Directional Deep Brain Stimulation Programming: Is the Segment Clearly Identifiable and Stable Over Time?

BACKGROUND: In our early experience programming directional deep brain stimulation (d-DBS) in PD, we found the optimal directional segment changed over time in some patients. To determine the frequency/reasons for this we examined whether (1) different programmers would identify the same segment as "optimal"; and (2) the same programmer would select the same "optimal" segment over time. We hypothesized there would be a moderately high level of agreement on optimal electrode selection between different assessors and repeated assessments by the same evaluator. METHODS: This was a prospective, double-blind investigation evaluating the reliability and stability of programming d-DBS. Each patient underwent a mono-polar survey four times (2 time points by 2 separate assessors). The primary aim was the inter-rater agreement of selecting the optimal electrode at 1 and 6 months. The secondary aim was to determine the intra-rater agreement of selecting the optimal electrode from 1 to 6 months. RESULTS: Twenty-one patients were enrolled. There was fair inter-rater agreement at 1 month and moderate at 6 months. There was minimal intra-rater agreement between 1 and 6 months. DISCUSSION: The data refuted our hypothesis. Potential reasons for low agreement include (1) the arduous/subjective nature of identifying the optimal electrode in d-DBS systems, especially in well-placed electrodes; and/or (2) acute changes to the location of stimulation delivery offering temporary improvement in symptoms. Key takeaways gathered were it may, (1) behoove the programmer to explore different electrode montages after a period of time; and (2) be more efficient to review the directional electrode montage only when dictated by clinical symptoms/disease progression.

Potential subjects' responses to an ethics questionnaire in a phase I study of deep brain stimulation in early Parkinson's disease.

BACKGROUND: Central to ethically justified clinical trial design is the need for an informed consent process responsive to how potential subjects actually comprehend study participation, especially study goals, risks, and potential benefits. This will be particularly challenging when studying deep brain stimulation and whether it impedes symptom progression in Parkinson's disease, since potential subjects will be Parkinson's patients for whom deep brain stimulation will likely have therapeutic value in the future as their disease progresses. METHOD: As part of an expanded informed consent process for a pilot Phase I study of deep brain stimulation in early stage Parkinson's disease, an ethics questionnaire composed of 13 open-ended questions was distributed to potential subjects. The questionnaire was designed to guide potential subjects in thinking about their potential participation. RESULTS: While the purpose of the study (safety and tolerability) was extensively presented during the informed consent process, in returned responses 70 percent focused on effectiveness and 91 percent included personal benefit as poten- tial benefit from enrolling. However, 91 percent also indicated helping other Parkinson's patients as motivation when considering whether or not to enroll. CONCLUSIONS: This combination of responses highlights two issues to which investigators need to pay close attention in future trial designs: (1) how, and in what ways, informed consent processes reinforce potential subjects' preconceived understandings of benefit, and (2) that potential subjects see themselves as part of a community of Parkinson's sufferers with responsibilities extending beyond self-interest. More importantly, it invites speculation that a different paradigm for informed consent may be needed.

A New Pathologic KMT2B Variant Associated with Childhood Onset Dystonia Presenting as Variable Phenotypes among Family Members.

Background: KMT2B-related dystonia is a primarily childhood-onset movement disorder characterized by progressive dystonia, spasticity, and developmental delay. A minority of individuals possess an inherited KMT2B variant. Case Report: As a child, the proband experienced mild developmental delay and laryngeal dystonia which progressed to generalized dystonia. Patellar hyperreflexia, postural tremor, and everted gait were documented. Whole exome sequencing identified a heterozygous pathogenic KMT2B variant in the proband, proband's sister, and proband's mother who had milder presentations. Discussion: This novel KMT2B variant reflects intrafamilial variable expressivity in KMT2B-related dystonia. Further identification of variants will allow for better appreciation of the phenotypic spectrum.

Deep brain stimulation for early-stage Parkinson's disease: an illustrative case.

