Sleep 12(5):400-404, Raven Press, Ltd., New York 1989 Association of Professional Sleep Societies Cerebral Anoxic Attacks in Sleep Apnea Syndrome Fabio Cirignotta, Marco Zucconi, Susanna Mondini, Roberto Gerardi, and Elio Lugaresi Institute of Neurology, University of Bologna, Italy Summary: In a 52-year-old man who presented with an obstructive sleep apnea (OSAS) syndrome, we observed cerebral anoxic attacks during rapid eye movement (REM) sleep. Polysomnography showed that the attacks were due to severe hypoxia provoked by apneas lasting up to 220 s. Electroencephalogram (EEG) and clinical features clearly differentiate cerebral anoxic attacks from epileptic seizures. The length of apneas in our patient is very unusual, indicating an impairment of the mechanism terminating apneas. The cause of this impairment is unknown. However, this case report documents a possible pathogenetic mechanism other than heart arrhythmias responsible for sudden death or coma arising during sleep. Key Words: Sleep apnea-cerebral anoxic attack. In 1960, Houdart et al. (1) reported epileptic seizures during sleep in a patient with Pickwickian syndrome, and ascribed the fits to apnea-induced anoxia. Few other reports of seizures in sleep apnea syndrome are available in the literature (2,3). On the other hand, without electroencephalogram (EEG) monitoring it is not easy to discriminate epileptic seizures from cerebral anoxic attacks. This is the first polygraphically documented report of cerebral anoxic attacks provoked by obstructive sleep apneas. CASE REPORT A 52-year-old man working in a factory for orthopedic fittings since age 14 was referred to us for daytime sleepiness and heavy snoring. He had been snoring since age 20, and at age 51, had experienced a hypercapnic coma during sleep which lasted several hours. His wife reported that during the last few months he had presented sporadic "jerks" during sleep. Neurological examination and electromyogram (EMG) showed a mild polyneuropathy in the lower limbs, attributed to solvents, (including n-hexane), which he had been exposed to for over 30 years. Autonomic studies included tilt table test, Valsalva maneuver, and deep breathing Accepted for publication May 1989. Address correspondence and reprint request to Dr. F. Cirignotta, Institute of Neurology, via U. Foscolo 7,40123, Bologna, Italy. 400
CEREBRAL ANOXIA IN SLEEP APNEA 401 test, which were normal. On testing the diving reflex, however, the patient had a cardiac arrest lasting 5 s as soon as his face was immersed. Pulmonary function evaluation during wakefulness demonstrated a mild restrictive syndrome (forced expiratory volume in 1 s/forced vital capacity = 85.5%) with slight hypoxemia (arterial P0 2 74.5 mm Hg) and mild hypercapnia (arterial PC0 2 45.7 mm Hg), normalized by hyperventilation. The ventilatory response to inhaled CO 2 was normal (1.6 Llmin/mm Hg). Ventilatory response to hypoxia was not investigated. Electrocardiogram (ECG) was normal. The patient underwent all-night TV -monitored polysomnographic recording, including EEG, electrooculogram, submental and intercostal EMG, ECG, oral-nasal, thoracic, and abdominal respirogram, ear oximetry (Biox III, BTl, Boulder, CO), and snoring noise. During non-rapid-eye-movement (NREM) sleep the breathing pattern was characterized by heavy snoring and obstructive apneas. The apneas were 40.9/h, lasting 49 ± 23 s, with a mean low arterial oxygen saturation (Sa0 2 ) of 70.6 ± 17% and a lowest Sa0 2 of 40%. During continuous snoring, a progressive hypoxia occurred (lowest Sa0 2 54%) (Fig. O. At the onset of each rapid-eye-movement (REM) period, the apneas immediately became more prolonged, lasting 166 ± 51 s. Seven of 10 apneas in REM led to an attack characterized by slowing and then flattening of EEG activity, followed by a generalized spasm lasting 5-10 s. Before, during, and after the attacks, no epileptic activity was recorded in the EEG: heart rate did not change significantly during the apneas (Figs. 2 and 3). After the attacks, the patient did not wake up; the EEG showed generalized theta activity for 1-2 min and then a stage 2 or REM sleep reappeared. The patient was not aware of the attacks on awakening in the morning. Sleep structure was disrupted by 311 arousals; total sleep time = 427 min; sleep latency == 9 min; Stl = 137 min (32.1%); St2 = 266 min (62.4%); St 3 == 3 min (0.7%); St 4 = 0 min; REM sleep 21 min (4.6%); first REM latency = 30 min. Given the risks, the patient underwent tracheostomy combined with uvulopalato-pharyngo-plasty surgery. Three months later, he was again hospitalized and slept for 7 consecutive nights with his tracheal stoma closed. Polysomnographic recordings were made on the 7th night and showed regular breathing, even in REM sleep, N:~E ~ ------.U --...,UU ------,UU -------,U 85 Sa02 70 55 40 25 II It Microph. 20 mv 24 FIG. 1. Top to bottom: schematic hypnogram (arousals are not marked), SaOz, snoring noise, time. Arrows indicate the anoxic attacks appearing after the first or second apnea of each REM sleep period. Snoring, associated with progressive hypoxia, is evident from the continuous noise picked up by the microphone (h 22-22.30; h 3.55-4.10). Sleep, Vol. 12, No.5, 1989
