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Rapid cycling in severely multidisabled children: A form of bipolar affective disorder?
Rapid Cycling in Severely Multidisabled Children: A Form of Bipolar Affective Disorder? James E. Jan, MD**, Israel F. Abroms, MD ~, Roger D. Freeman, MD t, Gregory M. Brown, MD, PhD II, Hilary Espezel, RN, BSN*, and Mary B. Connolly, MB ~ A debilitating, regularly recurring, biphasic disorder is described in 6 severely multidisabled children. It was characterized by several days of lethargy, withdrawal, loss of abilities, irritability, and hypersomnolence followed or preceded by a high-energy state for several days during which the children slept very little, at times were euphoric, had improved mental ability, and were hyperactive. These cyclic episodes had been present for years but unexpectedly disappeared in one child. The etiology is unknown, in spite of detailed neurologic, metabolic, and endocrine investigations. All patients had family histories positive for affective disorder. Melatonin treatment helped to regulate the coexisting chronic sleep disorders of 3 children but failed to eliminate the cycles. Antiepileptic drug treatment, lithium, sedatives, stimulants, tranquilizers, and light therapy were largely ineffective. The children's symptoms and signs fit the diagnostic criteria of a bipolar affective illness, as it was modified for patients with associated neurologic disability; therefore, the patients appeared to have a unique disorder that closely resembles or is a variant of rapid cycling affective disorder. Jan JE, Abroms IF, Freeman RD, Brown GM, Espezel H, Connolly MB. Rapid cycling in severely multidisabled children: A form of bipolar affective disorder? Pediatr Neurol 1994;10:34-39.
Introduction Bipolar affective illness in children was documented initially by Kraepelin in 1921 [1] and since then numerous case reports have been published which were recently summarized [2,3]. The affliction was observed in otherwise neurologically normal children, as well as in mentally retarded individuals [4]. When 4 or more episodes of either mania or depression occur in a year the term "rapid
From the Departments of *Pediatrics and *Child Psychiatry; University of British Columbia;° Visually Impaired Program; Children's Hospital; Vancouver, Canada ~Department of Pediatric Neurology; University of Massachusetts; Worcester, Massachusetts; IClarke Institute of Psychiatry; Toronto, Canada; ~Children's Hospital; Boston, Massachusetts.
34 PEDIATRIC NEUROLOGY Vol. 10 No. 1
cycling" is applied. The clinical characteristics of rapid cycling affective disorders (RCAD) were described initially by Dunner and Fieve in 1974 [5] and the disorder was later reviewed by Alacron in 1985 [6]. RCAD manifests mainly in adults, more so in women than in men and with or without associated disabilities [5-9]. This unusual clinical phenomenon is much more commonly associated with bipolar, rather than unipolar affective illness. On rare occasions the cycles are remarkably regular [8,10]. RCAD does not seem to aggregate in families and it appears to be determined by multiple factors [11]. Jones and Berney suggested that although the cause of RCAD is multifactorial, cerebral dysfunction is the major determinant [12]; therefore, they suggested that the disorder should be more frequent in individuals with severe mental and neurologic problems. In children, RCAD has been reported in those with normal intellect [3,10] and in adolescents with mild mental retardation [13] but not in the profoundly disabled; however, the diagnosis of affective disorder is not only more difficult in persons with neurologic problems, but there is an almost complete lack of awareness of this illness among professionals working with the disabled. For this reason, in 1986, Sovner modified the diagnostic criteria of patients with associated neurologic disabilities
[14]. Depression was defined by Sovner as a "disturbance of mood characterized by sadness, withdrawal or agitation with any four of the following symptoms: change in sleep, change in appetite and/or weight, onset or increase in selfinjurious behavior, apathy, psychomotor retardation, loss of activities of daily living skills, catatonic stupor and/or rigidity, spontaneous crying and fearfulness" [14]. Mania was defined as a "disturbance of mood characterized by elation, irritability or excitability with any four of the following seven symptoms: decreased sleep, overactivity, biphasic course, onset or increase in severity of distractibility, increase in rate or frequency of verbalizations, onset
Communications should be addressed to: Dr. Jan; Visually Impaired Program; BC's Children's Hospital; 4480 Oak Street; Vancouver, BC V6H 3V4 Canada. Received August 16, 1993; accepted November 22, 1993.
© 1994 by Elsevier Science Inc. • 0887-8994/94/$7.00
or increase in severity of aggressiveness, onset or increase in severity of noncompliance." In our study, 6 severely multidisabled, low-functioning children who had regularly occurring, cyclic episodes of debilitating, biphasic behavioral disturbances are presented. With remarkable accuracy, their symptoms and signs fit the diagnostic criteria of a bipolar affective illness; therefore, our patients appeared to have a disorder that closely resembled or was a variant of RCAD. Case Reports Patient 1. This 7-year-old, severely mentally retarded boy was the second child of nonconsanguineous, caucasian parents. He could sit and crawl, but was not able to walk independently and had no verbal communication. The pregnancy was uncomplicated. He was born at term after a normal delivery, weighing 3A kg. Episodes of depression recurred in several family members on the maternal side. At age 6 months, head circumference (42 cm) was normal, length was 62.2 cm ( - 2 SD), and weight was 6.9 kg, ( - 1 . 5 SD). He had a prominent forehead, broad nasal bridge, a small nose, and bilateral undescended testes. He had severe cortical visual impairment and generalized hypotonia without focal neurologic signs. His eye examination was normal. Karyotype analysis disclosed a balanced translocation between chromosomes 13 and 14. Electroencephalography (EEG) was slow and dysrhythmic, without epileptiform activity. Visual evoked potential map studies demonstrated severe cortical visual impairment. Plasma amino acid chromatography and cranial computed tomography (CT) were normal. He was an extremely poor sleeper, despite rigid bedtime schedules and sedatives. At age 2 years, he developed recurring periods of irritability, distractibility, aggressiveness, overactivity, and sleeplessness. Total daily sleep was 1-2 hours at irregular times, sometimes for only 5-10 min. His appetite increased. After about 3 days of this behavioral state, he would become lethargic, weepy, and sleep for most of the next 2-3 days. His appetite decreased, his daily living skills declined, and he became floppy. These cycles occurred with some regularity every 1-3 months. Repeated EEG studies during the various phases continued to demonstrate a slow and dysrhythmic background without epileptiform activity. At 2 years of age neuroendocrine investigations during hypersomnolence revealed a blunted growth hormone response to arginine and levodopa with a peak of 6.7 p~g/L. Thyrotrophin stimulating hormone (TSH) response to thyrotropbin releasing hormone (TRH) was also blunted, (peak: 5.8 mlU/ml). Ta was normal (107 nmol/L) but T 3 was slightly low (0.78 nmol/L). Repeat T 3 4 months later was normal (2.5 nmol/L). The basal cortisol level was 309 nmol/L and adrenocorticotrophin hormone (ACTH) was 7.3 pmol/L. Serum sodium, serum and urine osmolalities, and fasting blood glucose were normal. Bone age was within 2 standard deviations of chronologic age. Over the subsequent year his growth rate was normal (7.4 cm/yr). At 4 years of age the growth hormone response to arginine and levodopa was normal, with a peak of 10. l I~g/L. TSH response to TRH stimulation was also normal (peak: 22. l mIU/L) as were Ta and T 3. Bone age was more than 2 standard deviations below the mean for chronologic age. He continued to have these cycles of abnormal behavior at intervals of 3-4 months. At age 7 years, the cycles suddenly became more frequent, occurring every 14-15 days. With this change, his management also became more difficult and his parents, who became sleep deprived and exhausted, were contemplating placing him in foster care. Continuous 24-hour sleep charting, documented by the parents for several weeks, revealed that even between his cycles he slept poorly, in a fragmented fashion for 8-9 hours a day. Temperature recording, taken twice a day, did not document significant fluctuations between cycles. In a double-blind placebo study, he was given 5-l0 mg melatonin (N-acetyl5-methoxytryptamine) at the desired bedtime; this treatment improved
