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We describe the novel association of Horner syndrome and contralateral paroxysmal facial flushing and sweating (Harlequin syndrome) with overlap parasomnia.
A 66 year old woman suffered right jaw and multiple limb fractures when she was 45. Since then she had recurrent sudden onset episodes of right hemifacial flushing and sweating, occurring with physical exertion and heat, rarely spontaneously, and lasting 20 to 30 minutes. Approximately one year after the trauma, her sleep became restless, being interrupted by excessive motor activity, seemingly purposeful and sometimes harmful, associated with vocalisation and a report of dreaming corresponding to the motor manifestations. Hypnagogic hallucinations and sleep paralysis could also rarely occur. Both facial flushing and sleep disturbances worsened after another accident to her face when she was 64.
Examination at age 66 showed partial ptosis of the left eyelid, myosis, and iris heterochromia with subtle enophthalmos. Anisocoria increased in dim light, and 0.01% epinephrine eye drops did not modify the size of the left pupil. Brain magnetic resonance imaging (MRI), somatosensory evoked potentials, transcranial magnetic stimulation, blink reflexes and palmar sympathetic skin responses, baseline and tilt test cardiovascular reflexes, and circadian body core temperature rhythm were all normal. Sweating—assessed by the application of alizarin powder during a heating test1—was absent on the left side of the face and reduced on the right upper limb. After heating, only the right side of the face showed flushing. These changes were replicated by physical exercise. There was no lacrimal or gustatory sweating.
Twenty four hour videopolysomnographic recordings (PSG) documented five nocturnal sudden and short lasting (20 to 40 seconds) awakenings during non-rapid eye movement (NREM) sleep, during which there was mumbling vocalisation, head and trunk raising from the bed, and a subsequent change in posture. These episodes were characterised by EEG α rhythms intruding upon light or deep NREM sleep activity. During NREM sleep an EEG showed short sequences of REM-like patterns (sawtooth waves and desynchronised high frequency/low amplitude activity), sometimes with chin muscle atonia. During REM (rapid eye movement) sleep, her EEG showed typical elements but also frequent intrusions of spindles and α activities, with partial chin atonia on electromyography (EMG) and bursts of phasic EMG activity associated with vocalisation and facial movements. These transitional patterns of “mixed EEG” accounted for about 20% of total REM and S2 sleep time (fig 1). During a subsequent 48 hour Vitaport® evaluation, which confirmed the presence of “mixed EEG patterns,” the patient reported vivid dream contents related to awakenings from both REM and NREM sleep. A multiple sleep latency test showed borderline daytime somnolence (mean sleep latency, 8 minutes and 48 seconds) with frequent early microsleeps during all sessions. Chin EMG was unstable during each session, without a clear cut relation to the microsleeps.
A 52 year old woman presented with a two year history of sudden sweating and flushing of the left hemiface. Physical exercise and heat could cause these episodes, which also occurred spontaneously. Lacrimal and gustatory sweating were absent. At age 51, abnormal motor activities had appeared during sleep, associated with vocalisation resulting from vivid frightening dreams which the patient could report after waking. During admission, episodes characterised by sudden arousal during nocturnal sleep with screaming and fearful vocalisation were observed by room mates. From this time, nocturnal sleep became non-refreshing and was interrupted by brief and abrupt awakenings; there was excessive daytime sleepiness.
On physical examination the right pupil was smaller than the left and did not dilate to dark. Right iris heterochromia with right ptosis and subtle enophthalmos were also present, and epinephrine 0.01% eye drops did not change the size of the right pupil. A body heating test with alizarin powder application1 showed absent sweating in the right hemiface. Brain and spinal cord MRI and neurophysiological investigations including neurovegetative tests as in patient 1 were all normal.
Twenty four hour video PSG showed long sequences in which NREM and REM PSG features were intermingled: in particular runs of rapid eye movements and sawtooth waves intruded during stage 2 sleep associated with chin EMG fluctuations, and K complexes and sleep spindles were observed during REM sleep patterns. Chin muscle atonia was not complete during REM sleep, with brief sudden twitches and tonic EMG bursts; full blown REM sleep behaviour disorder (RBD) could not be recorded; chin muscle atonia could also appear suddenly during NREM sleep, randomly or before a leg movement. These intermingled NREM-REM sleep PSG patterns occupied 33.5% of total REM and stage 2 NREM sleep time.
Our patients had anhydrosis of one side of the face and long standing ipsilateral Horner’s syndrome associated with both spontaneously occurring and heating/exertion induced paroxysmal hemifacial sweating, consistent with Harlequin syndrome.1 They probably suffered a lesion of the first sympathetic neurone. While the negative dilute epinephrine eye drop test result suggested an absence of adrenergic supersensitivity secondary to a third sympathetic neurone lesion, absent lacrimal and gustatory sweating excluding a second or third sympathetic neurone lesion.2,3 The exact lesion site, however, eluded us because of the negative MRI findings. In addition, our patients suffered abnormalities of nocturnal sleep, with recurrent seemingly purposeful motor activities like enacted dreams intruding into NREM and REM sleep, and PSG patterns characterised by an admixture of wake, NREM, and REM sleep EEG elements. Thus our patients had evidence for both a disorder of arousal and RBD because, from a behavioural point of view, they presented with atypical sleep with frequent muscle twitchings, vocalisation, and dream-like mentation on waking. Such a mixed state of wakefulness and sleep is typical of the state dependent failure of control of the so called “parasomnia overlap” syndrome.4 Hypnagogic hallucinations and sleep paralysis were also reported by patient 1. Remarkably, the Harlequin syndrome was temporally linked and preceded the parasomnia overlap syndrome by one year, suggesting a possible connection between the two. Overlap parasomnia has been noted after lesions, even trauma, of the brain stem and forebrain regions,5 but ours is the first report of an association between Harlequin syndrome and sleep disorders in the form of overlap parasomnia syndrome. Our findings emphasise the need for an integrated approach to patients with autonomic and sleep disorders.
We thank the sleep laboratory staff for excellent technical skills, Ms Candela Carmina for neurovegetative tests, Ms E. Zoni for help with the iconography, Ms A Laffi for secretarial assistance, and A Collins for editing the text. The work was supported by COFIN MURST ex-40% 1999 No 9906037938, 2000 No MM06244347-004, and MURST ex-60% 2000 and 2001 grants.