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The selection of patients with Tourette syndrome (TS) for deep brain stimulation (DBS) surgery rests on 5 fundamental pillars. However, the operationalization of the multidisciplinary screening process to evaluate these pillars remains highly diverse, especially across sites. High tic severity and tic-related impact on quality of life (first 2 pillars) require confirmation from objective, validated measures, but malignant features of TS should per se suffice to fulfill this pillar. Failure of behavioral and pharmacologic therapies (third pillar) should be assessed taking into account refractoriness through objective and subjective measures supporting lack of efficacy of all interventions of proven efficacy, as well as true lack of tolerability, adherence, or access. Educational interventions and use of remote delivery formats (for behavioral therapies) play a role in preventing misjudgment of treatment failure. Stability of comorbid psychiatric disorders for 6 months (fourth pillar) is needed to confirm the predominant impact of tics on quality of life, to prevent pseudo-refractoriness, and to maximize the future DBS response. The 18-year age limit (fifth pillar) is currently under reappraisal, considering the potential impact of severe tics in adolescence and the predictive effect of tic severity in childhood on tic severity when transitioning into adulthood. Future advances should aim at a consensus-based definition of failure of specific, noninvasive treatment strategies for tics and of the minimum clinical observation period before considering DBS treatment, the stability of behavioral comorbidities, and the use of a prospective international registry data to identify predictors of positive response to DBS, especially in younger patients.

ObjectiveTo empirically test whether apathy and impulse control disorders (ICDs) represent independent, opposite ends of a motivational spectrum.MethodsIn this single-center, cross-sectional study, we obtained retrospective demographics and clinical data for 887 patients with idiopathic Parkinson disease (PD) seen at a tertiary care center. Mood and motivation disturbances were classified using recommended cutoff scores from self-reported measures of apathy, ICD, anxiety, and depression.ResultsPrevalence rates included 29.0% of patients with PD with depression, 40.7% with anxiety, 41.3% with apathy, 27.6% with ICDs, and 17.0% with both apathy and ICD. The majority (61.6%) of people reporting clinically significant ICDs also reported clinically significant apathy, and more than a third of patients with apathy (41.3%) also reported elevated ICD. Anxiety and depression were highest in patients with both apathy and ≥1 ICDs. Dopamine agonist use was higher in people with only ICD compared to people with only apathy. Mood significantly interacted with demographic variables to predict motivational disturbances.ConclusionsMotivational disturbances are common comorbid conditions in patients with PD. In addition, these complex behavioral syndromes interact with mood in clinically important ways that may influence the design of future clinical trials and the development of novel therapies. This study challenges the concept of apathy and ICD in PD as opposite ends of a spectrum.

Objective: To explore longitudinal changes in brain activity in patients with Parkinson disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP) using task-based functional MRI (fMRI). Methods: A total of 112 individuals were scanned 1 year apart while performing a unimanual grip force task: 46 PD, 13 MSA, 19 PSP, and 34 healthy controls. The outcome measure was percent signal change in prespecified regions of interest: putamen, primary motor cortex (M1), supplementary motor area (SMA), and superior motor regions of the cerebellum (lobules V–VI). Results: Patients with PD showed a decline in functional activity over the course of 1 year in the putamen and M1 compared to controls. Changes after 1 year in MSA were exclusively extrastriatal, and included a reduction in functional activity in M1, SMA, and superior cerebellum. In PSP, all regions of interest were less active at 1 year compared to baseline. The functional activity of these regions did not change in the control group. Conclusions: We provide evidence using task-based fMRI for cortical and striatal functional deterioration in PD over a 1-year period of time. Results also describe more widespread and unique patterns of functional changes in MSA and PSP compared to PD, suggesting distinct rates of disease progression in parkinsonian disorders that may assist in future clinical studies testing the potential efficacy of disease-modifying therapies.

