Theresa A. Zesiewicz

Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Scale Presentation and Clinimetric Testing Results

We present a clinimetric assessment of the Movement Disorder Society (MDS)‐sponsored revision of the Unified Parkinsons Disease Rating Scale (MDS‐UPDRS). The MDS‐UDPRS Task Force revised and expanded the UPDRS using recommendations from a published critique. The MDS‐UPDRS has four parts, namely, I: Non‐motor Experiences of Daily Living; II: Motor Experiences of Daily Living; III: Motor Examination; IV: Motor Complications. Twenty questions are completed by the patient/caregiver. Item‐specific instructions and an appendix of complementary additional scales are provided. Movement disorder specialists and study coordinators administered the UPDRS (55 items) and MDS‐UPDRS (65 items) to 877 English speaking (78% non‐Latino Caucasian) patients with Parkinsons disease from 39 sites. We compared the two scales using correlative techniques and factor analysis. The MDS‐UPDRS showed high internal consistency (Cronbachs alpha = 0.79–0.93 across parts) and correlated with the original UPDRS (ρ = 0.96). MDS‐UPDRS across‐part correlations ranged from 0.22 to 0.66. Reliable factor structures for each part were obtained (comparative fit index > 0.90 for each part), which support the use of sum scores for each part in preference to a total score of all parts. The combined clinimetric results of this study support the validity of the MDS‐UPDRS for rating PD.

Practice Parameter: Therapies for essential tremor Report of the Quality Standards Subcommittee of the American Academy of Neurology

Background: Essential tremor (ET) is one of the most common tremor disorders in adults and is characterized by kinetic and postural tremor. To develop this practice parameter, the authors reviewed available evidence regarding initiation of pharmacologic and surgical therapies, duration of their effect, their relative benefits and risks, and the strength of evidence supporting their use. Methods: A literature review using MEDLINE, EMBASE, Science Citation Index, and CINAHL was performed to identify clinical trials in patients with ET published between 1966 and August 2004. Articles were classified according to a four-tiered level of evidence scheme and recommendations were based on the level of evidence. Results and Conclusions: Propranolol and primidone reduce limb tremor (Level A). Alprazolam, atenolol, gabapentin (monotherapy), sotalol, and topiramate are probably effective in reducing limb tremor (Level B). Limited studies suggest that propranolol reduces head tremor (Level B). Clonazepam, clozapine, nadolol, and nimodipine possibly reduce limb tremor (Level C). Botulinum toxin A may reduce hand tremor but is associated with dose-dependent hand weakness (Level C). Botulinum toxin A may reduce head tremor (Level C) and voice tremor (Level C), but breathiness, hoarseness, and swallowing difficulties may occur in the treatment of voice tremor. Chronic deep brain stimulation (DBS) (Level C) and thalamotomy (Level C) are highly efficacious in reducing tremor. Each procedure carries a small risk of major complications. Some adverse events from DBS may resolve with time or with adjustment of stimulator settings. There is insufficient evidence regarding the surgical treatment of head and voice tremor and the use of gamma knife thalamotomy (Level U). Additional prospective, double-blind, placebo-controlled trials are needed to better determine the efficacy and side effects of pharmacologic and surgical treatments of ET.

Clinical Predictors of Abnormality Disclosed by Computed Tomography after Mild Head Trauma

We prospectively studied 712 consecutive patients during a 1-year period who presented with amnesia or loss of consciousness after nonpenetrating head trauma and who had a perfect Glasgow Coma Scale score of 15. Of the 67 (9.4%) patients with acute traumatic lesions disclosed by computed tomography (CT) of the head, 2 required neurosurgical intervention and 1 died. Four factors were statistically correlated (P < 0.05) with abnormal CT findings: Older age, white race, signs of basilar skull fracture, and being either a pedestrian hit by a motor vehicle or a victim of an assault. Sex, length of antero- or retrograde amnesia, forward and reverse digit spans, object recall, focal abnormality on the general neurological exam, and subjective complaints were not statistically correlated with CT abnormality. Using step-wise discriminant function analysis, no single item or combination of items could be used to classify 95% of the patients into either the normal or abnormal CT group. Therefore, regardless of age, mechanism of injury, or clinical findings, intracranial lesions cannot be completely excluded clinically on head-trauma patients who have loss of consciousness or amnesia, even if the Glasgow Coma Scale score is 15. However, only two patients (0.3%) required neurosurgical intervention.

