Rescue levodopa-carbidopa intestinal gel (LCIG) therapy in Parkinson's disease patients with suboptimal response to deep brain stimulation.

OBJECTIVE: To evaluate the effectiveness of levodopa-carbidopa intestinal gel (LCIG) as an add-on rescue therapy following deep brain stimulation (DBS) for treatment of motor fluctuations. BACKGROUND: Both DBS and LCIG are FDA-approved therapies for treatment of motor fluctuations in advanced PD. Few studies have examined dual therapy for refractory motor fluctuations and it is unknown what the effect on quality of life will be in advanced PD. METHODS: We conducted a retrospective study using a large database of all medical and surgical PD cases at the University of Florida. Six patients were identified with DBS who subsequently received rescue LCIG therapy. The clinical histories, indications for intervention and outcomes were reviewed. RESULTS: All patients were managed initially with DBS (bilateral STN DBS (n = 3), bilateral GPi DBS (n = 1), unilateral GPI DBS (n = 2)). Patients with well-placed (n = 3) and suboptimally placed DBS leads (n = 3) had significant reduction in their motor fluctuations with improvement in the off-medication time after rescue LCIG therapy. Improvement in quality of life scores (PDQ-39) was appreciated in four DBS patients following the addition of LCIG therapy. CONCLUSIONS: LCIG is a promising add-on rescue therapy for select patients with existing DBS devices. The LCIG may possibly reduce motor fluctuations and improve quality of life in advanced PD irrespective of the DBS target or the accuracy of lead placement. Dual therapy may also be ideal for patients who are considered high risk for additional DBS surgeries.

DBS Programming: An Evolving Approach for Patients with Parkinson's Disease.

Deep brain stimulation (DBS) surgery is a well-established therapy for control of motor symptoms in Parkinson's disease. Despite an appropriate targeting and an accurate placement of DBS lead, a thorough and efficient programming is critical for a successful clinical outcome. DBS programming is a time consuming and laborious manual process. The current approach involves use of general guidelines involving determination of the lead type, electrode configuration, impedance check, and battery check. However there are no validated and well-established programming protocols. In this review, we will discuss the current practice and the recent advances in DBS programming including the use of interleaving, fractionated current, directional steering of current, and the use of novel DBS pulses. These technological improvements are focused on achieving a more efficient control of clinical symptoms with the least possible side effects. Other promising advances include the introduction of computer guided programming which will likely impact the efficiency of programming for the clinicians and the possibility of remote Internet based programming which will improve access to DBS care for the patients.

Outcomes, management, and potential mechanisms of interleaving deep brain stimulation settings.

INTRODUCTION: DBS is a therapeutic option for patients with Parkinson disease (PD), tremor and dystonia. In patients who experience suboptimal clinical results with conventional programming (monopolar, double monopolar or bipolar settings), interleaved pulses can sometimes be used to provide differential therapeutic benefits with the possibility of fewer side effects. Interleaving allows a clinician to define two "programs" that automatically alternate. The goal of this paper is to 1) present clinical scenarios where DBS interleaving was used across two clinics to provide improved symptom control in three patients with suboptimal results from conventional programming; 2) address the potential mechanisms of interleaving; and 3) provide practical tips on the use of interleaving. METHODS: Three patients were formally compared for therapeutic benefit on interleaved and conventional parameter settings. RESULTS: Interleaving is most likely to be useful in two clinical scenarios: 1) different contacts are beneficial for specific symptoms, but each at a different stimulation amplitude; or 2) symptoms are resolved incompletely, and further voltage increase is limited by side effects. The factors underpinning the differences in outcomes with interleaving are unknown but may be highly dependent on specific symptoms and to electrode positioning. Interleaving is a relatively new programming platform and there is no data to demonstrate long-term benefits. CONCLUSIONS: Interleaving is a tool that may augment outcomes, and possibly obviate the need for surgical revisions, although in our experience across two large centers it has been effective for only a small number of patients.

Brittle Dyskinesia Following STN but not GPi Deep Brain Stimulation.

BACKGROUND: The aim was to describe the prevalence and characteristics of difficult to manage dyskinesia associated with subthalamic nucleus (STN) deep brain stimulation (DBS). A small subset of STN DBS patients experience troublesome dyskinesia despite optimal programming and medication adjustments. This group of patients has been referred to by some practitioners as brittle STN DBS-induced dyskinesia, drawing on comparisons with brittle diabetics experiencing severe blood sugar regulation issues and on a single description by McLellan in 1982. We sought to describe, and also to investigate how often the "brittle" phenomenon occurs in a relatively large DBS practice. METHODS: An Institutional Review Board-approved patient database was reviewed, and all STN and globus pallidus internus (GPi) DBS patients who had surgery at the University of Florida from July 2002 to July 2012 were extracted for analysis. RESULTS: There were 179 total STN DBS patients and, of those, four STN DBS (2.2%) cases were identified as having dyskinesia that could not be managed without the induction of an "off state," or by the precipitation of a severe dyskinesia despite vigorous stimulation and medication adjustments. Of 75 GPi DBS cases reviewed, none (0%) was identified as having brittle dyskinesia. One STN DBS patient was successfully rescued by bilateral GPi DBS. DISCUSSION: Understanding the potential risk factors for postoperative troublesome and brittle dyskinesia may have an impact on the initial surgical target selection (STN vs. GPI) in DBS therapy. Rescue GPi DBS therapy may be a viable treatment option, though more cases will be required to verify this observation.

Rescue GPi-DBS for a Stroke-associated Hemiballism in a Patient with STN-DBS.

BACKGROUND: Hemiballism/hemichorea commonly occurs as a result of a lesion in the subthalamic region. CASE REPORT: A 38-year-old male with Parkinson's disease developed intractable hemiballism in his left extremities due to a small lesion that was located adjacent to the right deep brain stimulation (DBS) lead, 10 months after bilateral subthalamic nucleus (STN)-DBS placement. He underwent a right globus pallidus internus (GPi)-DBS lead implantation. GPi-DBS satisfactorily addressed his hemiballism. DISCUSSION: This case offered a unique look at basal ganglia physiology in human hemiballism. GPi-DBS is a reasonable therapeutic option for the treatment of medication refractory hemiballism in the setting of Parkinson's disease.

Management of deep brain stimulator battery failure: battery estimators, charge density, and importance of clinical symptoms.

OBJECTIVE: We aimed in this investigation to study deep brain stimulation (DBS) battery drain with special attention directed toward patient symptoms prior to and following battery replacement. BACKGROUND: Previously our group developed web-based calculators and smart phone applications to estimate DBS battery life (http://mdc.mbi.ufl.edu/surgery/dbs-battery-estimator). METHODS: A cohort of 320 patients undergoing DBS battery replacement from 2002-2012 were included in an IRB approved study. Statistical analysis was performed using SPSS 20.0 (IBM, Armonk, NY). RESULTS: The mean charge density for treatment of Parkinson's disease was 7.2 µC/cm(2)/phase (SD = 3.82), for dystonia was 17.5 µC/cm(2)/phase (SD = 8.53), for essential tremor was 8.3 µC/cm(2)/phase (SD = 4.85), and for OCD was 18.0 µC/cm(2)/phase (SD = 4.35). There was a significant relationship between charge density and battery life (r = -.59, p<.001), as well as total power and battery life (r = -.64, p<.001). The UF estimator (r = .67, p<.001) and the Medtronic helpline (r = .74, p<.001) predictions of battery life were significantly positively associated with actual battery life. Battery status indicators on Soletra and Kinetra were poor predictors of battery life. In 38 cases, the symptoms improved following a battery change, suggesting that the neurostimulator was likely responsible for symptom worsening. For these cases, both the UF estimator and the Medtronic helpline were significantly correlated with battery life (r = .65 and r = .70, respectively, both p<.001). CONCLUSIONS: Battery estimations, charge density, total power and clinical symptoms were important factors. The observation of clinical worsening that was rescued following neurostimulator replacement reinforces the notion that changes in clinical symptoms can be associated with battery drain.

Mixed results for GPi-DBS in the treatment of cranio-facial and cranio-cervical dystonia symptoms.

