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CARBAMAZEPINE FOR KLEINE-LEVIN SYNDROME
LETTERS TO T H E E D I T O R
CARESAMAZEPINE FOR IUEINE-LEVIN SYNDROME
To the Editor: The Kleine-Levin syndrome is rare episodic disorder that manifests a rich spectrum of psychiatric and vegetative symptoms such as sleeping and eating abnormalities. The most frequent psychological symptoms are irritability, excitation, motor uneasiness, and social and sexual disinhibition (Gillberg, 1987; Sagar et al., 1990). Lithium has been implicated as a drug of choice, but here we will report 2 cases who responded well to carbamazepine treatment. Both patients were referred by child neurologists. Case 1. A 10-year-old boy was referred because of hypersomnia (18 hours a day), aggressive behaviors, and shouting which had lasted for 1 week. An initial episode, 1 month earlier, had also lasted for l week. His psychomotor development, academic accomplishments, and peer relations were normal; there was no report of a medical illness except for a fall when he was 7 which caused no complications. The patient did not exhibit hyperphagia, although he could eat food he would previously have refused. His neurological examination, blood assays, and cerebrospinal fluid findings were normal. A cranial magnetic resonance imaging scan revealed isolated hypodense areas which were interpreted to be consistent with his fall. Repeated EEGs showed diffuse disorganization with no active epileptic foci. In psychiatric evaluations he was quite irritable and uncooperative, tending to sleep. He was thought to be primarily psychotic, and haloperido1 0.9 mg/day was started. The next day he was totally awake, behaved normally, and did not exhibit any disinhibition. While on haloperidol, after 10 days of remission his symptoms relapsed. Evaluations revealed no signs of an explainable neurological disorder. Carbamazepine 400 mg/day was started and he recovered in a week and stayed symptom-free for 6 months. When his parents withdrew carbamazepine, he exhibited the same symptoms. Repeated evaluations revealed no explanations. Episodicity of this disorder, predominance of excessive daytime sleepiness, and accompanying disinhibition were consistent with Kleine-Levin syndrome, and carbamazepine was restarted. After 8 months with this therapy he has not had any additional episodes. Case 2. A 13-year-old boy began to show behavioral changes 3 days after a mild influenza infection. He had increased interest in sex and masturbation, ate huge amounts, slept 16 to 18 hours a day, and reported anxiety. His neurological findings (examination, biochemistry, computed tomogra-
J . A M , ACAD. C H I L D A D O L E S C . PSYCHIATRY, 38:7, JULY 1999
phy) were normal. His orientations were intact except for time, and he was irritable and anxious. He frequently attacked his parents, especially when his sexual interests were prohibited. His past, family, and academic history were insignificant; no precipitators were identified. One year earlier there had been a period of 3 or 4 days when he was irritable and had excessive appetite and sleepiness. Kleine-Levin syndrome was diagnosed, and carbamazepine 600 mg/day was started. He began to recover in 5 days with this medication and was totally symptom-free in 20 days. In his evaluations he could remember some of his experiences but was amnestic of his sexual behaviors. After 7 months with this treatment he has not had any additional episodes. The 2 cases presented here are considered examples of the Kleine-Levin syndrome because of the episodic cluster of behaviors, mainly hypersomnia and related psychiatric symptomatology. The first patient's symptoms aggregated around a general disinhibition and hypersomnia, which is episodic in nature. His young age may be partially responsible for the incomplete presentation, especially with regard to hypersexuality and the disappearance of food selection, which some authors argue for (Billiard and Cadilhac, 1988). The second patient is a typical case of Kleine-Levin syndrome with hypersexuality, hypersomnia, hyperphagia, periodicity of his complaints, and onset of the symptoms. Both patients responded to carbamazepine rather abruptly. This finding is consistent with other but scarce reports concerning the efficacy of carbamazepine in Kleine-Levin syndrome (Savet et al., 1986; Wurthmann et al., 1989). Kleine-Levin syndrome needs further scrutiny in terms of cyclical affective disorders that respond well to mood stabilizers.