his sleep pattern and within 30 min he fell asleep. Melatonin is an investigational drug, obtained from Sigma Company in St. Louis and approved for use in this study by the Health Protection Branch, Department of Health, Ottawa. During the day, he became more alert and his naps became less frequent. The stress on the parents decreased significantly, so much so that foster care placement was no longer considered. The educators also noted that the child became more alert. There were no adverse side effects; however, while melatonin improved his sleep, he continued to have his behavioral cycles. Subsequently, he was given therapeutic doses of carbamazepine, then valproic acid, and finally lithium but the cycles persisted. Patient 2. This 13-year-old. multidisabled, low-functioning male was born prematurely, at 37 weeks gestation, weighing 3.1 kg. His mother had been diagnosed earlier as having an affective disorder. Due to hypoxic-ischemic insults in the neonatal period, he now has spastic quadriplegia, marked mental retardation, blindness, shunted hydrocephalus, and epilepsy, which is well controlled by valproic acid. He cannot talk or walk and is totally dependent on others for his care. His health is satisfactory. CT demonstrated marked periventricular leukomalacia, while EEG was slow and dysrhythmic, but was free of epileptiform discharges. Funduscopic examination was normal with symmetrically reactive pupils, yet he only had light perception. EEG, visual evoked potential, and CT studies confirmed the diagnosis of severe cortical visual impairment. His sleep pattern has been poor since infancy, in spite of strict bedtime scheduling and various sedations, which tended to make him agitated. Eventually the parents stopped asking for help because they assumed that this type of sleep disturbance was part of being disabled. He always had periods of hypersomnolence for a few days, followed by several days of hyperactivity in which he slept less. After age 11 years, he began to experience a more severe, cyclic sleep-wake disturbance regularly once a month. During the initial part of his cycle he became increasingly lethargic, irritable, self-abusive, and with excessive appetite and thirst. He appeared to be in discomfort, noises bothered him, and the skin of his lower extremities manifested red blotches with mild peripheral edema. He slept 16-22 hours daily. After 5-7 days of this state, he entered the "high phase" gradually over 48-72 hours, during which he required very little sleep. For 5-6 days he was hyperactive, urinated excessively, was euphoric, sang for hours, and banged the side of his bed with his fists without apparent pain. His appetite also decreased. Then his "normal" behavior and sleep pattern returned. His basic metabolic and hematologic tests demonstrated no abnormalities. Treatment with lithium after several weeks failed to abolish his cycles although they were less severe. Melatonin (5 mg) administration at bedtime improved his nocturnal sleep, but failed to stop his cycles, although the biphasic behavioral changes were mainly evident during the daytime. As a result his care was easier to maintain. Patient 3. This 14-year-old, severely mentally retarded female was born at term after a normal pregnancy, to nonconsanguineous, caucasian parents. The maternal history was positive for an affective illness. The perinatal period was normal and birth weight was 3.42 kg. She developed normally but at 6 months a diagnosis of infantile spasms was made. Investigations at 1 year revealed a normal cranial CT. EEG was diffusely slow and dysrhythmic, with multifocal spikes and sharp waves. Detailed metabolic investigations, including thyroid studies, plasma amino acids, and lipoprotein profile were normal. She was on valproic acid with good seizure control. At 5 years of age, she developed focal and secondary generalized seizures. The treatment was changed to carbamazepine and she has been seizure-free since then. At 9 years of age, she developed a debilitating cyclic behavior, recurring every 3-4 months. For 7-8 days she became weepy, lethargic, and sleeping excessively, 18-20 hours a day. Her appetite and weight decreased, she was constipated, and her extremities felt cold. During this time she could not go to school and there was marked deterioration in her daily living skills. Following this state, she developed agitation, distractibility, overactivity, and sleeplessness for 7-14 days. She slept at irregular times, but for a total of only 3-5 hours a day. Her appetite increased,
Jan et al: Rapid Cycling and Multidisabled
35
she drank excessively, and her weight increased. There were no temperature changes. In school her teachers were impressed with her temporary developmental progress, but her overactivity made discipline difficult. Sedatives had only a minimal effect on the overactive state and methylphenidate had no effect on the lethargic phase. Between these cycles she was predictable and her sleep pattern normal. On re-examination, head circumference was 48.6 cm ( - 2 SD), height was 123.4 cm ( - 2 SD), and weight 21.3 kg which was appropriate for her height. She was prepubertal. Physical examination was normal, but neurologic assessment disclosed normal cranial nerves, tone, strength, deep tendon reflexes, cerebeUar function, and peripheral sensation but coordination was impaired and intellectual development was markedly slow. Her mental age appeared to be about 2-3 years. Investigation during her hypersomnolent state revealed normal growth hormone response to stimulation with arginine and levodopa (peak: 16.7 ~g/L). TRH stimulation demonstrated an appropriate TSH prolactin response, serum thyroxine (T4), and triiodothyronine (T3). Her cortisol response to ACTH was normal. Fasting blood glucose, serum sodium, and serum and urine osmolalities were normal. Repeat cranial CT was normal. Clinical and EEG studies eliminated recurrent seizures as the cause of her cycles. At age 12 years, she unexpectedly stopped having cycles which have not recurred for over 2 years, although occasional periods of "highs" were observed. Patient 4. This 8-year-old boy was born following an uncomplicated pregnancy to nonconsanguineous, caucasian parents. His mother had been diagnosed as having a severe bipolar affective disorder. The neonatal period was complicated by seizures, hypoglycemia, and Clostridium welchii septicemia. Total blindness, caused by bilateral optic nerve hypoplasia, was observed at 3 months. Cranial CT revealed mild, diffuse cerebral atrophy. At age 2V2 years, height was 87 cm ( - 1.5 SD) and weight 12.4 kg ( - 1 SD). Neuroendocrine investigations demonstrated a blunted growth hormone response to arginine (peak: 3.3 ng/ml). The TSH response to TRH was suggestive of a hypothalamic defect (peak: 26.0 mlU/L at 120 min). Serum T 4 and T 3 were normal. At age 5 years, the growth rate had declined and repeat assessment confirmed growth hormone deficiency (peak: 1.6 ~,g/L). Serum thyroxine was normal. Serum cortisol was low (132 nmol/L at 60 min) and there was a blunted response to ACTH (455 nmol/L at 60 rain) suggesting partial ACTH deficiency. Bone age was within 2 standard deviations of the chronologic age. Growth hormone therapy began 3 times weekly and hydrocortisone at times of illness. During his early childhood he developed recurring, unexplained episodes of drowsiness, excessive sleeping, and reduced appetite with occasional nose bleeds once every 1-2 months. These episodes would last for 1-3 days and were followed by a couple of days of hyperactivity and excessive wakefulness. He slept well between cycles. Blood glucose, when checked, was always normal. No seizures occurred, although EEG revealed bioccipital sharp waves. After commencing growth hormone therapy he demonstrated good catch-up growth such that his height was only 0.3 standard deviations from the mean. He had evidence of marked global neurodevelopmental delay and continued to have these abnormal cycles of behavior, but during the last 2 years they have occurred only once or twice a year. Patient 5. This 51/2-year-old, totally blind boy was neurologically mulfidisabled by near-miss sudden infant death occurring at age 10 weeks. His mother had previously been diagnosed as having frequent episodes of a bipolar disorder. He could not walk or sit unsupported and had no language. He had spastic quadriplegia, bilateral optic nerve atrophy, epilepsy, marked developmental delay, and severe, chronic sleep disorder. He had difficulty falling asleep, his sleep pattern was fragmented, and he awakened 3-5 times during the night and early in the morning. Since infancy, he had been having regularly occurring behavioral cycles, characterized by 4-5 days of agitation, whining, imtability, hyperactivity, and overexcitability followed 1-2 days later by marked lethargy, developmental regression, and excessive sleep. During the "hyper" phase, he slept 1-2 hours a day, whereas during the hypersomnolence, he tended to sleep 16-18 hours. The cycles have occurred every 2V2-3 weeks during the last 4 years.
