Parkinson Disease: Foote KD

Okun MS, Foote KD. · No affiliation provided · Arch Neurol. · Pubmed #15824249 links to  free full text

This publication has no abstract.

Hooper AK, Okun MS, Foote KD, Fernandez HH, Jacobson C, Zeilman P, Romrell J, Rodriguez RL. · University of Florida, Movement Disorders Center, Gainesville, FL 32601, USA. · Stereotact Funct Neurosurg. · Pubmed #18334856 No free full text.

Abstract: Deep brain stimulation (DBS) surgery has become the gold standard for treatment of select refractory cases of Parkinson disease and essential tremor. Despite the usefulness of DBS surgery in many cases, there remain situations where lesion therapy (subthalamotomy, pallidotomy or thalamotomy) may provide a reasonable alternative to DBS. We reviewed the University of Florida Institutional Review Board-approved database for movement disorders surgery and identified 286 DBS leads placed in 189 patients as well as 4 additional patients who had lesion therapy. In these 4 cases we reviewed the clinical presentations that resulted in a multidisciplinary team opting for lesion therapy over DBS. Lesion therapy represents a viable alternative and has several important advantages, including a decreased need for access to specialists and clinical follow-up, improved affordability, and a lower infection risk.

Sudhyadhom A, Bova FJ, Foote KD, Rosado CA, Kirsch-Darrow L, Okun MS. · Department of Neurology, McKnight Brain Institute, 100 South Newell Drive, Gainesville, FL 32610, USA. · Curr Neurol Neurosci Rep. · Pubmed #17618533 No free full text.

Abstract: The use of deep brain stimulation (DBS) has recently been expanding for the treatment of many neurologic disorders such as Parkinson disease, dystonia, essential tremor, Tourette's syndrome, cluster headache, epilepsy, depression, and obsessive compulsive disorder. The target structures for DBS include specific segregated territories within limbic, associative, or motor regions of very small subnuclei. In this review, we summarize current clinical techniques for DBS, the cognitive/mood/motor outcomes, and the relevant neuroanatomy with respect to functional territories within specific brain targets. Future development of new techniques and technology that may include a more direct visualization of "motor" territories within target structures may prove useful for avoiding side effects that may result from stimulation of associative and limbic regions. Alternatively, newer procedures may choose and specifically target non-motor territories for chronic electrical stimulation.

Okun MS, Fernandez HH, Rodriguez RL, Foote KD. · Department of Neurology, University of Florida Movement Disorders Center, McKnight Brain Institute, Gainesville, USA. · Geriatrics. · Pubmed #17489644 No free full text.

Abstract: Deep brain stimulation (DBS) can improve symptoms in well-selected patients with Parkinson's disease. Primary care physicians must take into account many important issues when considering referral for DBS. The Florida Surgical Questionnaire for PD (FLASQ-PD), a 5-section screening tool that can help primary care providers identify appropriate DBS candidates, can be filled out and scored by a general practitioner, advanced clinical nurse practitioner, physician assistant, or trained nurse. Potential candidates who score well on this questionnaire can be referred for presurgical multidisciplinary evaluation at an experienced DBS implanting center.

Skidmore FM, Rodriguez RL, Fernandez HH, Goodman WK, Foote KD, Okun MS. · Department of Neurology, McKnight Brain Institute, University of Florida College of Medicine in Gainesville, 32610, USA. · CNS Spectr. · Pubmed #16816792 links to  free full text

Abstract: The introduction of deep brain stimulation (DBS) as a treatment for medication-refractory essential tremor in the late 1980s revealed, for the first time, that "chronically" implanted brain hardware had the potential to modulate neurologic function with surprisingly low morbidity. Over time, the therapeutic promise of DBS has become evident in Parkinson's disease and dystonia. In some experienced centers, complex tremor disorders, such as posttraumatic Holmes tremor and the tremor of multiple sclerosis, are being increasingly targeted. More recently, other indications, including obsessive-compulsive disorder, Tourette's syndrome, major depression, and chronic pain, have been proposed. As the field has expanded, our knowledge about potential cognitive side effects of DBS has also expanded. This article reviews the current knowledge regarding the impact of stimulation of the subthalamic nucleus, globus pallidus internus, and ventralis intermedius nucleus of the thalamus on symptoms in essential tremor, Parkinson's disease, and dystonia. Also discussed are the emerging targets, what is known about the cognitive sequelae of DBS, and what has been learned about the complications and therapeutic failures.

