Confined Thalamic Deep Brain Stimulation in Refractory Essential Tremor.

BACKGROUND: Thalamic ventral intermediate nucleus (VIM) deep brain stimulation (DBS) is an effective therapy for medication-refractory essential tremor (ET). However, 13-40% of patients with an initially robust tremor efficacy lose this benefit over time despite reprogramming attempts. At our institution, a cohort of ET patients with VIM DBS underwent implantation of a second anterior (ventralis oralis anterior; VOA) DBS lead to permit "confined stimulation." We sought to assess whether confined stimulation conferred additional tremor capture compared to VIM or VOA stimulation alone. METHODS: Seven patients participated in a protocol-based programming session during which a video-recorded Fahn-Tolosa-Marin Part A (FTM-A) tremor rating scale was used in the following 4 DBS states: off stimulation, VIM stimulation alone, VOA stimulation alone, and dual lead (confined) stimulation. RESULTS: The average (SD) baseline FTM-A off score was 17.6 (4.0). VIM stimulation alone lowered the average FTM-A total score to 6.9 (4.0). Confined stimulation further attenuated the tremor, reducing the total score to 5.7 (2.8). CONCLUSIONS: Confined thalamic DBS can provide additional symptomatic benefits in patients with unsatisfactory tremor control from VIM or VOA stimulation alone.

Clustering of dystonia in some pedigrees with autosomal dominant essential tremor suggests the existence of a distinct subtype of essential tremor.

BACKGROUND: There is an ongoing debate whether essential tremor (ET) represents a monosymptomatic disorder or other neurologic symptoms are compatible with the diagnosis of ET. Many patients with clinically definite ET develop dystonia. It remains unknown whether tremor associated with dystonia represent a subtype of ET. We hypothesized that ET with dystonia represents a distinct subtype of ET. METHODS: We studied patients diagnosed with familial ET and dystonia. We included only those patients whose first-degree relatives met diagnostic criteria for ET or dystonia with tremor. This cohort was ascertained for the presence of focal, segmental, multifocal, hemidystonia or generalized dystonia, and ET. RESULTS: We included 463 patients from 97 kindreds with autosomal dominant mode of inheritance (AD), defined by the vertical transmission of the disease. ET was the predominant phenotype in every ascertained family and each was phenotypically classified as AD ET. "Pure" ET was present in 365 individuals. Focal or segmental dystonia was present in 98 of the 463 patients; 87 of the 98 patients had ET associated with dystonia, one had dystonic tremor and ten had isolated dystonia. The age of onset and tremor severity did not differ between patients with "pure" ET and ET associated with dystonia. We did not observe a random distribution of dystonia in AD ET pedigrees and all patients with dystonia associated with ET were clustered in 28% of all included pedigrees (27/97, p < 0.001). CONCLUSIONS: Our results suggest that familial ET associated with dystonia may represent a distinct subtype of ET.

Prevalence of unilateral tremor in autosomal dominant essential tremor.

The presence of bilateral arm tremor is a key diagnostic feature of essential tremor (ET). We analyzed the presence of unilateral arm tremor in familial ET cohort of 133 autosomal dominant ET kindreds with 412 affected individuals. Inclusion criteria in patients with unilateral arm postural and/or kinetic tremor required the duration of tremor for at least 5 years, without hypokinetic-rigid syndrome, dystonic posturing, or history of sudden onset of tremor. Only subjects with at least one living first degree relative who met diagnostic criteria for definite ET were included. Eighteen subjects met the inclusion criteria and five had postural tremor only, while the majority (13/18) had a combination of postural and kinetic tremor. Our data shows that unilateral tremor associated with ET is relatively rare and can be identified in 4.4% patients in a cohort of familial ET.

Positive family history of essential tremor influences the motor phenotype of Parkinson's disease.