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The child's health has been satisfacto~, tie has been treated with multiple antiepileptic drugs for seizures, including valproic acid and carbamazepine, but continues to have staring episodes, sudden body jerks, and rare, generalized convulsions. EEG has always been abnor. mal, demonstrating muttifocal spikes superimposed on a stow. dysrhythmic and suppressed background. Cranial CT revealed multicystic leukomalacia; metabolic investigations, including thyroid tests, were normal. His sleep disorder did not respond to sedatives, strict bedtime routines, or psychologic measures. Melatonin (5 mg) given orally at the desired bedtime minimally improved his sleep but the cycles continued. Patient 6. This 11-year-old boy had severe, spastic quadriparesis and generalized tonic and myoclonic seizures. The paternal history was positive for affective illness. He was born follo~ving an uneventful pregnancy and delivery and developed normally until age 8 months. At that time he contracted eastern equine encephaliti.~ which left him with severe neurologic impairment and no expressive language. He does understand some verbal commands and responds by eye blinking. He required a fundoplication and gastrostomy at 18 months and ventricular peritoneal shunt for hydrocephalus at age 3 years. Numerous antiepileptic drugs have been used, the most effective ones being carbamazepine, mephobarbital, and nitrazepam. A ketogenic diet also was attempted. He probably has 20/50 distance visual acuity bu~ appears to have limited visual perceptual integration skills. At age 4 years, his parents realized that be was having monthly episodes when he was attentive and alert, slept little, and his spasticity was decreased and bad days characterized by irritability, lethargy, intermittent dozing, increased seizures, frequent crying, and extreme sensitivity to touch. He had more "alert" periods in the summer months and by the fall was having more irritable and spastic days. By 6 years of age, he was having 2 "good days" and 4 "bad days" every month. At age 7 years, daily phototherapy was introduced, 2 hours between 5 and 7 a.m. Four weeks later he was having improved high-energy states, lasting up to 3 days, but no change in low-energy phases. Since the age of 10 years he has exhibited the pattern of 4-5 "good days" and 3 "b',u:l days" monthly. He had increased urination during his "bad days." It appears that he may have developed migraine headaches recently during his hypersomnolence states because he appeared to be photophobic with unilateral headache. His father and older brother had migraine. Thioridazine, given during his "high" episodes, minimally improved his sleep. Recently, it was replaced by melatonin/7.5 rag) which was more effective.
Discussion For several years, these 6, low-functioning, multidisabled children have had highly debilitating, regularly recurring biphasic behavioral states. Their care and treatment had been extremely difficult, at times leading to sleep deprivation and parental "bum-out." The cycles may begin with hypersomnolence or hyperactivity (Table 1). Each phase lasts for several days. The "lows" as some parents call them, consist of hypersomnolence, withdrawal, lethargy, excessive irritability, weepiness, and loss of abilities. During their overactive state the children are hyperactive, agitated, and sleep very little; however, their mental abilities are improved. Mood changes are characterized by euphoria with prolonged episodes of laughing, increased verbalization, and aggressiveness. The appetite tends to increase during hypersomnolence and decrease during the overactive state, but in one child it was the reverse. Temperature changes are not apparent. During the lethargic state some patients have cold, blotchy skin, increased urination, and in one instance, edematous extremities. One child in his overactive
Table 1.
Diagnostic criteria for depression and m a n i a in relationship to s y m p t o m s of patients
Depression (1) Increase in sleep (2) C h a n g e in appetite, thirst, and/or weight (3) Onset or increase in self-injurious behavior (4) A p a t h y (5) P s y c h o m o t o r retardation (6) Loss of daily living skills (7) Spontaneous c r y i n g Mania (1) Decrease in sleep (2) Overactivity (3) Biphasic course (4) Increased distractibility (5) Increased verbalization (6) Increased aggressiveness
1
2
Patient N u m b e r 3 4
5
6
+ + + + + + +
+ +
+ +
+ +
+ --
+ + + + +
phase became so euphoric that while laughing he kept banging his fists against the wall, seemingly unable to feel pain. The cycles are more or less regular, occurring once every 1-3 months, although at times they unexpectedly change in frequency, yet still remain regular. Three children slept poorly even between episodes. The hypothalamus, through its connection to the limbic system, has a central role in the modulation of complex behavior. Hypersomnolence has been observed following head injury, cerebral arteriosclerosis, encephalitis, and intracranial tumors involving the posterior part of the hypothalamus [15]. Hypothalamic lesions may present with disturbance of appetite, temperature control, sleep/wake cycles, and behavior. In 1925, Kleine described cyclic hypersomnia among young males ]16]. In 1936, Levin added bulimia as an additional manifestation [17]. Critchley, in 1962, described marked behavioral and psychologic changes that accompanied these periods [18]. Between episodes the patients usually were normal. The disorder now known as Kleine-Levin syndrome occurs mainly in adolescent males, but a young female was reported by Duffy and Davidson in 1968 ]19]. These individuals sleep almost constantly for days to weeks, awakening only to eat gluttonously. The episodes may recur from 2-12 times a year and remit spontaneously. The etiology of periodic hypersomnolence is unknown and no consistent abnormality, either chemical or electroencephalographic, can generally be observed between or during the episodes [20]. Our disorder is strongly biphasic and manifests in much younger patients with profound neurologic impairment than in those described with KleineLevin syndrome. Seasonal affective disorders are characterized by episodes of depression most often in the fall and winter and recovery or even hypomania in the spring and summer seasons [21-23]. The depression phase is often associated with increased eating, carbohydrate craving, weight gain, and oversleeping. The majority of patients with seasonal affective disorder are women, and older than 30 years of
+ +
4-
.
+ + +
+ + +
.
+ + +
.
.