Bruce BB, Foote KD, Rosenbek J, Sapienza C, Romrell J, Crucian G, Okun MS. · Department of Neurology, McKnight Brain Institute, Movement Disorders Center, University of Florida, Gainesville, FL 32610, USA. · Stereotact Funct Neurosurg. · Pubmed #15557767 No free full text.

Abstract: Patients may present with classical symptoms suggesting aphasia following thalamotomy (repetition, comprehension, fluency and naming abnormalities). They may also present with 'freezing of speech', and this symptom should not be considered as a speech disorder or a symptom of Parkinson's disease progression, without careful testing to rule out language deficits, particularly dysfluency. There are important issues related to all language complications of thalamotomy, including (1) the time course of problems following surgery, (2) the impact of preexistingspeech problems, (3) the importance of the size and location of lesions, (4) the potential circuits important in the pathogenesis of a thalamic language disturbance and (5) whether laterality makes a difference (left- versus right-sided thalamic lesions). As more centers switch from thalamotomy to deep brain stimulation, the issues regarding aphasia will need to be addressed.

Okun MS, Green J, Saben R, Gross R, Foote KD, Vitek JL. · University of Florida McKnight Brain Institute, Gainesville, Florida 32610, USA. · J Neurol Neurosurg Psychiatry. · Pubmed #14617726 links to  free full text

Abstract: The results of this study suggest that there are mood changes associated with deep brain stimulation of the subthalamic nucleus (STN) and the globus pallidus interna (GPi). Further, optimal placement of electrodes in both STN and GPi seems to result in overall improvement in mood and is associated with a lower incidence of adverse mood effects than stimulation outside the optimal site. Preliminary data from this study, however, suggest that slight movement dorsal or ventral to the site of optimal motor performance may be associated with more adverse changes in mood with STN stimulation than with GPi stimulation.

Okun MS, Foote KD. · Department of Neurology, University of Florida Movement Disorders Center, McKnight Brain Institute, PO Box 100236, Gainesville, FL 32610, USA. · Arch Neurol. · Pubmed #19506140 No free full text.

This publication has no abstract.

Plowman-Prine EK, Okun MS, Sapienza CM, Shrivastav R, Fernandez HH, Foote KD, Ellis C, Rodriguez AD, Burkhead LM, Rosenbek JC. · Department of Neurology, University of Florida, Gainesville, FL 32610, USA. · NeuroRehabilitation. · Pubmed #19339752 No free full text.

Abstract: The purpose of this study was to: (1) define perceptual speech characteristics of idiopathic Parkinson disease (IPD) across 35 speech dimensions adapted from Darley et al. [19] and grouped under six speech-sign clusters (respiration, phonation, resonance, articulation, prosody and rate); (2) examine the effects of levodopa on the 35 perceptual speech dimensions and speech-sign clusters; and (3) to compare the relative effectiveness of levodopa on global motor functioning vs. speech production. Sixteen patients with IPD read the 'Grandfather Passage' both 'on' and 'off' levodopa. Three blinded speech-language pathologists performed perceptual speech analyses using a seven-point scale. The diagnosis of IPD was made by a movement disorders fellowship trained neurologist who applied UK Brain bank criteria and administered the Unified Parkinson Disease Rating Scale. Concordant with previous studies, the results of this experiment indicated that IPD disrupted multiple speech production subsystems, with prosody being the most severely affected domain. The perceptual dimensions that were most severely affected included: (1) sound imprecision; (2) mono-loudness; (3) mono-pitch; (4) reduced stress and (5) harsh voice. No significant differences were obtained between medicated states ('on'/'off') for any of the 35 individual speech dimensions and speech-sign clusters. Global motor function significantly improved following dopaminergic medications.

Okun MS, Fernandez HH, Wu SS, Kirsch-Darrow L, Bowers D, Bova F, Suelter M, Jacobson CE, Wang X, Gordon CW, Zeilman P, Romrell J, Martin P, Ward H, Rodriguez RL, Foote KD. · Movement Disorders Center, University of Florida, McKnight Brain Institute, College of Medicine, Department of Neurology, Gainesville, FL 32611, USA. · Ann Neurol. · Pubmed #19288469 No free full text.