Previous reports have suggested that essential tremor (ET) represents a risk factor for the development of Parkinson's disease (PD). Patients with long-standing ET who develop PD tend to have a tremor-dominant subtype. To further clarify this association, we examined patients from kindreds with autosomal dominant ET who had signs of isolated PD but did not meet criteria for overlapping ET. We identified 22 patients with PD meeting these diagnostic criteria, and 90% (20 of 22) had tremor-predominant subtype of PD. Unilateral rest tremor was the presenting symptom in 15 of 22 patients, bradykinesia or rigidity in 5 of 22, and gait problems in 2 of 22. Postural tremor was relatively mild, and the severity of kinetic tremor tightly correlated with rest tremor (r = 0.83, P < 0.001). Tremor-dominant subtype of PD in patients with a positive family history of ET suggests that these patients have inherited a genetic susceptibility factor for tremor, which affects the motor phenotype of PD.

Progranulin gene mutation with an unusual clinical and neuropathologic presentation.

Progranulin gene (PGRN) mutations cause frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Patients usually present with a frontotemporal dementia syndrome and have prominent atrophy and neuronal loss in frontal and temporal cortices and the striatum, with neuronal intranuclear and cytoplasmic inclusions. Clinical, neuropathological, and genetic studies are reported on an individual with PGRN mutation and her family members. We describe a patient with a PGRN c.26C>A mutation who presented with progressive stuttering dysarthria, oculomotor abnormalities, choreic buccolingual movements, and mild parkinsonism. Two other family members were affected, one with a behavioral variant frontotemporal dementia syndrome, the other with a diagnosis of probable Alzheimer's disease. At autopsy there was no neuronal loss in the cortex or medial temporal lobe structures, but there was striatal gliosis. Immunohistochemistry for ubiquitin and TDP-43 revealed neuronal cytoplasmic and intranuclear inclusions as well as neurites. This study further expands the clinical and pathological spectrum of PGRN mutations, and suggests the diagnosis could be missed in some individuals with atypical presentations.

Reappraisal of the role of the DRD3 gene in essential tremor.

OBJECTIVES: Analyze the distribution of polymorphism in the dopamine receptor D3 (DRD3) gene, which was previously reported as a susceptibility risk for essential tremor (ET), in a large cohort of ET. METHODS: The role of 312G>A DRD3 polymorphism was analyzed using linkage analysis, association study and transmission disequilibrium test in a group of 433 ET patients, and two unrelated control groups with 121 and 151 individuals. RESULTS: Allelic frequencies of glycine and serine forms of the DRD3 gene did not differ between patients and both control groups, and were in Hardy-Weinberg equilibrium. Linkage analysis identified obligatory recombinants in every large pedigree, even in those with relatively high frequency of glycine allele, thus excluding the linkage to this locus. Both alleles were transmitted with an equal likelihood to affected offspring. We also failed to replicate the relationship between glycine homozygosity and an earlier age of onset or more severe tremor course. CONCLUSIONS: Our comprehensive genetic analysis in a large ET cohort strongly argues against the role of the DRD3 gene in ET pathogenesis.

The role of deep brain stimulation in Parkinson's disease: an overview and update on new developments.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of neuronal dopamine production in the brain. Oral therapies primarily augment the dopaminergic pathway. As the disease progresses, more continuous delivery of therapy is commonly needed. Deep brain stimulation (DBS) has become an effective therapy option for several different neurologic and psychiatric conditions, including PD. It currently has US Food and Drug Administration approval for PD and essential tremor, as well as a humanitarian device exception for dystonia and obsessive-compulsive disorder. For PD treatment, it is currently approved specifically for those patients suffering from complications of pharmacotherapy, including motor fluctuations or dyskinesias, and a disease process of at least 4 years of duration. Studies have demonstrated superiority of DBS and medical management compared to medical management alone in selected PD patients. Optimal patient selection criteria, choice of target, and programming methods for PD and the other indications for DBS are important topics that continue to be explored and remain works in progress. In addition, new hardware options, such as different types of leads, and different software options have recently become available, increasing the potential for greater efficacy and/or reduced side effects. This review gives an overview of therapeutic management in PD, specifically highlighting DBS and some of the recent changes with surgical therapy.