+ + +
4+ +
+
+
--
+
4-
4+ 4-4--
4+ + 444-
444444-
44+ + -+
44-_ --
age, but seasonal affective disorder occasionally occurs in children [22]. Light therapy is the recommended treatment. It is clear that our patients do not have this disorder. Persistent seizures can produce prolonged periods of hypersomnolence, lethargy, and irritability but repeated EEGs during the two phases excluded epilepsy. No clinical evidence of persistent seizures exists. Although prolonged EEG recordings were not conducted in our multidisabled patients for technical reasons, epilepsy was still satisfactorily eliminated as the cause of the biphasic disorder. The endogenous sleep-wake rhythm of humans under time-cue-free running conditions is about 25 hours. This finding was well demonstrated by cave experiments in which individuals lived in total darkness. Their sleep cycles shifted approximately 1 hour daily, so that periodically they were awake all night and slept during the day. Adults, totally blinded by ocular disorders, frequently had similar difficulties which caused them considerable hardship [24-26]. Free-running sleep-wake cycles are less common in blind children [27]. Our patients clearly did not have this type of difficulty. As with others who examined these children, we were puzzled by these regular, highly debilitating behavioral cycles. We contacted numerous physicians working with the multidisabled in various countries and a psychiatrist believed that our patients' affliction resembled RCAD. The clinical characteristics of our patients fit the diagnostic criteria of bipolar affective illness as modified by Sovner for persons with associated neurologic disabilities [14]. Although RCAD has not been described in severely multidisabled children, our patients appear to have a unique disorder that closely resembles or is a variant of RCAD. Affective disorders on the maternal side of the family were reported in 5 patients and on the paternal side in the remaining child. This observation is very interesting and must be explored further. These case reports strongly suggest the possibility that when children with the hereditary tendency for affective disorder sustain brain damage
Jan et al: Rapid Cycling and Multidisabled
37
they are more likely to develop rapid cycling. This possibility was suspected by Jones and Berney [12]. Probably RCAD is more common in severely multidisabled individuals, but is not diagnosed because of the lack of awareness that such an illness can affect them. The cause of RCAD is unknown; however, the hypothalamus, with its close relationship with the limbic system, must be involved. Hypothyroidism has been observed in some of these patients [6], but none of our patients had any evidence of a thyroid disorder. A strong female preponderance also was observed in adult RCAD [6] but this finding was reversed in our study population. In most instances RCAD is unpredictable, whereas the cycles of our children were strikingly regular. The treatment of RCAD, especially in the mentally retarded, is very difficult [6]. Valproic acid is considered to be the first drug of choice followed by carbamazepine [8]; the mechanism of their action on RCAD is unknown. Valproic acid and carbamazepine alone or in combination with other antiepileptic drugs were used in 5 of our patients but failed to prevent or abolish their cycles. Lithium, which was administered to 2 children, did not stop the cycles, but did diminish the severity in 1 child. Although lithium can be a very effective treatment in bipolar disorders, patients with RCAD often do not respond to it [9]. Light therapy in one child disclosed minimal benefits. In 1991, Palm et al. reported a multidisabled, blind child with a chronic sleep disorder who was successfully treated with melatonin [27]. As a result, we also began treating chronic sleep disorders in multidisabled children [28]. The study demonstrated melatonin to be a very important drug in the management of endogenous wake/sleep rhythm disturbance. Because 3 of our patients experienced marked, chronic sleep difficulties, we also treated them. Melatonin plays an important role in the induction of sleep. It is produced by pinealocytes in the pineal gland. Tryptophan is converted to serotonin, then to N-acetylserotonin and finally to melatonin (N-acetyl-5-methoxytryptamine). The secretion of melatonin is controlled by an endogenous rhythm-generating system in the brain which is synchronized by the light/dark cycle so that melatonin levels are high in darkness and low in light. The process begins at the retina, the signal proceeds to the suprachiasmatic nucleus of the hypothalamus, through the reticular system, spinal cord, cervical ganglia and postganglionic sympathetic fibers to the pineal gland [29]. The suprachiasmatic nucleus is a major sleep and body rhythm regulator and melatonin appears to influence this structure [30,31]. Melatonin has been synthesized and is available for experimental use. Its usefulness has been reported for shift workers [32] and those combating jet-lag [33], chronic insomnia [34], and delayed sleep phase syndrome [35]. Adverse side-effects were not observed in any of the studies. Oral melatonin given at bedtime improved the sleep pattern of 3 children who slept poorly between cycles, yet
38 PEDIATRIC NEUROLOGY
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their cycles continued. Melatonin, prescribed only in the "high" phases, also improved the sleep of another child. Sleep difficulties in the mentally disabled are very common. Bartlett et al. reported that 86% of those younger than 6 years of age, 81% of ages 6-11 years, and 77% of ages 12-16 years were reported by their parents as having sleep problems [36]. Quine subsequently substantiated these findings 137]. Because only one-half of the children in our report had sleep difficulties between their cycles, it is reasonable to assume that the chronic sleep problems were coincidental. The disorder of these 6 severely multidisabled children results in a profound burden for the families. In spite of antiepileptic drug treatment, lithium, melatonin, light therapy, stimulants, sedatives, and tranquilizers, the cycles persist. The clinical characteristics of their affliction fit the diagnostic criteria of affective disorder well modified by Sovner for patients with associated neurologic disabilities [14]; however, it is difficult to state with certainty whether they have a unique disorder or simply a variant of RCAD. Although psychiatrists are more aware of RCAD than other specialists, we wish to bring this unique disorder more to the attention of pediatric neurologists and developmental pediatricians because they tend to diagnose and treat multidisabled children most frequently. It is hoped that this report will promote the documentation of similar patients and thus a clearer pattern of this unusual biphasic behavior might emerge
The authors thank Dr. E. J. Garland, Mood Disorders Clinic, Department of Psychiatry, University of British Columbia, for her review of this article.