Abstract: 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.

Mann JM, Foote KD, Garvan CW, Fernandez HH, Jacobson CE, Rodriguez RL, Haq IU, Siddiqui MS, Malaty IA, Morishita T, Hass CJ, Okun MS. · Department of Neurology, University of Florida College of Medicine/Shands Hospital, Movement Disorders Center, McKnight Brain Institute, Gainesville, Florida 32610, USA. · J Neurol Neurosurg Psychiatry. · Pubmed #19237386 No free full text.

Abstract: OBJECTIVE: To determine how intraoperative microelectrode recordings (MER) and intraoperative lead placement acutely influence tremor, rigidity, and bradykinesia. Secondarily, to evaluate whether the longevity of the MER and lead placement effects were influenced by target location (subthalamic nucleus (STN) or globus pallidus interna (GPi)). BACKGROUND: Currently most groups who perform deep brain stimulation (DBS) for Parkinson disease (PD) use MER, as well as macrostimulation (test stimulation), to refine DBS lead position. Following MER and/or test stimulation, however, there may be a resultant "collision/implantation" or "microlesion" effect, thought to result from disruption of cells and/or fibres within the penetrated region. These effects have not been carefully quantified. METHODS: 47 consecutive patients with PD undergoing unilateral DBS for PD (STN or GPi DBS) were evaluated. Motor function was measured at six time points with a modified motor Unified Parkinson Disease Rating Scale (UPDRS): (1) preoperatively, (2) immediately after MER, (3) immediately after lead implantation/collision, (4) 4 months following surgery-off medications, on DBS (12 h medication washout), (5) 6 months postoperatively-off medication and off DBS (12 h washout) and (6) 6 months-on medication and off DBS (12 h washout). RESULTS: Significant improvements in motor scores (p<0.05) (tremor, rigidity, bradykinesia) were observed as a result of MER and lead placement. The improvements were similar in magnitude to what was observed at 4 and 6 months post-DBS following programming and medication optimisation. When washed out (medications and DBS) for 12 h, UPDRS motor scores were still improved compared with preoperative testing. There was a larger improvement in STN compared with GPi following MER (p<0.05) and a trend for significance following lead placement (p<0.08) but long term outcome was similar. CONCLUSION: This study demonstrated significant acute intraoperative penetration effects resulting from MER and lead placement/collision in PD. Clinicians rating patients in the operating suite should be aware of these effects, and should consider pre- and post-lead placement rating scales prior to activating DBS. The collision/implantation effects were greater intraoperatively with STN compared with GPi, and with greater disease duration there was a larger effect.

Hooper AK, Okun MS, Foote KD, Haq IU, Fernandez HH, Hegland D, Robicsek SA. · University of Florida Movement Disorders Center, Gainesville, Fla. 32601, USA. · Stereotact Funct Neurosurg. · Pubmed #19039260 No free full text.

Abstract: BACKGROUND/AIMS: During the placement of electrodes for deep brain stimulation (DBS), patients are commonly in a seated position, awake, and spontaneously breathing. Air may be entrained through bone or dural veins causing venous air emboli (VAE) and this phenomenon can result in significant hemodynamic changes. Although VAEs have been described in many types of neurosurgical procedures, their incidence during DBS surgery is unknown. METHODS: Following approval from the Institutional Review Board, the University of Florida Movement Disorders Center database comprising 286 DBS leads placed since 2002 was reviewed. Intraoperative cough, which has been associated with VAE, as well as hemodynamic instability were the focus of the review. Additionally, a prospective evaluation of the incidence of VAE using precordial Doppler ultrasound was undertaken over a 3-month period (June 2007-August 2007). RESULTS: The retrospective review revealed a 3.2% incidence of cough per lead. Prospective monitoring in 21 consecutive patients with 22 leads yielded the detection of 1 VAE, and an incidence of 4.5% per lead. CONCLUSION: VAEs are rare but potentially serious complications of DBS surgery unless recognized. Patient positioning and the occurrence of cough are two important predictors to consider in VAE. Precordial Doppler is a safe, non-invasive monitor that can be used in the early detection of VAE in these procedures.

