William G. Ondo

Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome

BACKGROUND There is a need for an easily administered instrument which can be applied to all patients with restless legs syndrome (RLS) to measure disease severity for clinical assessment, research, or therapeutic trials. The pathophysiology of RLS is not clear and no objective measure so far devised can apply to all patients or accurately reflect severity. Moreover, RLS is primarily a subjective disorder. Therefore, a subjective scale is at present the optimal instrument to meet this need. METHODS Twenty centers from six countries participated in an initial reliability and validation study of a rating scale for the severity of RLS designed by the International RLS study group (IRLSSG). A ten-question scale was developed on the basis of repeated expert evaluation of potential items. This scale, the IRLSSG rating scale (IRLS), was administered to 196 RLS patients, most on some medication, and 209 control subjects. RESULTS The IRLS was found to have high levels of internal consistency, inter-examiner reliability, test-retest reliability over a 2-4 week period, and convergent validity. It also demonstrated criterion validity when tested against the current criterion of a clinical global impression and readily discriminated patient from control groups. The scale was dominated by a single severity factor that explained at least 59% of the pooled item variance. CONCLUSIONS This scale meets performance criteria for a brief, patient completed instrument that can be used to assess RLS severity for purposes of clinical assessment, research, or therapeutic trials. It supports a finding that RLS is a relatively uniform disorder in which the severity of the basic symptoms is strongly related to their impact on the patients life. In future studies, the IRLS should be tested against objective measures of RLS severity and its sensitivity should be studied as RLS severity is systematically manipulated by therapeutic interventions.

International Multicenter Pilot Study of the First Comprehensive Self-Completed Nonmotor Symptoms Questionnaire for Parkinson's Disease: The NMSQuest Study

Nonmotor symptoms (NMS) of Parkinsons disease (PD) are not well recognized in clinical practice, either in primary or in secondary care, and are frequently missed during routine consultations. There is no single instrument (questionnaire or scale) that enables a comprehensive assessment of the range of NMS in PD both for the identification of problems and for the measurement of outcome. Against this background, a multidisciplinary group of experts, including patient group representatives, has developed an NMS screening questionnaire comprising 30 items. This instrument does not provide an overall score of disability and is not a graded or rating instrument. Instead, it is a screening tool designed to draw attention to the presence of NMS and initiate further investigation. In this article, we present the results from an international pilot study assessing feasibility, validity, and acceptability of a nonmotor questionnaire (NMSQuest). Data from 123 PD patients and 96 controls were analyzed. NMS were highly significantly more prevalent in PD compared to controls (PD NMS, median = 9.0, mean = 9.5 vs. control NMS, median = 5.5, mean = 4.0; Mann–Whitney, Kruskal–Wallis, and t test, P < 0.0001), with PD patients reporting at least 10 different NMS on average per patient. In PD, NMS were highly significantly more prevalent across all disease stages and the number of symptoms correlated significantly with advancing disease and duration of disease. Furthermore, frequently, problems such as diplopia, dribbling, apathy, blues, taste and smell problems were never previously disclosed to the health professionals.

Mitochondrial Polymorphisms Significantly Reduce the Risk of Parkinson Disease

Mitochondrial (mt) impairment, particularly within complex I of the electron transport system, has been implicated in the pathogenesis of Parkinson disease (PD). More than half of mitochondrially encoded polypeptides form part of the reduced nicotinamide adenine dinucleotide dehydrogenase (NADH) complex I enzyme. To test the hypothesis that mtDNA variation contributes to PD expression, we genotyped 10 single-nucleotide polymorphisms (SNPs) that define the European mtDNA haplogroups in 609 white patients with PD and 340 unaffected white control subjects. Overall, individuals classified as haplogroup J (odds ratio [OR] 0.55; 95% confidence interval [CI] 0.34-0.91; P=.02) or K (OR 0.52; 95% CI 0.30-0.90; P=.02) demonstrated a significant decrease in risk of PD versus individuals carrying the most common haplogroup, H. Furthermore, a specific SNP that defines these two haplogroups, 10398G, is strongly associated with this protective effect (OR 0.53; 95% CI 0.39-0.73; P=.0001). SNP 10398G causes a nonconservative amino acid change from threonine to alanine within the NADH dehydrogenase 3 (ND3) of complex I. After stratification by sex, this decrease in risk appeared stronger in women than in men (OR 0.43; 95% CI 0.27-0.71; P=.0009). In addition, SNP 9055A of ATP6 demonstrated a protective effect for women (OR 0.45; 95% CI 0.22-0.93; P=.03). Our results suggest that ND3 is an important factor in PD susceptibility among white individuals and could help explain the role of complex I in PD expression.

