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Advances in the diagnosis and management of pediatric seizure disorders in the twentieth century
ADVANCES IN PEDIATRICS
in the diagnosis and management of pediaric seizure disorders in the twentieth century iili!~¸¸....................................... !~iii!ili}!iiii!!!
P e t e r Camfieldp MD, FRCP(C), a n d C a r o l Camfie[x)p MD, FRCP(C)
The Hippocratic School produced the first book devoted to epilepsy, On the Sacred Disease Epilepsy, although epilepsy was clearly described up to 3000 years ago in Mesopotamia, Egypt, China, and India.1 Gowers,s 2 sentinel publication in 1881 described many of the clinical features. Enthusiasm for the great advances in the past 100 years in our understanding and treatment of pediatric seizure disorders is tempered by the realization of how far we have to go. There is no cure for these heterogeneous illnesses, and treatment still involves medications that may profoundly affect the function of every neuron in the brain for what may be a very localized area of dysfunction.
ELECTROENCEPHALOGRAPHY Hans Berger is credited with the first human documentation of the electroencephalogram as a tool for assessing
Fromthe DepartmentofPediatrics,DalhousieUniversity and theIWK GraceHealthCentre,Halifax,Nova Scotia,Canada. Reprint requests: Peter Camfield, MD, FRCP(C), IWK Grace Health Centre, PO Box 3070, Halifax, Nova Scotia, Canada B3H 3J9. J Pediatr 2000;136:847-9. Copyright © 2000 by Mosby, Inc. 0022-3476/2000/$12.00 + 0 9/821107182 doi: 10.1067/rnpd.2000.107182
brain disorders in 1929.1 In 1935, Gibbs, Davis, and Lennox first recorded the spike wave discharge of absence (petit mal).a It was now possible to understand that seizures were correlated with rhythmic synchronized neuronal discharges, "Petit mal" was defined based on the classical 3-Hz spike and wave discharge that is so characteristic. Epilepsy clearly emerged as a biologic disorder-not an emotional disorder or one produced by evil humors. EEG has improved with better amplifiers and filters. Video-EEG allows simultaneous analysis of the clinical and electrical event for better classification of seizures with localization of seizure onset when surgery is contemplated. EEG has significant limits, especially interietal EEG. Some children without seizures have "epileptiform" E E G discharges, and other children with severe epilepsy have normal interictal EEG findings. 4 This test continues to supplement the clinical history and assist in syndrome diagnosis.
BRAIN IMAGING Computed tomography and magnetic resonance imaging scanning have revolutionized our understanding of the cause of epilepsy for many children, especially those with partial epilepsies. Unfortunately, finding the cause often does not dictate specific treatment. For example, neuronal migrational defects are of great interest and many have a genetic etiology, but this knowledge
does not assist with treatment decisions. However, sometimes a specific diagnosis from imaging is critical to treatment. For example, infantile spasms caused by tuberous sclerosis seem to respond remarkably well to vigabatrin. A few children with small, benign brain tumors diagnosed by means of brain imaging have had their lives immeasurably improved by surgery. Other children with seizures from unsuspected cysticercosis have had a new treatment mandated by the characteristic lesions on imaging. The current standard of practice is to include brain imaging in the assessment of most children with newly diagnosed epilepsy.