Ellis TM, Foote KD, Fernandez HH, Sudhyadhom A, Rodriguez RL, Zeilman P, Jacobson CE, Okun MS. · Department of Neurology, Movement Disorders Center, University of Florida, McKnight Brain Institute, Gainesville, Florida, USA. · Neurosurgery. · Pubmed #18981887 No free full text.

Abstract: OBJECTIVE: To examine a case series of reoperations for deep brain stimulation (DBS) leads in which clinical scenarios revealed suboptimal outcome from a previous operation. Suboptimally placed DBS leads are one potential reason for unsatisfactory results after surgery for Parkinson's disease (PD), essential tremor (ET), or dystonia. In a previous study of patients who experienced suboptimal results, 19 of 41 patients had misplaced leads. Similarly, another report commented that lead placement beyond a 2- to 3-mm window resulted in inadequate clinical benefit, and, in 1 patient, revision improved outcome. The goal of the current study was to perform an unblinded retrospective chart review of DBS patients with unsatisfactory outcomes who presented for reoperation. METHODS: Patients who had DBS lead replacements after reoperation were assessed with the use of a retrospective review of an institutional review board-approved movement disorders database. Cases of reoperation for suboptimal clinical benefit were included, and cases of replacement of DBS leads caused by infection or hardware malfunction were excluded. Data points studied included age, disease duration, diagnosis, motor outcomes (the Unified Parkinson Disease Rating Scale III in PD, the Tremor Rating Scale in ET, and the Unified Dystonia Rating Scale in dystonia), quality of life (Parkinson's Disease Questionnaire-39 in PD), and the Clinician Global Impression scale. The data from before and after reoperation were examined to determine the estimated impact of repeat surgery. RESULTS: There were 11 patients with PD, 7 with ET, and 4 with dystonia. The average age of the PD group was 52 years, the disease duration was 10 years, and the average vector distance of the location of the active DBS contact was adjusted 5.5 mm. Six patients (54%) with PD had preoperative off medication on DBS Unified Parkinson Disease Rating Scale scores that could be compared with postoperative off medication on DBS scores. The average improvement across this group of patients was 24.4%. The Parkinson's Disease Questionnaire-39 improved in the areas of mobility (28.18), activities of daily living (14.77), emotion (14.72), stigma (17.61), and discomfort (17.42). The average age of the ET group was 66 years, the disease duration was 29 years, and the average adjusted distance was 6.1 mm. Five ET patients (83.3%) in the cohort had a prereplacement on DBS Tremor Rating Scale and a postreplacement on DBS Tremor Rating Scale with the average improvement of 60.4%. The average age of the dystonia group was 39 years, the average disease duration was 7 years, and the average adjusted lead distance was 6.7 mm. Three patients (75%) with dystonia had prereplacement on DBS Unified Dystonia Rating Scale and postreplacement on DBS Unified Dystonia Rating Scale scores. Across these 3 dystonia patients, the improvement was 12.8%. Clinician Global Impression scale scores (1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; 7, very much worse) after replacement revealed the following results in patients with PD: 1, 7 patients; 2, 3 patients; 3, 1 patient); with ET (1, 4 patients; 2, 3 patients); and with dystonia (1, 1 patient; 2, 2 patients; 3, 1 patient). The latency from original lead placement to reoperation (repositioning/revision) overall was 28.9 months (range, 2-104 mo); however, in leads referred from outside institutions (n = 11 patients), this latency was 48 months (range, 12-104 mo) compared with leads implanted by surgeons from the University of Florida (n = 11 patients), which was 9.7 months (range, 2-19 mo). The most common clinical history was failure to achieve a perceived outcome; however, history of an asymmetric benefit was present in 4 (18.2%) of 22 patients, and lead migration was present in 3 (13.6%) of 22 patients. CONCLUSION: There are many potential causes of suboptimal benefit after DBS. Timely identification of suboptimal lead placements followed by reoperation and repositioning/replacement in a subset of patients may improve outcomes.

Zahodne LB, Okun MS, Foote KD, Fernandez HH, Rodriguez RL, Kirsch-Darrow L, Bowers D. · Clinical and Health Psychology, University of Florida, Gainesville, FL 32610-0165, USA. · Clin Neuropsychol. · Pubmed #18821180 No free full text.

