Unexpected REM sleep excess associated with a pontine lesion in multiple sclerosis

Abstract

Sleep disorders are prevalent in patients with multiple sclerosis. In contrast, a frank increase of rapid eye movement (REM) sleep time is a rare phenomenon, mostly described in the context of REM sleep rebound (after sleep deprivation, abrupt withdrawal of antidepressants or neuroleptics, and during the first night of ventilation for severe sleep apnea), but not in link with specific brain lesions. We incidentally found an isolated, marked increase in REM sleep time (200 min, 40% of total sleep time, normative values: 18.2–20.3%) and in rapid eye movements density during REM sleep in a patient with a secondary progressive multiple sclerosis, associated with an anterior pontine demyelinating lesion on magnetic resonance imaging. This result suggests that a network blocking REM sleep in the pons has been damaged.

Citation:

Zeidan S, Redolfi S, Papeix C, et al. Unexpected REM sleep excess associated with a pontine lesion in multiple sclerosis. J Clin Sleep Med. 2021;17(5):1117–1119.

INTRODUCTION

An increased prevalence of sleep disorders is reported in patients with multiple sclerosis, including insomnia, restless legs syndrome, periodic limb movement disorder, sleep-related breathing disorders, narcolepsy, hypersomnia and rapid eye movement (REM) sleep behavior disorder.^1,2 A frank increase of REM sleep time is a rare phenomenon, which has been mostly described in the context of REM sleep rebound after REM sleep deprivation,³ after abrupt withdrawal of antidepressants or neuroleptics (which reduce REM sleep) and during the first night of treatment of severe sleep apnea.⁴ However, an increase of REM sleep time has not been reported in relationship with specific brain lesions. We report a case of incidental increased REM sleep time in a patient with secondary progressive multiple sclerosis.

REPORT OF CASE

A 47-year-old woman followed for a secondary progressive multiple sclerosis underwent a video polysomnography in the setting of a study describing respiratory disorders in patients with severe multiple sclerosis. She had been diagnosed with multiple sclerosis when she was 28 years old, and developed a secondary progressive phenotype 7 years later. She had no other medical history. Expanded Disability Status Scale score was 7/10, as she was able to walk only 5 m with 2 aids. The ongoing treatments included fampridine (prolonged-release, 10 mg twice daily), baclofene (10 mg daily), fluoxetine (20 mg daily), and occasionally bromazepam (1.5 mg at bedtime). She reported a mildly increased daytime sleepiness (score at the Epworth sleepiness scale: 12/24) and, on average, 8 h of sleep per night, which was felt as restorative. She had no snoring, nycturia, restless legs, abnormal behavior during sleep, sleep paralysis, hypnagogic hallucinations, cataplexy, or lucid dreams. Dream recall frequency was 3.5 dreams/month. She had no current symptom of depression. Importantly, she had not recently discontinued or reduced her antidepressant treatment with fluoxetine, and there was no recent sleep deprivation.

The video polysomnography showed mildly increased total sleep time (TST, 494.5 min, normative values: 371.4–401.9 min)⁵ and sleep efficiency (94.2%, normative values: 83.7–87.1%) and mildly decreased sleep onset (8.5 min) and REM sleep latencies (75.5 min). The duration of REM sleep was dramatically increased, representing 200 min and 40.4% of TST (normative values: 18.2–20.3%) (Figure 1A), to the expense of N2 sleep, which represented 32.8% of TST (normative values: 50.6–53.8%), whereas N3 sleep was mildly increased (26.8% of TST, normative values: 18.5–22.2%). In REM sleep, there was a normal atonia (REM sleep without atonia: 1.3% of REM duration, normal < 18%),⁶ but the density of rapid eye movements was increased (67.5% of REM sleep duration, when 20% is expected on average).⁷ The arousal plus awakening index was normal (12.9 events/h). There was no sleep-related breathing disorder (apnea-hypopnea index was 1.2 events/h, absence of hypoventilation on transcutaneous CO₂ monitoring). The periodic leg movement index was 15.3 events/h, and the periodic leg movement arousal index was 0.5 events/h. Brain magnetic resonance imaging showed disseminated supratentorial and cerebellar demyelinating lesions, as well as a lesion in the ventral part of the pons, as shown in Figure 1B.

