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Obstructive sleep apnoea following rapid weight gain secondary to treatment with vigabatrin (Sabril®)
Seizure 1997; 6: 233-235
CASE REPORT
Obstructive sleep apnoea following rapid weight gain secondary to treatment with vigabatrin (Sabril@) M.V. LAMBERT & J.M. BIRD Burden
Neurological
Hospital,
Stoke Lane,
Stapleton,
Bristol,
BS16
lQT, UK
A caseof a patient with medically intractable epilepsy, who developed obstructive sleepapnoea (OSA), and an increasein seizurefrequency, asa consequenceof weight gain following treatment with vigabatrin is described.The relationship between exacerbation of epilepsy and sleepdisruption secondaryto OSA is discussed.Recommendations regarding the choice of anticonvulsantsin patients at risk of developing OSA are made. Key words:epilepsy; obstructive sleepapnoea;vigabatrin; weight gain.
INTRODUCTION
Weight gain is a known side-effect of treatment with the anticonvulsant vigabatrin (Sabril@)‘. This case shows the consequences of rapid weight gain, in the form of generalized pitting oedema in a person predisposed to developing obstructive sleep apnoea.
CASE HISTORY
CW is a 42-year-old married and employed man, with normal birth and development. He developed idiopathic complex partial seizures with secondary generalization at the age of 16. There was no relevant past medical history including chest disease and no family history of epilepsy (although his son subsequently developed similar seizures in adulthood). His fits occurred approximately weekly and were unresponsive to phenobarbitone, phenytoin, carbamazepine, ethosuximide, lamotrigine and gabapentin. They were partially responsive to sodium valproate but he suffered a weight gain of 38 kg on this treatment. His fits were exacerbated by sleep loss secondary to worry about potential redundancy. He was a non-smoker and rarely consumed alcohol. He had a collar size of 18.5 inches (which had increased from 15 inches since early adulthood), and a weight of 111.5 kg with a body mass 1059-131 l/97/030233
+ 03 $12.00/O
index of 34.5 kg/m2. He had a normal computerized tomography (CT) scan and electroencephalograph (EEG). His magnetic resonance imaging (MRI) scan however, showed a volume loss in the right hippocampus with temporal horn
dilatation on the same side. Although he had no previous history of psychiatric illness, he developed episodes during which he felt low and tearful, but had a normal appetite and sleep pattern. He did not appear to be clinically depressed and these episodes were thought to be secondary to worry abut his seizures and potential redundancy. However because of these episodes of low mood, he was hospitalized for a trial of vigabatrin (Sabril@) as an adjunct to sodium valproate (Epilim Chrono@). As an inpatient, on 2g of vigabatrin, he was fit-free for 5 weeks and his mood improved to the extent that he felt able to resume his normal activities, so he was discharged home. Three weeks later, he was re-admitted as an emergency with excessive daytime sleepiness and restless nights. His wife reported that he had a disturbed nights sleep and had started snoring. He had also gained over 11 kg of weight over these three weeks (a 10.3% increase in his usual weight). The control of his epilepsy had deteriorated and he was suffering weekly seizures. On admission, he was constantly falling asleep and had developed signs of fluid retention with generalized pitting oedema, tachycardia and 0 1997 British Epilepsy Association
234
hypertension. There were no other signs of right heart failure. His electrocardiogram (ECG) and routine haematology and biochemistry were normal. EEG monitoring showed no epileptic activity but he repeatedly fell asleep, during which frequent periods of apnoea, each lasting approximately lo-15 s were noted. During the apnoeas, his oxygen saturation dropped to below 70%; they were terminated by a snore. He was thought to have developed obstructive sleep apnoea (OSA) secondary to rapid weight gain, following treatment with vigabatrin. The vigabatrin was reduced and then stopped and he was given one dose of the diuretic frusemide. His weight decreased by 7 kg in 4 days and he no longer had signs of fluid retention. His sleep pattern returned to normal with no snoring and no further seizures occurred. A repeat sleepdeprived EEG 4 days after admission, again showed periods of apnoea lasting up to 13 s; however, his oxygen saturation did not drop below 92%. When seen as an outpatient, 6 weeks after stopping vigabatrin, his weight had returned to 111 kg, and he had continued to have restful nights free from snoring and apnoeas. He had only experienced one seizure since discharge. DISCUSSION
