Nelson Hwynn

Update on deep brain stimulation for neuropsychiatric disorders.

Deep brain stimulation (DBS) has proven a powerful treatment for medication refractory movement disorders. Success in this group of patients has allowed preliminary studies of DBS to proceed in severe and medication resistant cases of depression, obsessive-compulsive disorder (OCD) and Tourettes syndrome (TS). Pathophysiological and imaging studies along with attempts at lesioning the basal ganglia, have offered clues as to nodes in the circuitry that may be amenable to neuromodulation. DBS in neuropsychiatric illness has offered hope, but at this time rigorous screening by interdisciplinary and ethical teams should be employed when establishing treatment candidacy. A cautious approach to these disorders utilizing institutional review board approved research protocols will hopefully shed light onto patient selection and brain target(s) for each disorder. We need to keep an open mind as we move forward and especially that rational therapy may need to be patient and symptom specific. This review will summarize each disorder (depression, OCD and TS), review pathophysiology (both known and speculated), and update the current observations on DBS in each neuropsychiatric condition.

Differential Response of Dystonia and Parkinsonism following Globus Pallidus Internus Deep Brain Stimulation in X-Linked Dystonia-Parkinsonism (Lubag)

Background: X-linked dystonia-parkinsonism (XDP; DYT3; Lubag) is an adult-onset hereditary progressive dystonia/parkinsonism which is typically minimally responsive to pharmacological treatment. Case Report: We report a 63- year-old man with a diagnosis of XDP who underwent bilateral globus pallidus internus deep brain stimulator (GPi-DBS) placement. His course initially began with right hand tremor and dystonia at age 57 and progressed to also include bradykinesia and rigidity. The patient tolerated the procedure without significant complications. GPi-DBS improved his right hand dystonia, but did not significantly improve his parkinsonism. Conclusion: DBS may be a therapeutic option for select cases of XDP, but its specificindications must be carefully discussed, as the available cases have had mixed responses. Whether other targets may be more effective is not known.

Botulinum toxin type A for the treatment of gastroparesis in Parkinson’s disease patients ☆

Gastroparesis is a very common non-motor feature in Parkinsons disease (PD) patients. However, treatment options are limited and difficult. We present 2 cases of PD patients with excellent response to botulinum toxin type A as treatment for PD-related gastroparesis.

Tests of dorsolateral frontal function correlate with objective tests of postural stability in early to moderate stage Parkinson’s disease

A substantial number of individuals with Parkinsons disease who display impaired postural stability experience accelerated cognitive decline and an increased prevalence of dementia. To date, studies suggest that this relationship, believed to be due to involvement of nondopaminergic circuitry, occurs later in the disease process. Research has yet to adequately investigate this cognitive-posturomotor relationship especially when examining earlier disease states. To gain greater understanding of the relationship between postural stability and cognitive function/dysfunction we evaluated a more stringent, objective measure of postural stability (center of pressure displacement), and also more specific measures of cognition in twenty-two patients with early to moderate stage Parkinsons disease. The magnitude of the center of pressure displacement in this cohort was negatively correlated with performance on tests known to activate dorsolateral frontal regions. Additionally, the postural stability item of the UPDRS exhibited poor correlation with the more objective measure of center of pressure displacement and all specific measures of cognition. These results may serve as rationale for a more thorough evaluation of postural stability and cognition especially in individuals with mild Parkinsons disease. Greater understanding of the relationship between motor and cognitive processes in Parkinsons disease will be critical for understanding the disease process and its potential therapeutic possibilities.

A genome sequencing program for novel undiagnosed diseases

Purpose:The Scripps Idiopathic Diseases of Man (IDIOM) study aims to discover novel gene–disease relationships and provide molecular genetic diagnosis and treatment guidance for individuals with novel diseases using genome sequencing integrated with clinical assessment and multidisciplinary case review. Here we describe the operational protocol and initial results of the IDIOM study.Methods:A total of 121 cases underwent first-tier review by the principal investigators to determine whether the primary inclusion criteria were satisfied, 59 (48.8%) underwent second-tier review by our clinician–scientist review panel, and 17 patients (14.0%) and their family members were enrolled.Results:60% of cases resulted in a plausible molecular diagnosis, and 18% of cases resulted in a confirmed molecular diagnosis. Two of three confirmed cases led to the identification of novel gene–disease relationships. In the third confirmed case a previously described but unrecognized disease was revealed. In all three confirmed cases a new clinical management strategy was initiated based on the genetic findings.Conclusion:Genome sequencing provides tangible clinical benefit for individuals with idiopathic genetic disease, not only in the context of molecular genetic diagnosis of known rare conditions but also in cases where prior clinical information regarding a new genetic disorder is lacking.Genet Med 17 12, 995–1001.