Abstract: Conflicting research suggests that deep brain stimulation surgery, an effective treatment for medication-refractory Parkinson's disease (PD), may lead to selective cognitive declines. We compared cognitive performance of 22 PD patients who underwent unilateral DBS to the GPi or STN to that of 19 PD controls at baseline and 12 months. We hypothesized that compared to PD controls, DBS patients would decline on tasks involving dorsolateral prefrontal cortex circuitry (letter fluency, semantic fluency, and Digit Span Backward) but not on other tasks (Vocabulary, Boston Naming Test), and that a greater proportion of DBS patients would fall below Reliable Change Indexes (RCIs). Compared to controls, DBS patients declined only on the fluency tasks. Analyses classified 50% of DBS patients as decliners, compared to 11% of controls. Decliners experienced less motor improvement than non-decliners. The present study adds to the literature through its hypothesis-driven method of task selection, inclusion of a disease control group, longer-term follow-up and use of Reliable Change. Our findings provide evidence that unilateral DBS surgery is associated with verbal fluency declines and indicate that while these changes may not be systematically related to age, cognitive or depression status at baseline, semantic fluency declines may be more common after left-sided surgery. Finally, use of Reliable Change highlights the impact of individual variability and indicates that fluency declines likely reflect significant changes in a subset of patients who demonstrate a poorer surgical outcome overall.

Crucian GP, Heilman K, Junco E, Maraist M, Owens WE, Foote KD, Okun MS. · Department of Neurology, University of Florida, Gainesville, FL, USA. · Neurocase. · Pubmed #17786774 No free full text.

Abstract: Patients with Parkinson's disease (PD) have dysfunction in frontal-basal ganglia networks. Many of these patients have difficulties with mental processing speed, response inhibition, and shifting between different conceptual sets, suggesting frontal-executive dysfunction. Since frontal lobe dysfunction is associated with disengagement deficits such as perseveration and echopraxia we wanted to learn if patients with PD demonstrated defective response inhibition. Using a brief clinical test called the crossed response inhibition (CRI) task we assessed patients with PD (n = 17), and a group of age matched controls (n = 30). In addition to the CRI, subjects were asked to perform two tests of frontal lobe function: verbal word fluency, anti-saccade test. In the CRI task, patients are instructed to lift the hand opposite to the one the examiner touches. An error is scored whenever the patient makes any movement of the touched (ipsilateral) extremity after stimulation (from shoulder to fingers). The task is performed with the patient's eyes closed. Whereas no differences were found between PD and control subjects on the verbal fluency or anti-saccade tasks, PD patients made significantly more errors on the CRI than did controls. Subsequent analyses found no difference in performance associated with the laterality (asymmetry) of PD symptoms or signs. In addition, there was no difference between PD patients' CRI performance when they were "on" their dopaminergic medications versus when they were "off" these medicines. Based on these findings, it appears that PD is associated with a disengagement-inhibition defect that is not induced by a dopaminergic deficit. In addition, the CRI task might be a brief sensitive bedside task for evaluating frontal dysfunction in PD.

Johnson J, Paisán-Ruíz C, Lopez G, Crews C, Britton A, Malkani R, Evans EW, McInerney-Leo A, Jain S, Nussbaum RL, Foote KD, Mandel RJ, Crawley A, Reimsnider S, Fernandez HH, Okun MS, Gwinn-Hardy K, Singleton AB. · Laboratory of Neurogenetics, National Institute on Aging, Porter Neuroscience Research Center, National Institutes of Health, Bethesda, MD 20892, USA. · Neurodegener Dis. · Pubmed #17622782 No free full text.

Abstract: BACKGROUND: Recently, mutations in LRRK2 encoding the protein dardarin have been linked to an autosomal dominant form of parkinsonism. OBJECTIVE: To identify mutations causing Parkinson's disease (PD) in a cohort of North Americans with familial PD. METHODS: We sequenced exons 1-51 of LRRK2 in 79 unrelated North American PD patients reporting a family history of the disease. RESULTS: One patient had a missense mutation (Thr2356Ile) while two others had the common Gly2019Ser mutation. In addition, 1 patient had a 4-bp deletion in close proximity to the exon 19 splice donor (IVS20+4delGTAA) that in vitro abrogates normal splicing. CONCLUSIONS: Our observations in the 79 North American patients indicate that mutations in LRRK2 are associated with approximately 5% of PD cases with a positive family history. The results also show that G2019S represents approximately half of the LRRK2 mutations in United States PD cases with a family history of the disease. We have identified two novel mutations in LRRK2.