Practice Parameter: Diagnosis and prognosis of new onset Parkinson disease (an evidence-based review) Report of the Quality Standards Subcommittee of the American Academy of Neurology

Objective: To define key issues in the diagnosis of Parkinson disease (PD), to define features influencing progression, and to make evidence-based recommendations. Two clinical questions were identified: 1) Which clinical features and diagnostic modalities distinguish PD from other parkinsonian syndromes? 2) Which clinical features predict rate of disease progression? Methods: Systematic review of the literature was completed. Articles were classified according to a four-tiered level of evidence scheme. Recommendations were based on the evidence. Results and Conclusions: 1. Early falls, poor response to levodopa, symmetry of motor manifestations, lack of tremor, and early autonomic dysfunction are probably useful in distinguishing other parkinsonian syndromes from Parkinson disease (PD). 2. Levodopa or apomorphine challenge and olfactory testing are probably useful in distinguishing PD from other parkinsonian syndromes. 3. Predictive factors for more rapid motor progression, nursing home placement, and shorter survival time include older age at onset of PD, associated comorbidities, presentation with rigidity and bradykinesia, and decreased dopamine responsiveness. Future research into methods for earlier and more accurate diagnosis of the disease and identification and clarification of predictive factors of rapid disease progression is warranted.

Practice Parameter: Treatment of nonmotor symptoms of Parkinson disease Report of the Quality Standards Subcommittee of the American Academy of Neurology

Objective: Nonmotor symptoms (sleep dysfunction, sensory symptoms, autonomic dysfunction, mood disorders, and cognitive abnormalities) in Parkinson disease (PD) are a major cause of morbidity, yet are often underrecognized. This evidence-based practice parameter evaluates treatment options for the nonmotor symptoms of PD. Articles pertaining to cognitive and mood dysfunction in PD, as well as treatment of sialorrhea with botulinum toxin, were previously reviewed as part of American Academy of Neurology practice parameters and were not included here. Methods: A literature search of MEDLINE, EMBASE, and Science Citation Index was performed to identify clinical trials in patients with nonmotor symptoms of PD published between 1966 and August 2008. Articles were classified according to a 4-tiered level of evidence scheme and recommendations were based on the level of evidence. Results and Recommendations: Sildenafil citrate (50 mg) may be considered to treat erectile dysfunction in patients with Parkinson disease (PD) (Level C). Macrogol (polyethylene glycol) may be considered to treat constipation in patients with PD (Level C). The use of levodopa/carbidopa probably decreases the frequency of spontaneous nighttime leg movements, and should be considered to treat periodic limb movements of sleep in patients with PD (Level B). There is insufficient evidence to support or refute specific treatments for urinary incontinence, orthostatic hypotension, and anxiety (Level U). Future research should include concerted and interdisciplinary efforts toward finding treatments for nonmotor symptoms of PD.

Heterozygosity for a mutation in the parkin gene leads to later onset Parkinson disease

Background: The vast majority of the parkin mutations previously identified have been found in individuals with juvenile or early onset PD. Previous screening of later onset PD cohorts has not identified substantial numbers of parkin mutations. Methods: Families with at least two siblings with PD were ascertained to identify genes contributing to PD susceptibility. Screening of the parkin gene, by both quantitative PCR and exon sequencing, was performed in those families with either early onset PD (age onset ≤50 years) or positive lod score with a marker in intron 7 of the parkin gene. Results: A total of 25 different mutations in the parkin gene were identified in 103 individuals from 47 families. Mutations were found in both parkin alleles in 41 of the individuals, whereas a single mutation in only one of the two parkin alleles was observed in 62 individuals. Thirty-five of the subjects (34%) with a parkin mutation had an age at onset of 60 years or above with 30 of these 35 (86%) having a detectable mutation on only one parkin allele. Few significant clinical differences were observed among the individuals with two, one, or no mutated copies of the parkin gene. Conclusion: Mutations in the parkin gene occur among individuals with PD with an older age at onset (≥60 years) who have a positive family history of the disease. In addition, the clinical findings of parkin-positive individuals are remarkably similar to those without mutations.