The success of device-based research in the clinical neurosciences has overshadowed a critical and emerging problem in the biomedical research environment in the United States. Neuroprosthetic devices, such as deep brain stimulation (DBS), have been shown in humans to be promising technologies for scientific exploration of neural pathways and as powerful treatments. Large device companies have, over the past several decades, funded and developed major research programs. However, both the structure of clinical trial funding and the current regulation of device research threaten investigator-initiated efforts in neurologic disorders. The current atmosphere dissuades clinical investigators from pursuing formal and prospective research with novel devices or novel indications. We review our experience in conducting a federally funded, investigator-initiated, device-based clinical trial that utilized DBS for thalamic pain syndrome. We also explore barriers that clinical investigators face in conducting device-based clinical trials, particularly in early-stage studies or small disease populations. We discuss 5 specific areas for potential reform and integration: (1) alternative pathways for device approval; (2) eliminating right of reference requirements; (3) combining federal grant awards with regulatory approval; (4) consolidation of oversight for human subjects research; and (5) private insurance coverage for clinical trials. Careful reformulation of regulatory policy and funding mechanisms is critical for expanding investigator-initiated device research, which has great potential to benefit science, industry, and, most importantly, patients.

Objective: To explore how amantadine transitioned from an anti-flu drug to antiparkinsonian agent. Methods: A review of the historical literature on the use of amantadine from 1966 to the present was performed. Results: Amantadine was originally introduced and utilized as an antiviral medication. A single patient noticed relief in her Parkinson disease (PD) symptoms after taking amantadine for a flu infection, and this observation sparked an interest, and several important studies that eventually led to a new drug indication. Conclusion: Amantadine has over the years fallen out of favor as a drug to address influenza infection; however, it has become part of the arsenal utilized for early symptomatic treatment of PD, as well an option for treating dyskinesia.

Background: This evidence-based guideline is an update of the 2005 American Academy of Neurology practice parameter on the treatment of essential tremor (ET). Methods: A literature review using MEDLINE, EMBASE, Science Citation Index, and CINAHL was performed to identify clinical trials in patients with ET published between 2004 and April 2010. Results and Recommendations: Conclusions and recommendations for the use of propranolol, primidone (Level A, established as effective); alprazolam, atenolol, gabapentin (monotherapy), sotalol, topiramate (Level B, probably effective); nadolol, nimodipine, clonazepam, botulinum toxin A, deep brain stimulation, thalamotomy (Level C, possibly effective); and gamma knife thalamotomy (Level U, insufficient evidence) are unchanged from the previous guideline. Changes to conclusions and recommendations from the previous guideline include the following: 1) levetiracetam and 3,4-diaminopyridine probably do not reduce limb tremor in ET and should not be considered (Level B); 2) flunarizine possibly has no effect in treating limb tremor in ET and may not be considered (Level C); and 3) there is insufficient evidence to support or refute the use of pregabalin, zonisamide, or clozapine as treatment for ET (Level U). Neurology ® 2011;77:1752–1755

Objective: Dysphagia is the main cause of aspiration pneumonia and death in Parkinson disease (PD) with no established restorative behavioral treatment to date. Reduced swallow safety may be related to decreased elevation and excursion of the hyolaryngeal complex. Increased submental muscle force generation has been associated with expiratory muscle strength training (EMST) and subsequent increases in hyolaryngeal complex movement provide a strong rationale for its use as a dysphagia treatment. The current study’s objective was to test the treatment outcome of a 4-week device-driven EMST program on swallow safety and define the physiologic mechanisms through measures of swallow timing and hyoid displacement. Methods: This was a randomized, blinded, sham-controlled EMST trial performed at an academic center. Sixty participants with PD completed EMST, 4 weeks, 5 days per week, for 20 minutes per day, using a calibrated or sham, handheld device. Measures of swallow function including judgments of swallow safety (penetration–aspiration [PA] scale scores), swallow timing, and hyoid movement were made from videofluoroscopic images. Results: No pretreatment group differences existed. The active treatment (EMST) group demonstrated improved swallow safety compared to the sham group as evidenced by improved PA scores. The EMST group demonstrated improvement of hyolaryngeal function during swallowing, findings not evident for the sham group. Conclusions: EMST may be a restorative treatment for dysphagia in those with PD. The mechanism may be explained by improved hyolaryngeal complex movement. Classification of evidence: This intervention study provides Class I evidence that swallow safety as defined by PA score improved post EMST. Neurology ® 2010;75:1912–1919

