The four diagnostic criteria for Restless Legs Syndrome are unable to exclude confounding conditions ("mimics").

BACKGROUND: Epidemiological survey studies have suggested that a large fraction of the adult population, from five to more than 10%, have symptoms of Restless Legs Syndrome (RLS). Recently, however, it has become clear that the positive predictive value of many questionnaire screens for RLS may be fairly low and that many individuals who are identified by these screens have other conditions that can "mimic" the features of RLS by satisfying the four diagnostic criteria. We noted the presence of such confounders in a case-control family study and sought to develop methods to differentiate them from true RLS. METHODS: Family members from the case-control study were interviewed blindly by an RLS expert using the validated Hopkins telephone diagnostic interview (HTDI). Besides questions on the four key diagnostic features of RLS, the HTDI contains open-ended questions on symptom quality and relief strategies and other questions to probe the character of provocative situations and modes of relief. Based on the entire HDTI, a diagnosis of definite, probable or possible RLS or Not-RLS was made. RESULTS: Out of 1255 family members contacted, we diagnosed 1232: 402 (32.0%) had definite or probable RLS, 42 (3.3%) possible RLS, and 788 (62.8%) Not-RLS. Of the 788 family members who were determined not to have RLS, 126 could satisfy all four diagnostic criteria (16%). This finding indicates that the specificity of the four criteria was only 84%. Those with mimic conditions were found to have atypical presentations whose features could be used to assist in final diagnosis. CONCLUSION: A variety of conditions, including cramps, positional discomfort, and local leg pathology can satisfy all four diagnostic criteria for RLS and thereby "mimic" RLS by satisfying the four diagnostic criteria. Definitive diagnosis of RLS, therefore, requires exclusion of these other conditions, which may be more common in the population than true RLS. Short of an extended clinical interview and workup, certain features of presentation help differentiate mimics from true RLS.

Validation of the Hopkins telephone diagnostic interview for restless legs syndrome.

BACKGROUND: Because the diagnosis of restless legs syndrome (RLS) depends on clinical features ascertained by interview, it is important to have structured diagnostic instruments that can guide a diagnostician to an accurate diagnosis. With this aim in mind, the RLS Center at Johns Hopkins has been developing the Hopkins telephone diagnostic interview (HTDI). A previous validation was performed on a patient group. In the current report, we have extended that validation to a non-patient group drawn from on ongoing family study. METHODS: Family members from a case-control RLS study were diagnosed by telephone. Once all available family members in a given family had been interviewed, those who lived locally and had responded were asked to come to Johns Hopkins-Bayview Medical center and had dual clinical interviews to ascertain RLS diagnosis. We then compared the results between the two clinical interviews and between the HTDI and the clinical interviews. RESULTS: Diagnostic agreement between two expert clinicians was 93-96% (kappa 0.87-0.92). Compared to those subjects on whom the clinicians agreed, the HTDI agreed at least 90% of the time; sensitivity was at least 0.90, specificity 0.91, positive predictive value 0.86, and negative predictive value 0.94. CONCLUSION: The HTDI managed a high level of diagnostic accuracy, showing only slightly less agreement than the two clinical interviewers. Because of a mean 12-month period between HTDI and clinical interview, this result also indicates that the subjects' reports of symptoms are consistent and stable. The HTDI should be useful for confirming questionnaire diagnoses or screening subjects to enter basic or therapeutic trials.

Segregation analysis of restless legs syndrome: possible evidence for a major gene in a family study using blinded diagnoses.

OBJECTIVE: The objective of this study was to ascertain the most likely inheritance pattern of restless legs syndrome (RLS) using segregation analysis. METHODS: Probands were RLS patients presenting to the Neurology and Sleep clinics of the Johns-Hopkins Bayview medical center with willing first and second degree relatives. Blinded diagnosis was made in those who exhibited the four diagnostic features of RLS. Analysis was performed on RLS as a dichotomous trait and considering age of onset models on 590 phenotyped subjects from 77 pedigrees. RESULTS: All non-genetic models were rejected considering RLS as a dichotomous trait. A single locus Mendelian dominant model with gender as a covariate had best fit with allele frequency of 0.077 and complete penetrance. RLS frequency in non-carrier subjects was estimated to be 0.14. Two underlying distributions of age of onset, with a possible dichotomy at 26.3 years, were identified. Contrary to the results for RLS as a dichotomous trait, age of onset models did not indicate single major gene inheritance. CONCLUSION: This segregation analysis suggests that the pattern of segregation is consistent with that of a single major locus, when RLS is treated as a dichotomous trait without considering age of onset. The high rate of phenocopies matches known population frequencies and taken with significant residual familial effects and the lack of evidence for a major gene controlling age of onset, indicates that non-genetic causes of RLS may exist and RLS is a complex disorder.