Some Studies of Treatments for Seizures

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Clinical course of untreated tonic-clonic seizures in childhood
Prospective, Hospital-based Study
Donselaar CA, et al.
BMJ 1997;314:401 (8 February).

The results of this study show that, contrary to common beliefs, newly diagnosed epilepsy does not necessarily have a progressive course in untreated patients. Researchers analyzed the pattern of disease in 204 children aged 1 month to 16 years with newly diagnosed tonic-clonic seizures. Patients were followed up until drug treatment was initiated (78 children), until the occurrence of the fourth untreated seizures (41 children), or until the end of the follow up period of 2 years (85 children).

During the follow-up period 83 children became free of seizures without treatment (decelerating pattern). The disease pattern in 110 children could not be evaluated mainly because they were initiated on drug treatment after the first, second, or third seizure. Overall, the disease was defined as decelerating in 86 children, uncertain in 110, and accelerating in 8. The authors concluded that in a minimum of 42% of children with newly diagnosed tonic-clonic seizure the disease can be expected to have a decelerating pattern, and therefore fear of progressive disease should not be advocated as a reason for initiation of treatment.

Controversies in Management: Case for early treatment is not established.
Chadwick, D.
BMJ 1995;310:177-178 (21 January).

The author of this study affirms that current clinical evidence does not support the belief that early treatment with anti-epileptic drugs alters the evolution of the disease. Among other studies, the article reports on the results of a trial conducted by Keranen and Riekkinen, showing that the remission rate in a group of untreated epileptic patients is 52%, approximately equal to that reported among treated individuals. Another randomized trial by Temkin et al., conducted on a cohort of patients with seizure following head injury, showed that individuals taking the antiepileptic drug phenytoin experienced more seizures than those receiving placebo. As the author concludes, "None of the available clinical trials comparing early treatment with deferred treatment seemed to show any great benefit to longer term outcomes." These data cast serious doubts on the value of early treatment for epilepsy.

Incidence of death in patients with intractable epilepsy during nitrazepam treatment.
Rintahaka PJ, Nakagawa JA, Shewmon DA, Kyyronen P, Shields WD.
Epilepsia 1999 Apr;40(4):492-6.

The results of this study show that patients with intractable epilepsy treated with nitrazepam have a 3.5-fold increased risk of dying, compared to untreated patients. The risk is particularly high in children younger than 3.4 years, in whom treatment with nitrazepam is associated with a 15-fold increase in rates of mortality.

Risk factors for sudden unexpected death in epilepsy: a case-control study.
Nilsson L, Farahmand BY, Persson PG, Thiblin I, Tomson T.
Lancet 1999 Mar 13;353(9156):888-93.

The results of this study show that the risk of sudden death in epileptic patients increases by 10-fold in patients taking three or more antiepileptic drugs, compared to those taking only one drug, and by 6-fold in patients with frequent changes in drug dosage, compared to those with steady drug concentrations. In addition, the study found a 10- and 8-fold increase in risk of sudden death in patients with more than 50 seizures per year and with early onset disease, respectively, compared to those with one or two seizures per day and late onset disease. This data suggests that preventable factors, such as avoidance of multiple drugs treatment regimens and maintenance of stable drug concentrations, can substantially lower the risk of sudden death in epileptic patients.

Changes in arrhythmia profile and heart rate variability during abrupt withdrawal of antiepileptic drugs. Implications for sudden death.
Kenneback G, Ericson M, Tomson T, Bergfeldt L.
Seizure 1997 Oct;6(5):369-75.

The results of this study show that a lowering in blood concentrations of antiepileptic drugs is associated with changes in heart function associated with an increased risk of sudden death. The study was conducted on 10 patients who discontinued treatment with carbamazepine and phenytoin due to side effects. In the 4 days following drug withdrawal, patients' heart rate variability was significantly decreased, and 3 patients exhibited a 10-fold increase in number of ventricular premature beats. Since both of these changes have been associated with an increased risk of death in other groups of patients, the authors conclude that these 2 findings might partly explain the highest incidence of sudden death in epileptic patients.

Comparison of anti-epileptic drug levels in different cases of sudden death.
George JR; et al.
J Forensic Sci, 43(3):598-603 1998 May.

This article indicates that sudden unexpected death occurs in 5% to 30% of patients with epilepsy, a fatality that seems to be associated with low blood levels of anticonvulsants.

Cohort study of incidence of sudden unexplained death in persons with seizure disorder treated with antiepileptic drugs in Saskatchewan, Canada.
Tennis P. et al.
Epilepsia, 36(1):29-36 1995 Jan.

The results of this study, conducted on a cohort of 3,688 epileptic patients treated with more than four prescription drugs, show that the incidence of sudden unexplained death increases with the number of antiepileptic and psychotropic drugs received.

Changes in arrhythmia profile and heart rate variability during abrupt withdrawal of antiepileptic drugs. Implications for sudden death.
Kennebšack G; et al.
Seizure, 6(5):369-75 1997 Oct.

The results of this study show that 3 out of 10 epileptic patients who discontinued treatment with carbamazepine and phenytoin, developed significant reduction of heart rate variability and a 10-fold increase in ventricular premature beats. These changes in cardiac function have been associated with increased mortality in other groups of patients, and may contribute to the increased incidence of sudden unexpected death in epileptic patients.

Sudden unexpected death in epilepsy: is carbamazepine implicated?
Timmings PL.
Seizure, 7(4):289-91 1998 Aug.

This article emphasizes that the incidence of sudden unexpected death (SUD) in treated epileptic patients is increasing. While all of the currently available anticonvulsants have been associated with an increased incidence of SUD, the risk seems particularly elevated among users of carbamazepine. In particular, data from the Cardiff Epilepsy Unit revealed that of 13 sudden deaths occurring in epileptic patients, 11 (85%) were in users of carbamazepine, a percentage significantly higher than the prevalence of use of this drug in the remaining patients of the unit (38%).

Antiepileptic drugs as a cause of worsening seizures.
Perucca E, et al.
Epilepsia 1998 Jan;39(1):5-17.

This review discusses the well-known phenomenon of paradoxical exacerbation of seizures that occurs in epileptic patients treated with antiepileptic drugs. The mechanism by which antiepileptic drugs can worsen seizures is not completely understood, but it is believed to be mediated either by toxicity from drug overdose, or by the primary mechanism of action of these drugs. Carbamazepine, phenytoin, vigabratin, gabapentin, and occasionally benzodiazepines, have been associated with the precipitation or worsening of a variety of seizures. The authors conclude that this effect is a common and serious complication related to anticonvulsant treatment, which is often overlooked by the treating physician.

Quantifying the costs of serious adverse drug reactions to antiepileptic drugs.
Schlienger RG, et al.
Epilepsia 1998;39 Suppl 7:S27-32.

This study evaluated the incidence of severe skin reactions and hypersensitivity reactions to anti-epileptic drug treatment that occurred at one institution. There were a total of 384 cases identified during the 6-year study period. The cost of these adverse drug reactions was estimated at Canadian $3,128 per patient. The authors highlight the importance of including the costs of treatment-related adverse reactions when evaluating the economic impact of antiepileptic drugs.

Antiepileptic medication and oral contraceptive interactions: a national survey of neurologists and obstetricians.
Krauss GL, Brandt J, Campbell M, Plate C, Summerfield M.
Neurology 1996 Jun;46(6):1534-9.

The results of this study show that the majority of neurologists and obstetricians are not aware of the interaction between antiepileptic drugs and oral contraceptives, nor are informed on the exact risk of malformations in the offspring associated with treatment. According to the responses to a mailed survey, only 4% of neurologists and 0% of obstetricians knew that antiepileptic drugs lower the effectiveness of the pill, even though 27% and 21% of them, respectively, reported unwanted pregnancies in their patients taking oral contraceptives together with antiepileptic drugs. In addition, approximately half of the respondents were not able to correctly define the risk of birth defects in the offspring of epileptic treated women, the majority of them substantially underestimating such risk and some greatly overestimating it. These data indicate that misinformation leading to potential suboptimal care of epileptic women is pervasive among U.S. neurologists and obstetricians.

Consensus guidelines: preconception counseling, management, and care of the pregnant woman with epilepsy.
Delgado-Escueta AV, Janz D.
Neurology 1992 Apr;42(4 Suppl 5):149-60.

This article emphasizes that women who take antiepileptic drugs during pregnancy should be informed that their risk of giving birth to children with malformations is 2-3 times higher than that of the general population. For this reason treatment of epilepsy, when possible, should be avoided, or, if this is not possible, should be limited to only one drug at the lowest effective dosage. In addition, women should be counseled to supplement their diet before and during pregnancy with folic acid, as this vitamin has been shown to reduce the risk of congenital malformations in their offspring.

Gender difference in management of epilepsy-what women are hearing.
Crawford P, Lee P.
Seizure 1999 May;8(3):135-9.

The results of this study show that women with epilepsy are not properly informed on the interaction between the drugs they take and pregnancy and contraception. Survey of 1855 women with epilepsy aged 16 and older revealed that half of them had not received any information about the reduced effectiveness of oral contraceptives when taken together with antiepileptic drugs, and one-third of them had not received any advise regarding the effects of epilepsy on pregnancy. In addition, only 15% of women who were planning a pregnancy in the next two years received any information about the potential of antiepileptic drugs to induce malformation in the fetus, and only 5% of women were told to supplement their diet with folic acid to reduce the risk of malformations in their offspring. These data indicate that in spite of a plethora of articles and reviews published in the literature documenting the interaction between epilepsy and its treatment and women's conception and pregnancy and their offspring's health, this information failed to translate in changes in clinical practice and improved patient care.

Drugs for epilepsy have teratogenic risks. Letter.
Rosser E, et al.
BMJ 1999;318:1289 ( 8 May ).

This letter aims at bringing more awareness on the possible occurrence of neurological deficits in the offspring of women taking anticonvulsant drugs during pregnancy. The author highlights that while an increased risk of major malformations is well documented, the occurrence of more subtle effects such as neurological impairment is only recently being recognized, and with increasing frequency. No anti-epileptic drug is free of risk to the fetus, and is extremely important for clinicians to inform women on the existence of such risks. The author also notes that failure to fully explain the implications of continuing treatment throughout pregnancy has resulted in several occasions in litigation.

Outcome of children born to epileptic mothers treated with carbamazepine during pregnancy.
Ornoy A, et al.
Arch Dis Child 1996; 75: 517-520.

This study evaluated the pregnancy outcome of 47 women who took the anti-epileptic drug carbamazepine while expecting, and compared it to that of 47 women of similar socioeonomic status without epilepsy. Six of the 47 children exposed to the drug in uterus had facial features of "carbamazepine syndrome" and all of them had mild mental retardation. Overall, the IQ of the group exposed to the drug was significantly lower than that of the control group, primarily because the IQ of the 6 children with "carbamazepine syndrome" was below 90.

Prenatal exposure to valproic acid during pregnancy and limb deficiencies: a case-control study.
Rodriguez-Pinilla E, Arroyo I, Fondevilla J, Garcia MJ, Martinez-Frias ML.
Am J Med Genet 2000 Feb 28;90(5):376-81.

The results of this study show that children who have been exposed to the antiepileptic drug valproic acid while in uterus have an over 6-fold increased risk of having limb deficiencies, compared to unexposed children.

Malformations in offspring of women with epilepsy: a prospective study.
Canger R, Battino D, Canevini MP, Fumarola C, Guidolin L, Vignoli A, et al.
Epilepsia 1999 Sep;40(9):1231-6.

The results of this study show that use of antiepileptic drugs during pregnancy is associated with a significant risk of severe malformations in the offspring. In the study, 517 pregnancies in treated epileptic women were followed-up with monthly obstetric and neurologic evaluations and monthly monitoring of drugs blood levels. The incidence of malformations in the offspring of these women was approximately 10% (9.7%). Of these, 5.3% were structurally severe, 2.2% were mild, 0.4% were genetic, and 1.8% were deformities. No malformations occurred in the offspring of 25 women with epilepsy who did not take antiepileptic drugs during pregnancy.

Antiepileptic Drug Regimens and Major Congenital Abnormalities in the Offspring.
Samren EB, van Duijn CM, Christiaens GC, Hofman A, Lindhout D.
Ann Neurol 1999 Nov;46(5):739-46.

The results of this study show that most antiepileptic drugs used during pregnancy significantly increase the risk of congenital malformations in the offspring. The risk is particularly elevated with valproic acid and carbamazepine used in single drug regimens, and with benzodiazepine and caffeine medications used in politherapy regimens.

Epilepsy, antiepileptic drugs, and malformations in children of women with epilepsy
A French prospective cohort study.
Dravet C. et al.
Neurology, 42(4 Suppl 5):75-82 1992 Apr.

The results of this study show that the rate of malformations in children of women who used antiepileptic drugs during pregnancy is 7%, five times higher than the rate of malformations in the general population (1.36%). None of the malformations observed in the offspring of women treated with antiepileptic drugs occurred in children of epileptic women who did not undergo treatment. All the malformations were related to use of valproate and phenytoin.

Congenital malformations due to antiepileptic drugs.
Kaneko S, et al.
Epilepsy Res 1999 Feb;33(2-3):145-58.

This study evaluated the incidence of malformations in 983 children of epileptic mothers. Congenital malformations occurred in 3% of children of epileptic women who did not receive any treatment during pregnancy, and in 9% of children of women who used antiepileptic drugs throughout pregnancy. Primidone, followed by valproate, phenytoin, carbamazepine and phenobarbital, were the drugs most often associated with malformations. The incidence of congenital abnormalities increased with increasing doses and number of antiepileptic drugs used, an indication of a causal association.

Antiepileptic medication in pregnancy: late effects on the children's central nervous system development.
van der Pol MC; et al.
Am J Obstet Gynecol, 164(1 Pt 1):121-8 1991 Jan.

The results of this study show that children of epileptic mothers who used phenobarbital during pregnancy had smaller head circumference and possibly impaired cognitive development, compared to children of epileptic mothers who used carbamazepine or no drugs during pregnancy.

Cognitive effects of long-term treatment with phenobarbital and valproic acid in school children.
Calandre EP; et al.
Acta Neurol Scand, 81(6):504-6 1990 Ju.

The results of this study show that 9 to 12 months of treatment with phenobarbital results in significant loss of learning ability in epileptic children.

Changes in serum lipids and lipoproteins in epileptic children treated with anticonvulsants.
Verrotti A. et al.
J Paediatr Child Health, 33(3):242-5 1997 Jun.

The results of this study show that long-term treatment with phenobarbital and carbamazepine in epileptic children adversely affects lipid metabolism, causing an increase in serum levels of total cholesterol and low-density lipoproteins (LDL). On the other hand, treatment with sodium valproate is associated with decreased levels of triglycerides and LDL and increased levels of high-density lipoprotein, a favorable modification of lipid profile.

A comparative review of the adverse effects of anticonvulsants in children with epilepsy.
Wallace SJ.
Drug Saf, 15(6):378-93 1996 Dec.

This article discusses the principal adverse effects associated with anticonvulsant treatment in children with epilepsy. Neurological effects such as double vision, tremor, motor disturbances, and changes in cognitive performance have been associated with all types of anticonvulsants. Gastrointestinal toxicity, liver disease, weight gain, skin rash, hair loss, precipitation of metabolic bone disease and renal stone formation, occur at different frequencies according to the type of drug used. Of all the drugs, phenytoin and felbamate are associated with the highest rates of adverse effects and with the highest rates of treatment interruption.

Acute hepatic failure associated with valproic acid in children. Report of 3 cases.
Antoniuk SA. et al.
Arq Neuropsiquiatr, 54(4):652-4 1996 Dec.

This article reports on the cases of three epileptic children who developed acute hepatic failure secondary to valproic acid treatment. Hepatic failure was followed by death in one child. All children were being treated concurrently with several antiepileptic drugs.

Reversible pseudoatrophy of the brain and mental deterioration associated with valproate treatment.
Guerrini R, Belmonte A, Canapicchi R, Casalini C, Perucca E.
Epilepsia 1998 Jan;39(1):27-32.

This article reports on the case of an 11-year-old girl who developed severe deterioration of mental function and brain pseudoatrophy while on treatment with valproic acid for epilepsy. The reaction occurred after 2 and half years of treatment, and was accompanied by a sharp drop in IQ levels (by 18 points), and diminution in size of the brain documented with magnetic resonance imaging. After discontinuation of treatment, the girl's IQ improved by 20 points and the brain structure reverted to normal. The authors conclude that deterioration of mental function is a complication of treatment with valproic acid that can occur isolated or with concomitant signs of drug-related toxicity or parkinsonism.

Psychiatric outcome of temporal lobectomy for epilepsy: incidence and treatment of psychiatric complications.
Blumer D. et al.
Epilepsia, 39(5):478-86 1998 May.

This study evaluated the presence of psychiatric symptoms before and after surgery in 44 patients who underwent temporal lobectomy (the surgical removal of a part of the brain) for focal epilepsy. Before surgery, 25 patients (57%) patients had dysphoric disorders. After surgery, 17 (39%) patients experienced either new psychiatric complications such as psychosis, depressive events and dysphoric disorders, or worsening of previous dysphoric disorders, while 8 (42%) of the 19 patients who had no psychiatric symptoms before surgery developed dyshoric disorders after the operation. These data indicate that lobectomy in epileptic patients is associated with an unacceptably high rate of psychiatric morbidity.

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