Objective: We aimed to review the English and Chinese literature on Pa Ping and to confirm by personal interview the story of how its pathogenesis was uncovered. Background: In 1930, Dr. Alexander Stewart Allen noticed a pattern of illness arising in the region of Kiating, China. Area residents began presenting to local hospitals with nausea, vomiting, and diarrhea, and what emerged was a clinical picture of a gradual ascending paralysis that could result in death, termed Pa Ping. All 3 patients observed by Dr. Allen were male, had no family history of the disease, and had recently eaten before the onset of paralysis. Pa Ping developed in Dr. Allen himself, but he survived. Methods: Medical literature was reviewed for primary sources. Interviews of living descendants and friends of the doctors in China and North America were conducted and information was corroborated by written records. Results: Dr. Huang, with the National Central University College of Medicine, noticed a striking similarity between Pa Ping and familial periodic paralysis in 12 patients and reported 2 patients with Pa Ping treated with potassium citrate who experienced a reversal of the paralysis. Dr. K.T. Du analyzed meals of patients with Pa Ping seen by Dr. Zhe Tung and found barium in concentrations as high as 25.7%. This finding was confirmed by administering barium chloride to animals, which recapitulated the human syndrome. Conclusions: Although Dr. Huang had correctly noticed an underlying potassium depletion in patients with Pa Ping, the observations of Dr. Zhe Tung and Dr. K.T. Du ultimately established barium-induced hypokalemia as the underlying cause.

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.

Background: Historians have suggested that MacArthur had Parkinson disease (PD), and that this may have influenced his military judgment. There is little evidence to support or to refute this suggestion. Objective: We aimed in this article to review multiple cinematic images, as well as the personal writings of Douglas MacArthur to determine the likelihood that he had PD. Methods: A complete review of the Western literature on Douglas MacArthur, including YouTube, Google Scholar/Google Images/Google Video, PubMed, and HighWirePress was undertaken. Over 200 minutes of film footage was analyzed, including such factors as MacArthur9s facial profiles, facial expression, gait, posture, and movement. Handwriting samples from over 6 decades were compared for evidence of micrographia. Videos and handwriting samples were independently reviewed by 3 fellowship-trained movement disorders neurologists. Results: Examination of video footage showed evidence of progression of head tremors, postural action tremors, and voice tremors. There were no clear indications of a masked face, rigidity, bradykinesia, or a resting tremor on film footage recorded from 1906 to 1964. There was no evidence of micrographia in handwriting samples. Oral testimony and letters written by an attending gastroenterologist present at MacArthur9s death in 1964 revealed no evidence of parkinsonian features. Conclusions: We conclude that MacArthur had mild essential tremor that was more evident in his postmilitary career. There was no evidence to suggest that he had a clinical diagnosis of progressive PD.

Objective: To study the context in which Hoover described his sign for differentiating hysterical and organic hemiplegia. Background: At the turn of the 20th century, many physicians were looking for signs to distinguish organic from hysterical hemiparesis. In 1908, Hoover described his sign of “complementary opposition.” Other signs based on associated movements of the upper extremities, lower extremities, and trunk were also described during and before this period and might have contributed to Hoover’s understanding of complementary opposition. Methods: A complete literature review of the original relevant articles by Babinski, Bychowski, Grasset and Gaussel, and Hoover was performed. Results: Several similar maneuvers were described before the Hoover sign. Babinski described the trunk-thigh test in 1897. Bychowski in Warsaw (performed since 1902, published in 1907) and Grasset and Gaussel in Paris (1905) independently described a phenomenon in which the separate elevation of each leg was performed more easily than simultaneous elevation. Moreover, Bychowski, although not emphasizing it as a sign, described what became known as Hoover sign. Hoover sign (1908) has been considered a further elaboration of these previous observations. Interestingly, Hoover had studied in Europe, and although no direct relationship between his discovery and these observations has been elucidated, the authors postulate that he was influenced by Babinski, Bychowski, and Grasset and Gaussel. Conclusion: Although Babinski, Bychowski, and Grasset and Gaussel described similar signs, only Hoover sign is still in wide use by practitioners.