OBJECTIVES: Subthalamic nucleus (STN) deep brain stimulation (DBS) is an effective intervention in advanced Parkinson's disease (PD), but its efficacy and safety in early PD are unknown. We are conducting a randomized pilot trial investigating DBS in early PD. This report describes one participant who received bilateral STN-DBS. MATERIALS AND METHODS: Thirty subjects have been randomized to either optimal drug therapy (ODT) or DBS + ODT. Microelectrode recordings from the STN and substantia nigra are collected at implantation. The Unified Parkinson's Disease Rating Scale Motor Subscale (UPDRS-III) is administered in the ON and OFF states semi-annually and neuropsychological function and quality of life are assessed annually. We describe a 54-year-old man with a two-year history of PD who was randomized to DBS + ODT and followed for two years. RESULTS: The subject showed a lower STN to substantia nigra ratio of neuronal activity than advanced PD patients, and higher firing rate than non-PD patients. The subject's total UPDRS and UPDRS-III scores improved during the two-year follow-up, while his OFF UPDRS-III score and levodopa equivalent daily dose increased. Quality of life, verbal fluency, and verbal learning improved. He did not experience any serious adverse events. CONCLUSIONS: This report details the first successful application of bilateral STN-DBS for early-stage PD during a clinical trial.

Long-Term Care Resident Awareness and Interest in Spasticity Treatments.

Spasticity is common in long-term care settings (affecting up to one in three residents), yet it remains under-treated despite safe and effective, Food and Drug Administration (FDA)-approved therapies. One barrier to treatment may be lack of awareness of available therapies for long-term care residents living with spasticity. A standardized spasticity treatment awareness and interest interview was conducted with 18 nursing home residents and 11 veterans' home residents in this cross-sectional study. Veterans' home residents were also asked about potential barriers to receiving spasticity treatment. Many residents across both long-term care facilities were unaware of most of the treatment options for spasticity. Participants were most aware of physical/occupational therapy (83%, 95% CI: 65-93%) and least aware of intrathecal baclofen (21%, 95% CI: 9-39%). After learning about treatments, only 7% of participants (95% CI: 0-23%) were not interested in receiving any form of spasticity treatment. Among residents previously unaware of spasticity treatments, at least one quarter became interested in receiving treatment and at least one-fifth indicated possibly being interested in the treatment after learning about it. Potential barriers to receiving treatment included traveling to see a doctor and limited knowledge of insurance coverage of spasticity treatments. These results suggest that patient-centered approaches, including education and discerning patient preferences, may improve spasticity treatment in long-term care settings.

Spasticity treatment facilitates direct care delivery for adults with profound intellectual disability.

Many adults with intellectual disabilities (ID) have spasticity, where increased muscle tone impairs activities of daily living (ADL) self-performance and care delivery. There are few reports of spasticity treatment for people with ID, and none of functionally meaningful outcomes. Our objective is to determine the effect of comprehensive spasticity management on ADL self-performance and care delivery. Baseline evaluation included repeated modified Ashworth and range of motion assessments, and timed and videotaped care task observations. Spasticity treatment was initiated immediately thereafter. Follow-up evaluation was conducted after spasticity management was optimized, one year after initiation. All individuals with spasticity at a single developmental center for whom treatment goals could be identified were included. Treatment was recommended by a neurologist from any accepted treatment for spasticity except oral medications, including botulinum neurotoxin A, intrathecal baclofen and orthopedic procedures. The main outcome measure is comparison of ease of videotaped care delivery, rated by direct caregivers blinded to participant treatment status. Spasticity treatment resulted in significant improvement across all outcome measures. Range of motion improved by 9 degrees (P = 0.005) and MAS by 0.4 (P = 0.022). Participants took 14% percent less time to complete tasks post-treatment (P = 0.01). Thirteen caregivers completed evaluations of 35 video pairs with an intra-class correlation of 0.9. After treatment, undergarment change (P = 0.031) and shirt change (P = 0.017) were rated easier, and all goals (P = 0.0006). Transfers trended toward improvement (P = 0.053). This study shows comprehensive spasticity management provides meaningful improvement in ADL care for patients with ID, which may improve quality of life and reduce caregiver burden.

Clinical Features of Tourette Syndrome.