Nahit Motavalli Mukaddes, M.D. Meltem Erocal Kora, M.D. Sumru Bilge, M.D. Child and Adolescent Psychiatry Istanbul Medical Faculty, Istanbul University Istanbul, Turkey Billiard M, Cadilhac J (1988), Les hypersomnies rkcurrentes. Rev Neurol (Paris) 144:249-2 58 Gillberg C (1987), Kleine-Levin syndrome: unrecognized diagnosis in adolescent psychiatry. ] A m Acad ChildAdoksc PSyChiAhy 26:793-794 Sagar RS, Khandelwal SK, Gupta S (1990), Interepisodic morbidity in Kleine-Levin syndrome. Br J PSychiuhy 157:139-141 Savet JF, Robert H, Angel C (19861,A case of Kleine-Levin syndrome stabilized for over 1 year with carhamazepine (letter, in French) PresseMed 15:1281 Wurthrnann C, Hartung HI? Dengler W, Gerhardt P (1989), Kleine-Levin syndrome: the provocation of manic symptoms by an antidepressant and
79 1
LETTERS TO T H E E D I T O R
a therapeutic trial of carbamazepine (in German). Dtsch Med Wochenschr
1141528-1531
APPETITE AND WEIGHT IN CHILDREN TREATED FOR ADHD
To the Editor: Several of my pediatric patients who were losing weight with stimulants then began to gain weight with the addition of bupropion (Wellbutrin@).I am interested in learning whether other readers have had similar observations. I first observed this phenomenon serendipitously. I had added bupropion to a patient’s stimulant medication to allow a switch to bupropion from the stimulant at a later point when bupropion had reached its full efficacy. The patient, a 10-year-old child whose weight had decreased from 58 kg to 51 kg over a period of 15 months, then regained weight up to 56 kg over the next 4 months with the addition of bupropion. Several other children had similar gains. Adding bupropion to stimulants for children with weight loss from stimulants has seemed effective in allowing weight gain slightly less than half the time. In one child, the mother had tapered bupropion on her own and then reinstituted the higher dose when she saw her child’s appetite plummet. When the higher dose was reinstituted, this child’s appetite again improved. I believe this phenomenon deserves further study, especially because stimulants are often the most effective medications for attention problems and weight loss is a common and often troubling stimulant side effect. I would be interested in any thoughts about a possible mechanism of action.
In childhood studies, bupropion monotherapy has not been associated with any statistically significant changes in weight (Conners et al., 1996). There are no systematic studies that have looked at coadministration of bupropion with psychostimulant medication. Thus, both the potential efficacy of this approach, as well as possible side effects, have yet to be defined. This is a necessary first step. Thereafter, preliminary reports like the one offered by Dr. Callaghan might lead to more rigorous studies that will allow us to better define the specific niche for bupropion. Joseph I? Horrigan, M.D. University of North Carolina, Chapel Hill Conners CK, Casat CD, Gualtieri C T et al. (1996), Bupropion hydrochloride in attention deficit disorder with hyperactivity J A m Acud Child Adolesc Psychiatry 35: 1314-132 1 Glaxo Wellcome (1996), Product information: WellbutrinB (bupropion hydrochloride), Research Triangle Park, N C Harto-Truax N, Stern WC, Miller LL Sat0 TL, Cat0 AE (1983), Effects of bupropion on body weight. 1Clin Psychiatry 44:5(part 2):183-186 Physicians’ Desk Reference (1998). Montvale, NJ: Medical Economics Company, pp 1120-1123 Settle EC (1993), Bupropion: general side effects. 1Clin Psychiatry Monogr 11(1):33-39
Comment by Drs. Casat and Hartnagal, at the invitation of the Editor:
This letter is intriguing, in light of bupropion’s reputation as an agent that can cause stimulant-like side effects, including weight loss. The manufacturer’s product information for Wellbutrin@ (bupropion) describes its “weight reducing potential,” at least in adults, and the drug is described as contraindicated in cases of anorexia (primarily due to concerns about an elevated risk of seizures) (Glaxo Wellcome, 1996). Nonetheless, in placebo-controlled trials with adults, weight gain occurred in 13.6% of patients (while weight loss occurred in 23.2%) (Physicians’Desk Reference, 1998). In fact, in the management of depressed adults with a pretreatment weight that is below average, bupropion may have “weight stabilizing properties” (Settle, 1993). However, the mechanism behind this is uncertain, as no overt changes in appetite, body temperature, or metabolic rate have been associated with bupropion (Harto-Truax et al., 1983).