ANTIEPILEPTIC DRUGS The development of antiepileptic drug treatment is a sto W of serendipity. Phenobarbital was introduced in 1912, when Hauptmann noted improved seizure control in a few patients with epilepsy who were being treated with phenobarbital for its sedative effects.5 Phenobarbital became the first satisfactory treatment for epilepsy. Bromides had been discovered in 1857, but they were toxic and their spectrum of action did not rival the remarkable efficacy of phenobarbital. Phenobarbital has recently fallen from favor because of cognitive side effects, 847
THE JOURNALOF PEDIATRICS JUNE 2000
CAMFIELDAND CAMFIELD
although some of the newer agents, particularly topiramate, probably have serious adverse effects on learning. Merrit and Putman 6 introduced phenytoin in the early 1940s. Their great contribution was to develop the maximal electroshock technique in animals for screening drugs. They reasoned that compounds would exist with anti-seizure properties separate from sedative effects. The Parke Davis company provided them with 19 compounds to test: the first was phenytoin! Thousands of additional compounds have been screened in a variety of animal models with some successes. Most successes have not been the result of an understanding of epilepsy--just good luck. Carbamazepine was discovered in a search for better antipsychotic medications, z The story of valproic acid is extraordinary. Valproic acid is a well-known organic solvent. In the Berthier Laboratories in France, it was noted that a whole series of compounds had good antiepileptic properties. The brilliant deduction was that the solvent, valproic acid, was the active ingredient. 8 In our opinion, valproic acid remains the most effective drug for many childhood epilepsies despite some significant side effects such as frequent weight gain and very rare liver failure or pancreatitis. As mechanisms of neuronal excitation and inhibition became better understood, it was surmised that drugs that increased inhibition might be effective AEDs, Since gamma-aminobutyric acid had emerged as the major cortical inhibltory neurotransmitter, drugs that looked like GABA were sought. Gabapentin was synthesized as a GABA analogue; it has antl-selzure properties but apparently not through the GABA system! The only truly rational AEDs to date have been tiagabine and vigabatrln, both of which were specifically developed to interfere with GABA metabolism. Tiagabine blocks GABA reuptake and vigabatrin prevents its degradation by blocking GABA transaminase. Each has good efficacy, but neither is a 848
"blockbuster." It is surprising that drugs that enhance the brain's inhibitory system do not have more side effects.
EPILEPSY SURGERY At the turn of the century, Hughlings Jackson recognized the localized onset ' of partial seizures. The concept that epilepsy arises from an irritative lesion meant that it might be possible to remove the lesion and cure the epilepsy but not induce serious deficits. During this century, Victor Horsley performed the first successful cortical resection for epilepsy. Wilder Penfield developed and popularized the technique of localized resection while learning much about brain function. 9 Herbert Jasper was the key electroencephalographer who worked alongside Penfield at the Montreal Neurologic Hospital. Surgery is helpful for only a small number of children, but for those children, it may be miraculous. Brain imaging, particularly magnetic resonance imaging, allows much better selection of surgical candidates and guides the surgical resection. There continue to be advances in patient selection and operative technique and improved results with surgery in the very young. New techniques including vagal nerve stimulation are of interest but as yet of uncertain value.
CLASSIFICATION AND NATURAL HISTORY Not all epilepsy is the same. The first important distinction was between partial or focal epilepsy and generalized epilepsy. In 1981, the International League Against Epilepsy 10 first codified the many types of seizures--an enormous improvement all over the world. Then in 1989, came the critical classification of epilepsy syndromes. 11 When the clinician puts together all of the information about the child (seizure type, etiology, EEG, etc) then groups ofpa-