Practice Parameter: Neuroprotective strategies and alternative therapies for Parkinson disease (an evidence-based review) Report of the Quality Standards Subcommittee of the American Academy of Neurology

Objective: To define key issues in the management of Parkinson disease (PD) relating to neuroprotective strategies and alternative treatments, and to make evidence-based treatment recommendations. Methods: Two clinical questions were identified. 1) In a patient diagnosed with PD, are there any therapies that can slow disease progression? 2) Are there any nonstandard pharmacologic or nonpharmacologic therapies that have been shown to improve motor function in PD? Articles were classified according to a four-tiered level of evidence scheme. Recommendations were based on the evidence. Results and conclusions: 1. Levodopa does not appear to accelerate disease progression. 2. No treatment has been shown to be neuroprotective. 3. There is no evidence that vitamin or food additives can improve motor function in PD. 4. Exercise may be helpful in improving motor function. 5. Speech therapy may be helpful in improving speech volume. 6. No manual therapy has been shown to be helpful in the treatment of motor symptoms, although studies in this area are limited. Further studies using a rigorous scientific method are needed to determine efficacy of alternative therapies. NEUROLOGY 2006;66:976–982 Statement of purpose. The Quality Standards Subcommittee (QSS) develops scientifically sound, clinically relevant practice parameters to aid in the practice of neurology. This article addresses neuroprotective and alternative treatments for the management of Parkinson disease (PD). These recommendations are meant to address the needs of specialists and nonspecialists caring for people with PD. Background and justification. PD is a neurodegenerative disorder characterized by the classic symptoms of bradykinesia, rigidity, and rest tremor. Although symptomatic therapy can provide benefit for many years, the disorder slowly progresses, evenAdditional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the April 11 issue to find the title link for this article. Editorial, see page 966 See also pages 968, 983, and 996 This article was previously published in electronic format as an Expedited E-Pub at www.neurology.org. From University of Calgary (O.S.), Calgary, AB, Canada; University of Kansas (G.G.), Kansas City; Division of Radiation Sciences (J.P.), Saint Louis, MO; University of Maryland Hospital (S.R.), Baltimore; Movement Disorder Center (T.Z.), Tampa, FL; and University of Maryland School of Medicine (W.J.W.),Objective:To define key issues in the management of Parkinson disease (PD) relating to neuroprotective strategies and alternative treatments, and to make evidence-based treatment recommendations. Methods:Two clinical questions were identified. 1) In a patient diagnosed with PD, are there any therapies that can slow disease progression? 2) Are there any nonstandard pharmacologic or nonpharmacologic therapies that have been shown to improve motor function in PD? Articles were classified according to a four-tiered level of evidence scheme. Recommendations were based on the evidence. Results and conclusions:1. Levodopa does not appear to accelerate disease progression. 2. No treatment has been shown to be neuroprotective. 3. There is no evidence that vitamin or food additives can improve motor function in PD. 4. Exercise may be helpful in improving motor function. 5. Speech therapy may be helpful in improving speech volume. 6. No manual therapy has been shown to be helpful in the treatment of motor symptoms, although studies in this area are limited. Further studies using a rigorous scientific method are needed to determine efficacy of alternative therapies.

A home diary to assess functional status in patients with Parkinson's disease with motor fluctuations and dyskinesia

