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.

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.

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.

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.

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.

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.

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.

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.

Continuation of long-term care for cervical dystonia at an academic movement disorders clinic.

Patients with cervical dystonia (CD) receive much of their care at university based hospital outpatient clinics. This study aimed to describe the clinical characteristics and treatment experiences of patients who continued care at our university based movement disorders clinic, and to document the reasons for which a subset discontinued care. Seventy patients (77% female) were recruited from all patients at the clinic (n = 323). Most (93%) were treated with botulinum neurotoxin (BoNT) injection, and onabotulinumtoxinA was initially used in 97%. The average dose of onabotulinumtoxinA was 270.4 U (range 50-500) and the median number of injections was 14 (range: 1-39). Twenty one patients later received at least one cycle of rimabotulinumtoxinB (33%); of those, 10 switched back to onabotulinumtoxinA (48%). The initial rimabotulinumtoxinB dose averaged 11,996 units (range: 3000-25,000 over 1-18 injections). Twenty one patients (30%) discontinued care. Reasons cited included suboptimal response to BoNT therapy (62%), excessive cost (24%), excessive travel burden (10%), and side effects of BoNT therapy (10%). Most patients (76%) did not seek further care after leaving the clinic. Patients who terminated care received fewer treatment cycles (5.5 vs. 13.0, p = 0.020). There were no other identifiable differences between groups in gender, age, disease characteristics, toxin dose, or toxin formulation. These results indicate that a significant number of CD patients discontinue care due to addressable barriers to access, including cost and travel burden, and that when leaving specialty care, patients often discontinue treatment altogether. These data highlight the need for new initiatives to reduce out-of-pocket costs, as well as training for community physicians on neurotoxin injection in order to lessen the travel burden patients must accept in order to receive standard-of-care treatments.

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.

Pilot study assessing the feasibility of applying bilateral subthalamic nucleus deep brain stimulation in very early stage Parkinson's disease: study design and rationale.

BACKGROUND: Deep brain stimulation provides significant symptomatic benefit for people with advanced Parkinson's disease whose symptoms are no longer adequately controlled with medication. Preliminary evidence suggests that subthalamic nucleus stimulation may also be efficacious in early Parkinson's disease, and results of animal studies suggest that it may spare dopaminergic neurons in the substantia nigra. OBJECTIVE: We report the methodology and design of a novel Phase I clinical trial testing the safety and tolerability of deep brain stimulation in early Parkinson's disease and discuss previous failed attempts at neuroprotection. METHODS: We recently conducted a prospective, randomized, parallel-group, single-blind pilot clinical trial of deep brain stimulation in early Parkinson's disease. Subjects were randomized to receive either optimal drug therapy or deep brain stimulation plus optimal drug therapy. Follow-up visits occurred every six months for a period of two years and included week-long therapy washouts. RESULTS: Thirty subjects with Hoehn & Yahr Stage II idiopathic Parkinson's disease were enrolled over a period of 32 months. Twenty-nine subjects completed all follow-up visits; one patient in the optimal drug therapy group withdrew from the study after baseline. Baseline characteristics for all thirty patients were not significantly different. CONCLUSIONS: This study demonstrates that it is possible to recruit and retain subjects in a clinical trial testing deep brain stimulation in early Parkinson's disease. The results of this trial will be used to support the design of a Phase III, multicenter trial investigating the efficacy of deep brain stimulation in early Parkinson's disease.

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.

Discordance in informed consent response on the basis of demographic factors: brief report.

During an outcomes study of spasticity treatment at a developmental center for 62 residents with profound intellectual disabilities, either botulinum toxin A (BTX-A), intrathecal baclofen (ITB), or both were recommended with physical and occupational therapy. Conservators consented to BTX-A more than ITB (p = .021). Court-appointed conservators were more likely to provide consent for treatment than family members (p = .026). Nonparents consented more than parents (p = .009). Finally, Caucasian conservators were more likely to consent to treatment than African American conservators (p = .036), but ethnicity of the resident did not influence consent. Gender of resident or conservator did not influence rate of consent. This report highlights disparities in surrogate consent giving for individuals with intellectual disabilities and indicates a need for more research to ensure that this vulnerable population has access to appropriate treatments.

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.

Neurotoxin injection for movement disorders.

The therapeutic use of botulinum neurotoxin has exploded since the first US Food and Drug Administration indication was obtained in 1989, and today it represents the first-line therapy for several hyperkinetic movement disorders. Of the seven serotypes (A to G), types A and B have been approved for use in the United States. Two type A toxins, onabotulinumtoxinA (Botox) and abobotulinumtoxinA (Dysport), are available, and one type B toxin, rimabotulinumtoxinB (Myobloc) is available. The commercially available toxins differ by protein target, duration of action, and adverse event profile; no formula exists for interconversion. The clinical development of the toxin is outlined and methods for muscle targeting are compared. Treatment regimens should be designed to achieve a specific care or functional goal by interdisciplinary teams consisting of physicians, patients, caregivers, and therapists, when appropriate. We discuss dosing considerations and safety profiles in the context of hyperkinetic movement disorders commonly encountered by neurologists, including cervical dystonia, spasticity, pediatric spasticity, blepharospasm, focal limb dystonias, and essential tremor. Finally, the multiple illustrative cases sprinkled throughout the chapter demonstrate the highly individualized, goal-focused nature of treatment with neurotoxins.

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.