The aim of the study is to determine clinical outcomes in patients undergoing Globus Pallidus Internus Deep Brain Stimulation (GPi-DBS) for cranio-facial and cranio-cervical dystonia (Meige) symptoms. A total of 6 patients seen between 2002 and 2010 with cranio-facial and cranio-cervical dystonia symptoms were identified from the University of Florida Institutional Review Board approved database. Patients were videotaped using a standardized protocol, and tapes were randomized and blindly reviewed by a movement disorders neurologist. The Unified Dystonia Rating Scale improved 31.6 ± 23.2% (range: 3.4-63.2%) at 6 months and 63.7 ± 35.3% (range: 6.3-100%) at 12 months. The Burke-Fahn-Marsden Dystonia Rating Scale improved 45.3 ± 29.5% (range: 4.7-75.0%) at 6 months and 61.8 ± 30.9% (range: 16.6-100%) at 12 months. One patient significantly had a very large improvement with little evidence of residual dystonia. Blepharospasm improved in all patients, whereas speech and swallowing did not improve in this cohort. Two patients improved with unilateral GPi-DBS, although one required a contralateral DBS later in the disease course. Two patients were managed with low frequency stimulation (<100 Hz). Two patients had less than 20% benefit. GPi-DBS for cranio-facial and cranio-cervical symptoms is an effective strategy to manage a subset of patients who remain unresponsive to optimized medical management. Unilateral stimulation may be an option for some patients, but it remains unclear whether response to single-sided stimulation will be sustainable. The mixed results of this GPi-DBS case series highlight the need for a careful re-examination of selection criteria, alternative brain targets, and possibly rescue leads for patients who are non-responders to the GPi target.

Do patient's get angrier following STN, GPi, and thalamic deep brain stimulation.

OBJECTIVE: The objective of the study was to examine whether deep brain stimulation (DBS) of the subthalamic nucleus (STN), the globus pallidus internus (GPi), and/or the ventralis intermedius thalamic nucleus (Vim) was associated with making patients angrier pre to post-surgical intervention. BACKGROUND: Secondary outcome analysis of the NIH COMPARE Parkinson's Disease DBS trial revealed that participants were angrier and had more mood and cognitive side effects following DBS. Additionally blinded on/off analysis did not change anger scores. The sample size was small but suggested that STN DBS may have been worse than GPi in provoking anger. We endeavored to examine this question utilizing a larger dataset (the UF INFORM database), and also we included a third surgical target (Vim), which has been utilized for a different disease, essential tremor. METHODS: Consecutive patients from the University of Florida Movement Disorders Center who were implanted with unilateral DBS for Parkinson's disease (STN or GPi) or essential tremor (Vim) were included. Patients originally implanted at outside institutions were excluded. Pre-operative and 4- to 6-month post-operative Visual Analog Mood Scale (VAMS) scores for all three groups were compared; additionally, pre-operative and 1- to 3-month scores were compared for STN and GPi patients. A linear regression model was utilized to analyze the relationship between the VAMS anger score and the independent variables of age, years with symptoms, Mini-Mental Status Examination (MMSE) score, handedness, ethnicity, gender, side of surgery, target of surgery, baseline Dementia Rating Scale (DRS) total score, baseline Beck Depression Index (BDI) score, micro- and macroelectrode passes, and years of education. Levodopa equivalent dosages and dopamine agonist use were analyzed for a potential impact on anger scores. RESULTS: A total of 322 unilateral DBS procedures were analyzed, with STN (n=195), Vim (n=71), and GPi (n=56) making up the cohort. An ANOVA was used to detect significant differences among the three targets in the changes pre- to post-operatively. Similar to the COMPARE dataset, at 4 months, the only subscore of VAMS to reveal a significant difference between the three targets was the angry subscore, with GPi revealing a mean (standard) change of 2.38 (9.53); STN, 4.82 (14.52); and Vim, -1.17 (11.51) (p=0.012). At 1-3 months post-operation, both STN and GPi groups were significantly angrier (p=0.004), but there was no significant difference between the two groups. However, GPi patients were significantly more confused as compared to STN patients (p=0.016). The linear regression model which sought independent explanatory variables revealed a relationship between the VAMS anger score and the surgical target and the disease duration. The mean changes for STN and GPi DBS pre- to post-operation were 11.67 (p=0.001) and 8.21 (p=0.022) units more than those with Vim, respectively. For every year added of disease duration, the VAMS anger score increased by 0.24 (p=0.022). For the GPi and STN groups, number of microelectrode passes was significantly associated with angry score changes (p=0.014), with the anger score increasing 2.29 units per microelectrode pass. Independent variables not associated with the VAMS anger score included the surgery side, handedness, gender, ethnicity, education, age at surgery, MMSE, DRS, and BDI scores. Although the STN group significantly decreased in LED when compared to GPi, there was no relationship to anger scores. Similarly, dopamine agonist use was not different between STN and GPi groups and did not correlate with the VAMS anger score changes. CONCLUSIONS: STN and GPi DBS for Parkinson's disease were associated with significantly higher anger scores pre- to post-DBS as compared to Vim for essential tremor. Anger score changes in STN and GPi patients seem to be associated with microelectrode passes, suggesting that it may be a lesional effect. PD patients with longer disease duration may be particularly susceptible, and this should be kept in mind when discussing the potential of DBS surgery for an individual patient. Essential tremor patients who on average have much longer disease durations did not get angrier. The changes in anger scores were not related to LED change or dopamine agonist use. Whether the induction of anger is disease-specific or target-specific is not currently known; however, our data would suggest that PD patients implanted in STN or GPi are at a potential risk. Finally, on closer inspection of the COMPARE DBS data, VAMS anger scores did not change on or off DBS, suggesting that anger changes may be more of a lesional effect rather than a stimulation induced one (Okun et al., 2009).

