Progressive multifocal leukoencephalopathy without overt immunosuppression.

Progressive multifocal leukoencephalopathy (PML) is a central nervous system disease caused by the human polyomavirus 2 that usually occurs in a setting of immunodeficiency. PML without overt immunosuppression is considered a rare occurrence but has been described in multiple previous case reports and series. Its prevalence, overall frequency, and prognosis are largely unknown. This is a single-center retrospective review of all University of Florida cases with the ICD10 PML diagnosis code (A81.2). PML without overt immunosuppression was defined as absence of human immunodeficiency virus (HIV) infection, hematological malignancy, immunomodulatory/-suppressive medications, autoimmune conditions with a propensity for PML (sarcoidosis, systemic lupus erythematosus). Cases that did not fulfill criteria for clinically or histologically definite PML were excluded. Of 52 patients with the ICD10 code A 81.2, 17 fulfilled definite diagnostic criteria for PML. Overt immunosuppression was identified in 15/17 (88.2%) cases (10/17 (58.8%): human immunodeficiency virus; 5/17 (29.4%): immunomodulatory/-suppressive medication). Two/seventeen (11.8%) cases were consistent with PML without overt immunosuppression. Possible contributing factors were a preceding dog bite and mild hypogammaglobulinemia M (39 mg/dL) in case 1 and significant alcohol use without evidence for liver disease in case 2. Both cases were fatal within 6 (case 1) and 2 (case 2) months. The results suggest that PML without overt immunosuppression may be more common than previously described. Therefore, PML should be considered even in the absence of overt immunosuppression if clinical and radiographic findings are suggestive of the diagnosis.

Hematoma-induced Twiddler-like phenomenon as a presentation of DBS hardware failure: Case report.

Deep brain stimulators (DBS) may fail for a multitude of reasons. We present a 79-year-old Parkinson's disease patient who suffered a DBS failure following impulse generator (IPG) replacement surgery due to the IPG flipping within an expanded capsular pocket. This creation of the pocket was unintentional, and the pocket formed around an undiagnosed postoperative hemorrhage. The syndrome could be considered "Twiddler-like" because it resulted in device flipping. There were, however, many characteristic differences between our case and classical Twiddler's syndrome. DBS neurostimulator failure due to hematoma induced device flipping should be suspected when device interrogation is impossible or there are abnormally high impedances across multiple DBS lead contacts. A plain film X-ray series should be ordered and can be useful in providing radiological evidence of device flipping. In cases like ours the extensive braiding encountered in Twiddler's syndrome may be absent. Anchoring the IPG to a deep fascial layer as well as the use of an antimicrobial pouch are two methods that may be employed to prevent or to treat this complication.

Evolution of Globus Pallidus Targeting for Parkinson's and Dystonia Deep Brain Stimulation: A 15-Year Experience.

Objective: The aim of this study is to evaluate the evolution of GPi DBS targeting. Methods: This retrospective, single-center study included patients implanted with GPi DBS leads for dystonia or PD during the years 2004 to 2018 at the University of Florida Fixel Institute for Neurological Diseases. Each patient underwent a high-resolution targeting study on the day prior to the surgery, which was fused with a high resolution CT scan that was acquired on the day of the procedure. Intraoperative target location was selected using a digitized 3D Schaltenbrand-Bailey atlas. All patients underwent a high-resolution head CT scan without contrast approximately one month after lead implantation and accurate measurement of neuroanatomical lead position was acquired after fusion of pre-operative and post-operative image studies. Results: We analyzed 253 PD patients with 352 leads and 80 dystonia patients with 141 leads. During 15 years of follow-up, lead locations in the PD group migrated more laterally (ß = 0.09, p < 0.0001), posteriorly [slope (ß) = 0.04, p < 0.05], and dorsally (ß = 0.07, p < 0.001), whereas leads in the dystonia group did not significantly change position aside from a trend in the dorsal direction (ß = 0.06, p = 0.053). Conclusion: The evolving target likely results from multiple factors including improvements in targeting techniques and clinical feedback intraoperatively and post-operatively. Our demonstrates the potential importance of a systematic post-operative DBS lead measurement protocol to ensure quality control and to inform and optimize DBS programming.

