Sleep Deficiency and Stroke Outcome
Condition: Sleep Apnea Syndromes; Sleep Initiation and Maintenance Disorders; Insomnia; Restless Legs Syndrome; Stroke
MeSH terms: Sleep Apnea Syndromes; Stroke; Sleep Initiation and Maintenance Disorders; Psychomotor Agitation; Restless Legs Syndrome; Syndrome
Study type: Observational

Summary: 
      Deficient sleep duration and sleep disturbances - such as insomnia, sleep disordered
      breathing (SDB) and restless legs syndrome (RLS)- are associated with hypertension and
      cardio-cerebrovascular morbidity and mortality. Several studies suggest that sleep disorders
      are frequent after stroke and detrimental for stroke outcome. However, more prospective
      studies in a large unselected sample of stroke survivors are needed to better investigate the
      short- and long-term consequences of sleep disturbances on mortality and occurrence of new
      cardio-cerebrovascular events. Also their pathophysiological mechanisms and their influence
      on stroke recovery should be better understood.

      Therefore, the aim of this study is to assess the impact of sleep deficiency and sleep
      fragmentation on the frequency of new cerebro- and cardiovascular events and death after
      stroke or transient ischemic attacks, and clinical outcome within one and two years after
      stroke.

      The working hypotheses are that stroke survivors with sleep deficiency and sleep
      fragmentation due to insomnia, sleep-disordered breathing or restless leg syndrome will
      present: (1) higher mortality from all causes and higher frequency of new cardio-/
      cerebrovascular events; and (2) a less favorable clinical outcome. Outcomes will be compared
      between patients with and without sleep deficiency and fragmentation.

      Since current clinical practice in cerebrovascular patients does not sufficiently consider
      sleep disorders in patient's management, this study can help to bring attention to a still
      overlooked medical problem and change the current standard of management of stroke survivors.
    

Detailed description: 
      Background

      Experimental and clinical data suggest a detrimental effect of sleep deficiency/sleep
      fragmentation on stroke outcome. In rodents, sleep fragmentation and sleep deprivation
      induced in the acute phase of stroke enhance the extension of the lesion and impair
      functional recovery - inversely, sleep-promoting drugs have a positive effect on functional
      recovery. In humans, a negative effect of sleep deficiency and sleep fragmentation due to
      sleep-disordered breathing (SDB), restless legs syndrome (RLS) and insomnia on stroke outcome
      has also been suggested but only insufficiently tested.

      SDB is found in 50-70% of patients with transient ischemic attacks and acute ischemic stroke.
      Patients with SDB demonstrate a more rapid progression of stroke severity as well as higher
      blood pressure and longer hospitalization in the acute phase of stroke. Over time, they also
      exhibit a higher mortality. Functional outcome is also negatively affected by the presence of
      SDB. Moreover, SDB was shown to represent an independent risk for hypertension and
      cardiovascular morbidity and mortality, and for stroke.

      The frequency of insomnia in patients with stroke in a prospective study achieved 68% in the
      acute phase decreasing to 49% after 18 months. However, systematic large scale observational
      studies on the frequency of insomnia in stroke patients are lacking. Sleep duration after
      stroke has been assessed in few studies only (e.g. in patients with paramedian thalamic
      stroke), in some of them a good correlation with actigraphic measurements was found.
      Moreover, over the last three decades a link was found between sleep deficiency and
      fragmentation and cardiocerebrovascular morbidity and mortality based on epidemiological
      data. In particular, short sleepers (e.g. sleep duration < 6 hours) and poor sleepers
      (reporting a non-restorative sleep) presented a higher risk of cardiovascular events
      including death, coronary heart disease and stroke. Insomnia and sleep duration in the
      general population were also reported to predispose to an increased risk of hypertension,
      cardiovascular events and mortality.

      A high association between RLS and stroke was demonstrated in a few studies. RLS was found in
      12% of 137 patients after stroke and predicted a worse outcome. Few case reports reported
      high numbers of periodic limb movements during sleep (PLMS), which are often associated with
      RLS, in stroke patients. An association of RLS/PLMS with hypertension, cardiovascular
      diseases and stroke was also discussed in recent years. However, the large scale data on the
      impact of RLS for the stroke outcomes are lacking.

      The possible mechanisms linking sleep deficiency, poor sleep and sleep fragmentation with
      cardiovascular disorders (including stroke) are multiple and include an elevated sympathetic
      activation, procoagulatory and inflammatory changes, increased atherosclerosis, and changes
      in cerebral hemodynamics and oxygenation. However, the clinical relevance and the association
      with clinical outcomes needs further investigation.

      Objective

      The aim of this study is to assess the impact of sleep deficiency and sleep fragmentation
      resulting from insomnia, SDB or RLS on the frequency of new cerebro- and cardiovascular
      events after stroke or TIA including death of any cause, and clinical outcome within one and
      two years after stroke.

      Primary objective of the study is the assessment of the frequency of all-cause deaths and new
      cerebro- and cardiovascular events within 24 months after stroke or transient ischemic attack
      in patients with and without sleep deficiency/fragmentation.

      The main secondary objective is an assessment of clinical outcome 12 months after stroke in
      patients with and without sleep deficiency/fragmentation.

      Methods

      Patients with acute ischemic stroke or TIA will be recruited at two Neurology Departments in
      Switzerland (Inselspital Bern & Neurocenter of Southern Switzerland Lugano). Two groups will
      be formed based on the presence or absence of sleep deficiency/fragmentation assessed at one
      month following stroke by questionnaires and telephone interviews. Examinations (at baseline
      & 3, 12 and 24 months follow up after stroke) will include standardized and validated
      questionnaires assessing stroke outcome (independence and activities of daily living) as well
      as insomnia, RLS, risk for sleep apnea, depression and apathy. Additional non-invasive
      physiological assessments will be performed in about every fifth of all recruited patients in
      the acute phase of stroke and after 3 and 12 months. They include ambulatory blood pressure
      measurements and wrist activity assessing 24h physical activity patterns over 3 weeks,
      assessment of arterial stiffness/endothelial function and basic cognitive performance.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Patients suffering from ischemic stroke or transient ischemic attack (TIA) will be
        recruited at the Stroke Unit and the ward of the Department of Neurology, Inselspital Bern,
        and the Stroke Unit and ward of the Neurocenter of Southern Switzerland, Lugano, and
        followed-up for (at least) 2 (maximum 4) years. They will be evaluated for pre-existing and
        new-onset sleep disturbances that result in sleep deficiency (< 6h sleep /night and/or
        post-stroke reduction of average sleep time/night ≥ 2h) or sleep fragmentation (insomnia,
        sleep-disordered breathing, restless legs syndrome).
      
Keywords: Stroke; Ischemic Attack, Transient; Cardiovascular Diseases; Sleep Apnea Syndromes; Sleep Initiation and Maintenance Disorders; Insomnia; Restless Legs Syndrome; Sleep Deprivation