tients emerge. Syndromes have proliferated. The power of the syndromic approach is well illustrated by 2 examples: juvenile myoclonic epilepsy and benign partial epilepsy of childhood with centrotemporal spikes. Juvenile myoclonlc epilepsy starts in healthy children in early adolescence with generalized tonic-clonic seizures, myoclonus, and absence. The EEG shows fast spike and wave. The disorder is inherited in a complex fashion, is usually lifelong, and responds well to valproate but poorly to most other AEDs. Benign partial epilepsy of childhood with centrotemporal spikes begins in earlier childhood; the seizures are partial and nocturnal and start in the mouth and tongue. This disorder is always outgrown, and there is increasing evidence that treatment is not needed. The natural history of childhood epilepsy has been clarified in the past 20 years. 12 The benign nature of febrile seizures was clearly understood for the first time with the pioneering study by Nelson and Ellenberg 13 in 1976. Several population-based studies have verified that more than half of the children with epilepsy will outgrow it, an optimistic statement in comparison with that of Gowers, who noted at the turn of the century "the spontaneous resolution of this disease is an event too rare to be reasonably anticipated in any given case. ''2 Predictors of outcome of epilepsy have come into focus: younger age at onset, idiopathic or cryptogenle etiology, normal neurologic function and intelligence, and early seizure control. It is now clear that AEDs do not alter the natural history: the epilepsy resolves on its own. AEDs hide the symptoms until brain maturation somehow solves the problem.t4
GENETICS AND MOLECULAR BIOLOGY The most exciting advance in the past decade has been the understand-
CAMFIELDAND CAMFIELD
THE JOURNALOF PEDIATRICS
VOLUME 136, NUMBER6
ing of the biochemical mechanism for some inherited epilepsies.15 At least 3 are now clear. Benign familial neonatal convulsions is an autosomal dominant disorder with neonatal seizures that are eventually outgrown. The disorder results from a defect in membrane potassium channels. Nocturnal dominant frontal lobe epilepsy is also dominantlY inherited and caused by a defect in the acetylcholine receptor. Generalized Epilepsy with Febrile Seizures Plus is a more complex clinical disorder with febrile seizures that persist beyond 5 years of age that are followed by generalized epilepsy in adolescence. The disorder may be quite common and appears to result from a defect in the sodium channel. These 3 discoveries and others are important because they clearly indicate that genetically based, structural defects in neuronal cell m e m b r a n e ion channels are the causes of some forms of epilepsy.
WHAT COMES NEXT? The stage is now set for more rational treatment. We predict very specific treatment for well-defined epilepsy
syndromes. There has been some documented improvement in the public's understanding and acceptance of epilepsy, an understanding that must grow as better treatments are designed.
8.
9.
REFERENCES 10. 1. Goldensohn E. Historical perspectives. In: Engel J, Pedley TA, editors. Epilepsy: a comprehensive textbook. Philadelphia: Lippincott-Raven; 1997. p. 15-40. 2. Gowers WR. Epilepsy and other chronic convulsive disorders. London: T and A Churchill; 1881. 3. Gibbs FA, Davis H, Lennox WG. The EEG in epilepsy and in the impaired states of consciousness. Arch Neurol Psychiatry 1935;34:1133-42. 4. Petersen O, Eeg-Olofsson O. Paroxysmal activity in EEG of normal children. In: Kelleway P, Petersen I, editors. Clinical electroencephalography of children. New York: Grune & Stratton; 1968. p. 167-88. 5. Hauptman A. Luminal bei epilepsie. Munch Med Wochenschr 1907. 6. Merritt HH, Putman TJ. A new series of anticonvulsant drugs tested by experiments in animals. Arch Neurol Psychiatry 1938;39:1003-15. 7. Sillanpaa NI. Carbamazepine. In: Wyllie E, editor. The treatment of epilepsy: principles and practice. 2rid
11.
12.
13.
14.
15.
ed. Baltimore: Williams and Wilkins; 1997. p. 808-23. Dean JC. Valproate. In: Wyllie E, editor. The treatment of epilepsy: principles and practice. 2nd ed. Baltimore: Williams and Wilkins; 1997. p. 824-32. Penfield W, Jasper H. Epilepsy and the functional anatomy of the human brain. Boston: Little Brown & Co; 1954. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:489-501. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389-99. Camfield PR, Camfield CS. Prognosis of childhood epilepsy. Semin Pediatr Neurol 1994;1:90-110. Nelson KB, Ellenberg JH. Prediction of epilepsy in children who have experienced febrile seizures. N Engl J Med 1976;295:1029-33. Shlnnar S, Berg AT. Does antiepileptic drug therapy alter the prognosis of childhood seizures and prevent the development of chronic epilepsy? Semin Pediatr Neurol 1994; 1:111-7. Prasad AN, Prasad C, Stafstrom. Recent advances in the genetics of epilepsy: insights from human and animal studies. Epilepsia 1999;40:1329-54.