References [1] Kraepelin E. Manic-depressive insanRy and paranoia. Edinburgh: E & S Livingstone, 1921. [2] Fristad MA, Weller, EB, WeUer RA. Bipolar disorder in children and adolescents. Child Adolesc Psychiatr Clin North Am 1992;1: 13-29. [3] Sovner R, Hurley AD. Affective disorder update. Habilitative Mental Health Care Newsletter 1990;9:103-8. [4] Sorrier R. Hurley AD. Do the mentally retarded suffer from affective illness? Arch Gen Psychiatry 1983;40:61-7. [5l Dunner DL, Fieve, RR. Clinical factors in lithium carbonate prophylaxis failure. Arch Gen Psychiatry 1974;30:229-33. [6] ~ RD. Rapid cycling affective disorders: A clinical review. Compr Psychiatry 1985;26:522-40. [7] Naylor GJ, Donald JM, LePoidevin D, Reid AH. A double-blind trial of long-term lithium therapy in mental defectives. Br J Psychiatry 1974;124:52-7. [8] Sorrier R. The use of valproate in the treatment of mentally retarded persons with typical and atypical bipolar disorders: J clin Psychiatry 1989;50:40-3. [9] Glue P. Rapid cycling affective disorders in the mentally retarded. Biol Psychiatry 1989;26:250-6. [10] ll)eLong GR. Lithium carbonate treatment of select behavior disorders in children suggesting manic-depressive iIlness~ J Pediatr t978; 93:689-94. [Ill Nurnberger J Jr, Guroff JJ, Hamovit J, Verrettini W, Gershon
E. A family study of rapid-cycling bipolar illness. J Affective Disord 1988;15:87-91. [12] Jones PM, Berney TP. Early onset rapid cycling bipolar affective disorder. J Child Psychol Psychiatry 1987;28:731-8. [13] MeCracken JJ, Diamond RP. Bipolar disorder in mentally retarded adolescents. J Am Acad Child Adolesc Psychiatry 1988;27:494-9. [14] Sorrier R. Limiting factors in the use of DSM-III criteria with mentally ill / mentally retarded persons. Psychopharmacol Bull 1986;22: 1055-9. [15] Gallinek A. Syndrome of episodes of hypersomnia, bulimia and abnormal mental states. JAMA 1954;154:1081-3. [16] Kleine W. Periodische Schlafsucht. Monatsschr Psychiatr Neurol 1925;57:285-320. [17] Levin M. Periodic somnolence and morbid hunger: A new syndrome. Brain 1936;59:494-504. [18] Critchley M. Periodic hypersomnia and megaphagia in adolescent males. Brain 1962;85:627-56. [19] Dully JB, Davidson K. A female case of the Kleine-Levin syndrome. Br J Psychiatry 1968;114:77-84. [20] Orlosky MJ. The Kleine-Levin syndrome: A review. Psychosomatics 1982;23:609-21. [21] Rosenthal NE, Sac DA, Gillin C, et al. Seasonal affective disorder. Arch Gen Psychiatry 1984;41:72-80. [22] Rasenthal NE, Carpenter CJ, James SP, et al. Seasonal affective disorder in children and adolescents. Am J Psychiatry 1986;143:356-8. [23] Rosenthal NE, Wehr TA. Seasonal affective disorders. Psychiatr Ann 1987;17:670-4. [24] Miles LEM, Raynal DM, Wilson MA. Blind man living in normal society has circadian rhythms of 24.9 hours. Science 1977;198: 421-3. [25] Folkard S, Arendt T, Aldhous M, Kennett H. Melatonin stabilizes sleep onset time in a blind man without entrainment of cortical or temperature rhythms. Neurosci Lett 1990; 113:193-8. [26] Sack RL, Lewy AJ, Blood ML, Stevenson J, Keith LD. Mel-
atonin administration to blind people: Phase advances and entrainment. J Biol Rhythms 1991;6:249-61. [27] Palm L, Blennow G, Wetterberg L. Correction of non-24 hour sleep/wake cycle by melatonin in a blind retarded boy. Ann Neurol 1991;29:336-9. [28] Jan JE, Espezel H, Appleton R. The treatment of sleep disorders with melatonin. Dev Med Child Neurol 1994;36:97-107. [29] Rusak B. The role of the suprachiasmatic nuclei in the generation of circadian rhythms in the golden hamster, mesocricetus auratus. J Comp Physiol 1977;118:145-64. [30] Cassone VM, Chesworth MJ, Armstrong SM. Entrainment of rat circadian rhythms by daily injections of melatonin depends upon the hypothalamic suprachiasmatic nuclei. Physiol Behav 1986;36:1111-21. [31] Vaneeek J, Paulik A, Illnerova H. Hypothalamic melatonin receptor sites revealed by autoradiography. Brain Res 1987;435:359-62. [32] Weitzman ED, Cseizler CA, Coleman RM, Spielman AJ, Zimmerman JC, Dement WC. Delayed sleep phase syndrome, a chronobiological disorder with sleep-onset insomnia. Arch Gen Psychiatry 1981 ;38:737-46. [33] Arendt JM, Aldhous J, English V, et al. Some effects of jet-lag and their alleviation by melatonin. Ergonomics 1987;30:1379-93. [34] MacFarlane JG, Cleghorn JM, Brown GM, Streiner DL. The effects of exogenous melatonin on the total sleep time and daytime alertness of chronic insomniacs: A preliminary study. Biol Psychiatry 1991;30:371-6. [35] Dahlitz M, Alvarez B, Vignau J, English J. Arendt J, Parkes JD. Delayed sleep phase syndrome response to melatonin. Lancet 1991; 337:1121-4. [36] Bartlett LB, Rooney V, Spedding S. Nocturnal difficulties in a population of mentally handicapped children. Br J Ment Subnorm 1985; 31:54-9. [37] Quine L. Sleep problems in children with mental handicap. J Ment Defic Res 1991;35:269-90.
Jan et al: Rapid Cycling and Multidisabled
39
Introduction Bipolar affective illness in children was documented initially by Kraepelin in 1921 [1] and since then numerous case reports have been published which were recently summarized [2,3]. The affliction was observed in otherwise neurologically normal children, as well as in mentally retarded individuals [4]. When 4 or more episodes of either mania or depression occur in a year the term "rapid
From the Departments of *Pediatrics and *Child Psychiatry; University of British Columbia;° Visually Impaired Program; Children's Hospital; Vancouver, Canada ~Department of Pediatric Neurology; University of Massachusetts; Worcester, Massachusetts; IClarke Institute of Psychiatry; Toronto, Canada; ~Children's Hospital; Boston, Massachusetts.
34 PEDIATRIC NEUROLOGY Vol. 10 No. 1
cycling" is applied. The clinical characteristics of rapid cycling affective disorders (RCAD) were described initially by Dunner and Fieve in 1974 [5] and the disorder was later reviewed by Alacron in 1985 [6]. RCAD manifests mainly in adults, more so in women than in men and with or without associated disabilities [5-9]. This unusual clinical phenomenon is much more commonly associated with bipolar, rather than unipolar affective illness. On rare occasions the cycles are remarkably regular [8,10]. RCAD does not seem to aggregate in families and it appears to be determined by multiple factors [11]. Jones and Berney suggested that although the cause of RCAD is multifactorial, cerebral dysfunction is the major determinant [12]; therefore, they suggested that the disorder should be more frequent in individuals with severe mental and neurologic problems. In children, RCAD has been reported in those with normal intellect [3,10] and in adolescents with mild mental retardation [13] but not in the profoundly disabled; however, the diagnosis of affective disorder is not only more difficult in persons with neurologic problems, but there is an almost complete lack of awareness of this illness among professionals working with the disabled. For this reason, in 1986, Sovner modified the diagnostic criteria of patients with associated neurologic disabilities
[14]. Depression was defined by Sovner as a "disturbance of mood characterized by sadness, withdrawal or agitation with any four of the following symptoms: change in sleep, change in appetite and/or weight, onset or increase in selfinjurious behavior, apathy, psychomotor retardation, loss of activities of daily living skills, catatonic stupor and/or rigidity, spontaneous crying and fearfulness" [14]. Mania was defined as a "disturbance of mood characterized by elation, irritability or excitability with any four of the following seven symptoms: decreased sleep, overactivity, biphasic course, onset or increase in severity of distractibility, increase in rate or frequency of verbalizations, onset
Communications should be addressed to: Dr. Jan; Visually Impaired Program; BC's Children's Hospital; 4480 Oak Street; Vancouver, BC V6H 3V4 Canada. Received August 16, 1993; accepted November 22, 1993.