Okun MS, Rodriguez RL, Mikos A, Miller K, Kellison I, Kirsch-Darrow L, Wint DP, Springer U, Fernandez HH, Foote KD, Crucian G, Bowers D. · Department of Neurology, Movement Disorders Center, University of Florida, Gainesville, FL 32610, USA. · Clin Neuropsychol. · Pubmed #17366283 No free full text.

Abstract: Deep brain stimulation (DBS) now plays an important role in the treatment of Parkinson's disease, tremor, and dystonia. DBS may also have a role in the treatment of other disorders such as obsessive-compulsive disorder, Tourette's syndrome, and depression. The neuropsychologist plays a crucial role in patient selection, follow-up, and management of intra-operative and post-operative effects (Pillon, 2002; Saint-Cyr & Trepanier, 2000). There is now emerging evidence that DBS can induce mood, cognitive, and behavioral changes. These changes can have dramatic effects on patient outcome. There have been methodological problems with many of the studies of DBS on mood, cognition, and behavior. The neuropsychologist needs to be aware of these issues when following up patients, and constructing future studies. Additionally, this article will review all aspects of the DBS procedure that can result in mood, cognitive, and behavioral effects and what role(s) the neuropsychologist should play in screening and follow-up.

Scholz S, Mandel RJ, Fernandez HH, Foote KD, Rodriguez RL, Barton E, Munson S, Singleton A, Okun MS. · Molecular Genetics Unit, National Institute on Aging, National Institutes of Health, Bethsda, MD, USA. · Eur J Neurol. · Pubmed #17116211 No free full text.

Abstract: In the last decade, major breakthroughs in the understanding of genetic contributions to Parkinson's disease (PD) have been achieved. Recently, mutations in LRRK2, encoding dardarin, have been found to be responsible for an autosomal dominant parkinsonism (OMIM 607060). We screened 311 subjects (cases: n = 202, controls: n = 109) for the three previously reported LRRK2 mutations. Our investigation revealed a sporadic case of PD with a heterozygous mutation G2019S (c.6055G>A). Here, we present the clinical phenotype of this patient and discuss the implications of genetic testing for the G2019S mutation in patients with sporadic PD.

Fung HC, Scholz S, Matarin M, Simón-Sánchez J, Hernandez D, Britton A, Gibbs JR, Langefeld C, Stiegert ML, Schymick J, Okun MS, Mandel RJ, Fernandez HH, Foote KD, Rodríguez RL, Peckham E, De Vrieze FW, Gwinn-Hardy K, Hardy JA, Singleton A. · Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. · Lancet Neurol. · Pubmed #17052657 No free full text.

Abstract: BACKGROUND: Several genes underlying rare monogenic forms of Parkinson's disease have been identified over the past decade. Despite evidence for a role for genetics in sporadic Parkinson's disease, few common genetic variants have been unequivocally linked to this disorder. We sought to identify any common genetic variability exerting a large effect in risk for Parkinson's disease in a population cohort and to produce publicly available genome-wide genotype data that can be openly mined by interested researchers and readily augmented by genotyping of additional repository subjects. METHODS: We did genome-wide, single-nucleotide-polymorphism (SNP) genotyping of publicly available samples from a cohort of Parkinson's disease patients (n=267) and neurologically normal controls (n=270). More than 408,000 unique SNPs were used from the Illumina Infinium I and HumanHap300 assays. FINDINGS: We have produced around 220 million genotypes in 537 participants. This raw genotype data has been and as such is the first publicly accessible high-density SNP data outside of the International HapMap Project. We also provide here the results of genotype and allele association tests. INTERPRETATION: We generated publicly available genotype data for Parkinson's disease patients and controls so that these data can be mined and augmented by other researchers to identify common genetic variability that results in minor and moderate risk for disease.

