Proton pump inhibitors associated with rapid eye movement sleep behaviour disorder

Abstract

We present the case of a 65-year-old woman diagnosed with rapid eye movement sleep behaviour disorder (REMBD) based on typical symptoms and confirmed with an inpatient polysomnogram. She was prescribed clonazepam and later temazepam but continued to have intrusive symptoms. She subsequently recalled that the onset of dream enactment coincided with starting high-dose omeprazole for acid reflux. With this insight, she stopped the omeprazole. Within days, the dream enactment and nocturnal movements subsided. She stopped taking the temazepam and was symptom free for a few months. However, she was started on lansoprazole for recurrent dyspepsia. Once again she experienced violent movements in sleep. This is the first time an association between proton pump inhibitors (PPIs) and REMBD has been reported. PPIs have many effects on the central nervous system and should be considered as a possible provoking factor in people presenting with REMBD.

Background

Rapid eye movement sleep behaviour disorder (REMBD) is a parasomnia characterized by dream enactment behaviours that occur with loss of REM sleep atonia. It can be either idiopathic or symptomatic of other conditions, especially neurodegenerative disorders such as Parkinson’s disease. Certain antidepressants have also been implicated in the onset of Rapid eye movement sleep behaviour disorder (REMBD). Proton pump inhibitors (PPIs) are commonly prescribed for gastro oesophageal reflux disease. They are H⁺/K⁺ ATPase inhibitors, which interfere with the intracellular H⁺ signalling pathway and have effects on many organ systems including the central nervous system. They have been associated with, for example, hallucinations and insomnia but to our knowledge no link with REMBD has previously been reported.

Case presentation

A 65-year-old woman was referred to the sleep service for evaluation of abnormal behaviours at night. She recalled the onset of the nocturnal movements when she was on holiday a year previously. She was travelling with a friend who witnessed the first episodes. She had been dreaming of an argument and jumped out of bed, ran at the wall and hit her head. Since then, she had nocturnal movements including flailing her arms, shouting and screaming and apparently acting out dreams, almost always in the context of a threatening figure being present, and sometimes associated with minor injuries. She would usually go to bed at 10pm and the events would occur around 4–5 hours later. There was no history of parasomnia. She was not a sleepwalker as a child.

She did not report daytime sleepiness. Her Epworth Sleepiness Score was 6/24. She did not have features of Parkinson’s disease or narcolepsy. On a 2-week sleep diary, her average sleep time was 7.7 hours and no daytime naps were recorded. Both alcohol and caffeine intake were minimal. She was taking omeprazole 40 mg nocte but no other medication. In particular she was not taking antidepressants.

She underwent an inpatient polysomnogram. She was unaware of any abnormal behaviour herself overnight but on video recording it was clear that she was acting out her dreams and talking during REM sleep, with a clear loss of atonia, which confirmed the diagnosis of REMBD (figure 1). Respiratory analysis did not demonstrate sleep disordered breathing although she did snore at times. There was no evidence of significant periodic limb movement disorder. She was prescribed clonazepam 0.5 mg at night and took this for a few months but reported unacceptable new daytime drowsiness and did not feel the behaviours were well controlled. She was changed to temazepam with reduced drowsiness, but she still had violent movements in sleep.

Figure 1.

Two 30 s epochs from the polysomnogram done at the initial diagnosis of rapid eye movement sleep behaviour disorder. REM, rapid eye movement.

She subsequently recalled that the onset of nightmares and dream enactment had coincided with a flare of her gastro-oesophageal reflux disease due to spicy food, eaten when she was on holiday, and starting on high dose omeprazole. She described that the same night she started to have violent movements in sleep, which went on to become nightly occurrences. With this recollection, she discontinued the omeprazole and her symptoms of REMBD subsided within days. She then stopped the benzodiazepine treatment. On review, she described only occasional disturbed nights, but no apparent dream enactment and no falls or injuries.

Outcome and follow-up

After approximately 6 months without taking a PPI, she was started on lansoprazole by her family doctor due to recurrence of dyspepsia. The symptoms of nightmares, dream enactment and shouting in sleep recurred.

She did not wish to try any other medication for REMBD and elected to practise safety precautions to prevent injury. At her most recent review there were no other features to suggest Parkinson’s disease.

Discussion

In normal REM sleep, the sleeper does not act out their dreams because of axial muscle atonia. REMBD, first described in 1986,¹ is a parasomnia characterised by the loss of the normal REM-related muscle atonia resulting in recurrent episodes of dream enactment.² It can result in disrupted sleep and injuries to both patient and any bed partner. The prevalence is between 0.5% and 2% in the population.^{3 4} It is much more frequent in men and in those over 50 years of age.⁵

REMBD can be idiopathic or symptomatic of neurodegenerative disorders including Parkinson’s disease. It may predate the diagnosis of neurodegenerative conditions by many years and so the label of idiopathic is always provisional. In young adults the the most common association is narcolepsy. REMBD is also seen as an adverse effect of medication, most commonly antidepressants of various classes. There are case reports of different antidepressant medications causing REMBD including paroxetine, fluoxetine, imipramine and mirtazapine.⁶ A population study showed an association between antidepressants and early onset REMBD with an OR of 12.0.⁷ Bisoprolol has also been associated with REMBD in a couple of cases.⁸

There are no prior reports of REM behaviour disorder apparently caused by a PPI. While PPIs are prescribed primarily to reduce acid secretion in the stomach, they affect other organ systems and reported side effects include neurological symptoms such as dizziness, paraesthesia and hallucinations and sleep related side effects including insomnia and drowsiness.

REM sleep is mediated by mutually activating and inhibitory ‘REM-on’ and ‘REM-off’ neurones in the brain stem. Cholinergic REM-on neurones in the laterodorsal and pedunculopontine nuclei in the tegmenum, inhibit the REM-off neurones in the pontine locus coeruleus (LC) and dorsal raphe nucleus to initiate REM sleep. Similarly, the REM-off group of cells inhibits REM-on neurones, which either terminate REM sleep or does not allow REM sleep to occur.⁵ A study on male Wistar rats has shown that administering a PPI can hyperpolarise the REM-off neurones leading to their inactivation and an increase in the duration of REM sleep.⁹ It has also been shown that change in intracellular pH is a major part of intracellular signalling pathway, which alters the firing rate of LC neurones in the brain stem, thus potentially affecting REM sleep.¹⁰ It is not yet explored in humans whether a PPI could result in persistent intracellular acidosis causing hyperpolarisation of the LC neurones inhibiting the REM-off cells, thus facilitating REM sleep.

The present case demonstrates that REMBD confirmed on polysomnography was closely linked in onset with the prescription of a PPI and resolved when that drug was withdrawn. Recurrence of symptoms associated with taking another PPI further substantiated the potential causal link. Actigraphy, which is a non-invasive method of monitoring sleep patterns and commonly used in the diagnosis of circadian rhythm disorder, may have been useful to identify movement with and without PPI in this case. This investigation was not performed in this patient, as actigraphy is not part of the usual assessment of REM behaviour disorder in our centre. Well-designed case–control studies will be valuable to further explore the true association of this proposed link between PPIs and REMBD.

Learning points.

• It is important to be aware that medications can trigger sleep disorders and underlines the importance of a good clinical history.

• Rapid eye movement behaviour disorder is a parasomnia with many associations which have to considered during diagnosis and review.

• Proton pump inhibitors have effects on the central nervous system which may have implications in the interfering with sleep signals in the brain stem.

Ethics statements

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