Objective: To elucidate the role of Dr. Americo Negrette in diagnosing and reclassifying the dancing mania in Maracaibo, Venezuela as Huntington disease (HD). Methods: All of the medical and nonmedical books and articles by Negrette were collected and reviewed. Personal interviews with Negrette were performed to confirm the details of his life and original work. His childhood, medical education, and contribution to HD, as well as contributions to medicine, art, and poetry, were covered in interview sessions. Excerpts from his autobiography, Ciudad de Fuego, were translated into English for publication. A complete bibliography of 70 books and research articles authored by Negrette was assembled. Negrette himself reviewed the compilation of this manuscript just days before his sudden death on September 14, 2003. Results: Americo Negrette, a Venezuelan physician, biochemist, artist, and poet, observed a dancing epidemic in 1952. He acquired, through interviews with locals, the knowledge that there were two other small towns along Lake Maracaibo devastated by a syndrome called el mal (the bad). Negrette changed the diagnosis of these patients from a dancing mania to what he believed was Huntington chorea, later termed HD. He presented his findings at the Venezuelan Sixth Congress of Medical Science in 1955. He was met with reluctance in the local scientific community and a passive ear from government authorities. His description, written in Spanish, was not widely distributed beyond Venezuela, and its importance would have to wait until one of his students shared his observations (more than a decade later) with the HD research community and the rest of the world. Conclusion: The “dancing mania” of Maracaibo, because of the work of Americo Negrette, has been reclassified as Huntington disease.

Background: Testosterone deficiency, a treatable condition commonly seen in aging men, has been linked to Parkinson disease (PD) and Alzheimer disease (AD). In normal subjects, low testosterone levels are associated with cognitive and neuropsychiatric symptoms, yet the relationship between testosterone levels and cognitive function in PD and AD remains unclear. Objective: To examine the relationship of testosterone levels to age and cognitive function in PD and AD. Methods: Plasma testosterone levels were determined in men enrolled in a clinical registry of subjects with PD and AD, and neuropsychological testing was performed on subjects who consented. Testosterone levels in men with PD were compared with those in men with AD. In both groups, the relationship between testosterone levels and neuropsychological test scores was analyzed, adjusting for age and education. Results: Linear regression analysis revealed that testosterone levels decreased with age in male PD patients (p 0.03) and male AD patients (p 0.07). The rate of decline was similar for the two groups. In PD patients, lower testosterone levels were associated with poorer performance on Trails B Seconds (p 0.02). Conclusions: There is a similar age-related decline in plasma testosterone levels in men with either PD or AD. Previously described associations between low testosterone levels and frontal lobe dysfunction in normal aged men, together with these results, suggest that the hormonal deficiency may act as a "second hit" to impair cognitive function in neurodegenerative disease.