© 1994 by Elsevier Science Inc. • 0887-8994/94/$7.00
or increase in severity of aggressiveness, onset or increase in severity of noncompliance." In our study, 6 severely multidisabled, low-functioning children who had regularly occurring, cyclic episodes of debilitating, biphasic behavioral disturbances are presented. With remarkable accuracy, their symptoms and signs fit the diagnostic criteria of a bipolar affective illness; therefore, our patients appeared to have a disorder that closely resembled or was a variant of RCAD. Case Reports Patient 1. This 7-year-old, severely mentally retarded boy was the second child of nonconsanguineous, caucasian parents. He could sit and crawl, but was not able to walk independently and had no verbal communication. The pregnancy was uncomplicated. He was born at term after a normal delivery, weighing 3A kg. Episodes of depression recurred in several family members on the maternal side. At age 6 months, head circumference (42 cm) was normal, length was 62.2 cm ( - 2 SD), and weight was 6.9 kg, ( - 1 . 5 SD). He had a prominent forehead, broad nasal bridge, a small nose, and bilateral undescended testes. He had severe cortical visual impairment and generalized hypotonia without focal neurologic signs. His eye examination was normal. Karyotype analysis disclosed a balanced translocation between chromosomes 13 and 14. Electroencephalography (EEG) was slow and dysrhythmic, without epileptiform activity. Visual evoked potential map studies demonstrated severe cortical visual impairment. Plasma amino acid chromatography and cranial computed tomography (CT) were normal. He was an extremely poor sleeper, despite rigid bedtime schedules and sedatives. At age 2 years, he developed recurring periods of irritability, distractibility, aggressiveness, overactivity, and sleeplessness. Total daily sleep was 1-2 hours at irregular times, sometimes for only 5-10 min. His appetite increased. After about 3 days of this behavioral state, he would become lethargic, weepy, and sleep for most of the next 2-3 days. His appetite decreased, his daily living skills declined, and he became floppy. These cycles occurred with some regularity every 1-3 months. Repeated EEG studies during the various phases continued to demonstrate a slow and dysrhythmic background without epileptiform activity. At 2 years of age neuroendocrine investigations during hypersomnolence revealed a blunted growth hormone response to arginine and levodopa with a peak of 6.7 p~g/L. Thyrotrophin stimulating hormone (TSH) response to thyrotropbin releasing hormone (TRH) was also blunted, (peak: 5.8 mlU/ml). Ta was normal (107 nmol/L) but T 3 was slightly low (0.78 nmol/L). Repeat T 3 4 months later was normal (2.5 nmol/L). The basal cortisol level was 309 nmol/L and adrenocorticotrophin hormone (ACTH) was 7.3 pmol/L. Serum sodium, serum and urine osmolalities, and fasting blood glucose were normal. Bone age was within 2 standard deviations of chronologic age. Over the subsequent year his growth rate was normal (7.4 cm/yr). At 4 years of age the growth hormone response to arginine and levodopa was normal, with a peak of 10. l I~g/L. TSH response to TRH stimulation was also normal (peak: 22. l mIU/L) as were Ta and T 3. Bone age was more than 2 standard deviations below the mean for chronologic age. He continued to have these cycles of abnormal behavior at intervals of 3-4 months. At age 7 years, the cycles suddenly became more frequent, occurring every 14-15 days. With this change, his management also became more difficult and his parents, who became sleep deprived and exhausted, were contemplating placing him in foster care. Continuous 24-hour sleep charting, documented by the parents for several weeks, revealed that even between his cycles he slept poorly, in a fragmented fashion for 8-9 hours a day. Temperature recording, taken twice a day, did not document significant fluctuations between cycles. In a double-blind placebo study, he was given 5-l0 mg melatonin (N-acetyl5-methoxytryptamine) at the desired bedtime; this treatment improved
his sleep pattern and within 30 min he fell asleep. Melatonin is an investigational drug, obtained from Sigma Company in St. Louis and approved for use in this study by the Health Protection Branch, Department of Health, Ottawa. During the day, he became more alert and his naps became less frequent. The stress on the parents decreased significantly, so much so that foster care placement was no longer considered. The educators also noted that the child became more alert. There were no adverse side effects; however, while melatonin improved his sleep, he continued to have his behavioral cycles. Subsequently, he was given therapeutic doses of carbamazepine, then valproic acid, and finally lithium but the cycles persisted. Patient 2. This 13-year-old. multidisabled, low-functioning male was born prematurely, at 37 weeks gestation, weighing 3.1 kg. His mother had been diagnosed earlier as having an affective disorder. Due to hypoxic-ischemic insults in the neonatal period, he now has spastic quadriplegia, marked mental retardation, blindness, shunted hydrocephalus, and epilepsy, which is well controlled by valproic acid. He cannot talk or walk and is totally dependent on others for his care. His health is satisfactory. CT demonstrated marked periventricular leukomalacia, while EEG was slow and dysrhythmic, but was free of epileptiform discharges. Funduscopic examination was normal with symmetrically reactive pupils, yet he only had light perception. EEG, visual evoked potential, and CT studies confirmed the diagnosis of severe cortical visual impairment. His sleep pattern has been poor since infancy, in spite of strict bedtime scheduling and various sedations, which tended to make him agitated. Eventually the parents stopped asking for help because they assumed that this type of sleep disturbance was part of being disabled. He always had periods of hypersomnolence for a few days, followed by several days of hyperactivity in which he slept less. After age 11 years, he began to experience a more severe, cyclic sleep-wake disturbance regularly once a month. During the initial part of his cycle he became increasingly lethargic, irritable, self-abusive, and with excessive appetite and thirst. He appeared to be in discomfort, noises bothered him, and the skin of his lower extremities manifested red blotches with mild peripheral edema. He slept 16-22 hours daily. After 5-7 days of this state, he entered the "high phase" gradually over 48-72 hours, during which he required very little sleep. For 5-6 days he was hyperactive, urinated excessively, was euphoric, sang for hours, and banged the side of his bed with his fists without apparent pain. His appetite also decreased. Then his "normal" behavior and sleep pattern returned. His basic metabolic and hematologic tests demonstrated no abnormalities. Treatment with lithium after several weeks failed to abolish his cycles although they were less severe. Melatonin (5 mg) administration at bedtime improved his nocturnal sleep, but failed to stop his cycles, although the biphasic behavioral changes were mainly evident during the daytime. As a result his care was easier to maintain. Patient 3. This 14-year-old, severely mentally retarded female was born at term after a normal pregnancy, to nonconsanguineous, caucasian parents. The maternal history was positive for an affective illness. The perinatal period was normal and birth weight was 3.42 kg. She developed normally but at 6 months a diagnosis of infantile spasms was made. Investigations at 1 year revealed a normal cranial CT. EEG was diffusely slow and dysrhythmic, with multifocal spikes and sharp waves. Detailed metabolic investigations, including thyroid studies, plasma amino acids, and lipoprotein profile were normal. She was on valproic acid with good seizure control. At 5 years of age, she developed focal and secondary generalized seizures. The treatment was changed to carbamazepine and she has been seizure-free since then. At 9 years of age, she developed a debilitating cyclic behavior, recurring every 3-4 months. For 7-8 days she became weepy, lethargic, and sleeping excessively, 18-20 hours a day. Her appetite and weight decreased, she was constipated, and her extremities felt cold. During this time she could not go to school and there was marked deterioration in her daily living skills. Following this state, she developed agitation, distractibility, overactivity, and sleeplessness for 7-14 days. She slept at irregular times, but for a total of only 3-5 hours a day. Her appetite increased,