Graff-Radford J, Foote KD, Rodriguez RL, Fernandez HH, Hauser RA, Sudhyadhom A, Rosado CA, Sanchez JC, Okun MS. · Department of Neurology, University of Florida Movement Disorders Center, University of Florida, Gainesville, FL, USA. · Arch Neurol. · Pubmed #16908749 links to  free full text

Abstract: BACKGROUND: Dyskinesias that occur during a period without medication after embryonic cell transplantation have been commonly reported in double-blind trials; however, to date, they have not been reported in the few patients who participated in open-label pilot studies. DESIGN: Single case observation with preoperative and postoperative data, and intraoperative single-cell physiology. PATIENT: A patient who underwent embryonic cell transplantation in 1993 as part of the University of South Florida open-label study was referred for evaluation of intractable dyskinesia of the right arm. The dyskinesia was present during evaluation of the patient after a 12-hour period without medication and was clinically disabling. It was manifested as a severe groping movement of the hand. Intraoperative physiologic evaluation revealed decreased firing rates in the internal segment of the globus pallidus. RESULTS: Deep brain stimulation of the internal segment of the globus pallidus resulted in resolution of the dyskinesia. CONCLUSION: This case highlights the delayed development of runaway dyskinesia after a period without medication as an important potential long-term adverse effect of embryonic cell transplantation in patients with Parkinson disease.

Okun MS, Tagliati M, Pourfar M, Fernandez HH, Rodriguez RL, Alterman RL, Foote KD. · Department of Neurology, University of Florida, Movement Disorders Center, McKnight Brain Institute, Gainesville, FL 32610, USA. · Arch Neurol. · Pubmed #15956104 No free full text.

Abstract: BACKGROUND: Since the Food and Drug Administration approved DBS, there has been a surge in the number of centers providing the procedure. There is currently no consensus regarding appropriate screening procedures, necessary training of individuals providing the therapy, the need for an interdisciplinary team, or guidelines for the management of complications. An increasing number of patients come to experienced DBS centers after unsatisfactory results from DBS surgery. An attempt is made herein to evaluate the reasons for DBS failure in a series of such patients and to make recommendations to improve overall DBS outcomes. OBJECTIVE: To improve outcomes of deep brain stimulation (DBS) surgery by analyzing a series of patients who had suboptimal results from DBS. METHODS: Forty-one consecutive patients complaining of suboptimal results from DBS surgery came to the University of Florida Movement Disorders Center, or to Beth Israel Movement Disorders Center, over a 24-month period. All patients had undergone implantation of DBS devices at outside medical centers. Each patient was evaluated by a movement disorders neurologist, and the complete medical record was reviewed. The DBS device for each patient was interrogated for adverse effects and programmed for maximal benefit. Postoperative imaging studies were evaluated whenever possible. RESULTS: The average age of patients was 63.4 years (range, 49-84 years). The indication for surgery (by record review) included 9 patients with essential tremor, 31 with Parkinson disease, and 1 with dystonia. The diagnoses after referral examination included 5 with essential tremor, 26 with Parkinson disease, 3 with Parkinson disease and dementia, 1 with Parkinson disease and essential tremor, 1 with corticobasal degeneration, 1 with dystonia, 2 with multiple system atrophy, 1 with progressive supranuclear palsy, and 1 with myoclonus. Issues related to inadequate preoperative screening: Thirty (73%) of 41 patients saw a movement disorders specialist prior to DBS implantation. Fourteen (34%) patients had neuropsychological testing, 4 (10%) did not have testing, and in 23 cases (56%), it could not be determined whether or not they were tested. Five (12%) of 41 patients had an inadequate medication trial, and 5 patients (12%) had significant cognitive dysfunction prior to their DBS implantation. Surgical and device-related complications: Nineteen (46%) of 41 patients had suboptimally placed electrodes. Seven electrodes (17%) were replaced with improvement. Three patients' devices had failed due to end of battery life, 2 had infections, and 1 had a fractured lead. Programming and medication adjustments: Seven (17%) of 41 patients had no or poor access to programming. Two patients (5%) moved, and 2 physicians (5%) moved, creating issues with access to care. Eight patients (20%) required local follow-up (they flew to remote centers to have the surgery performed). Fifteen patients (37%) were inadequately programmed and improved significantly with reprogramming. Six patients (15%) experienced partial improvement with reprogramming, and 21 patients (51%) failed to improve despite extensive reprogramming. Thirty patients (73%) benefited from medication changes, 4 (10%) had antidepressants added to their regimens, and 1 (2%) had donepezil hydrochloride added. One patient's carbidopa/levodopa (2%) was restarted after complete discontinuation. Outcomes: With the various postoperative interventions described, 21 (51%) of 41 patients had good outcomes, 6 (15%) had modest clinical improvement, and 14 (34%) did not improve. CONCLUSIONS: With appropriate intervention, 51% of patients who complained of "failed" DBS procedures ultimately had good outcomes. Thirty-four percent of these patients had persistently poor outcomes despite maximal intervention. This case series provides important insights into reasons for "DBS failure" and proposes strategies to manage patients with DBS more effectively.