The neural underpinnings for normal and abnormal basal ganglia functions and functional connectivities remain unknown, although several important pieces to the puzzle have emerged over 3 decades. First was the identification of segregated basal ganglia circuits.1 This discovery was closely paralleled by the realization that these circuits communicated through the use of a special physiologic language,2 which proved to be more complex than initially thought, as it was not the simple firing rate of neurons, but rather specific patterns of oscillatory neuronal discharges that were …

Depression associated with Parkinson's disease (PD) is common and affects 25 to 40% of patients. Recognition of the signs and symptoms of depression associated with PD is essential for clinical practitioners. Treatment of depression in this subset of patients can have a direct and dramatic impact on functional disability and quality of life. A review of the literature concerning depression and depression associated with PD was undertaken, with specific attention given to disease mechanisms, clinical presentation, association with thyroid disease, and the principles of management and treatment. Specific signs and symptoms of depression can be easily identified in patients with PD. Practitioners should be aware of these signs and symptoms when diagnosing and treating depression associated with PD. Practitioners should also be aware of the pros and cons of each treatment option and should choose a therapy appropriate for each individual patient's needs. It is important to identify the features of depression associated with PD in order to render early diagnosis and institute practical and efficacious therapy.

There was only one catch, and that was Catch-22, which specified that a concern for one’s safety in the face of dangers that were real and immediate was the process of a rational mind. Orr, a pilot and one of the main characters, was crazy and could be grounded. All he had to do was ask; and as soon as he did, he would no longer be crazy and he would have to fly more missions. Orr would be crazy to fly more missions and sane if he didn’t, but if he was sane he had to fly them. If he flew them he was crazy and didn’t have to, but if he didn’t want to, he was sane and had to. Yossarian was moved very deeply by the absolute simplicity of this clause of “Catch-22” and let out a respectful whistle. —Joseph Heller, Catch-22 These words from Joseph Heller’s dark and satirical novel have always stayed with us, reminding us of the vicious cycles that we get caught in as we proceed through our lives. The Oxford English Dictionary defines catch-22 as a “set of circumstances in which one requirement, etc., is dependent upon another, which is in turn dependent upon the first.” Into his first novel, Heller interweaves a series of these circular dilemmas, and, in doing so, has placed himself into the pages of literary history. But is there something more to this novel—does it provide an early example of a cyclic and pathologic behavior that might have a neurologic origin? …

Neurologists and psychiatrists were willing to embrace the revolution of the serotonin reuptake inhibitor (SSRI) which in most offices replaced the standard tricyclic antidepressants (TCA) for treatment of depression in patients with Parkinson disease (PD). It is not hard to imagine how such a drastic transition occurred so rapidly, as there was a desire for a more refined and targeted therapy with fewer side effects (such as dry mouth, dry eyes, constipation, and confusion). The switch occurred, however, in the absence of a prospective, randomized, head-to-head comparison between SSRIs and TCAs. Menza et al.1 offer a true evidence-based comparison in this issue of Neurology ®. With depression reported to occur in 40% or more of patients with PD,2,3 this is an important clinical study. The authors presented a simple study design that compared paroxetine CR, nortriptyline, and placebo in a 52-patient randomized trial. The doses were escalated up to three times, based on the clinician’s discretion, up to a top …

To learn if limb-kinetic apraxia (LKA) is associated with Parkinson disease (PD), participants with PD (on medications) and control subjects performed finger tapping (FT), measuring movement speed, and performed coin rotation (CR), measuring precise coordinated but independent finger movements and speed. There were no group differences in FT, a measure of bradykinesia-rigidity, but CR rotation was impaired in PD. Thus, LKA, not related to bradykinesia-rigidity, is associated with PD.