Vigabatrin is an irreversible inhibitor of gammaaminobutyric acid (GABA) transaminase, and thus increases levels of GABA (the inhibitory neurotransmitter) in the brain. The main reported side-effects in adults are: somnolence, fatigue, irritability, dizziness, depression (4%), headache, confusion, poor concentration, abdominal pain and anorexia2. Psychiatric sideeffects are seen in approximately 5%3, and psychosis with paranoid ideation occurs in around 1.3-1.7%4, although Sander et al, found 14 out of 210 patients developed a schizophrenia-like syndrome5. Tartara et al, in a 6-year follow-up study, found weight gain occurred in 12 out of 215 (48%) patients in the first 12 months and varied between 5 and 33% of the initial weight’. Obstructive sleep apnoea occurs when the pharyngeal airway collapses during sleep. It occurs in l-9% of the population and is characterized by repetitive apnoeas, loud snoring and excessive daytime sleepiness. Other symptoms include nocturnal choking attacks, morning headaches, nocturia, impotence, poor memory and concentration. Chronic OSA can result in hypertension, myocardial infarction, stroke and death6. Psychiatric disorders are also associated with OSA, including paranoid psychosis and
M.V.
Lambert
& J.M.
Bird
depression. Treatment of the OSA may improve the patient’s cognitive and affective status’. The major risk factor for OSA in adults is obesity, as increased peripharyngeal soft tissue (in the form of neck fat deposition) reduces the calibre of the airway during sleep. Neck circumference >43 cm (17 inches) has been found to be a better predictor of risk than overall obesity’. Other risk factors in the adult include male sex, age, retrognathia, craniofacial abnormalities, nasal obstruction and sedatives (especially alcohol and benzodiazepines)6q9. In 1994, Devinsky et af” reported a series of seven patients with obstructive sleep apnoea and medically refractory epilepsy. They found that treatment of the OSA could reduce seizure frequency and severity. They commented that OSA may aggravate or precipitate seizures by causing sleep disruption and deprivation, hypoxaemia, decreased cerebral blood flow and decreased cardiac output. Vaughn et al”, in 1996, also reported 10 patients with recurrent seizures and sleep disruption related to OSA. Treatment of the OSA alone (either by positional therapy or continuous positive airways pressure) resulted in a marked improvement in seizures in four patients. A further three patients had a reduction in seizure frequency following treatment of their OSA in combination with a change in anticonvulsant medication. They concluded that treatment of OSA, in patients with epilepsy may lower the frequency of recurrent seizures. This patient had risk factors for the development of OSA (male sex and collar size >17 inches). However, he only developed symptoms of OSA-snoring, apnoeas and excessive daytime somnolence-after experiencing rapid weight gain whilst taking vigabatrin. Since the weight gain and development of generalized pitting oedema coincided with starting vigabatrin and the weight loss and resolution of the oedema followed its reduction, it seems likely that the vigabatrin was responsible. The weight loss was both dramatic and rapid (7 kg in 4 days), which would imply that the weight gain was secondary to fluid retention rather than fat deposition. Thus, it would appear that treatment with vigabatrin produced fluid retention in the form of pitting oedema, and it was this oedema around the neck that was responsible for the OSA. Although his seizure frequency initially reduced on the combination of vigabatrin and valproate, it increased again following the development of OSA. When his sleep pattern returned to normal after stopping vigabatrin, his seizure frequency lessened. This is in agreement with the findings of
Obstructive
sleep apnoea following
rapid weight gain
Devinsky et aI” and Vaughn et al”, that sleep disruption secondary to OSA exacerbates epilepsy and treatment of the OSA can reduce seizure frequency. Since OSA may aggravate epilepsy and in itself be a cause of morbidity and mortality, caution should be exercised in prescribing anticonvulsant drugs that are known to have a side-effect of weight gain in patients with, or at risk of developing, OSA.