Rogaeva E, Johnson J, Lang AE, Gulick C, Gwinn-Hardy K, Kawarai T, Sato C, Morgan A, Werner J, Nussbaum R, Petit A, Okun MS, McInerney A, Mandel R, Groen JL, Fernandez HH, Postuma R, Foote KD, Salehi-Rad S, Liang Y, Reimsnider S, Tandon A, Hardy J, St George-Hyslop P, Singleton AB. · Centre for Research in Neurodegenerative Diseases and Division of Neurology, Department of Medicine, Toronto Western Hospital, University of Toronto, Ontario, Canada. · Arch Neurol. · Pubmed #15596610 links to  free full text

Abstract: BACKGROUND: Mutations in the PTEN-induced kinase (PINK1) gene located within the PARK6 locus on chromosome 1p35-p36 have recently been identified in patients with recessive early-onset Parkinson disease. OBJECTIVE: To assess the prevalence of PINK1 mutations within a series of early- and late-onset Parkinson disease patients living in North America. DESIGN: All coding exons of the PINK1 gene were sequenced in a series of 289 Parkinson disease patients and 80 neurologically normal control subjects; the mutation frequencies were evaluated in additional controls (100 white and 50 Filipino subjects). RESULTS: We identified 27 variants, including the first reported compound heterozygous mutation (Glu240Lys and Leu489Pro) and a homozygous Leu347Pro mutation in 2 unrelated young-onset Parkinson disease patients. CONCLUSION: Autosomal recessive mutations in PINK1 are a rare cause of young-onset Parkinson disease.

Okun MS, Foote KD. · Department of Neurology, Movement Disorders Center, University of Florida McKnight Brain Institute, Gainesville, Florida 32610, USA. · Neurologist. · Pubmed #15335446 No free full text.

Abstract: Patients considering deep brain stimulation (DBS) for Parkinson disease (PD) may be exposed to videotapes, media coverage, or literature which show dramatic improvements in PD symptoms after surgical intervention. Based on this information, patients may seek a medical center with expertise in DBS for an evaluation and assessment of their candidacy for surgery. If patients receive a device, they may be disappointed or despondent following surgery because of a failure to achieve a preconceived and unrealistic outcome. In order to address the important issue of patient misconception of potential outcome, we have introduced a simple mnemonic device. The device may be taught and then reviewed with patients and families both before and after surgery. Use of this mnemonic device may allow the patient and family the time necessary to alter the perception of perceived benefit. This education can help to ensure that outcome meets or exceeds expectation, and as a result they become a more satisfied and easy-to-manage DBS patient.

Okun MS, Fernandez HH, Pedraza O, Misra M, Lyons KE, Pahwa R, Tarsy D, Scollins L, Corapi K, Friehs GM, Grace J, Romrell J, Foote KD. · Department of Neurology, University of Florida McKnight Brain Institute, 100 S. Newell Dr., 3rd fl., rm. L3-100, PO Box 100236, Gainesville, FL 32610, USA. · Neurology. · Pubmed #15249630 No free full text.

Abstract: As there is currently no standardized assessment tool for evaluating Parkinson disease (PD) patients for deep brain stimulation (DBS), the authors developed the Florida Surgical Questionnaire for Parkinson Disease (FLASQ-PD). Part I of the study was a retrospective analysis of 174 patients presenting for a surgical screening. Part II was a multicenter study to assess the correlation of FLASQ-PD scores. The results of this study suggest that the FLASQ-PD may be a useful triage tool for screening PD patients for DBS surgery.