Tourette syndrome is a multifaceted disorder characterized by multiple motor and at least one vocal tics that start in childhood, persist for at least 1 year, and cannot be attributed to another medical condition or exposure to medications/drugs. Clinical diagnostic criteria are available, and identification of tics is typically straightforward based on characteristic appearance and features. Diagnostic uncertainty can rarely arise in cases of mild tics, atypical features, certain psychiatric comorbidities, and other non-tic movement disorders. Comorbid psychopathology, including attention-deficit hyperactivity disorder (ADHD) and obsessive-compulsive behaviors/obsessive-compulsive disorder, affects the majority of patients and is correlated with disease severity and the presence of additional psychiatric behaviors. The severity of tics often improves after adolescence, whereas psychiatric symptoms typically persist. The subset of patients in whom tics persist into adulthood experience higher rates of anxiety, and lower self-esteem, socioeconomic status, and quality of life; the relative contribution of motor tics and psychopathology is not fully understood. This article summarizes the clinical features of Tourette syndrome, including major diagnostic criteria, unique features of tics, and key aspects that differentiate tics from common mimics and chameleons. Comorbid psychiatric conditions and their impact on phenotype and quality of life are described. Finally, current understanding of the natural history is summarized, including limited research in adults with Tourette syndrome.

Prevalence of Spasticity in Nursing Home Residents.

OBJECTIVES: To determine the prevalence, rate of underdiagnosis and undertreatment, and association with activities of daily living dependency of spasticity in a nursing home setting. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: This study is an analysis of a deidentified data set generated by a prior quality improvement project at a 240-bed nursing home for residents receiving long-term care or skilled nursing care services. METHODS: Each resident was examined by a movement disorders specialist neurologist to determine whether spasticity was present and, if so, the total number of spastic postures present in upper and lower limbs was recorded. Medical records, including the Minimum Data Set, were reviewed for neurologic diagnoses associated with spasticity, activities of daily living (ADL) dependency, and prior documentation of diagnosis and past or current treatments. Ordinary least squares linear regression models were used to evaluate the association between spasticity and ADL dependency. RESULTS: Two hundred nine residents (154 women, 81.9 ± 10.9 years) were included in this analysis. Spasticity was present in 22% (45/209) of residents examined by the neurologist. Only 11% of residents (5/45) had a prior diagnosis of spasticity and were receiving treatment. Presence of spasticity was associated with greater ADL dependency (χ2 = 51.72, P < .001), which was driven by lower limb spasticity (χ2 = 14.56, P = .006). CONCLUSIONS AND IMPLICATIONS: These results suggest that spasticity (1) is common in nursing homes (1 of 5 residents), (2) is often not diagnosed or adequately treated, and (3) is associated with worse ADL dependency. Further research is needed to enhance the rates of diagnosis and treatment of spasticity in long-term care facilities.

Testing for HIV-1 infection in a public developmental center.

The discovery of human immunodeficiency virus type 1 (HIV) infection in an individual who recently moved from a developmental center prompted the center to offer HIV testing to current and former residents. The guardians of 199 (93 percent) of the Center's current residents consented to testing. The remaining 14 current residents (seven percent) were not tested because informed consent for testing was not received. Consent for testing of 41 former residents was also obtained. All people who underwent testing were seronegative. Whether former residents who were not included in the present analysis received testing from other sources is not known.

Postseizure aphasia in Wernicke's encephalopathy: a case report and review of literature.