In clinical trials for patients with Parkinsons disease (PD) with motor fluctuations, efficacy is generally ascribed to an intervention if motor function is significantly improved or if “off” time is significantly reduced. However, we have argued that patients might not be improved if off time is reduced only to the extent that unwanted dyskinesia is increased. Therefore, a home diary should include an assessment of dyskinesia to provide an accurate reflection of clinical status over a period of time. We undertook two studies to develop a home diary to assess functional status in patients with PD with motor fluctuations and dyskinesia. In both studies, patients concurrently completed a test and a reference diary. In Study I, we evaluated the impact of different severities of dyskinesia on patient-defined functional status. There were 1,149 evaluable half-hour time periods from 24 patients; 94.3% of off time was considered “bad” time and 90.2% of “on” time without dyskinesia, 72.6% of on time with mild dyskinesia, 43.0% of on time with moderate dyskinesia, and 15.2% of on time with severe dyskinesia was considered “good” time. In Study II, we evaluated a new home diary designed to separate dyskinesia that had a negative impact on patient-defined functional status from dyskinesia that did not. There were 816 evaluable time periods from 17 patients; 84.9% of off time and 89.9% of on time with troublesome dyskinesia was considered bad time while 85.5% of on time without dyskinesia and 93.8% of on time with nontroublesome dyskinesia was considered good time. With this diary (Diary II), the effect of an intervention can be expressed as the change in off time and the change in on time with troublesome dyskinesia (bad time). The sum can be used as an outcome variable and compared to baseline or across groups. In evaluating the efficacy of an intervention, assessment of change in off time and change in on time with troublesome dyskinesia provides a more accurate reflection of clinical response than change in off time alone.

Significant Linkage of Parkinson Disease to Chromosome 2q36-37

Parkinson disease (PD) is the second most common neurodegenerative disorder, surpassed in frequency only by Alzheimer disease. Elsewhere we have reported linkage to chromosome 2q in a sample of sibling pairs with PD. We have now expanded our sample to include 150 families meeting our strictest diagnostic definition of verified PD. To further delineate the chromosome 2q linkage, we have performed analyses using only those pedigrees with the strongest family history of PD. Linkage analyses in this subset of 65 pedigrees generated a LOD score of 5.1, which was obtained using an autosomal dominant model of disease transmission. This result strongly suggests that variation in a gene on chromosome 2q36-37 contributes to PD susceptibility.

Pramipexole-induced somnolence and episodes of daytime sleep

Pramipexole is a non‐ergot dopamine agonist used to treat Parkinsons disease (PD). Because of concern regarding driving safety, we evaluated the incidence and nature of somnolence experienced by patients receiving pramipexole in clinical trials at our center. A retrospective chart review was performed and structured interviews were conducted with patients who had reported moderate or severe somnolence. In addition, two patients underwent polysomnography (PSG) and multiple sleep latency tests (MSLT) while on and 2 weeks after discontinuation of pramipexole. Forty patients with PD participating in pramipexole clinical trials were identified. In the double‐blind phases of the studies, 22 patients were randomized to pramipexole and 18 were randomized to placebo. Six patients assigned to pramipexole reported somnolence as an adverse event (1 moderate, 5 mild) compared with two patients assigned to placebo (1 severe, 1 moderate; p = 0.19, one‐tailed Fishers exact test). Thirty‐seven patients participated in open‐label extension studies. Twenty‐one (57%) reported somnolence as an adverse event. Eleven (30%) patients reported moderate somnolence and three (8%) patients reported severe somnolence. For patients with moderate or severe somnolence, the onset of worst‐reported somnolence occurred at a mean (± standard error) pramipexole dose of 4.0 ± 0.4 mg (range, 0.75–4.5 mg) per day. Patients had been taking pramipexole for a total of 10.0 ± 1.5 months (range, .03–22 mos) and at their maximal dose for 6.7 ± 1.5 months (range, .03–20 mos). During structured interviews with 12 of the 14 patients reporting moderate or severe somnolence, seven reported falling asleep while driving and two reported minor motor vehicle accidents caused by falling asleep. Most patients reported relatively continuous drowsiness that led to falling asleep without acute warning during periods of inactivity. Three patients reported discreet waves of irresistible sleepiness heralded by prodromal symptoms occurring against a background of normal wakefulness. MSLT in two of these patients revealed decreased latency to sleep without early onset of rapid eye movements. Sleep latency normalized after withdrawal of pramipexole. Intensive patient education is necessary to prevent motor vehicle accidents in patients taking pramipexole. We recommend that patients who are experiencing generalized drowsiness and falling asleep during periods of inactivity be instructed not to drive because these patients do fall asleep without acute warning. Somnolence usually resolves with pramipexole dose reduction or discontinuation. Patients should also be alerted to pull over and stop driving immediately if they feel a wave of sleepiness coming on. Patient education and compliance are critical to maximize safety.