Appetite suppression is a common accompaniment of stimulant use in children with attention-deficit/hyperactivitydisorder (ADHD). Not infrequently, there is a slowing in growth parameters with stimulant treatment, although the ultimate impact of stimulants on growth has been characterized as negligible. In some children, however, weight loss may be significant, leading the clinician and parent to consider stopping treatment. This may present a considerable dilemma because the symptoms themselves may lead to exclusion from important academic and social experiences vital to a child’s development. In the accompanying Letter to the Editor, Dr. Callaghan has described several examples from his practice of children whose weight loss was apparently reversed when bupropion was added to each child’s stimulant medication regimen. However, it is not clear whether stimulant dose was reduced as bupropion was added, and the daily dosing was not described. Also, the presence of any comorbid clinical conditions, especially depression, was not mentioned. Appetite is under complex control of endocrine (insulin and leptin) and neural (norepinephrine, opioids, and neuropeptide Y) mechanisms, mediated especially through the ventromedial hypothalamus (Kalra, 1997). Although progress has been made recently in understanding the control of appetite, much remains still to be elucidated. With regard to weight changes associated with medications, a large variety of drugs will impact such changes. Those with significant histamine-blocking effect will generally dispose to weight gain, while medications with significant noadrenergic activity may cause weight loss.
792
J . A M . A C A D . C H I L D A D O L E S C . PSYCHIATRY, 38:7, JULY 1999
R. Stephen Callaghan, M.D. Psychiatric Services of Racine and Kenosha Racine, WI Comment by Dr. Horrigan, at the invitation of the Editor:
CARESAMAZEPINE FOR IUEINE-LEVIN SYNDROME
To the Editor: The Kleine-Levin syndrome is rare episodic disorder that manifests a rich spectrum of psychiatric and vegetative symptoms such as sleeping and eating abnormalities. The most frequent psychological symptoms are irritability, excitation, motor uneasiness, and social and sexual disinhibition (Gillberg, 1987; Sagar et al., 1990). Lithium has been implicated as a drug of choice, but here we will report 2 cases who responded well to carbamazepine treatment. Both patients were referred by child neurologists. Case 1. A 10-year-old boy was referred because of hypersomnia (18 hours a day), aggressive behaviors, and shouting which had lasted for 1 week. An initial episode, 1 month earlier, had also lasted for l week. His psychomotor development, academic accomplishments, and peer relations were normal; there was no report of a medical illness except for a fall when he was 7 which caused no complications. The patient did not exhibit hyperphagia, although he could eat food he would previously have refused. His neurological examination, blood assays, and cerebrospinal fluid findings were normal. A cranial magnetic resonance imaging scan revealed isolated hypodense areas which were interpreted to be consistent with his fall. Repeated EEGs showed diffuse disorganization with no active epileptic foci. In psychiatric evaluations he was quite irritable and uncooperative, tending to sleep. He was thought to be primarily psychotic, and haloperido1 0.9 mg/day was started. The next day he was totally awake, behaved normally, and did not exhibit any disinhibition. While on haloperidol, after 10 days of remission his symptoms relapsed. Evaluations revealed no signs of an explainable neurological disorder. Carbamazepine 400 mg/day was started and he recovered in a week and stayed symptom-free for 6 months. When his parents withdrew carbamazepine, he exhibited the same symptoms. Repeated evaluations revealed no explanations. Episodicity of this disorder, predominance of excessive daytime sleepiness, and accompanying disinhibition were consistent with Kleine-Levin syndrome, and carbamazepine was restarted. After 8 months with this therapy he has not had any additional episodes. Case 2. A 13-year-old boy began to show behavioral changes 3 days after a mild influenza infection. He had increased interest in sex and masturbation, ate huge amounts, slept 16 to 18 hours a day, and reported anxiety. His neurological findings (examination, biochemistry, computed tomogra-