This case discusses the course of a woman with a history of epilepsy, alcohol use disorder, herpes simplex virus (HSV) encephalitis, and Wernicke encephalopathy (WE) who presented with altered mental status following approximately 48 hours of vomiting. After experiencing a tonic-clonic seizure in the emergency department, she developed a fluent aphasia. Aphasias are ordinarily attributed to structural changes in the brain parenchyma, often from stroke, neoplasm, or infection. When the magnetic resonance imaging of brain failed to show changes that could explain her fluent aphasia, the neurology team consulted psychiatry to workup psychogenic aphasia. During an admission 9 months earlier, she had been diagnosed with HSV encephalitis and possible WE. There was a high degree of suspicion for recurrent HSV infection, intermittent focal seizure activity, postictal psychosis, pseudobulbar affect, or a vascular cause of her fluent aphasia. After 3 days of treatment with levetiracetam, high-dose intravenous thiamine, and aripiprazole, the patient's fluent aphasia reversed. The authors conclude that the patient's reversible fluent aphasia was not psychiatric in etiology but likely caused by her seizures, the result of subtherapeutic phenytoin levels; her electroencephalogram showed focal seizure activity in the temporal lobes, possibly affecting her language centers. Language-related neurological conditions, or aphasias, can mimic psychiatric conditions such as conversion disorder or psychosis. In patients with substance use disorders, the line between psychiatric and neurological conditions becomes even more difficult to distinguish. The paper also discusses how unique aspects of her medications - levetiracetam conferring neuron membrane fluidity; aripiprazole, a drug shown to halt brain atrophy in mouse models; and parenteral thiamine to address her deficiency and WE - have aided in the reversal of the fluent aphasia. Levetiracetam should be considered in WE and the rare occurrence of aphasia after seizures.

Comparison of botulinum neurotoxin preparations for the treatment of cervical dystonia.

BACKGROUND: Comparative studies of botulinum neurotoxin preparations to date have generally examined 2 preparations at prespecified dose ratios in relatively homogeneous groups of patients under controlled study conditions. It is unclear whether the differences in adverse-event rates that have been noted under these controlled conditions can be generalized to the broader population of cervical dystonia patients, who are treated with a wider range of doses in a variety of settings. OBJECTIVE: We conducted a systematic review and analysis of the published literature to compare rates of dysphagia and dry mouth in studies of botulinum neurotoxin products. METHODS: We searched the MEDLINE, EMBASE, Biosis, SciSearch, JICST (Japan Science and Technology Center), and Pascal databases from 1985 through 2006 using the terms cervical dystonia, spasmodic torticollis, and botulinum toxin for original English-language studies of Botox, Dysport, or Myobloc in the treatment of cervical dystonia (or spasmodic torticollis) that documented adverse events by treatment or patient. Studies that involved patients with various types of dystonias or movement disorders were included as long as adverse events were reported separately for those with cervical dystonia. Rates of dysphagia with the original preparation of Botox were considered separately from those with the current preparation of Botox. RESULTS: Seventy published articles were included in the analysis (30 Botox, 24 Dysport, 3 Botox + Dysport, 11 Myobloc, 2 Botox + Myobloc). Mean total doses per treatment ranged from 60 to 374 U for Botox, 125 to 1200 U for Dysport, and 579 to 19,853 U for Myobloc. Botox was associated with a significantly lower rate of dysphagia than Dysport, with mean dysphagia rates of 10.5% for original Botox, 8.9% for current Botox, and 26.8% for Dysport (both, P < 0.05). Myobloc was associated with dry mouth (3.2%-90.0%) in 9 of 13 studies, but this adverse event was not reported in a sufficient number of studies of botulinum toxin type A preparations (Botox, n = 2; Dysport, n = 6) to permit statistical comparison. In the weighted analysis, the duration of effect differed between botulinum neurotoxin products (current Botox > Myobloc > original Botox > Dysport; all, P < 0.001), but only 43 (61.4%) of the 70 studies reported duration, and the definitions varied. CONCLUSION: The results of this analysis indicate differences in adverse-event rates between botulinum neurotoxin preparations, suggesting that use of these products should be based on their individual dosing, efficacy, and safety profiles.

Deep brain stimulation for Parkinson's disease: the Vanderbilt University Medical Center experience, 1998-2004.

Deep brain stimulation (DBS) has become increasingly popular to treat the symptoms of Parkinson's disease (PD) that are no longer adequately controlled by oral medications. This report summarizes safety and efficacy outcomes for 72 patients who underwent DBS surgery at Vanderbilt University Medical Center between September 1998 and December 2004. Efficacy was measured by reduction in anti-PD medications; patients saved an average of $2,292 per year after surgery. The most common adverse event was intracranial hemorrhage (12.5 percent), which led to permanent deficits in one patient (1.4 percent) and transient deficits in five patients (6.9 percent). The next most common event was DBS lead infection in seven patients (9.7 percent). Our experience provides further evidence that DBS is one of the safest and most effective treatments for PD patients suffering from motor complications.