REFERENCES 1. Tartara, A., Manni, R., Galimberti, C.A., ef al. Six-year follow-up study on the efficacy of vigabatrin in patients with epilepsy. Acra Neurological Scandinavia 1992; 86: 247-251. 2. Reynolds, E.H. Gamma-vinyl GABA (vigabatrin): clinical experience in adult and adolescent patients with intractable epilepsy. Epilepsia 1992; 33 (Suppl.5): 30-35. 3. Sander, J.W., Trevisol-Bittencourt, P.C., Hart, Y.M. and Shorvon, S.D. Evaluation of vigabatrin as an add-on drug in the management of severe epilepsy. Journal of
4. 5.
6. 7. 8. 9. 10. 11.
Neurology, Neurosurgery and Psychiatry 1990; 53: lOO81010. Srinivasan, J. and Richens, A. A risk-benefit assessment of vigabatrin in the treatment of neurological disorders. Drug Safety 1994; 10:395-405. Sander, J.W.A.S., Hart, Y.M. and Trimble, M.R. and Shorvon, S.D. Vigabatrin and psychosis. Journal of Neurology, Neurosurgery and Psychiatry 1991; 54: 435439. McNamara, S.G., Grunstein, R.R., and Sullivan, C.E. Obstructive sleep apnoea. Thorax 1993; 48: 754-764. Kaplan, R. Obstructive sleep apnoea and depressiondiagnostic and treatment implications. Australian and New Zealand Journal of Psychiatry 1992; 26: 586-591. Davies, R.J.O., Ah, N.J. and Stradling, J.R. Neck circumference and other clinical features in the diagnosis of the sleep apnoea syndrome. Thorax 1992; 47: 101-105. Davies R.J.O. and Stradling, J.R. Acute effects of obstructive sleep apnoea. British Journal of Anaesthesia 1993; 71: 725-729. Devinsky, O., Ehrenberg, B., Barthlen, G.M., Abramson, H.S. and Luciano, D. Epilepsy and. sleep apnoea syndrome. Neurology 1994; 44: 2060-2064. Vaughn, B.V., D’Cruz, O’N.F., Beach, R. and Messenheimer, J.A. Improvement of epileptic seizure control with treatment of obstructive sleep apnoea. Seizure 1996; 5: 13-78.
CASE REPORT
Obstructive sleep apnoea following rapid weight gain secondary to treatment with vigabatrin (Sabril@) M.V. LAMBERT & J.M. BIRD Burden
Neurological
Hospital,
Stoke Lane,
Stapleton,
Bristol,
BS16
lQT, UK
A caseof a patient with medically intractable epilepsy, who developed obstructive sleepapnoea (OSA), and an increasein seizurefrequency, asa consequenceof weight gain following treatment with vigabatrin is described.The relationship between exacerbation of epilepsy and sleepdisruption secondaryto OSA is discussed.Recommendations regarding the choice of anticonvulsantsin patients at risk of developing OSA are made. Key words:epilepsy; obstructive sleepapnoea;vigabatrin; weight gain.
INTRODUCTION
Weight gain is a known side-effect of treatment with the anticonvulsant vigabatrin (Sabril@)‘. This case shows the consequences of rapid weight gain, in the form of generalized pitting oedema in a person predisposed to developing obstructive sleep apnoea.