Factors associated with falling in early, treated Parkinson's disease: The NET-PD LS1 cohort.

BACKGROUND: Recognizing the factors associated with falling in Parkinson's disease (PD) would improve identification of at-risk individuals. OBJECTIVE: To examine frequency of falling and baseline characteristics associated with falling in PD using the National Institute of Neurological Disorders and Stroke (NINDS) Exploratory Trials in PD Long-term Study-1 (NET-PD LS-1) dataset. METHODS: The LS-1 database included 1741 early treated PD subjects (median 4year follow-up). Baseline characteristics were tested for a univariate association with post-baseline falling during the trial. Significant variables were included in a multivariable logistic regression model. A separate analysis using a negative binomial model investigated baseline factors on fall rate. RESULTS: 728 subjects (42%) fell during the trial, including at baseline. A baseline history of falls was the factor most associated with post-baseline falling. Men had lower odds of post-baseline falling compared to women, but for men, the probability of a post-baseline fall increased with age such that after age 70, men and women had similar odds of falling. Other baseline factors associated with a post-baseline fall and increased fall rate included the Unified PD Rating Scale (UPDRS) Activities of Daily Living (ADL) score, total functional capacity (TFC), baseline ambulatory capacity score and dopamine agonist monotherapy. CONCLUSION: Falls are common in early treated PD. The biggest risk factor for falls in PD remains a history of falling. Measures of functional ability (UPDRS ADL, TFC) and ambulatory capacity are novel clinical risk factors needing further study. A significant age by sex interaction may help to explain why age has been an inconsistent risk factor for falls in PD.

Longer Duration of MAO-B Inhibitor Exposure is Associated with Less Clinical Decline in Parkinson's Disease: An Analysis of NET-PD LS1.

BACKGROUND: Monoamine oxidase type B (MAO-B) inhibitors exhibit neuroprotective effects in preclinical models of PD but clinical trials have failed to convincingly demonstrate disease modifying benefits in PD patients. OBJECTIVE: To perform a secondary analysis of NET-PD LS1 to determine if longer duration of MAO-B inhibitor exposure was associated with less clinical decline. METHODS: The primary outcome measure was the Global Outcome (GO), comprised of 5 measures: change from baseline in the Schwab and England (ADL) scale, the 39-item Parkinson's Disease Questionnaire (PDQ-39), the UPDRS Ambulatory Capacity Scale, the Symbol Digit Modalities Test, and the most recent Modified Rankin Scale. A linear mixed model was used to explore the association between the cumulative duration of MAO-B inhibitor exposure and the GO, adjusting for necessary factors and confounders. Associations between MAO-B inhibitor exposure and each of the five GO components were then studied individually. RESULTS: 1616 participants comprised the analytic sample. Mean observation was 4.1 (SD = 1.4) years, and 784 (48.5%) participants received an MAO-B inhibitor. The regression coefficient of cumulative duration of MAO-B inhibitor exposure (in years) on the GO was - 0.0064 (SE = 0.002, p = 0.001). Significant associations between duration of MAO-B inhibitor exposure and less progression were observed for ADL (p < 0.001), Ambulatory Capacity (p < 0.001), and the Rankin (p = 0.002). CONCLUSIONS: Our analysis identified a significant association between longer duration of MAO-B inhibitor exposure and less clinical decline. These findings support the possibility that MAO-B inhibitors slow clinical disease progression and suggest that a definitive prospective trial should be considered.

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.

Neurosarcoidosis Presenting as Aseptic Meningitis in an Immunosuppressed Renal Transplant Recipient.

BACKGROUND: Sarcoidosis is a presumptive autoimmune disorder characterized by the presence of noncaseating granulomas and is usually treated successfully with immunosuppression. METHODS AND RESULTS: Here, we describe the case of a 63-year-old male renal transplant recipient with a remote history of pulmonary sarcoidosis on chronic immunosuppression who developed recurrent aseptic meningitis and underwent brain biopsy revealing a diagnosis of neurosarcoidosis. CONCLUSIONS: This case highlights the possibility of recurrence of sarcoidosis in the setting of maintenance immunosuppression, the need for heightened awareness of alternative sites of recurrence of autoimmune disease, and future studies to determine the underlying mechanism of recurrence in organ transplant recipients.