Combined treatment with BTX-A and ITB for spasticity: case report.

One woman with profound mental retardation and spasticity living in a public residential developmental center was treated with intrathecal baclofen therapy and botulinum toxin type A injections. After one year of regular injections, extension across the right elbow increased 49 degrees. After one year of ITB, range of motion for left hip abduction increased 28 degrees; right hip abduction 9 degrees; left hip flexion 3 degrees; right hip flexion 1 degree; right knee flexion 31 degrees. Our case demonstrates the importance of a multidisciplinary approach in order to ease care and prevent complications. Expanded investigations should be carried out to evaluate the efficacy of combined therapy in patients with mental retardation.

Difficulty in securing treatment for degenerative hip disease in a patient with Down syndrome: the gap remains open.

In 2002, the office of the U.S. surgeon general published a report detailing the discrepancies between the quality of healthcare afforded to persons with and without mental retardation. This article examines the case of a female resident of a developmental center with profound mental retardation due to Down syndrome and degenerative hip disease. Although she was in urgent need of a total hip replacement, the operation was denied or delayed by several different surgeons. Using a survey of physician attitudes, we examine several possible motivations behind the surgeons' reluctance to perform the procedure and conclude that these reasons were not appropriate in this case. Finally, we reiterate the surgeon general's call to eradicate preconceptions held in the medical community about the population of persons with mental retardation that result in similar failures to provide adequate care.

Depression and intelligence in patients with Parkinson's disease and deep-brain stimulation.

The goal of this study is to examine the association of depression with intelligence and education in patients with Parkinson's disease treated with bilateral subthalamic nucleus stimulation (STN-DBS). The literature has been contradictory concerning depression in Parkinson's disease patients. Some studies have shown less depression in Parkinson's disease patients with more education not treated with STN-DBS. Other recently published studies indicate that STN-DBS improves the depression associated with Parkinson's disease. No studies have examined the correlation of these factors with depression in Parkinson's disease patients treated with STN-DBS. We administered the Beck Depression Inventory (BDI) pre- and postoperatively to 21 Parkinson's disease patients (seven women, 14 men, ages 49-75) who underwent STN-DBS. The postoperative scores of the lower 50th percentile (n=8) of the Verbal Comprehensive Index of the Wechsler Adult Intelligence Scale (WAIS-III) decreased significantly (P=0.036), while the upper 50th percentile (n=13) remained nearly constant (P=0.802). Furthermore, as the education increased from highschool to graduate level, patients demonstrated less improvement in depressive symptoms postoperatively. These findings suggest that Parkinson's disease patients with lower intelligence test scores and less education benefit more with regards to depressive symptomatology after STN-DBS than patients with higher scores and education.

Neuropsychological effects of deep brain stimulation in subjects with early stage Parkinson's disease in a randomized clinical trial.

BACKGROUND: Deep brain stimulation (DBS) is an effective treatment for patients with advanced Parkinson's disease (PD) and motor symptom complications. Recently, attention has been focused on whether offering DBS earlier in the course of PD is beneficial. OBJECTIVE: The purpose of this study was to determine the effects of DBS on neuropsychological functioning in subjects with early stage PD. METHODS: Thirty subjects with early PD (Hoehn & Yahr Stage II off medication) were randomized to optimal drug therapy (ODT) (n = 15) or bilateral subthalamic nucleus (STN) DBS+ODT (n = 15) after completing an expanded informed consent process specially designed for the study and administered by a medical ethicist and the study team. Comprehensive neuropsychological testing was completed in the treatment-withdrawn state at baseline and at 12 month and 24 month follow-ups. RESULTS: Two serious adverse events occurred in the DBS+ODT group. One subject experienced a stroke and another developed infected hardware that contributed to specific declines in cognitive functioning. However, compared to the ODT group, the remaining subjects in the DBS+ODT group exhibited modest reductions on a few measures of attention, executive function, and word fluency at 12 months. These differences were largely diminished at 24 months, especially when those with the adverse events were excluded. CONCLUSIONS: The results of this trial provide novel data regarding the effects of DBS on cognitive function in early PD. We believe that the findings and insights from this trial can help guide the safety analysis and risk-benefit evaluations in future discussions of DBS in early stage PD.