Objective: To determine the prevalence of fatigue, excessive daytime somnolence (EDS) and sleep issues in patients with dystonia and examine its impact on quality of life (QOL). Background Dystonia is a movement disorder that is primarily described by its motor manifestations but is also associated with several non-motor symptoms. Prior research suggests tiredness and energy as important determinants of QOL independent of mood. However, there is a lack of specific data on fatigue, EDS and sleep disorders in dystonia determined using standardized questionnaires. Design/Methods: We administered the following scales to ninety-one patients with primary and secondary dystonia followed at a Movement Disorders clinic: the Fatigue Severity Scale, Epworth Sleepiness Scale, and Parkinson9s Disease Sleep Scale to measure fatigue, EDS and sleep issues respectively; Short Form 36 Health Survey questionnaire to measure QOL, Beck Depression Inventory for depression, and the Unified Dystonia Rating Scale to assess dystonia severity. Results: The mean age of the patients was 60 +/- 17 years, mean duration of dystonia was 7.5 +/- 8 years and dystonia types were focal (74%), segmental (21%) and generalized (5%). Patients with dystonia showed high rates of clinically significant fatigue (46%), EDS (27%) and sleep issues (26%). These prevalence rates did not vary significantly based upon dystonia type, dystonia severity or body parts affected. Depression showed strong correlations with fatigue (r = +0.47, p = 0.0003), EDS (r = +0.35, p = 0.003) and sleep issues (r = -0.40, p = 0.0007). While EDS, sleep issues and fatigue were all associated with reduced QOL, only fatigue remained correlated with QOL when controlling for depression (p = 0.04). Conclusions: This study demonstrates fatigue, EDS and sleep issues are common non-motor manifestations of dystonia that are associated with depression and adversely impact QOL. However amongst the three factors, fatigue affects QOL independent of depression. Disclosure: Dr. Heese has nothing to disclose. Dr. Wagle-Shukla has nothing to disclose. Dr. Okun has received personal compensation for activities with National Parkinson Foundation, Ask the Expert, and Neuropace Devices. Dr. Okun has received research support from the Michael J. Fox Foundation, the National Parkinson Foundation, the Parkinson Alliance and the National Institutes of Health. Dr. Kluger has received research support from Teva Neuroscience.

Objective: To ascertain the relationship between depression score and visual analogue mood scale, quality of life and motor severity in Parkinson9s disease. Background Depression is the most common non-motor manifestation of Parkinson disease (PD), affecting up to 40 to 50 % of PD patients, far in excess of its prevalence of 6.7% in the general American population. Design/Methods: All patients seen at the University of Florida Movement Disorders Center, with a confirmed PD diagnosis and a recorded Beck Depression Inventory (BDI) on their first visit were included in this study. Using a cutoff of 14, we determined the prevalence of depressive symptoms in our whole population, in men versus women and in drug naive versus those treated with levodopa. Results: The depressed cohort had a mean BDI score of 19.41 whereas the mean for the non-depressed was 7.06. The HY with the last two having negative coefficients. The best predictor, not surprisingly was the SadTscore. Overall there is not a strong correlation between VAMS and BDI. Conclusions: There is a correlation between the severity of motor symptoms and the presence of depression pointing to the possibility of both organic and reactive components in PD depression. There was only poor correlation between the VAMS score and BDI, but the quality of life PDQ-39 paralleled the BDI score raising questions whether this is cause or effect. Disclosure: Dr. Salardini has nothing to disclose. Dr. Rodriguez has received personal compensation for activities with Allergan, Merz Pharmaceuticals, Lundbeck and Teva Pharmaceuticals as a consultant. Dr. Malaty has received research support from The National Parkinson Foundation. Dr. Okun has received personal compensation for activities with National Parkinson Foundation, Ask the Expert, and Neuropace Devices. Dr. Okun has received research support from the Michael J. Fox Foundation, the National Parkinson Foundation, the Parkinson Alliance and the National Institutes of Health. Dr. Fernandez has received personal compensation for activities with USF CME, Cleveland Clinic CME, Medical Communications Media, Health Professions Conferencing, Ipsen, Merz Pharmaceuticals, and US World Meds Dr. Fernandez has received personal compensation in an editorial capacity for the Movement Disorders Society Website. Dr. Fernandez has received royalty payments from Demos Publishing, Manson Publishing, and Springer Publishing. Dr. Fernandez has received research support from Abbott, Acadia, Biotie Therapeutics, EMD-Serono, Huntington Study Group, Ipsen, Merz Pharmaceuticals, Michael J. Fox Foundation, Movement Disorders Society, National Parkinson Foundation, NIH/NINDS, Novartis, Parkinson Study Group, Teva, but has no owner interest in any pharmaceutical company.