Deep brain stimulation programming strategies: segmented leads, independent current sources, and future technology.

Introduction: Advances in neuromodulation and deep brain stimulation (DBS) technologies have facilitated opportunities for improved clinical benefit and side effect management. However, new technologies have added complexity to clinic-based DBS programming.Areas covered: In this article, we review basic basal ganglia physiology, proposed mechanisms of action and technical aspects of DBS. We discuss novel DBS technologies for movement disorders including the role of advanced imaging software, lead design, IPG design, novel programming techniques including directional stimulation and coordinated reset neuromodulation. Additional topics include the use of potential biomarkers, such as local field potentials, electrocorticography, and adaptive stimulation. We will also discuss future directions including optogenetically inspired DBS.Expert opinion: The introduction of DBS for the management of movement disorders has expanded treatment options. In parallel with our improved understanding of brain physiology and neuroanatomy, new technologies have emerged to address challenges associated with neuromodulation, including variable effectiveness, side-effects, and programming complexity. Advanced functional neuroanatomy, improved imaging, real-time neurophysiology, improved electrode designs, and novel programming techniques have collectively been driving improvements in DBS outcomes.

Globus Pallidus Internus (GPi) Deep Brain Stimulation for Parkinson's Disease: Expert Review and Commentary.

INTRODUCTION: The globus pallidus internus (GPi) region has evolved as a potential target for deep brain stimulation (DBS) in Parkinson's disease (PD). DBS of the GPi (GPi DBS) is an established, safe and effective method for addressing many of the motor symptoms associated with advanced PD. It is important that clinicians fully understand this target when considering GPi DBS for individual patients. METHODS: The literature on GPi DBS in PD has been comprehensively reviewed, including the anatomy, physiology and potential pitfalls that may be encountered during surgical targeting and post-operative management. Here, we review and address the implications of lead location on GPi DBS outcomes. Additionally, we provide a summary of randomized controlled clinical trials conducted on DBS in PD, together with expert commentary on potential applications of the GPi as target. Finally, we highlight future technologies that will likely impact GPi DBS, including closed-loop adaptive approaches (e.g. sensing-stimulating capabilities), advanced methods for image-based targeting and advances in DBS programming, including directional leads and pulse shaping. RESULTS: There are important disease characteristics and factors to consider prior to selecting the GPi as the DBS target of PD surgery. Prior to and during implantation of the leads it is critical to consider the neuroanatomy, which can be defined through the combination of image-based targeting and intraoperative microelectrode recording strategies. There is an increasing body of literature on GPi DBS in patients with PD suggesting both short- and long-term benefits. Understanding the GPi target can be useful in choosing between the subthalamic (STN), GPi and ventralis intermedius nucleus as lead locations to address the motor symptoms and complications of PD. CONCLUSION: GPi DBS can be effectively used in select cases of PD. As the ongoing DBS target debate continues (GPi vs. STN as DBS target), clinicians should keep in mind that GPi DBS has been shown to be an effective treatment strategy for a variety of symptoms, including bradykinesia, rigidity and tremor control. GPi DBS also has an important, direct anti-dyskinetic effect. GPi DBS is easier to program in the outpatient setting and will allow for more flexibility in medication adjustments (e.g. levodopa). Emerging technologies, including GPi closed-loop systems, advanced tractography-based targeting and enhanced programming strategies, will likely be future areas of GPi DBS expansion. We conclude that although the GPi as DBS target may not be appropriate for all PD patients, it has specific clinical advantages.

Brain Atrophy Following Deep Brain Stimulation: Management of a Moving Target.

Clinical vignette: A 51-year-old man with essential tremor (ET) had bilateral ventralis intermedius nucleus deep brain stimulation (VIM-DBS) placed to address refractory tremor. Despite well-placed DBS leads and adequate tremor response, he subsequently experienced worsening. Re-programming of the device and reconfirming the electrical thresholds for benefits and side effects were both performed. Six years following DBS implantation, repeat imaging revealed brain atrophy and a measured lead position change with a coincident change in clinical response. Clinical dilemma: What do we know about brain atrophy affecting lead placement and long-term DBS effectiveness? What are the potential strategies to combat narrowed therapeutic thresholds and to maximize DBS therapeutic benefit? Clinical solution: Decreasing the electrical field of stimulation and programming in a bipolar configuration are strategies to provide symptomatic tremor control and to minimize stimulation-induced side effects. Gaps in knowledge: Currently, effects of brain atrophy, and factors underpinning emergence of side effects and/or loss of benefit in chronic VIM-DBS remain largely unexplored.