J . A M , ACAD. C H I L D A D O L E S C . PSYCHIATRY, 38:7, JULY 1999
phy) were normal. His orientations were intact except for time, and he was irritable and anxious. He frequently attacked his parents, especially when his sexual interests were prohibited. His past, family, and academic history were insignificant; no precipitators were identified. One year earlier there had been a period of 3 or 4 days when he was irritable and had excessive appetite and sleepiness. Kleine-Levin syndrome was diagnosed, and carbamazepine 600 mg/day was started. He began to recover in 5 days with this medication and was totally symptom-free in 20 days. In his evaluations he could remember some of his experiences but was amnestic of his sexual behaviors. After 7 months with this treatment he has not had any additional episodes. The 2 cases presented here are considered examples of the Kleine-Levin syndrome because of the episodic cluster of behaviors, mainly hypersomnia and related psychiatric symptomatology. The first patient's symptoms aggregated around a general disinhibition and hypersomnia, which is episodic in nature. His young age may be partially responsible for the incomplete presentation, especially with regard to hypersexuality and the disappearance of food selection, which some authors argue for (Billiard and Cadilhac, 1988). The second patient is a typical case of Kleine-Levin syndrome with hypersexuality, hypersomnia, hyperphagia, periodicity of his complaints, and onset of the symptoms. Both patients responded to carbamazepine rather abruptly. This finding is consistent with other but scarce reports concerning the efficacy of carbamazepine in Kleine-Levin syndrome (Savet et al., 1986; Wurthmann et al., 1989). Kleine-Levin syndrome needs further scrutiny in terms of cyclical affective disorders that respond well to mood stabilizers.
Nahit Motavalli Mukaddes, M.D. Meltem Erocal Kora, M.D. Sumru Bilge, M.D. Child and Adolescent Psychiatry Istanbul Medical Faculty, Istanbul University Istanbul, Turkey Billiard M, Cadilhac J (1988), Les hypersomnies rkcurrentes. Rev Neurol (Paris) 144:249-2 58 Gillberg C (1987), Kleine-Levin syndrome: unrecognized diagnosis in adolescent psychiatry. ] A m Acad ChildAdoksc PSyChiAhy 26:793-794 Sagar RS, Khandelwal SK, Gupta S (1990), Interepisodic morbidity in Kleine-Levin syndrome. Br J PSychiuhy 157:139-141 Savet JF, Robert H, Angel C (19861,A case of Kleine-Levin syndrome stabilized for over 1 year with carhamazepine (letter, in French) PresseMed 15:1281 Wurthrnann C, Hartung HI? Dengler W, Gerhardt P (1989), Kleine-Levin syndrome: the provocation of manic symptoms by an antidepressant and
79 1
LETTERS TO T H E E D I T O R
a therapeutic trial of carbamazepine (in German). Dtsch Med Wochenschr
1141528-1531
APPETITE AND WEIGHT IN CHILDREN TREATED FOR ADHD
To the Editor: Several of my pediatric patients who were losing weight with stimulants then began to gain weight with the addition of bupropion (Wellbutrin@).I am interested in learning whether other readers have had similar observations. I first observed this phenomenon serendipitously. I had added bupropion to a patient’s stimulant medication to allow a switch to bupropion from the stimulant at a later point when bupropion had reached its full efficacy. The patient, a 10-year-old child whose weight had decreased from 58 kg to 51 kg over a period of 15 months, then regained weight up to 56 kg over the next 4 months with the addition of bupropion. Several other children had similar gains. Adding bupropion to stimulants for children with weight loss from stimulants has seemed effective in allowing weight gain slightly less than half the time. In one child, the mother had tapered bupropion on her own and then reinstituted the higher dose when she saw her child’s appetite plummet. When the higher dose was reinstituted, this child’s appetite again improved. I believe this phenomenon deserves further study, especially because stimulants are often the most effective medications for attention problems and weight loss is a common and often troubling stimulant side effect. I would be interested in any thoughts about a possible mechanism of action.