Deep brain stimulation of the subthalamic nucleus reduces antiparkinsonian medication costs.

This study reports a retrospective analysis of 16 patients to determine changes in medication costs associated with deep brain stimulation of the bilateral subthalamic nucleus (DBS B-STN). Antiparkinsonian medication (APMED) costs were evaluated pre- and post-operatively at 1 and 2 years, based on prescribed dosages. After treatment with DBS, patients experienced a 32% reduction in APMED costs after 1 year and a 39% reduction after 2 years. Hypothetical projections of total potential savings are presented, accounting for increasingly complex medication regimens and medication cost inflation. DBS patients may experience a significant long-term reduction in the cost of their pharmacologic treatment.

Bilateral globus pallidus internus deep brain stimulation therapy for primary generalized dystonia.

Primary generalized dystonia (PGD) associated with the early-onset generalized dystonia gene (DYT1) can cause severe disability, compromising an individual's ability to perform activities of daily living. Pharmacological treatment has been inadequate in alleviating the motor dysfunctions. Deep brain stimulation of the bilateral globus pallidus internus (DBS B-GPi) has been documented to reduce these debilitating motor abnormalities. This report details the successful treatment of a DYT1-positive 13 year-old boy suffering from PGD.

Subthalamic nucleus deep brain stimulation in early stage Parkinson's disease.

BACKGROUND: Deep brain stimulation (DBS) is an effective and approved therapy for advanced Parkinson's disease (PD), and a recent study suggests efficacy in mid-stage disease. This manuscript reports the results of a pilot trial investigating preliminary safety and tolerability of DBS in early PD. METHODS: Thirty subjects with idiopathic PD (Hoehn & Yahr Stage II off medication), age 50-75, on medication ≥6 months but ≤4 years, and without motor fluctuations or dyskinesias were randomized to optimal drug therapy (ODT) (n = 15) or DBS + ODT (n = 15). Co-primary endpoints were the time to reach a 4-point worsening from baseline in the UPDRS-III off therapy and the change in levodopa equivalent daily dose from baseline to 24 months. RESULTS: As hypothesized, the mean UPDRS total and part III scores were not significantly different on or off therapy at 24 months. Medication requirements in the DBS + ODT group were lower at all time points with a maximal difference at 18 months. With a few exceptions, differences in neuropsychological functioning were not significant. Two subjects in the DBS + ODT group suffered serious adverse events; remaining adverse events were mild or transient. CONCLUSIONS: This study demonstrates that subjects with early stage PD will enroll in and complete trials testing invasive therapies and provides preliminary evidence that DBS is well tolerated in early PD. The results of this trial provide the data necessary to design a large, phase III, double-blind, multicenter trial investigating the safety and efficacy of DBS in early PD.

Methods for Surgical Targeting of the STN in Early-Stage Parkinson's Disease.

Patients with Parkinson's disease (PD) experience progressive neurological decline, and future interventional therapies are thought to show most promise in early stages of the disease. There is much interest in therapies that target the subthalamic nucleus (STN) with surgical access. While locating STN in advanced disease patients (Hoehn-Yahr Stage III or IV) is well understood and routinely performed at many centers in the context of deep brain stimulation surgery, the ability to identify this nucleus in early-stage patients has not previously been explored in a sizeable cohort. We report surgical methods used to target the STN in 15 patients with early PD (Hoehn-Yahr Stage II), using a combination of image guided surgery, microelectrode recordings, and clinical responses to macrostimulation of the region surrounding the STN. Measures of electrophysiology (firing rates and root mean squared activity) have previously been found to be lower than in later-stage patients, however, the patterns of electrophysiology seen and dopamimetic macrostimulation effects are qualitatively similar to those seen in advanced stages. Our experience with surgical implantation of Parkinson's patients with minimal motor symptoms suggest that it remains possible to accurately target the STN in early-stage PD using traditional methods.