Case Report: Globus Pallidus Internus (GPi) Deep Brain Stimulation Induced Keyboard Typing Dysfunction.

Introduction:Typing on a keyboard requires complex collaboration between visuospatial/procedural memory, language, and motor function. The impaired ability to type, independent of motor deficits, apraxia, or aphasia has been coined "dystypia." Case Presentation: A 68-year-old woman with a history of blepharospasm, oromandibular, and segmental dystonia underwent bilateral pallidal deep brain stimulation (DBS) because of a waning response to botulinum toxin therapy. Following DBS, she discovered she no longer "remembered" how to type fluidly and had to "hunt and peck" for letters on the keyboard. This issue persisted at a 2-year follow-up. The patient underwent serial typing tests with the DBS ON vs. OFF. Post-operative lead reconstruction was performed using Lead-DBS. The volume of tissue activation (VTA) modeling was combined with whole-brain tractography. Results: Typing improved when the device was switched to the DBS OFF state. Cortical mapping revealed strong modulation of the right angular gyrus, left calcarine fissure, and left cuneus. There was also activation of bilateral supplemental motor areas and superior parietal gyri. Discussion: Shared lesion topography analysis of dystypia cases in the literature has suggested the involvement of the superior longitudinal fasciculus (SLF). The SLF involves the superior parietal lobe, angular gyrus, supramarginal gyrus, and arcuate fasciculus. Our patient's connectivity pattern suggested SLF involvement. The improvement in OFF state typing and her imaging together suggested that the dystypia in her case was a stimulation-induced side effect. Conclusion: Dystypia is a rare side effect of Globus Pallidus Internus (GPi) DBS therapy and may be associated with SLF involvement.

Dysarthria and Speech Intelligibility Following Parkinson's Disease Globus Pallidus Internus Deep Brain Stimulation.

BACKGROUND: Although earlier studies reported variable speech changes following subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) patients, the effects of globus pallidus internus (GPi) DBS on speech performance in PD remain largely unknown. OBJECTIVE: We aimed to characterize speech changes following PD GPi-DBS. METHODS: We retrospectively analyzed clinical and speech outcomes of 25 PD patients treated with bilateral GPi-DBS at a single center. Outcome measures included the Unified Parkinson's Disease Rating Scale (UPDRS), speech subsystem domains (respiratory, laryngeal, resonance, orofacial, rate, prosody, rhythm, and naturalness), and overall speech intelligibility. Scores at baseline were compared with those at 6 months, 1 year, and the longest clinical follow-up available. RESULTS: In the off-medication state, activities of daily living and motor function based on UPDRS II and III significantly improved postoperatively. We observed unique patterns of speech changes in patients with PD following GPi-DBS in the short- (n = 25) and longer-term (n = 8) follow-up periods. Velopharyngeal (resonance), laryngeal components, and prosody worsened after bilateral GPi-DBS (p < 0.015). Speech intelligibility did not worsen after GPi-DBS in the short-term, but there was a trend to deteriorate at long-term follow-up (e.g., one year and beyond). We observed worsening of hypokinetic dysarthria in individual patients. Also, a minority of patients developed stuttering, spastic dysarthria, or ataxic dysarthria. CONCLUSION: Bilateral GPi-DBS worsened several modalities of parkinsonian speech without compromising overall speech intelligibility. GPi-DBS can potentially worsen or induce hypokinetic dysarthria, stuttering, spastic dysarthria, or ataxic dysarthria. GPi-DBS may have different and variable effects on speech function when compared to STN-DBS.

Depressive Symptoms are Frequent in Atypical Parkinsonian Disorders.

