Sleep Disorders and Restless Legs Syndrome in Friedreich's Ataxia
Abstract & Commentary
By Claire Henchcliffe, MD, DPhil, Associate Professor of Neurology and Neuroscience, Weill Cornell Medical Center. Dr. Henchcliffe reports she is on the speaker's bureau and advisory board for Allergan and Teva; speaker's bureau for Boehringer-Ingelheim, GlaxoSmithKline, and Novartis; advisory board for Merz, and is a consultant for Gerson Lehman Group and Guidepoint Global.
Synopsis: Restless Legs Syndrome (RLS) was present in 50% of patients with Friedreich's ataxia (FA), a disorder of intramitochondrial iron accumulation. This study suggests that RLS treatment will potentially help the sleep disorder in appropriately screened FA patients.
Source: Frauscher B, Hering S, Hogl B, et al. Restless legs syndrome in Friedreich ataxia: A polysomnographic study. ePub Dec 13 2010. Mov Disord DOI: 10.1002/mds.22769
Friedreich ataxia affects 1/50,000 individuals and is the most common inherited ataxia. In addition to ataxia, it may result in cardiomyopathy, diabetes, and skeletal abnormalities, but this is the first study to systematically assess sleep disturbance as a non-motor feature of FA. Consecutive patients at Innsbruck Medical University with genetically proven FA underwent evaluation for RLS by a board-certified neurologist, assessment of severity by International RLS Study Group Rating Scale (IRLS), and associated periodic limb movements of sleep (PLMS) and of wakefulness (PLMW) were evaluated by 8-hour polysomnographic studies over two consecutive nights. Of 16 patients (mean age 35.4 ± 11.1 years, FA disease duration 16.5 ± 7.0 years), 8 met standard criteria for a diagnosis of RLS. Mean RLS duration was 8.4 ± 9.1 years, and in 7/8 RLS followed FA diagnosis. None were taking medication for RLS; 3 took antidepressant medications without temporal association with RLS onset, but other prescribed and over-the-counter medications were not reported. Polysomnographic studies recorded a PLMS index of > 15/hour in 7/16 subjects, and PLMW index of > 15/hour in all subjects. Only PLMW index associated with diagnosis of FA with RLS. FA with RLS was associated with lower serum ferritin (male: 124.8 ± 28.3 mg/L vs. 193.7 ± 98.2 mg/L; female: 27.8 ± 15.8 mg/L vs. 72.0 mg/L, P = 0.043). In addition to RLS, 1/16 had witnessed apneas, 2/16 had sleepwalking and reported confusional arousals, and REM sleep without atonia was recorded in polysomnographic studies in 2/16 (considered by the authors due to trazodone and fluoxetine intake).
Commentary
This is the first study to systematically investigate sleep disorders in FA using polysomnography. Although the number of subjects is low, the high prevalence of RLS in these 16 subjects, and the presence of other disorders (sleep apnea, rapid eye movement sleep without atonia) strongly suggests that this bears further study, both to better understand the disorders (FA and RLS) themselves and to directly impact patient care. FA displays autosomal recessive inheritance and is caused by GAA-trinucleotide repeat expansions in the frataxin gene. The corresponding protein, present in mitochondria, is critical to iron homeostasis. In FA, frataxin expression is reduced and iron accumulates in the nervous system, heart, and other tissues: indeed, attempts to translate this into novel therapies (including idebenone, and desferiprone) are ongoing. Iron dysregulation also occurs in RLS, with low ferritin levels in many. It is therefore tempting to postulate that aberrant iron homeostasis/metabolism is the underlying link between FA and RLS. The relationship, though, is obviously complex and by no means suggests extrapolating iron supplementation treatment sometimes given in RLS to FA with RLS. The anatomical underpinnings of RLS in FA may also be complex. The authors strongly suggest spinal cord pathology as the primary link between FA and RLS. Again, this is far from clear, as pathology in FA is widespread, involving the spinal cord, but also the cerebellum, brainstem, and cerebral hemispheres. It is therefore intriguing that Synofzik and colleagues,1 in addition to diagnosing RLS in 32% subjects with FA, reported sonographic hypoechogenicity likely reflecting decreased iron content present in the substantia nigra, that was significantly associated with RLS, as well as FA severity. Given the multi-system nature of FA, possible links to other sleep disorders need to be seriously consideredthe authors suggest that REM sleep without atonia was medication-related in their subjects, but this will need further characterization. Finally, this study is important in that, together with Synofzik and colleagues,1 it supports close questioning of patients' sleep habits in FA, with sleep studies where appropriate, and with a view to alleviating a subset of symptoms in this challenging disorder.
Reference
1. Synofzik M, Godau J, Lindig T, et al. Restless legs and substantia nigra hypoechogenicity are common features in Friedreich's ataxia. Cerebellum 2010. ePub ahead of print.