The metric properties of a novel non-motor symptoms scale for Parkinson's disease: Results from an international pilot study

Non‐motor symptoms (NMS) in Parkinsons disease (PD) are common, significantly reduce quality of life and at present there is no validated clinical tool to assess the progress or potential response to treatment of NMS. A new 30‐item scale for the assessment of NMS in PD (NMSS) was developed. NMSS contains nine dimensions: cardiovascular, sleep/fatigue, mood/cognition, perceptual problems, attention/memory, gastrointestinal, urinary, sexual function, and miscellany. The metric attributes of this instrument were analyzed. Data from 242 patients mean age 67.2 ± 11 years, duration of disease 6.4 ± 6 years, and 57.3% male across all stages of PD were collected from the centers in Europe, USA, and Japan. The mean NMSS score was 56.5 ± 40.7, (range: 0–243) and only one declared no NMS. The scale provided 99.2% complete data for the analysis with the total score being free of floor and ceiling effect. Satisfactory scaling assumptions (multitrait scaling success rate >95% for all domains except miscellany) and internal consistency were reported for most of the domains (mean α, 0.61). Factor analysis supported the a prori nine domain structure (63% of the variance) while a small test–retest study showed satisfactory reproducibility (ICC > 0.80) for all domains except cardiovascular (ICC = 0.45). In terms of validity, the scale showed modest association with indicators of motor symptom severity and disease progression but a high correlation with other measures of NMS (NMSQuest) and health‐related quality of life measure (PDQ‐8) (both, rS = 0.70). In conclusion, NMSS can be used to assess the frequency and severity of NMS in PD patients across all stages in conjunction with the recently validated non‐motor questionnaire.

Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome

Objective: To assess neuropathology in individuals with restless legs syndrome (RLS). Methods: A standard neuropathologic evaluation was performed on seven brains from individuals who had been diagnosed with RLS. The substantia nigra was examined in greater detail for iron staining and with immunohistochemistry for tyrosine hydroxylase and proteins involved in iron management. Five age-matched individuals with no neurologic history served as controls. Results: There were no histopathologic abnormalities unique to the RLS brains. Tyrosine hydroxylase staining in the major dopaminergic regions appeared normal in the RLS brains. Iron staining and H-ferritin staining was markedly decreased in the RLS substantia nigra. Although H-ferritin was minimally detected in the RLS brain, L-ferritin staining was strong. However, the cells staining for L-ferritin in RLS brains were morphologically distinct from those in the control brains. Transferrin receptor staining on neuromelanin-containing cells was decreased in the RLS brains compared to normal, whereas transferrin staining in these cells was increased. Conclusions: RLS may not be rooted in pathologies associated with traditional neurodegenerative processes but may be a functional disorder resulting from impaired iron acquisition by the neuromelanin cells in RLS. The underlying mechanism may be a defect in regulation of the transferrin receptors.

Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: Updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria - history, rationale, description, and significance

BACKGROUND In 2003, following a workshop at the National Institutes of Health, the International Restless Legs Syndrome Study Group (IRLSSG) developed updated diagnostic criteria for restless legs syndrome/Willis-Ekbom disease (RLS/WED). These criteria were integral to major advances in research, notably in epidemiology, biology, and treatment of RLS/WED. However, extensive review of accumulating literature based on the 2003 NIH/IRLSSG criteria led to efforts to improve the diagnostic criteria further. METHODS The clinical standards workshop, sponsored by the WED Foundation and IRLSSG in 2008, started a four-year process for updating the diagnostic criteria. That process included a rigorous review of research advances and input from clinical experts across multiple disciplines. After broad consensus was attained, the criteria were formally approved by the IRLSSG executive committee and membership. RESULTS Major changes are: (i) addition of a fifth essential criterion, differential diagnosis, to improve specificity by requiring that RLS/WED symptoms not be confused with similar symptoms from other conditions; (ii) addition of a specifier to delineate clinically significant RLS/WED; (iii) addition of course specifiers to classify RLS/WED as chronic-persistent or intermittent; and (iv) merging of the pediatric with the adult diagnostic criteria. Also discussed are supportive features and clinical aspects that are important in the diagnostic evaluation. CONCLUSIONS The IRLSSG consensus criteria for RLS/WED represent an international, interdisciplinary, and collaborative effort intended to improve clinical practice and promote further research.

