographia in the PD cohort and the clinical factors that correlate with micrographia. Results 68 subjects with PD were enrolled (68 men; mean age 72.3 years). Micrographia was identified in 63.2% of the cohort on verbal history and in 50% of the cohort when the handwriting test was used for ascertainment. Micrographia ascertained on history correlated significantly with disease severity (Hoehn & Yahr stage), motor impairment (Unified Parkinsons Disease Rating Scale), cognitive impairment (MMSE) and both bradykinesia and hypophonia determined by history and quantitative testing. Micrographia on handwriting test correlated with age (p=0.02), MMSE testing (p=0.04), hypophonia by history (p=0.01) and bradykinesia by quantitative testing (p=0.04). Conclusion Micrographia was found in nearly half of the PD cohort. Disease severity and impaired cognition were important clinical correlates. Micrographia had a significant relationship with bradykinesia and hypophonia, suggesting a possible overlap in their pathophysiology.

Functional Brain Activity Relates to 0–3 and 3–8 Hz Force Oscillations in Essential Tremor

It is well-established that during goal-directed motor tasks, patients with essential tremor have increased oscillations in the 0-3 and 3-8 Hz bands. It remains unclear if these increased oscillations relate to activity in specific brain regions. This study used task-based functional magnetic resonance imaging to compare the brain activity associated with oscillations in grip force output between patients with essential tremor, patients with Parkinsons disease who had clinically evident tremor, and healthy controls. The findings demonstrate that patients with essential tremor have increased brain activity in the motor cortex and supplementary motor area compared with controls, and this activity correlated positively with 3-8 Hz force oscillations. Brain activity in cerebellar lobules I-V was reduced in essential tremor compared with controls and correlated negatively with 0-3 Hz force oscillations. Widespread differences in brain activity were observed between essential tremor and Parkinsons disease. Using functional connectivity analyses during the task evidenced reduced cerebellar-cortical functional connectivity in patients with essential tremor compared with controls and Parkinsons disease. This study provides new evidence that in essential tremor 3-8 Hz force oscillations relate to hyperactivity in motor cortex, 0-3 Hz force oscillations relate to the hypoactivity in the cerebellum, and cerebellar-cortical functional connectivity is impaired.

Surgical Treatment of Parkinson’s Disease: Patients, Targets, Devices, and Approaches

Surgical treatment for Parkinson’s disease (PD) has evolved from ablative procedures, within a variety of brain regions, to implantation of electrodes into specific targets of the basal ganglia. Electrode implantation surgery, referred to as deep brain stimulation (DBS), is preferred to ablative procedures by many experts owing to its reversibility, programmability, and the ability to be safely performed bilaterally. Several randomized clinical studies have demonstrated the effectiveness of DBS surgery for control of PD symptoms. Many brain targets, including the subthalamic nucleus and the globus pallidus internus, have emerged as potentially effective, with each target being closely associated with important pros and cons. Selection of appropriate PD candidates through a methodical interdisciplinary screening is considered a prerequisite for a successful surgical outcome. Despite recent growth in DBS knowledge, there is currently no consensus on the ideal surgical technique, the best surgical approach, and the most appropriate surgical target. DBS is now targeted towards treating specific PD-related symptoms in a given individual, and not simply addressing the disease with one pre-defined approach. In this review we will discuss the historical aspects of surgical treatments, the selection of an appropriate DBS candidate, the current surgical techniques, and recently introduced DBS-related technologies. We will address important pre- and postoperative issues related to DBS. We will also discuss the lessons learned from the randomized clinical studies for DBS and the shifting paradigm to tailor to a more patient-centered and symptom-specific approach.

An eight-year clinic experience with clozapine use in a Parkinson's disease clinic setting.

Background To examine our eight year clinic-based experience in a Parkinson’s disease expert clinical care center using clozapine as a treatment for refractory psychosis in Parkinsons disease (PD). Methods The study was a retrospective chart review which covered eight years of clozapine registry use. Statistical T-tests, chi-square, correlations and regression analysis were used to analyze treatment response for potential associations of age, disease duration, and Hoehn & Yahr (H&Y) score, and degree of response to clozapine therapy. Results There were 36 participants included in the analysis (32 PD, 4 parkinsonism-plus). The characteristics included 30.6% female, age 45–87 years (mean 68.3±10.15), disease duration of 17–240 months (mean 108.14±51.13) and H&Y score of 2 to 4 (mean 2.51±0.51). The overall retention rate on clozapine was 41% and the most common reasons for discontinuation were frequent blood testing (28%), nursing home (NH) placement (11%) and leucopenia (8%). Responses to clozapine across the cohort were: complete (33%), partial (33%), absent (16%), and unknown (16%). Age (r = −0.36, p<0.01) and H&Y score (r = −0.41, p<0.01) were shown to be related to response to clozapine therapy, but disease duration was not an associated factor (r = 0.21, p>0.05). Conclusions This single-center experience highlights the challenges associated with clozapine therapy in PD psychosis. Frequent blood testing remains a significant barrier for clozapine, even in patients with therapeutic benefit. Surprisingly, all patients admitted to a NH discontinued clozapine due to logistical issues of administration and monitoring within that setting. Consideration of the barriers to clozapine therapy will be important to its use and to its continued success in an outpatient setting.