Effect of Deep Brain Stimulation on Parkinson's Nonmotor Symptoms following Unilateral DBS: A Pilot Study.

Parkinsons disease (PD) management has traditionally focused largely on motor symptoms. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi) are effective treatments for motor symptoms. Nonmotor symptoms (NMSs) may also profoundly affect the quality of life. The purpose of this pilot study was to evaluate NMS changes pre- and post-DBS utilizing two recently developed questionnaires. Methods. NMS-Q (questionnaire) and NMS-S (scale) were administered to PD patients before/after unilateral DBS (STN/GPi targets). Results. Ten PD patients (9 STN implants, 1 GPi implant) were included. The three most frequent NMS symptoms identified utilizing NMS-Q in pre-surgical patients were gastrointestinal (100%), sleep (100%), and urinary (90%). NMS sleep subscore significantly decreased (−1.6 points ± 1.8, P = 0.03). The three most frequent NMS symptoms identified in pre-surgical patients using NMS-S were gastrointestinal (90%), mood (80%), and cardiovascular (80%). The largest mean decrease of NMS scores was seen in miscellaneous symptoms (pain, anosmia, weight change, and sweating) (−7 points ± 8.7), and cardiovascular/falls (−1.9, P = 0.02). Conclusion. Non-motor symptoms improved on two separate questionnaires following unilateral DBS for PD. Future studies are needed to confirm these findings and determine their clinical significance as well as to examine the strengths/weaknesses of each questionnaire/scale.

Selective use of low frequency stimulation in Parkinson's disease based on absence of tremor.

BACKGROUND High frequency stimulation (HFS) of the subthalamic nucleus is one of the most effective treatments for advanced Parkinsons disease (PD). HFS has provided beneficial improvements in the cardinal features of PD, but has not been proven as effective for addressing the axial predominant levodopa resistant symptoms, such as speech disturbances, gait disturbances, and postural instability. Recent studies have suggested that changes in stimulation parameters may influence differing PD symptoms. OBJECTIVE The purpose of this study was to compare the effects of low frequency stimulation (LFS) versus HFS on the Unified Parkinsons Disease Rating Scale (UPDRS), gait, balance, and verbal fluency. METHODS Eight tremor dominant and nine non-tremor dominant participants with bilateral deep brain stimulation of the subthalamic nucleus were tested off stimulation, during LFS, and during HFS. RESULTS Results revealed that HFS significantly reduced UPDRS tremor score in the tremor dominant group; however no differences emerged within the non-tremor dominant group. No differences between groups or stimulation conditions were found for gait, balance, and verbal fluency measures. CONCLUSION These results may suggest that HFS is better than LFS for reducing tremor in tremor dominant patients. However, patients with mild or no tremor show no acute differences in benefit from LFS as compared to HFS.

Taking a Better History for Behavioral Issues Pre- and Post-Deep Brain Stimulation: Issues Missed by Standardized Scales

Objectives:  To screen for potentially underreported behavioral changes in patients with idiopathic Parkinsons disease (PD) pre‐ and post‐deep brain stimulation (DBS), a retrospective data base review was performed.

The Frequency of Nonmotor Symptoms among Advanced Parkinson Patients May Depend on Instrument Used for Assessment.

Background. Nonmotor symptoms (NMS) of Parkinsons disease (PD) may be more debilitating than motor symptoms. The purpose of this study was to determine the frequency and corecognition of NMS among our advanced PD cohort (patients considered for deep brain stimulation (DBS)) and caregivers. Methods. NMS-Questionnaire (NMS-Q), a self-administered screening questionnaire, and NMS Assessment-Scale (NMS-S), a clinician-administered scale, were administered to PD patients and caregivers. Results. We enrolled 33 PD patients (23 males, 10 females) and caregivers. The most frequent NMS among patients using NMS-Q were gastrointestinal (87.9%), sleep (84.9%), and urinary (72.7%), while the most frequent symptoms using NMS-S were sleep (90.9%), gastrointestinal (75.8%), and mood (75.8%). Patient/caregiver scoring correlations for NMS-Q and NMS-S were 0.670 (P < 0.0001) and 0.527 (P = 0.0016), respectively. Conclusion The frequency of NMS among advanced PD patients and correlation between patients and caregivers varied with the instrument used. The overall correlation between patient and caregiver was greater with NMS-Q than NMS-S.

Improvement of Both Dystonia and Tics With 60 Hz Pallidal Deep Brain Stimulation

ABSTRACT Deep brain stimulation has been utilized in both dystonia and in medication refractory Tourette syndrome. We present an interesting case of a patient with a mixture of disabling dystonia and Tourette syndrome whose coexistent dystonia and tics were successfully treated with 60 Hz-stimulation of the globus pallidus region.