Prevalence of nonmotor symptoms in Parkinson's disease in an international setting: study using nonmotor symptoms questionnaire in 545 patients

2006, there was, no single instrument (questionnaire or scale) for attempting a comprehensive assessment of the wide range of nonmotor symptoms (NMS) of Parkinsons disease (PD). The PD nonmotor group, a multidisciplinary group of experts including patient group representatives developed and validated the NMS screening questionnaire (NMSQuest) comprising 30 items. The NMSQuest is a self completed screening tool designed to draw attention to the presence of NMS. In this paper, we present the results gathered from 545 patients using the definitive version of the NMSQuest highlighting the prevalence of the wide range of NMS flagged in the NMSQuest from consecutive PD patients in an international setting.

Daytime sleepiness and other sleep disorders in Parkinson’s disease

Background: PD is associated with a variety of sleep problems. The dopamine agonists (DA) pramipexole and ropinirole were recently implicated in causing “sleep attacks” and motor vehicle accidents. Methods: In order to determine the overall rate of subjective sleep problems in PD and to determine if any factors, including specific medications, correlate with sleep pathology, the authors surveyed consecutive patients with PD seen over a 3-month period in a Movement Disorders Clinic. The authors collected demographic and medication data, and the patients completed the Epworth Sleepiness Scale (ESS), questions assessing the presence of restless legs syndrome (RLS), a modified National Sleep Foundation sleep survey, and specific questions regarding falling asleep while driving. Results: A total of 320 patients completed the questionnaire. The authors eliminated 17, six for incomplete data and 11 for having a primary diagnosis other than PD. The mean age of the remaining 303 patients was 67.1 ± 10.7 years, and the mean duration of PD was 9.1 ± 5.7 years. The ESS scores averaged 11.1 ± 5.9, and in 50.2% of patients the score was abnormally high (>10). Stepwise regression analysis found that sleepiness correlated with longer duration of PD (p < 0.001), more advanced PD (p < 0.004), male sex (p < 0.001), and the use of any DA (p < 0.003). The soporific effects of the three most common DA (pramipexole, ropinirole, and pergolide) were similar. Falling asleep while driving was reported by 63/279 (22.6%) of current drivers and correlated with higher ESS scores (p < 0.05). Other sleep disorders, including RLS, were also frequently reported. Conclusion: Daytime sleepiness is common in PD and correlates with more advanced and longer duration of PD, and male sex. The DA were also independently associated with daytime sleepiness, but in this group, no single DA was more culpable than the others.

Restless legs syndrome: Clinicoetiologic correlates

Despite recent attempts to better characterize restless legs syndrome (RLS), this neurologic disorder remains poorly understood.The relationship between idiopathic and secondary and between familial and sporadic (nonfamilial) cases have not been previously defined. We studied 54 patients (29 women and 25 men) who satisfied the diagnostic criteria for RLS. The mean age of the patients was 62.69 +/- 13.82 years, and the mean age at onset was 34.13 +/- 20.30 years. We found that 92% of patients with idiopathic RLS (without neuropathy) had a family history of RLS, whereas only 13% of those with neuropathic RLS (associated with peripheral neuropathy) had a positive family history. The sporadic/neuropathic patients were older at symptom onset and tended to have a more rapid progression than the familial/idiopathic patients. There were no other significant differences between the subgroups. Levodopa and dopamine agonists were the most effective treatments. We conclude that there are two major etiologic subgroups of RLS but that the two share central pathophysiologic mechanisms. NEUROLOGY 1996;47: 1435-1441

Clinical correlates of 6-hydroxydopamine injections into A11 dopaminergic neurons in rats: a possible model for restless legs syndrome.

Pursuant to the clinical suspicion that restless legs syndrome (RLS) may involve dopaminergic diencephalic spinal neurons (A11), we performed stereotaxic bilateral 6‐hydroxydopamine (6‐OHDA) lesions into the A11 nucleus to observe for any behavioral correlates similar to this clinical condition. Pathologic examination demonstrated a 54% reduction in A11 tyrosine hydroxylase staining cells in rats injected with 6‐OHDA versus sham treatment. Multiple blindly rated 90–120‐minute video epochs demonstrated an increased average number of standing episodes (14.4 ± 11.7 versus 7.3 ± 5.5 episodes/epoch) and increased total standing time (38.9 ± 20.5 versus 25.3 ± 12.2 minutes/epoch) but similar total sleep time in four lesioned rats when compared with two sham rats. Treatment of the lesioned rats with intramuscular pramipexole subsequently resulted in fewer standing episodes (4.4 ± 3.3 versus 14.4 ± 11.7 episodes/epoch) and less total standing time (20.9 ± 12.3 versus 38.9 ± 20.5 minutes/epoch) when compared with untreated lesioned rats. Despite a large number of observations, the small number of lesioned animals precluded formal statistical analysis. These behaviors are consistent, although not specific, with what would be expected in an animal model of RLS.