CASE HISTORY
CW is a 42-year-old married and employed man, with normal birth and development. He developed idiopathic complex partial seizures with secondary generalization at the age of 16. There was no relevant past medical history including chest disease and no family history of epilepsy (although his son subsequently developed similar seizures in adulthood). His fits occurred approximately weekly and were unresponsive to phenobarbitone, phenytoin, carbamazepine, ethosuximide, lamotrigine and gabapentin. They were partially responsive to sodium valproate but he suffered a weight gain of 38 kg on this treatment. His fits were exacerbated by sleep loss secondary to worry about potential redundancy. He was a non-smoker and rarely consumed alcohol. He had a collar size of 18.5 inches (which had increased from 15 inches since early adulthood), and a weight of 111.5 kg with a body mass 1059-131 l/97/030233
+ 03 $12.00/O
index of 34.5 kg/m2. He had a normal computerized tomography (CT) scan and electroencephalograph (EEG). His magnetic resonance imaging (MRI) scan however, showed a volume loss in the right hippocampus with temporal horn
dilatation on the same side. Although he had no previous history of psychiatric illness, he developed episodes during which he felt low and tearful, but had a normal appetite and sleep pattern. He did not appear to be clinically depressed and these episodes were thought to be secondary to worry abut his seizures and potential redundancy. However because of these episodes of low mood, he was hospitalized for a trial of vigabatrin (Sabril@) as an adjunct to sodium valproate (Epilim Chrono@). As an inpatient, on 2g of vigabatrin, he was fit-free for 5 weeks and his mood improved to the extent that he felt able to resume his normal activities, so he was discharged home. Three weeks later, he was re-admitted as an emergency with excessive daytime sleepiness and restless nights. His wife reported that he had a disturbed nights sleep and had started snoring. He had also gained over 11 kg of weight over these three weeks (a 10.3% increase in his usual weight). The control of his epilepsy had deteriorated and he was suffering weekly seizures. On admission, he was constantly falling asleep and had developed signs of fluid retention with generalized pitting oedema, tachycardia and 0 1997 British Epilepsy Association
234
hypertension. There were no other signs of right heart failure. His electrocardiogram (ECG) and routine haematology and biochemistry were normal. EEG monitoring showed no epileptic activity but he repeatedly fell asleep, during which frequent periods of apnoea, each lasting approximately lo-15 s were noted. During the apnoeas, his oxygen saturation dropped to below 70%; they were terminated by a snore. He was thought to have developed obstructive sleep apnoea (OSA) secondary to rapid weight gain, following treatment with vigabatrin. The vigabatrin was reduced and then stopped and he was given one dose of the diuretic frusemide. His weight decreased by 7 kg in 4 days and he no longer had signs of fluid retention. His sleep pattern returned to normal with no snoring and no further seizures occurred. A repeat sleepdeprived EEG 4 days after admission, again showed periods of apnoea lasting up to 13 s; however, his oxygen saturation did not drop below 92%. When seen as an outpatient, 6 weeks after stopping vigabatrin, his weight had returned to 111 kg, and he had continued to have restful nights free from snoring and apnoeas. He had only experienced one seizure since discharge. DISCUSSION
Vigabatrin is an irreversible inhibitor of gammaaminobutyric acid (GABA) transaminase, and thus increases levels of GABA (the inhibitory neurotransmitter) in the brain. The main reported side-effects in adults are: somnolence, fatigue, irritability, dizziness, depression (4%), headache, confusion, poor concentration, abdominal pain and anorexia2. Psychiatric sideeffects are seen in approximately 5%3, and psychosis with paranoid ideation occurs in around 1.3-1.7%4, although Sander et al, found 14 out of 210 patients developed a schizophrenia-like syndrome5. Tartara et al, in a 6-year follow-up study, found weight gain occurred in 12 out of 215 (48%) patients in the first 12 months and varied between 5 and 33% of the initial weight’. Obstructive sleep apnoea occurs when the pharyngeal airway collapses during sleep. It occurs in l-9% of the population and is characterized by repetitive apnoeas, loud snoring and excessive daytime sleepiness. Other symptoms include nocturnal choking attacks, morning headaches, nocturia, impotence, poor memory and concentration. Chronic OSA can result in hypertension, myocardial infarction, stroke and death6. Psychiatric disorders are also associated with OSA, including paranoid psychosis and
M.V.
Lambert
& J.M.