Figure 1. Increased REM sleep time associated with a pontine lesion.

(A) Hypnogram of the patient, showing excessive rapid eye movement (REM) sleep time, representing 200 minutes and 40.4% of total sleep time (normal: 18.2–20.3%). 1, 2, and 3 = non-REM sleep, stages N1, N2, and N3; EEG = electroencephalogram; R = REM stage; W = wake. (B) Magnetic resonance imaging of the patient (sequence T2), axial and sagittal sections, showing the pontine lesion (red arrows).

DISCUSSION

There was a major increase of REM sleep time and percentage in a patient with progressive multiple sclerosis, which was associated with an anterior pontine demyelinating lesion. REM sleep structure contained an excess of eye movements but a normal muscle atonia. This sleep pattern was not otherwise explained by a REM rebound after withdrawal of antidepressants or sleep deprivation, nor by a depression, which are the usual causes of increased REM sleep.⁸ On the contrary, the patient was routinely treated with drugs supposed to reduce REM sleep (including fluoxetine, baclofene, and bromazepam).

Dysregulation of REM sleep associated with demyelinating lesions in multiple sclerosis has been reported in rare cases, including pontine tegmentum lesions causing REM sleep behavior disorder or bilateral hypothalamic lesions causing narcolepsy.⁹ However, increased REM sleep time has not been linked to demyelinating lesions to the best of our knowledge. Polysomnographic studies have shown a normal REM sleep duration in patients with multiple sclerosis.^2,10

In animal models, REM sleep is generated by a group of neurons located in the dorsal pontine tegmentum, which include in the rat the caudal laterodorsal tegmental nucleus, sublaterodorsal nucleus and precoeruleus region and, in the cat, the peri-locus coeruleus alpha (equivalent to the locus subcoeruleus in human brain).¹¹ REM-on cells are blocked by monoaminergic pathways (including serotonergic fibers emerging from the raphe nucleus and norepinephrine fibers from the locus coeruleus), as well as by descending fibers from the hypothalamus (hypocretinergic and histaminergic nuclei) and gamma-aminobutyric acidergic neurons from the ventrolateral periaqueductal gray matter and lateral pontine tegmentum.¹² Damage in any of these tracts may cause excessive REM sleep time and possibly excessive REMs. Interestingly, this increase is selective of REM sleep, as NREM sleep time is normal and muscle atonia is maintained during REM sleep (indicating that the locus subcoeruleus is intact). However, we cannot be certain that the pontine lesion causes the REM sleep excess in absence of a time sequence showing that REM sleep time returns to normal values when the lesion disappears.

The clinical consequences of increased REM sleep time are not known. A mild increase of REM sleep (but not to the point of reaching 40% of total sleep time) is a trait marker of depression, although it remains unclear whether it is causative or only a common marker of low serotonin levels in the brain.⁸ Nevertheless, focal lesions of the brain stem associated with specific sleep disturbances are rare and need to be reported, especially in multiple sclerosis, as they support the role of the pons in REM sleep control in humans.

DISCLOSURE STATEMENT

All authors have seen and approved this manuscript. Work for this study was performed at Hôpital Pitié‐Salpêtrière, APHP-Sorbonne, Paris. The patient participated in a larger trial on respiratory disease in multiple sclerosis (RespiMus study, describing respiratory disorders among patients with severe multiple sclerosis, NCT03339817), funded by grants from Novartis Pharma and Roche Pharma. The authors report no conflicts of interest.

ABBREVIATIONS

REM

rapid eye movement

TST

total sleep time