402 F. CIRIGNOTTA ET AL. 1 ~ 2 + C 3 - A. """'Mf...w.""""..."..""""""""... """'-..,---"""f'v'{'-"~...,--.. O~-A, ~~~~~~~~~-v~~~~---v~~ C.A, ~~~~~~~~~~~~~~~~~~~~ ROC loc ~ ~r-~~~-f~~~~~-v~~~~ My'o EMG ----+-----------------'11'" EKG Intercostal EMG ~'" I, ~! I!, I! I I! 'd I (., 1. rasp. Duration of apnea Sa O 2 < 40... 3 +,'...,"',' """4~... d,..., 200.~.. 'FIG. 2. Polysomnographic recording of a anoxic attack in REM sleep. At first the EEG tracing slows (arrow 1), then after 200 s of apnea and 90 s of severe hypoxia (Sa02 < 40%), a flattening of EEG appears (arrow 2), followed 15 s later by muscular artifacts due to a generalized spasm (arrow 3). Opening of the upper airways occurs during the spasm. when the patient was lying on his side. When in a supine position, obstructive apneas were present but lasted under 40 s (lowest Sa02 = 60%). No attacks occurred. DISCUSSION REM sleep in our patient was disrupted by apneas of such duration (over 3 min) as to provoke anoxic cerebral attacks. As we did not monitor systemic arterial pressure, cerebral ischemia could not be ruled out as a cofactor of the attacks. Duration of the apnea-related anoxic state alone, however, could account for the attacks, irrespective of a reduction in cerebral blood flow. The anoxic origin of the attacks was confirmed by the flattening of the EEG tracings and the following generalized tonic spasm. These clinical and EEG patterns clearly differentiate the attacks from epileptic seizures (4). Pure anoxic cerebral attacks have been reported in children during wakefulness as "sobbing spasms" or "breath-holding spells." As far as we know, these attacks have never been described in adults or in patients with obstructive sleep apnea (OSAS). In the literature on OSAS, epileptic seizures have been reported previously (1-3), however, the clinical EEG features of these seizures arising during sleep were not reported in detail. Even in'those cases, the seizures could have been cerebral anoxic attacks. In our patient, apneas lengthened, provoking attacks immediately after the beginning of each REM sleep period. This can be explained considering the mechanism responsible for arousal which terminates the apneas. The hypoxia and reflexes triggered by the occluded airways seem to playa major role, probably mediated by the carotid bodies and oropharyngeal mechanoreceptors (5-6). Arousal response during REM sleep is reduced with respect to NREM sleep, and this explains why in OSAS the longest apneas occur during REM sleep (7-8). In our patient, the arousal response seems sufficiently impaired to lead to an anoxic attack. Such unusual duration of the apneas I 5 s, I Sleep, Vol, 12, No.5, 1989
CEREBRAL ANOXIA IN SLEEP APNEA 403 (a) (b) (c) FIG. 3. Video pictures of an attack occurring during REM sleep. The sequence lasts 75. At the end of a prolonged apnea (a) the patient suddenly pulls his legs up and throws his head back (b) then relaxes (c). was probably related to a reduced reactivity to the chemoreceptor stimuli. A chemoreceptorial impairment was also suggested by the tendency to hypoventilate during wakefulness, the hypoxia being induced by the only slight respiratory overload provoked by snoring and the scant variations in heart rate during the apneas. The causes of this autonomic impairment are unknown. However, we can speculate that, according to recent findings (9), more than 30 years' chronic exposure to solvents could have been responsible for the dysfunction observed in our patients. We could not perform serial polygraphic recordings to determine whether the patient presented such a high number of attacks every night. The anamnesis and the short latency of first REM sleep, however, suggest that REM disruption provoked by the attacks was not a chance finding. Tilkian et al. (10) have emphasized the importance of cardiac arrhythmias as major risk factors for death in patients with OSAS. Our case documents another pathogenetic mechanism responsible for sudden death or coma arising during sleep. REFERENCES 1. Houdart R, Mamo H, Tomkiewicz H. La forme epileptogene du syndrome de Pickwick. Rev Neural 1960; 103: 466-8. Sleep, Vol. 12. No.5, 1989
404 F. CIRIGNOTTA ET AL. 2. Kryger M, Quesney LF, Holder D, Gloor P, MacLeod P. The sleep deprivation syndrome of the obese patient. Ani J Afed 1974;56:531-9. 3. Guilleminault C. Natural history, cardiac impact and long-term follow-up of sleep apnea syndrome. In: Guilleminault C, Lugaresi E, eds. Sleep/wake disorders: natural history, epidemiology, and long-term evolution. New York: Raven Press, 1983: 107-25. 4. Gastaut H. Syncopes: generalized anoxic cerebral seizures. In: Vinken P, Bruin GW, eds. Handbook of clinical neurology, vol. 15. Amsterdam: Elsevier, 1974:815-35. 5. Bowes G, Phillipson EA. Arousal responses to respiratory stimuli during sleep. In: Saunders NA, Sullivan CE, eds. Sleep and breathing. New York: Marcel Dekker, 1984:137--61. 6. Sullivan CE, Saunders NA, Issa FG, Berthon-Jones M. Pathophysiology of sleep apnea. In: Saunders NA, Sullivan CE, eds. Sleep and breathing. New York: Marcel Dekker, 1984:299--363. 7. Phillipson EA. Control of breathing during sleep. Am Rev Respir Dis 1978;118:909--39. 8. Lugaresi E, Coccagna G, Mantovani M, Cirignotta F, Ambrosetto G, Baturic P. Hypersomnia with periodic breathing: periodic apneas and alveolar hypo ventilation during sleep. Bull Physiopath Resp 1972;8:1103-13. 9. Matikainen E, Juntunen 1. Autonomic nervous system dysfunction in workers exposed to organic solvents. J Neurol Neurosurg Psychiatry 1985;48: 1021-4. 10. Tilkian AG, Motta J, Guilleminault C. Cardiac arrhythmias in sleep apnea. In: Guilleminault C, Dement WC, eds. Sleep apnea syndromes. New York: Alan R. Liss, 1978:197-210. Sleep, Vol. 12, No.5, 1989