Bird
depression. Treatment of the OSA may improve the patient’s cognitive and affective status’. The major risk factor for OSA in adults is obesity, as increased peripharyngeal soft tissue (in the form of neck fat deposition) reduces the calibre of the airway during sleep. Neck circumference >43 cm (17 inches) has been found to be a better predictor of risk than overall obesity’. Other risk factors in the adult include male sex, age, retrognathia, craniofacial abnormalities, nasal obstruction and sedatives (especially alcohol and benzodiazepines)6q9. In 1994, Devinsky et af” reported a series of seven patients with obstructive sleep apnoea and medically refractory epilepsy. They found that treatment of the OSA could reduce seizure frequency and severity. They commented that OSA may aggravate or precipitate seizures by causing sleep disruption and deprivation, hypoxaemia, decreased cerebral blood flow and decreased cardiac output. Vaughn et al”, in 1996, also reported 10 patients with recurrent seizures and sleep disruption related to OSA. Treatment of the OSA alone (either by positional therapy or continuous positive airways pressure) resulted in a marked improvement in seizures in four patients. A further three patients had a reduction in seizure frequency following treatment of their OSA in combination with a change in anticonvulsant medication. They concluded that treatment of OSA, in patients with epilepsy may lower the frequency of recurrent seizures. This patient had risk factors for the development of OSA (male sex and collar size >17 inches). However, he only developed symptoms of OSA-snoring, apnoeas and excessive daytime somnolence-after experiencing rapid weight gain whilst taking vigabatrin. Since the weight gain and development of generalized pitting oedema coincided with starting vigabatrin and the weight loss and resolution of the oedema followed its reduction, it seems likely that the vigabatrin was responsible. The weight loss was both dramatic and rapid (7 kg in 4 days), which would imply that the weight gain was secondary to fluid retention rather than fat deposition. Thus, it would appear that treatment with vigabatrin produced fluid retention in the form of pitting oedema, and it was this oedema around the neck that was responsible for the OSA. Although his seizure frequency initially reduced on the combination of vigabatrin and valproate, it increased again following the development of OSA. When his sleep pattern returned to normal after stopping vigabatrin, his seizure frequency lessened. This is in agreement with the findings of
Obstructive
sleep apnoea following
rapid weight gain
Devinsky et aI” and Vaughn et al”, that sleep disruption secondary to OSA exacerbates epilepsy and treatment of the OSA can reduce seizure frequency. Since OSA may aggravate epilepsy and in itself be a cause of morbidity and mortality, caution should be exercised in prescribing anticonvulsant drugs that are known to have a side-effect of weight gain in patients with, or at risk of developing, OSA.
REFERENCES 1. Tartara, A., Manni, R., Galimberti, C.A., ef al. Six-year follow-up study on the efficacy of vigabatrin in patients with epilepsy. Acra Neurological Scandinavia 1992; 86: 247-251. 2. Reynolds, E.H. Gamma-vinyl GABA (vigabatrin): clinical experience in adult and adolescent patients with intractable epilepsy. Epilepsia 1992; 33 (Suppl.5): 30-35. 3. Sander, J.W., Trevisol-Bittencourt, P.C., Hart, Y.M. and Shorvon, S.D. Evaluation of vigabatrin as an add-on drug in the management of severe epilepsy. Journal of
4. 5.
6. 7. 8. 9. 10. 11.
Neurology, Neurosurgery and Psychiatry 1990; 53: lOO81010. Srinivasan, J. and Richens, A. A risk-benefit assessment of vigabatrin in the treatment of neurological disorders. Drug Safety 1994; 10:395-405. Sander, J.W.A.S., Hart, Y.M. and Trimble, M.R. and Shorvon, S.D. Vigabatrin and psychosis. Journal of Neurology, Neurosurgery and Psychiatry 1991; 54: 435439. McNamara, S.G., Grunstein, R.R., and Sullivan, C.E. Obstructive sleep apnoea. Thorax 1993; 48: 754-764. Kaplan, R. Obstructive sleep apnoea and depressiondiagnostic and treatment implications. Australian and New Zealand Journal of Psychiatry 1992; 26: 586-591. Davies, R.J.O., Ah, N.J. and Stradling, J.R. Neck circumference and other clinical features in the diagnosis of the sleep apnoea syndrome. Thorax 1992; 47: 101-105. Davies R.J.O. and Stradling, J.R. Acute effects of obstructive sleep apnoea. British Journal of Anaesthesia 1993; 71: 725-729. Devinsky, O., Ehrenberg, B., Barthlen, G.M., Abramson, H.S. and Luciano, D. Epilepsy and. sleep apnoea syndrome. Neurology 1994; 44: 2060-2064. Vaughn, B.V., D’Cruz, O’N.F., Beach, R. and Messenheimer, J.A. Improvement of epileptic seizure control with treatment of obstructive sleep apnoea. Seizure 1996; 5: 13-78.