Proceedings of the Third Annual Deep Brain Stimulation Think Tank: A Review of Emerging Issues and Technologies

The proceedings of the 3rd Annual Deep Brain Stimulation Think Tank summarize the most contemporary clinical, electrophysiological, imaging, and computational work on DBS for the treatment of neurological and neuropsychiatric disease. Significant innovations of the past year are emphasized. The Think Tanks contributors represent a unique multidisciplinary ensemble of expert neurologists, neurosurgeons, neuropsychologists, psychiatrists, scientists, engineers, and members of industry. Presentations and discussions covered a broad range of topics, including policy and advocacy considerations for the future of DBS, connectomic approaches to DBS targeting, developments in electrophysiology and related strides toward responsive DBS systems, and recent developments in sensor and device technologies.

Multifocal repetitive TMS for motor and mood symptoms of Parkinson disease: A randomized trial

Objective: To assess whether multifocal, high-frequency repetitive transcranial magnetic stimulation (rTMS) of motor and prefrontal cortex benefits motor and mood symptoms in patients with Parkinson disease (PD). Methods: Patients with PD and depression were enrolled in this multicenter, double-blind, sham-controlled, parallel-group study of real or realistic (electric) sham rTMS. Patients were randomized to 1 of 4 groups: bilateral M1 ( + sham dorsolateral prefrontal cortex [DLPFC]), DLPFC ( + sham M1), M1 + DLPFC, or double sham. The TMS course consisted of 10 daily sessions of 2,000 stimuli for the left DLPFC and 1,000 stimuli for each M1 (50 × 4-second trains of 40 stimuli at 10 Hz). Patients were evaluated at baseline, at 1 week, and at 1, 3, and 6 months after treatment. Primary endpoints were changes in motor function assessed with the Unified Parkinsons Disease Rating Scale-III and in mood with the Hamilton Depression Rating Scale at 1 month. Results: Of the 160 patients planned for recruitment, 85 were screened, 61 were randomized, and 50 completed all study visits. Real M1 rTMS resulted in greater improvement in motor function than sham at the primary endpoint (p < 0.05). There was no improvement in mood in the DLPFC group compared to the double-sham group, as well as no benefit to combining M1 and DLPFC stimulation for either motor or mood symptoms. Conclusions: In patients with PD with depression, M1 rTMS is an effective treatment of motor symptoms, while mood benefit after 2 weeks of DLPFC rTMS is not better than sham. Targeting both M1 and DLPFC in each rTMS session showed no evidence of synergistic effects. ClinicalTrials.gov identifier: NCT01080794. Classification of evidence: This study provides Class I evidence that in patients with PD with depression, M1 rTMS leads to improvement in motor function while DLPFC rTMS does not lead to improvement in depression compared to sham rTMS.

Proceedings of the Fourth Annual Deep Brain Stimulation Think Tank: A Review of Emerging Issues and Technologies

This paper provides an overview of current progress in the technological advances and the use of deep brain stimulation (DBS) to treat neurological and neuropsychiatric disorders, as presented by participants of the Fourth Annual DBS Think Tank, which was convened in March 2016 in conjunction with the Center for Movement Disorders and Neurorestoration at the University of Florida, Gainesveille FL, USA. The Think Tank discussions first focused on policy and advocacy in DBS research and clinical practice, formation of registries, and issues involving the use of DBS in the treatment of Tourette Syndrome. Next, advances in the use of neuroimaging and electrochemical markers to enhance DBS specificity were addressed. Updates on ongoing use and developments of DBS for the treatment of Parkinsons disease, essential tremor, Alzheimers disease, depression, post-traumatic stress disorder, obesity, addiction were presented, and progress toward innovation(s) in closed-loop applications were discussed. Each section of these proceedings provides updates and highlights of new information as presented at this years international Think Tank, with a view toward current and near future advancement of the field.

Update on deep brain stimulation in Parkinson's disease

Deep brain stimulation (DBS) is considered a safe and well tolerated surgical procedure to alleviate Parkinson’s disease (PD) and other movement disorders symptoms along with some psychiatric conditions. Over the last few decades DBS has been shown to provide remarkable therapeutic effect on carefully selected patients. Although its precise mechanism of action is still unknown, DBS improves motor functions and therefore quality of life. To date, two main targets have emerged in PD patients: the globus pallidus pars interna and the subthalamic nucleus. Two other targets, the ventralis intermedius and zona incerta have also been selectively used, especially in tremor-dominant PD patients. The main indications for PD DBS have traditionally been motor fluctuations, debilitating medication induced dyskinesias, unpredictable “off time” state, and medication refractory tremor. Medication refractory tremor and intolerable dyskinesia are potential palliative indications. Besides aforementioned targets, the brainstem pedunculopontine nucleus (PPN) is under investigation for the treatment of ON-state freezing of gait and postural instability. In this article, we will review the most recent literature on DBS therapy for PD, including cutting-edge advances and data supporting the role of DBS in advanced neural-network modulation.

Emerging Opportunities for Serotypes of Botulinum Neurotoxins

Background: Two decades ago, botulinum neurotoxin (BoNT) type A was introduced to the commercial market. Subsequently, the toxin was approved by the FDA to address several neurological syndromes, involving muscle, nerve, and gland hyperactivity. These syndromes have typically been associated with abnormalities in cholinergic transmission. Despite the multiplicity of botulinal serotypes (designated as types A through G), therapeutic preparations are currently only available for BoNT types A and B. However, other BoNT serotypes are under study for possible clinical use and new clinical indications; Objective: To review the current research on botulinum neurotoxin serotypes A-G, and to analyze potential applications within basic science and clinical settings; Conclusions: The increasing understanding of botulinal neurotoxin pathophysiology, including the neurotoxin’s effects on specific neuronal populations, will help us in tailoring treatments for specific diagnoses, symptoms and patients. Scientists and clinicians should be aware of the full range of available data involving neurotoxin subtypes A-G.