OBJECTIVE: To compare the incidence and prevalence of depressive symptoms in atypical parkinsonian (APD) syndromes versus Parkinson disease (PD). METHODS: In a large retrospective patient cohort we analyzed the incidence and prevalence of depressive symptoms using the Beck Depression Inventory (BDI) and evaluated subjects longitudinally on subsequent visits. For individuals who followed in subsequent visits we calculated incidence rates in person-years as a measure of incidence. RESULTS: We identified 361 patients with APD including Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), Multiple System Atrophy (MSA) and Dementia with Lewy Bodies (DLB), and 2352 PD controls. The mean BDI values were significantly higher in APD (F=14.19, p < 0.001). A significantly higher proportion of APD subjects screened positive for depressive symptoms both at initial and subsequent patient visits (p < 0.001), which appeared to be more severe in the APD subgroups. UPDRS part III and disease duration weakly correlated with depressive symptoms. CONCLUSIONS: Our results suggest that the incidence and prevalence of depressive symptoms are higher in APD and appear also to be more severe than in PD. Depressive symptoms in APD are common and affect patients regardless of disease duration or motor severity.

High-voltage VIM Region Deep Brain Stimulation Mimicking Progressive Supranuclear Palsy.

BACKGROUND: Deep brain stimulation (DBS) for essential tremor (ET) can cause unwanted side effects. CASE REPORT: A patient with ET underwent unilateral dual-lead thalamic DBS. He later developed parkinsonism with atypical features and was diagnosed with progressive supranuclear palsy. During presentation for a second opinion, stimulation-induced side effects were suspected. Inactivation of DBS resolved atypical features and superimposed idiopathic Parkinson disease (PD) was diagnosed. DISCUSSION: This case illustrates the importance of recognizing the possible influence of stimulation-induced side effects and discusses when to utilize dual-lead DBS for ET and the co-occurrence of ET and PD.

Occurrence of Dysphagia Following Botulinum Toxin Injection in Parkinsonism-related Cervical Dystonia: A Retrospective Study.

BACKGROUND: The aim was to compare the occurrence of post-injection dysphagia in parkinsonism-related cervical dystonia (PRCD) versus cervical dystonia (CD) of other etiologies (non-PRCD). A secondary objective was to explore potential clinical differences between PRCD and non-PRCD and their respective responses to botulinum toxin (BoNT). METHODS: A cross-sectional chart review was carried out of patients treated for CD with Onabotulinumtoxin A at the University of Florida. We collected demographic information, dose of BoNT injected, patient-reported presence of dysphagia as a side effect, patient-perceived duration of benefit and efficacy according to the Clinical Global Impression Scale (CGIS). RESULTS: Of the 144 patients included, 24 patients were diagnosed with PRCD and 120 were diagnosed as non-PRCD. Data analysis showed no significant differences in number of weeks of benefit from BoNT (PRCD 9.1±3.7 versus non-PRCD 9.4±3.7 weeks, p = 0.830), BoNT dosage (PRCD 235.0±95.6 versus non-PRCD 263.7±101.3 units, p = 0.181), median CGIS score (median = 2 or "much improved" for both groups, p = 0.88), or the presence of dysphagia after BoNT (PRCD 17% versus non-PRCD 19 %, p = 0.753, n = 132). In a subgroup analysis of the non-PRCD group, patients who experienced dysphagia were older than those who did not (63.9±8.9 years versus 58.1±14.4 years, p = 0.02). DISCUSSION: Despite an increased baseline risk of dysphagia in patients with PRCD, BoNT appears to be equally safe and equally beneficial in PRCD and non-PRCD patients.

Benign tremulous Parkinsonism: a unique entity or another facet of Parkinson's disease?

Benign tremulous parkinsonism (BTP) is characterized by a prominent tremor that occurs both at rest and with action in conjunction with other mild features of parkinsonism. The progression of symptoms is typically slow and there is often a positive family history. Although BTP is included within the phenotypic spectrum of Parkinsonism its exact relationship with idiopathic Parkinson's disease remains unclear. Treatment of BTP is challenging especially considering the poor response to levodopa, therefore surgical therapies such as deep brain stimulation surgery are sought for treatment of these tremors. In this review, we will summarize the clinical features, diagnosis, neuropathology and treatment for BTP.