In childhood studies, bupropion monotherapy has not been associated with any statistically significant changes in weight (Conners et al., 1996). There are no systematic studies that have looked at coadministration of bupropion with psychostimulant medication. Thus, both the potential efficacy of this approach, as well as possible side effects, have yet to be defined. This is a necessary first step. Thereafter, preliminary reports like the one offered by Dr. Callaghan might lead to more rigorous studies that will allow us to better define the specific niche for bupropion. Joseph I? Horrigan, M.D. University of North Carolina, Chapel Hill Conners CK, Casat CD, Gualtieri C T et al. (1996), Bupropion hydrochloride in attention deficit disorder with hyperactivity J A m Acud Child Adolesc Psychiatry 35: 1314-132 1 Glaxo Wellcome (1996), Product information: WellbutrinB (bupropion hydrochloride), Research Triangle Park, N C Harto-Truax N, Stern WC, Miller LL Sat0 TL, Cat0 AE (1983), Effects of bupropion on body weight. 1Clin Psychiatry 44:5(part 2):183-186 Physicians’ Desk Reference (1998). Montvale, NJ: Medical Economics Company, pp 1120-1123 Settle EC (1993), Bupropion: general side effects. 1Clin Psychiatry Monogr 11(1):33-39
Comment by Drs. Casat and Hartnagal, at the invitation of the Editor:
This letter is intriguing, in light of bupropion’s reputation as an agent that can cause stimulant-like side effects, including weight loss. The manufacturer’s product information for Wellbutrin@ (bupropion) describes its “weight reducing potential,” at least in adults, and the drug is described as contraindicated in cases of anorexia (primarily due to concerns about an elevated risk of seizures) (Glaxo Wellcome, 1996). Nonetheless, in placebo-controlled trials with adults, weight gain occurred in 13.6% of patients (while weight loss occurred in 23.2%) (Physicians’Desk Reference, 1998). In fact, in the management of depressed adults with a pretreatment weight that is below average, bupropion may have “weight stabilizing properties” (Settle, 1993). However, the mechanism behind this is uncertain, as no overt changes in appetite, body temperature, or metabolic rate have been associated with bupropion (Harto-Truax et al., 1983).
Appetite suppression is a common accompaniment of stimulant use in children with attention-deficit/hyperactivitydisorder (ADHD). Not infrequently, there is a slowing in growth parameters with stimulant treatment, although the ultimate impact of stimulants on growth has been characterized as negligible. In some children, however, weight loss may be significant, leading the clinician and parent to consider stopping treatment. This may present a considerable dilemma because the symptoms themselves may lead to exclusion from important academic and social experiences vital to a child’s development. In the accompanying Letter to the Editor, Dr. Callaghan has described several examples from his practice of children whose weight loss was apparently reversed when bupropion was added to each child’s stimulant medication regimen. However, it is not clear whether stimulant dose was reduced as bupropion was added, and the daily dosing was not described. Also, the presence of any comorbid clinical conditions, especially depression, was not mentioned. Appetite is under complex control of endocrine (insulin and leptin) and neural (norepinephrine, opioids, and neuropeptide Y) mechanisms, mediated especially through the ventromedial hypothalamus (Kalra, 1997). Although progress has been made recently in understanding the control of appetite, much remains still to be elucidated. With regard to weight changes associated with medications, a large variety of drugs will impact such changes. Those with significant histamine-blocking effect will generally dispose to weight gain, while medications with significant noadrenergic activity may cause weight loss.
792
J . A M . A C A D . C H I L D A D O L E S C . PSYCHIATRY, 38:7, JULY 1999
R. Stephen Callaghan, M.D. Psychiatric Services of Racine and Kenosha Racine, WI Comment by Dr. Horrigan, at the invitation of the Editor: