Paradoxical precipitation of tonic seizures by lorazepam in a child with atypical absence seizures

Paradoxical Precipitation of Tonic Seizures by Lorazepam in a Child with Atypical Absence Seizures Francis J. DiMario, Jr, MD and Robert R. Clancy, MD

A 10-year-old girl with Lennox-Gastaut syndrome who received intravenous lorazepam for atypical absence status seizures is reported. Tonic seizures occurred immediately and appeared to represent a paradoxical seizure exacerbation. We also review other patients with paradoxical seizure exacerbation by benzodiazepines.

spike-and-slow-wave discharges. Cranial computed tomography (CT) was normal. Despite treatment with phenobarbital she had frequent nocturnal generalized tonic-clonic seizures; therefore, supplemental phenytoin therapy was began with better control. Frequent atypical absence seizures began at 6 years of age. EEG during wakefulness revealed abundant generalized high-amplitude 2-2~/2 Hz spike-and-slow-wave discharges with a diffusely slowed background. Ethosuximide was added to her regimen. Learning and behavioral problems were evident at school and formal intelligence testing revealed a full scale IQ of 70. Seizure control waxed and waned. Clinical seizure types remained the same; however, she never experienced a pure tonic seizure. At 9 years of age, valproate was added to her regimen; phenytoin and ethosuximide were discontinued with excellent seizure control. Phenobarbital subsequently was reduced from 3.5 mg/kg/day to 1.0 mg/kg/day over 3 months. A further decrement to 0.5 mg/kg/day ensued 3 days prior to the patient entering a prolonged state of altered consciousness and responsiveness which was evident for approximately 12-18 hours prior to evaluation. Upon hospitalization, she displayed a fixed, vacant stare, continuous drooling, and episodic urinary incontinence. Simple verbal commands resulted in slow and inappropriate responses. EEG then revealed a dominant background of irregular 4-7 Hz theta activity interrupted by 60 sec runs of generalized, irregular, high-voltage 2-21/z Hz spike-and-slowwaves during more than 50% of the waking record (Fig 1). Lorazepam (1.5 mg, 0.05 mg/kg) was administered intravenously. Within 3 min the patient experienced the first of a series of brief, generalized pure tonic seizures accompanied on the EEG by widespread background attenuation followed by a generalized progressive build-up of rhythmic 9-10 Hz fast activity (Fig 2). The total duration of the activity was < 2 min with :",

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Introduction The benzodiazepines have been used extensively as antiepileptic drugs [1 ]. Their usefulness extends from acute seizure management to chronic antiepileptic drug therapy. There is growing awareness of the paradoxical worsening of seizures following antiepileptic drug administration in a small number of epileptic patients. We report the paradoxical effect of intravenously administered lorazepam for atypical absence status epilepticus in which tonic convulsive seizures were precipitated in a child with LennoxGastaut syndrome.

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Case Report This 10-year-old girl with Lennox-Gastaut syndrome had a normal birth and early developmental history. Her parents are nonconsanguineous and the remainder of her family history is negative. She was well until the onset of occasional generalized tonic-clonic seizures at 5 years of age. General physical and neurologic examinations were normal except for mental retardation. Electroencephalography (EEG) revealed a mildly abnormal waking record with diffuse 4-7 Hz slowing, and a markedly abnormal sleep tracing with generalized bursts of 1~/~Hz slow

From the Division of Neurology; Children's Hospital of Philadelphia; Departments of Neurology and Pediatrics; University of Pennsylvania School of Medicine; Philadelphia, Pennsylvania.

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Figure 1. A portion of the EEG during wakefulness demonstrating generalized, irregular, high-voltage 2-2~12 Hz spike-and-slow-waves (calibration: 50 pV; 1 sec).

Communications should be addressed to: Dr. DiMario; Division of Pediatric Neurology; University of Connecticut Health Center; Farmington Avenue; Farmington, CT 06032. Received June 10, 1988; accepted June 30, 1988.

DiMario and Clancy: Seizures and Lorazepam

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Figure2, A p•rti•n •f the EEG during absence status dem•nstrating widespread backgr•und attenuati•n and rhythmic 9-•• Hz fast activity; the patient clinically manifested a generalized tonic seizure (calibration: 50 ~tV,, 1 sec). n o o b s e r v e d cardiorespiratory c o m p r o m i s e . Subsequently, she was m a n a g e d with an increased dose o f valproate (70 mg/kg). G r a d u a l imp r o v e m e n t in her clinical state and E E G occurred over several days. Phenobarbital eventually w a s discontinued. The patient has not been treated a g a i n with lorazepam, but has received oral clorazepate without adverse effects. Discussion

Absence status (spike-and-wave stupor, petit-mal status) is a generalized nonconvulsive status epilepticus with continuous, bilaterally synchronous and symmetric epileptic activity which manifests primarily as mental confusion. Atypical forms also are recognized [2]. Benzodiazepines are included among the drugs of choice for this condition [1]; however, many children with atypical absence status are resistant to this therapy [1,3]. Tonic seizures have been reported as an adverse effect of lorazepam in the French literature by Amand and Evrard [4]. This paradoxical effect also was briefly mentioned by Waltregny and Dargent [5]. In 3 recently published series investigating the clinical efficacy of lorazepam in status epilepticus, no paradoxical seizures were reported [6-8]. These series included over 130 patients (112 children)and approximately 400 doses of medication. Other benzodiazepines (i.e., clonazepam, diazepam, nitrazepam) also have been reported to precipitate tonic seizures when used to treat absence status in patients with Lennox-Gastaut syndrome [3,9,10]. The paradoxical effect of benzodiazepines is poorly understood. Sleep does not appear to be a contributing factor [9]. As their blood concentrations diminish, benzodiazepines have produced rapid EEG rhythms characteristic of tonic seizures [5]. This process has been suggested as a possible explanation for the paradoxical effect. Although purely speculative, patients with the Lennox-Gastaut syndrome

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may be more susceptible to modulation of underlying EEG rhythms with antiepileptic drugs. Other patients with generalized seizure types occasionally may experience seizure exacerbation by some antiepileptic drugs. For example, phenobarbital may worsen absence seizures [11]. The co-administration of valproate and clonazepam may induce absence status [ 12] and carbamazepine may provoke myoclonic seizures [13]. Benzodiazepines generally enhance rapid EEG rhythms. Specific benzodiazepines may exaggerate these effects in susceptible individuals. This selective potential enhancement of rapid EEG rhythms may account for the fact that in our patient lorazepam contributed to the precipitation of tonic seizures, whereas clorazepate did not. Clorazepate is one henzodiazepine that has not been previously reported to precipitate tonic seizures. This paradoxical effect is rare. Benzodiazepines should continue to be considered among the drugs of choice for status epilepticus; however, a heightened awareness of the possibility of precipitating tonic seizures when treating absence status is prudent. This possibility is great in patients with Lennox-Gastaut syndrome who not only have more frequent bouts of absence status, but also have a greater vulnerability to this paradoxical effect. Primidone and methylphenidate have been utilized as therapies for drugprecipitated tonic status with variable success [14,15]. W e t h a n k L i n d a Celia for p r e p a r i n g the manuscript.

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[2] Gastaut H. Classification of status epilepticus. In: DelgadoEsqueta AV, Wasterlain CG, Treiman DM, Porter RJ, eds. Advances in neurology, vol 34. Status epilepticus. New York: Raven Press, 1983;15-35. [3] Livingston JH, Brown JK. Non-convulsive status epilepticus resistant to benzodiazepines. Arch Dis Child 1987;62:41-4. [4] Amand G, Evrard P. Le lorazepam injectable dans les etats de mal epileptique. Rev EEG Neurophysiol Clin 1976;6:532-3. [5] Waltregny A, Dargem J. Preliminary study of parenteral lorazepam in status epilepticus. Acta Neurol Belg 1975;75:219-29. [6] Walker JE, Homan RW, Vasko MR, Crawford IL, Bell RD, Tasker WG. Lorazepam in status epilepticus. Ann Neurol 1979; 6:207-13. [7] Lacey DJ, Singer WD, Horwitz SJ, Gilmore H. Lorazepam therapy of status epilepticus in children and adolescents. J Pediatr 1986; 108:771M. [8] Crawford TO, Mitchell WG, Snodgrass R. Lorazepam in childhood status epilepticus and serial seizures: Effectiveness and tachyphylaxis. Neurology 1987;37:190-5. [9] Tassinari CA, Dravet C, Roger J, Cano JP, Gastaut H. Tonic status epilepticus precipitated by intravenous benzodiazepine in five patients with Lennox-Gastaut syndrome. Epilepsia 1972; 13:421-35.

[10] Gastaut H, Courjon J, Poire R, Weber M. Treatment of status epilepticus with a new benzodiazepine more active than diazepam. Epilepsia 1971;12:197-214. [11] Wilder BJ, Bruni J. Barbiturates: Phenobarbital, mephobarbital and metharbital. In: Wilder BJ, Bruni J, eds. Seizure disorders: A pharmacological approach to treatment. New York: Raven Press, 1981 ;47-60. [12] Jeavons PM, Clark JE, Maheshwari MC. Treatment of generalized epilepsies of childhood and adolescence with sodium valproate. Dev Med Child Neurol 1977;19:9-25. [13] Snead OC, Hosey LC. Exacerbation of seizures in children by carbamazepine. N Engl J Med 1985;313:916-21. [14] Bittencourt PRM, Richens A. Anticonvulsant-induced status epilepticus in Lennox-Gastaut syndrome. Epilepsia 1981;22:129-34. [15] Fariello RG, Doro JM, Forster IM. Generalized cortical electrodecremental event: Clinical and neurophysiological observations in patients with dystonic seizures. Arch Neurol 1979;36:285-91.

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