Prevalence of Twiddler's syndrome as a cause of deep brain stimulation hardware failure.

We reviewed our deep brain stimulation patient database to describe hardware complications which resulted from implantable pulse generator mobility, a phenomenon referred to as Twiddler's syndrome. A prospectively collected database of adverse events for all patients operated on at the University of Florida was queried searching for hardware malfunctions. Of 362 total leads implanted in 226 patients since 2002, there were 17 hardware malfunctions. Three of them were due to Twiddler's syndrome, representing 1.3% of patients (3 of 226 patients) and 1.4% of leads (5 of 362 leads). The subjects had characteristic presentations including re-emergence of symptoms, pain along the path of the hardware, abnormal impedances/current drain and radiographic signs of twisting/fracture. In all cases securing the implantable pulse generator within the chest pocket resolved the issue. Twiddler's syndrome in the population of movement disorder patients treated with deep brain stimulation is an uncommon but important adverse event. It possesses a characteristic presentation and with appropriate diagnostic evaluation it is treatable and future occurrences are preventable.

Differential response of dystonia and parkinsonism following globus pallidus internus deep brain stimulation in X-linked dystonia-parkinsonism (Lubag).

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

Cognition and mood in Parkinson's disease in subthalamic nucleus versus globus pallidus interna deep brain stimulation: the COMPARE trial.

OBJECTIVE: Our aim was to compare in a prospective blinded study the cognitive and mood effects of subthalamic nucleus (STN) vs. globus pallidus interna (GPi) deep brain stimulation (DBS) in Parkinson disease. METHODS: Fifty-two subjects were randomized to unilateral STN or GPi DBS. The co-primary outcome measures were the Visual Analog Mood Scale, and verbal fluency (semantic and letter) at 7 months post-DBS in the optimal setting compared to pre-DBS. At 7 months post-DBS, subjects were tested in four randomized/counterbalanced conditions (optimal, ventral, dorsal, and off DBS). RESULTS: Forty-five subjects (23 GPi, 22 STN) completed the protocol. The study revealed no difference between STN and GPi DBS in the change of co-primary mood and cognitive outcomes pre- to post-DBS in the optimal setting (Hotelling's T(2) test: p = 0.16 and 0.08 respectively). Subjects in both targets were less "happy", less "energetic" and more "confused" when stimulated ventrally. Comparison of the other 3 DBS conditions to pre-DBS showed a larger deterioration of letter verbal fluency in STN, especially when off DBS. There was no difference in UPDRS motor improvement between targets. INTERPRETATION: There were no significant differences in the co-primary outcome measures (mood and cognition) between STN and GPi in the optimal DBS state. Adverse mood effects occurred ventrally in both targets. A worsening of letter verbal fluency was seen in STN. The persistence of deterioration in verbal fluency in the off STN DBS state was suggestive of a surgical rather than a stimulation-induced effect. Similar motor improvement were observed with both STN and GPi DBS.