Parkinson's disease severity and use of dopaminergic medications.

BACKGROUND: The effects of dopaminergic therapy in parkinson's disease (PD) can vary depending on the class of medication selected. OBJECTIVE: The aim of this post hoc study was to determine if the class of dopaminergic therapy correlated with disease severity in persons with early, treated PD. METHODS: A non-parametric global statistical test (GST) was used to assess the status of participants treated with dopamine agonist (DA) monotherapy, levodopa (LD) monotherapy or combined LD and DA therapy on multiple PD outcomes encompassing motor, cognitive, psychiatric and autonomic function, as well as disability and quality of life. RESULTS: The outcomes measured at the beginning of the study showed lower disease burden for participants on initial DA monotherapy compared to those taking combined LD and DA therapy after controlling for age, education, taking cog-meds and amantadine. CONCLUSION: This observation suggests that clinicians treating early PD patients favor combined LD and DA therapy in patients with more disabling features over DA monotherapy. As such, studies of PD progression in treated PD patients may be affected by the class of symptomatic dopaminergic therapy.

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.

Advances in the mechanisms of Parkinson's disease.

Parkinson's disease is the second most common neurodegenerative disorder. Despite fairly typical clinical and pathologic features, the etiology remains unknown. Many cellular mechanisms such as oxidative stress, mitochondrial dysfunction, lysosomal dysfunction, neuroinflammatory changes, and the formation of pathologic inclusions have been proposed as potential causes. Potential links between environmental and genetic changes appear to predispose individuals to develop Parkinson's disease. Considering these observations, albeit with different levels of evidence, it is becoming more probable that Parkinson's disease is a heterogeneous disorder or a syndrome that arises from the contribution of many different factors.

Update on the medical management of Parkinson disease.

Dopaminergic agents remain the principal treatments for patients with Parkinson disease (PD). In many patients, however, a combination of relatively resistant motor symptoms, motor complications such as dyskinesias, or nonmotor symptoms such as dysautonomia may lead to substantial disability in spite of dopaminergic therapy. This chapter will review both dopaminergic and nondopaminergic therapies for motor and nonmotor symptoms in PD.Although the basic principles of pharmacotherapy for the motor symptoms of PD have largely remained unchanged over the past decade, several new therapies have become available to refine treatment. In addition, there has been an increasing interest in agents targeting nonmotor symptoms, such as dementia and sleepiness. As patients with PD live longer and acquire additional comorbidities, addressing these nonmotor symptoms has become increasingly important. In this chapter, the major antiparkinsonian dopaminergic compounds will be reviewed, followed by a patient-focused guide to implementation of these treatments as part of an overall management plan.

Familial essential tremor with apparent autosomal dominant inheritance: should we also consider other inheritance modes?

A positive family history is present in many patients with essential tremor (ET), but twin studies and segregation analysis have suggested that ET is not entirely a genetic disorder. Two genetic loci have been identified in autosomal dominant (AD) ET and polymorphisms in the DRD3 and HS1-BP3 genes have been proposed as the possible susceptibility factors for ET. There is also evidence for further genetic heterogeneity. We evaluated 4 unrelated large kindreds with ET with an apparent AD mode of transmission. Each kindred spanned at least 3 generations and contained at least 13 living affected subjects who met criteria for definitive ET. None of the pedigrees had evidence for inheritance of ET from both parents. Known genetic ET loci were excluded in these families. We detected a preferential transmission of ET in every kindred and the proportion of affected offspring varied from 75% to 90% (P < 0.05) in the generations with complete ascertainment. Our data indicate that non-Mendelian preferential transmission of an affected allele is a feature in many ET kindreds with multiple affected members and an apparent AD mode of inheritance. ET may have a complex etiology. Additional genetic models need to be considered, including an interaction of susceptibility genes and environmental risk factors.