Sleep Complaints in Periodic Paralysis

Giorgio Buzzi, MD, Neurologist

Buzzi G, Mostacci B, Sancisi E, Cirignotta F. Sleep complaints in Periodic Paralyses: a web survey. Functional Neurology 2001, 17 (3). From the Sleep Medicine Unit - Dept. of Neurology S.Orsola-Malpighi Hospital - University of Bologna, Italy.

SUMMARY

Section 1. Background: K+ and REM sleep homeostasis.

Section 2. The Periodic Paralysis International/HKPP Listserv Survey: results and discussion.

Section 3. Conclusions: A Narcolepsy-like variant of periodic paralyses?

References.

Abbreviations: PP = Periodic Paralysis; HypoKPP = Hypokalemic Periodic Paralysis; HyperKPP = Hyperkalemic Periodic Paralysis; REM sleep = Rapid Eye Movements sleep.

Section 1:

BACKGROUND: K+ AND REM SLEEP HOMEOSTASIS

Two studies in rats published on the journal "Brain Research" and a case report of a man with HyperKPP published in the journal "Sleep" suggest that neuronal potassium conductance may influence REM sleep homeostasis. This, in turn, may result in abnormal REM sleep expression. The studies in rats. Apamin, a bee venom neurotoxin, is an amino acid peptide which selectively blocks one class of Ca2+ -dependent K+ channels, the small conductance SK channels, in neuronal as well as other excitable cells. Apamin-binding sites are also situated in the brain in areas associated with sleep control, so it appeared of interest to analyse the influence of low doses of apamin on the sleep-waking cycle.

Two recent studies addressed this issue. In the first study (1), the authors administered small doses of apamin into the lateral cerebral ventricle in rats, and characterized the resultant effects on REM-sleep expression. Apamin produced a dose-dependent reduction in REM-sleep expression, followed by small REM-sleep rebounds. In the second study (2), the authors found that apamin induced insomnia and a long-lasting suppression of deep slow sleep and REM sleep. Injected animals showed a late but important rebound of REM sleep. After the recovery of the normal circadian amounts of the sleep-waking stages, the day-night alternation of the cycle still remained disturbed until 96 hours after apamin administration.

According to the authors, the foregoing study failed to see the compensatory REM-sleep rebound since the animals were recorded for no more than 40 hours following injection of the toxin. The authors state that the effects of apamin on sleep are spectacular and that they are certainly associated with a blockade of SK type Ca2+-activated K+ channels since apamin is very specific for SK channels.

The case of a man with HyperKPP and abnormal REM sleep. Iranzo and Santamaria (3) reported the case of a 24-year-old man with sporadic HyperKPP who presented with moderate excessive daytime sleepiness and transitory episodes of weakness which occurred during and after sleep. Multiple sleep latency test (MSLT) demonstrated the presence of five sleep onset REM periods (SOREMPs) and a sleep latency of five minutes. MSLT consists of five nap recordings during one day (for example, at 9 a.m., 11a.m., 1 p.m., 3 p.m., 5 p.m.).

Sleepiness is indicated by a mean sleep latency below 10 minutes; a SOREMP is defined as a REM period occurring within 15 minutes of sleep onset. A mean sleep latency below 10 minutes and two or more SOREMPs are considered to be supporting evidence for the diagnosis of narcolepsy. Treatment with a diuretic which decreases serum potassium resolved all the clinical symptoms and a new MSLT showed the absence of SOREMPs and a sleep latency of 13.5 minutes. According to the authors, this case suggests that SOREMPs may be explained by an increased extracellular potassium conductance related to HyperKPP.

In summary, these studies suggest that neuronal potassium conductance may influence REM sleep homeostasis. On this ground, it's conceivable that both Hypo- and HyperKPP subjects may have periods of enhanced REM sleep expression: HyperKPP patients, due to an increased extracellular potassium conductance; and HypoKPP patients, as a rebound phenomenon following REM sleep suppression due to a decreased extracellular potassium conductance (on the analogy of the well known REM sleep rebound during withdrawal from serotonergic antidepressants, which suppress REM sleep). Enhanced REM sleep expression may result in unusual sleep phenomena such as sleep paralysis, nightmares / abnormal dreams and sleep-related hallucinations.

Section 2: THE PERIODIC PARALYSIS INTERNATIONAL NEWSDESK/HKPP LISTSERV SURVEY

Here I report a summary of the main results of a survey conducted among the members of the HKPP Listserv in August-September 1999. Forty-two Periodic Paralysis patients filled out a sleep questionnaire; 38 questionnaires (28 from hypoKPP patients, 10 from hyperKPP patients) were suitable for analysis. Items regarding excessive daytime sleepiness, insomnia, and three REM- sleep related disorders (nightmares/abnormal dreams; hypnagogic/hypnopompic hallucinations; sleep paralysis) were analyzed in PP patients and were compared with the following control groups: thirty-four (34) patients with untreated depression; Forty-eight (48) patients with depression under treatment; and 37 healthy subjects.

The Periodic Paralyses are a group of rare disorders characterized by episodes of muscular weakness associated with changes in the serum potassium levels and, therefore, with possible alterations in extracellular neuronal potassium conductance. (Sleep Paralysis consists of brief episodes of inability to move, at sleep onset or upon awakening, which differ from PP attacks because of a spontaneous and complete cessation within seconds or a few minutes. Hypnagogic (at sleep onset) and hypnopompic (upon waking) hallucinations consist of vivid perceptual experiences (including visual, tactile, kinetic, and auditory phenomena) or intense dream-like imagery just before falling asleep or just after awakening.

In our survey, both subjects with PP and untreated depression had a higher frequency of insomnia complaint and a higher number of nocturnal awakenings than healthy controls and patients with depression under treatment. PP subjects were more likely to report experiencing excessive daytime sleepiness, nightmares/abnormal dreams, and sleep related hallucinations in comparison with the three other groups. PP patients also reported experiencing sleep paralysis more frequently than the three other groups, but the difference was not statistically significant.

Abnormal dreams Several subjects (either with hypo- or hyperKPP) reported experiencing abnormal dreams associated with nocturnal PP episodes: "I have very vivid dreams when I'm going into an episode and will dream that I'm having difficulty walking, or unable to move, or trying to call for help and no sound comes out". "I might actually dream that I was in an episode, but most often I'd have a dream where my body would slow down". "I had the same dream in which I could not move and someone would come and help me and then I managed to come out of this and realized I was in a serious episode". "I am always weak in my dreams". "I recognize from the character of the dream that I am entering an episode, and that I need to awaken and get some potassium". "I have learned to recognize these dreams as signs of an episode and can now say to myself, even asleep, ‘You're having an episode. Wake up’. And then I wake myself, and if I can move I will get up and get potassium". "I'll realize that I am going into an episode and I'll wake myself up enough to flail around to get my husband's attention".

This kind of dream imagery strictly resembles dream imagery possibly associated with sleep paralysis. Sleep paralysis is supposed to be caused by abnormal REM sleep intruding into wakefulness. During REM sleep our body is paralyzed, so to prevent us from acting our dreams. Such physiologic paralysis occurs 4-5 times every night, in concomitance with every REM sleep phase, but we are not aware of it. Indeed, REM sleep has been defined as "a state of hyperattentiveness in which sensory input cannot address the machinery that generates conscious experience". In sleep paralysis, REM sleep atonia occurs at sleep onset or upon awakening, when the subject has a high level of alertness, and so s/he is aware to be paralyzed. This is probably due to a biochemical anomaly of the systems regulating the onset and/or offset of REM sleep. In Periodic Paralyses, the occurrence of episodes of flaccid paralysis out of REM sleep may generate the stereotypical "periodic paralysis nightmare" that somehow resembles the dream imagery associated with sleep paralysis. 

Sleep-related hallucinations These are characterized by REM sleep -like mentation occurring while the subject is aware of his/her surroundings: "In that state I can't tell reality from hallucination, and I have no idea I'm paralyzed, where in my dreams I recognize that I am having an episode immediately. The difference between dreams and hallucinations is I recognize a dream for what it is. A 'hallucination' appears so realistic, even if it isn't anything 'real,' that I often can't sort out if it actually happened or if it just happened in my head". Sleep-related (hypnagogic/hypnopompic) hallucinations have been pathophysiologically related to dissociated REM sleep intruding into wakefulness. Conditions enhancing the REM sleep propensity, such as periods of REM sleep rebound following pharmacologic REM sleep suppression, may facilitate the occurrence of these phenomena.

In hypoKPP, the occurrence of nocturnal episodes of hypokalemia, typical of this condition, may result in a reduced extracellular neuronal potassium conductance and this, in turn, may cause a reduction in REM sleep expression, followed by compensatory REM rebounds (see section 1). On the other hand, in hyperKPP, transitory episodes of weakness are associated with an increase in the serum potassium level which may enhance REM sleep propensity (see the report by Iranzo and Santamaria).

This could also be the case of a 59-year-old man with a clinically-defined diagnosis of hyperKPP and paramyotonia congenita who participated in our survey and reported brief episodes of hallucinations occurring regularly during each sleep-related attack and not at other times. In summary, our survey suggests that some persons with PP may have a disrupted sleep architecture (due to nocturnal episodes of paralysis which may cause abnormal dreams or nightmares and may awaken the patient) and a disrupted sleep homeostasis (due to alterations in neuronal potassium conductance, with possible REM sleep dysfunction).

Section 3: PERIODIC PARALYSES MISDIAGNOSED AS SLEEP DISORDERS?

This survey suggests that a subgroup of PP patients may have prominent sleep disorders. Moreover, since it is known that some subjects have only nocturnal PP attacks, in some cases these unusual sleep phenomena may be the only apparent symptoms of the disease. In these subjects, PP could be misdiagnosed as a sleep disorder. In particular, the sleep complaints detected in some PP patients by our survey (daytime sleepiness, insufficient sleep quality with nocturnal awakenings, nightmares, sleep-related hallucinations, sleep paralysis) may resemble symptoms of Narcolepsy.

Narcolepsy is a disorder characterized by excessive sleepiness and abnormal REM sleep phenomena such as sleep paralysis and hypnagogic hallucinations. Nocturnal sleep disruption with frequent awakenings occurs in many patients with narcolepsy. Narcolepsy, however, is a disorder involving a specific neuroanatomic wiring and specific neurochemical mechanisms. Recent findings have also suggested that hypocretins (neuropeptides made in the dorsal and lateral hypothalamic areas of the brain), are implicated in the pathogenesis of narcolepsy. So, pathologic conditions producing an increased propension to REM sleep (like PPs, according to the results of this survey) may cause sleep disorders resembling Narcolepsy, but not true Narcolepsy.

In particular, the most peculiar symptom of Narcolepsy, i.e., cataplexy, has never been found in other pathologic conditions. Cataplectic attacks are defined as sudden episodes of bilateral muscle weakness triggered by strong emotion (most typically, by laughing or by telling or hearing a joke). This doesn't mean that a patient with PP can't have true Narcolepsy too, but I think that this would be an highly unlikely coincidence (this may be, perhaps, the case of the List member "Hypo-Narco").

In summary, this study suggests that a subgroup of persons with Periodic Paralysis may have a prominent sleep disorder resembling Narcolepsy, but distinct from Narcolepsy in that an alteration in neuronal potassium conductance - rather than an alteration in the hypocretin pathway, like in Narcolepsy - is the most likely cause of the altered REM sleep expression in this subjects.

REFERENCES.

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Ptacek L. The familial periodic paralyses and nondystrophic myotonias. Am j Med 1998: 104:58-70

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Gottesmann C, Neurophysiological support of conciousness during waking and sleep. Prog Neurobiol 1999;59:469-508 Thorpy MJ ed. International Classification of Sleep Disorders: Diagnostic and Coding Manual. Rochester; Diagnostic Classification Steering Committee-American Sleep Disorders Association 1990

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Tricarico D, Barbieri M, Conte Camerino D, Acetazolamide opens the muscular KCa2+ channel: a novel mechanism of action that may explain the therapeutic effect of the drug in hypokalemic periodic paralysis. Ann Neurol 2000;48:304-312

Iranzo AI and Santamaria J. Hyperkalemic Periodic Paralysis associated with multiple sleep onset REM periods. Sleep 1999; 22 (8): 1123-1124

Our thanks to Dr. Buzzi for his kind permission to place this article on our website. He may be reached at: gbuzzi@linknet.it .

 

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