Idiopathic restless legs syndrome (RLS) frequently follows an autosomal dominant inheritance with a variable clinical expressivity of symptoms. We describe the largest German kindred of familial RLS with 20 affected and investigated members in four generations with a variety of clinical symptoms. Patients were examined clinically, and polysomnography was performed in selected cases. The diagnosis was set according to the diagnostic criteria of the International RLS Study Group. All patients showed sensory symptoms of their legs and a worsening of symptoms with increasing age. Older patients, who needed treatment, responded well to opioids. Segregation ratios were close to 0.5, confirming a virtually complete penetrance. The mean age of onset fell from 51.5 years in the second generation to 19.8 years in the fourth generation (ANOVA, p = 0.025). The identification of presymptomatic carriers in the fourth generation in the following years, however, may prejudice this result. This large family showed the variety of clinical RLS symptoms with decreasing age of onset in generations II-IV, suggesting at least the possibility of anticipation.

To investigate the long-term efficacy and safety of sustained-release (SR) in combination with regular-release (RR) levodopa/benserazide in the treatment of restless legs syndrome (RLS), an open-label, prospective, extension study of a preceding double-blind crossover trial was performed for 12 months. Twenty-three severely disturbed RLS patients (7 men, 16 women) received a combination of RR and SR levodopa. Patients were treated on average for 10 months with a mean daily dose of 203 +/- 101 mg of RR and of 185 +/- 93 mg of SR levodopa. The mean daily total dose was 388 +/- 162 mg levodopa. Efficacy was documented using patient's rating scales, sleep diaries, and investigator's global ratings with the Clinical Global Impressions (CGI). Ten of 23 patients completed the 1-year extension. Between baseline of the crossover trial and endpoint of the extension study (last-observation-carried-forward method, intention-to-treat population), quality of sleep improved (+3.5 +/- 1.9, 7-point scale), sleep latency was shortened (-131 +/- 152 minutes), and total sleep time lengthened (+ 190 +/- 136 minutes). Severity of RLS at time of falling asleep (-6.5 +/- 3.4, 11-point scale) and during the night (-6.0 +/- 3.5) was markedly lower at the end of the extension but severity of RLS during the day (+1.9 +/- 5.0) slightly increased. Of 13 dropouts, 8 patients discontinued therapy because of worsening RLS during the day. This trial shows that long-term treatment with the combination of RR and SR levodopa/benserazide in RLS patients with late-night problems was efficacious and not limited by tolerability problems in 40% of patients, whereas in the majority of patients, aggravating daytime problems required termination of the levodopa therapy within the 1-year treatment period.

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