Jan et al: Rapid Cycling and Multidisabled
35
she drank excessively, and her weight increased. There were no temperature changes. In school her teachers were impressed with her temporary developmental progress, but her overactivity made discipline difficult. Sedatives had only a minimal effect on the overactive state and methylphenidate had no effect on the lethargic phase. Between these cycles she was predictable and her sleep pattern normal. On re-examination, head circumference was 48.6 cm ( - 2 SD), height was 123.4 cm ( - 2 SD), and weight 21.3 kg which was appropriate for her height. She was prepubertal. Physical examination was normal, but neurologic assessment disclosed normal cranial nerves, tone, strength, deep tendon reflexes, cerebeUar function, and peripheral sensation but coordination was impaired and intellectual development was markedly slow. Her mental age appeared to be about 2-3 years. Investigation during her hypersomnolent state revealed normal growth hormone response to stimulation with arginine and levodopa (peak: 16.7 ~g/L). TRH stimulation demonstrated an appropriate TSH prolactin response, serum thyroxine (T4), and triiodothyronine (T3). Her cortisol response to ACTH was normal. Fasting blood glucose, serum sodium, and serum and urine osmolalities were normal. Repeat cranial CT was normal. Clinical and EEG studies eliminated recurrent seizures as the cause of her cycles. At age 12 years, she unexpectedly stopped having cycles which have not recurred for over 2 years, although occasional periods of "highs" were observed. Patient 4. This 8-year-old boy was born following an uncomplicated pregnancy to nonconsanguineous, caucasian parents. His mother had been diagnosed as having a severe bipolar affective disorder. The neonatal period was complicated by seizures, hypoglycemia, and Clostridium welchii septicemia. Total blindness, caused by bilateral optic nerve hypoplasia, was observed at 3 months. Cranial CT revealed mild, diffuse cerebral atrophy. At age 2V2 years, height was 87 cm ( - 1.5 SD) and weight 12.4 kg ( - 1 SD). Neuroendocrine investigations demonstrated a blunted growth hormone response to arginine (peak: 3.3 ng/ml). The TSH response to TRH was suggestive of a hypothalamic defect (peak: 26.0 mlU/L at 120 min). Serum T 4 and T 3 were normal. At age 5 years, the growth rate had declined and repeat assessment confirmed growth hormone deficiency (peak: 1.6 ~,g/L). Serum thyroxine was normal. Serum cortisol was low (132 nmol/L at 60 min) and there was a blunted response to ACTH (455 nmol/L at 60 rain) suggesting partial ACTH deficiency. Bone age was within 2 standard deviations of the chronologic age. Growth hormone therapy began 3 times weekly and hydrocortisone at times of illness. During his early childhood he developed recurring, unexplained episodes of drowsiness, excessive sleeping, and reduced appetite with occasional nose bleeds once every 1-2 months. These episodes would last for 1-3 days and were followed by a couple of days of hyperactivity and excessive wakefulness. He slept well between cycles. Blood glucose, when checked, was always normal. No seizures occurred, although EEG revealed bioccipital sharp waves. After commencing growth hormone therapy he demonstrated good catch-up growth such that his height was only 0.3 standard deviations from the mean. He had evidence of marked global neurodevelopmental delay and continued to have these abnormal cycles of behavior, but during the last 2 years they have occurred only once or twice a year. Patient 5. This 51/2-year-old, totally blind boy was neurologically mulfidisabled by near-miss sudden infant death occurring at age 10 weeks. His mother had previously been diagnosed as having frequent episodes of a bipolar disorder. He could not walk or sit unsupported and had no language. He had spastic quadriplegia, bilateral optic nerve atrophy, epilepsy, marked developmental delay, and severe, chronic sleep disorder. He had difficulty falling asleep, his sleep pattern was fragmented, and he awakened 3-5 times during the night and early in the morning. Since infancy, he had been having regularly occurring behavioral cycles, characterized by 4-5 days of agitation, whining, imtability, hyperactivity, and overexcitability followed 1-2 days later by marked lethargy, developmental regression, and excessive sleep. During the "hyper" phase, he slept 1-2 hours a day, whereas during the hypersomnolence, he tended to sleep 16-18 hours. The cycles have occurred every 2V2-3 weeks during the last 4 years.
36
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The child's health has been satisfacto~, tie has been treated with multiple antiepileptic drugs for seizures, including valproic acid and carbamazepine, but continues to have staring episodes, sudden body jerks, and rare, generalized convulsions. EEG has always been abnor. mal, demonstrating muttifocal spikes superimposed on a stow. dysrhythmic and suppressed background. Cranial CT revealed multicystic leukomalacia; metabolic investigations, including thyroid tests, were normal. His sleep disorder did not respond to sedatives, strict bedtime routines, or psychologic measures. Melatonin (5 mg) given orally at the desired bedtime minimally improved his sleep but the cycles continued. Patient 6. This 11-year-old boy had severe, spastic quadriparesis and generalized tonic and myoclonic seizures. The paternal history was positive for affective illness. He was born follo~ving an uneventful pregnancy and delivery and developed normally until age 8 months. At that time he contracted eastern equine encephaliti.~ which left him with severe neurologic impairment and no expressive language. He does understand some verbal commands and responds by eye blinking. He required a fundoplication and gastrostomy at 18 months and ventricular peritoneal shunt for hydrocephalus at age 3 years. Numerous antiepileptic drugs have been used, the most effective ones being carbamazepine, mephobarbital, and nitrazepam. A ketogenic diet also was attempted. He probably has 20/50 distance visual acuity bu~ appears to have limited visual perceptual integration skills. At age 4 years, his parents realized that be was having monthly episodes when he was attentive and alert, slept little, and his spasticity was decreased and bad days characterized by irritability, lethargy, intermittent dozing, increased seizures, frequent crying, and extreme sensitivity to touch. He had more "alert" periods in the summer months and by the fall was having more irritable and spastic days. By 6 years of age, he was having 2 "good days" and 4 "bad days" every month. At age 7 years, daily phototherapy was introduced, 2 hours between 5 and 7 a.m. Four weeks later he was having improved high-energy states, lasting up to 3 days, but no change in low-energy phases. Since the age of 10 years he has exhibited the pattern of 4-5 "good days" and 3 "b',u:l days" monthly. He had increased urination during his "bad days." It appears that he may have developed migraine headaches recently during his hypersomnolence states because he appeared to be photophobic with unilateral headache. His father and older brother had migraine. Thioridazine, given during his "high" episodes, minimally improved his sleep. Recently, it was replaced by melatonin/7.5 rag) which was more effective.
Discussion For several years, these 6, low-functioning, multidisabled children have had highly debilitating, regularly recurring biphasic behavioral states. Their care and treatment had been extremely difficult, at times leading to sleep deprivation and parental "bum-out." The cycles may begin with hypersomnolence or hyperactivity (Table 1). Each phase lasts for several days. The "lows" as some parents call them, consist of hypersomnolence, withdrawal, lethargy, excessive irritability, weepiness, and loss of abilities. During their overactive state the children are hyperactive, agitated, and sleep very little; however, their mental abilities are improved. Mood changes are characterized by euphoria with prolonged episodes of laughing, increased verbalization, and aggressiveness. The appetite tends to increase during hypersomnolence and decrease during the overactive state, but in one child it was the reverse. Temperature changes are not apparent. During the lethargic state some patients have cold, blotchy skin, increased urination, and in one instance, edematous extremities. One child in his overactive
Table 1.
Diagnostic criteria for depression and m a n i a in relationship to s y m p t o m s of patients
Depression (1) Increase in sleep (2) C h a n g e in appetite, thirst, and/or weight (3) Onset or increase in self-injurious behavior (4) A p a t h y (5) P s y c h o m o t o r retardation (6) Loss of daily living skills (7) Spontaneous c r y i n g Mania (1) Decrease in sleep (2) Overactivity (3) Biphasic course (4) Increased distractibility (5) Increased verbalization (6) Increased aggressiveness
1
2
Patient N u m b e r 3 4
5
6
+ + + + + + +
+ +
+ +
+ +
+ --
+ + + + +
phase became so euphoric that while laughing he kept banging his fists against the wall, seemingly unable to feel pain. The cycles are more or less regular, occurring once every 1-3 months, although at times they unexpectedly change in frequency, yet still remain regular. Three children slept poorly even between episodes. The hypothalamus, through its connection to the limbic system, has a central role in the modulation of complex behavior. Hypersomnolence has been observed following head injury, cerebral arteriosclerosis, encephalitis, and intracranial tumors involving the posterior part of the hypothalamus [15]. Hypothalamic lesions may present with disturbance of appetite, temperature control, sleep/wake cycles, and behavior. In 1925, Kleine described cyclic hypersomnia among young males ]16]. In 1936, Levin added bulimia as an additional manifestation [17]. Critchley, in 1962, described marked behavioral and psychologic changes that accompanied these periods [18]. Between episodes the patients usually were normal. The disorder now known as Kleine-Levin syndrome occurs mainly in adolescent males, but a young female was reported by Duffy and Davidson in 1968 ]19]. These individuals sleep almost constantly for days to weeks, awakening only to eat gluttonously. The episodes may recur from 2-12 times a year and remit spontaneously. The etiology of periodic hypersomnolence is unknown and no consistent abnormality, either chemical or electroencephalographic, can generally be observed between or during the episodes [20]. Our disorder is strongly biphasic and manifests in much younger patients with profound neurologic impairment than in those described with KleineLevin syndrome. Seasonal affective disorders are characterized by episodes of depression most often in the fall and winter and recovery or even hypomania in the spring and summer seasons [21-23]. The depression phase is often associated with increased eating, carbohydrate craving, weight gain, and oversleeping. The majority of patients with seasonal affective disorder are women, and older than 30 years of
+ +
4-
.
+ + +
+ + +
.
+ + +
.
.
+ + +
4+ +
+
+
--
+
4-
4+ 4-4--
4+ + 444-
444444-
44+ + -+
44-_ --
age, but seasonal affective disorder occasionally occurs in children [22]. Light therapy is the recommended treatment. It is clear that our patients do not have this disorder. Persistent seizures can produce prolonged periods of hypersomnolence, lethargy, and irritability but repeated EEGs during the two phases excluded epilepsy. No clinical evidence of persistent seizures exists. Although prolonged EEG recordings were not conducted in our multidisabled patients for technical reasons, epilepsy was still satisfactorily eliminated as the cause of the biphasic disorder. The endogenous sleep-wake rhythm of humans under time-cue-free running conditions is about 25 hours. This finding was well demonstrated by cave experiments in which individuals lived in total darkness. Their sleep cycles shifted approximately 1 hour daily, so that periodically they were awake all night and slept during the day. Adults, totally blinded by ocular disorders, frequently had similar difficulties which caused them considerable hardship [24-26]. Free-running sleep-wake cycles are less common in blind children [27]. Our patients clearly did not have this type of difficulty. As with others who examined these children, we were puzzled by these regular, highly debilitating behavioral cycles. We contacted numerous physicians working with the multidisabled in various countries and a psychiatrist believed that our patients' affliction resembled RCAD. The clinical characteristics of our patients fit the diagnostic criteria of bipolar affective illness as modified by Sovner for persons with associated neurologic disabilities [14]. Although RCAD has not been described in severely multidisabled children, our patients appear to have a unique disorder that closely resembles or is a variant of RCAD. Affective disorders on the maternal side of the family were reported in 5 patients and on the paternal side in the remaining child. This observation is very interesting and must be explored further. These case reports strongly suggest the possibility that when children with the hereditary tendency for affective disorder sustain brain damage
Jan et al: Rapid Cycling and Multidisabled
37
they are more likely to develop rapid cycling. This possibility was suspected by Jones and Berney [12]. Probably RCAD is more common in severely multidisabled individuals, but is not diagnosed because of the lack of awareness that such an illness can affect them. The cause of RCAD is unknown; however, the hypothalamus, with its close relationship with the limbic system, must be involved. Hypothyroidism has been observed in some of these patients [6], but none of our patients had any evidence of a thyroid disorder. A strong female preponderance also was observed in adult RCAD [6] but this finding was reversed in our study population. In most instances RCAD is unpredictable, whereas the cycles of our children were strikingly regular. The treatment of RCAD, especially in the mentally retarded, is very difficult [6]. Valproic acid is considered to be the first drug of choice followed by carbamazepine [8]; the mechanism of their action on RCAD is unknown. Valproic acid and carbamazepine alone or in combination with other antiepileptic drugs were used in 5 of our patients but failed to prevent or abolish their cycles. Lithium, which was administered to 2 children, did not stop the cycles, but did diminish the severity in 1 child. Although lithium can be a very effective treatment in bipolar disorders, patients with RCAD often do not respond to it [9]. Light therapy in one child disclosed minimal benefits. In 1991, Palm et al. reported a multidisabled, blind child with a chronic sleep disorder who was successfully treated with melatonin [27]. As a result, we also began treating chronic sleep disorders in multidisabled children [28]. The study demonstrated melatonin to be a very important drug in the management of endogenous wake/sleep rhythm disturbance. Because 3 of our patients experienced marked, chronic sleep difficulties, we also treated them. Melatonin plays an important role in the induction of sleep. It is produced by pinealocytes in the pineal gland. Tryptophan is converted to serotonin, then to N-acetylserotonin and finally to melatonin (N-acetyl-5-methoxytryptamine). The secretion of melatonin is controlled by an endogenous rhythm-generating system in the brain which is synchronized by the light/dark cycle so that melatonin levels are high in darkness and low in light. The process begins at the retina, the signal proceeds to the suprachiasmatic nucleus of the hypothalamus, through the reticular system, spinal cord, cervical ganglia and postganglionic sympathetic fibers to the pineal gland [29]. The suprachiasmatic nucleus is a major sleep and body rhythm regulator and melatonin appears to influence this structure [30,31]. Melatonin has been synthesized and is available for experimental use. Its usefulness has been reported for shift workers [32] and those combating jet-lag [33], chronic insomnia [34], and delayed sleep phase syndrome [35]. Adverse side-effects were not observed in any of the studies. Oral melatonin given at bedtime improved the sleep pattern of 3 children who slept poorly between cycles, yet
38 PEDIATRIC NEUROLOGY
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their cycles continued. Melatonin, prescribed only in the "high" phases, also improved the sleep of another child. Sleep difficulties in the mentally disabled are very common. Bartlett et al. reported that 86% of those younger than 6 years of age, 81% of ages 6-11 years, and 77% of ages 12-16 years were reported by their parents as having sleep problems [36]. Quine subsequently substantiated these findings 137]. Because only one-half of the children in our report had sleep difficulties between their cycles, it is reasonable to assume that the chronic sleep problems were coincidental. The disorder of these 6 severely multidisabled children results in a profound burden for the families. In spite of antiepileptic drug treatment, lithium, melatonin, light therapy, stimulants, sedatives, and tranquilizers, the cycles persist. The clinical characteristics of their affliction fit the diagnostic criteria of affective disorder well modified by Sovner for patients with associated neurologic disabilities [14]; however, it is difficult to state with certainty whether they have a unique disorder or simply a variant of RCAD. Although psychiatrists are more aware of RCAD than other specialists, we wish to bring this unique disorder more to the attention of pediatric neurologists and developmental pediatricians because they tend to diagnose and treat multidisabled children most frequently. It is hoped that this report will promote the documentation of similar patients and thus a clearer pattern of this unusual biphasic behavior might emerge
The authors thank Dr. E. J. Garland, Mood Disorders Clinic, Department of Psychiatry, University of British Columbia, for her review of this article.
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