849
in the diagnosis and management of pediaric seizure disorders in the twentieth century iili!~¸¸....................................... !~iii!ili}!iiii!!!
P e t e r Camfieldp MD, FRCP(C), a n d C a r o l Camfie[x)p MD, FRCP(C)
The Hippocratic School produced the first book devoted to epilepsy, On the Sacred Disease Epilepsy, although epilepsy was clearly described up to 3000 years ago in Mesopotamia, Egypt, China, and India.1 Gowers,s 2 sentinel publication in 1881 described many of the clinical features. Enthusiasm for the great advances in the past 100 years in our understanding and treatment of pediatric seizure disorders is tempered by the realization of how far we have to go. There is no cure for these heterogeneous illnesses, and treatment still involves medications that may profoundly affect the function of every neuron in the brain for what may be a very localized area of dysfunction.
ELECTROENCEPHALOGRAPHY Hans Berger is credited with the first human documentation of the electroencephalogram as a tool for assessing
Fromthe DepartmentofPediatrics,DalhousieUniversity and theIWK GraceHealthCentre,Halifax,Nova Scotia,Canada. Reprint requests: Peter Camfield, MD, FRCP(C), IWK Grace Health Centre, PO Box 3070, Halifax, Nova Scotia, Canada B3H 3J9. J Pediatr 2000;136:847-9. Copyright © 2000 by Mosby, Inc. 0022-3476/2000/$12.00 + 0 9/821107182 doi: 10.1067/rnpd.2000.107182
brain disorders in 1929.1 In 1935, Gibbs, Davis, and Lennox first recorded the spike wave discharge of absence (petit mal).a It was now possible to understand that seizures were correlated with rhythmic synchronized neuronal discharges, "Petit mal" was defined based on the classical 3-Hz spike and wave discharge that is so characteristic. Epilepsy clearly emerged as a biologic disorder-not an emotional disorder or one produced by evil humors. EEG has improved with better amplifiers and filters. Video-EEG allows simultaneous analysis of the clinical and electrical event for better classification of seizures with localization of seizure onset when surgery is contemplated. EEG has significant limits, especially interietal EEG. Some children without seizures have "epileptiform" E E G discharges, and other children with severe epilepsy have normal interictal EEG findings. 4 This test continues to supplement the clinical history and assist in syndrome diagnosis.
BRAIN IMAGING Computed tomography and magnetic resonance imaging scanning have revolutionized our understanding of the cause of epilepsy for many children, especially those with partial epilepsies. Unfortunately, finding the cause often does not dictate specific treatment. For example, neuronal migrational defects are of great interest and many have a genetic etiology, but this knowledge
does not assist with treatment decisions. However, sometimes a specific diagnosis from imaging is critical to treatment. For example, infantile spasms caused by tuberous sclerosis seem to respond remarkably well to vigabatrin. A few children with small, benign brain tumors diagnosed by means of brain imaging have had their lives immeasurably improved by surgery. Other children with seizures from unsuspected cysticercosis have had a new treatment mandated by the characteristic lesions on imaging. The current standard of practice is to include brain imaging in the assessment of most children with newly diagnosed epilepsy.
ANTIEPILEPTIC DRUGS The development of antiepileptic drug treatment is a sto W of serendipity. Phenobarbital was introduced in 1912, when Hauptmann noted improved seizure control in a few patients with epilepsy who were being treated with phenobarbital for its sedative effects.5 Phenobarbital became the first satisfactory treatment for epilepsy. Bromides had been discovered in 1857, but they were toxic and their spectrum of action did not rival the remarkable efficacy of phenobarbital. Phenobarbital has recently fallen from favor because of cognitive side effects, 847
THE JOURNALOF PEDIATRICS JUNE 2000
CAMFIELDAND CAMFIELD
although some of the newer agents, particularly topiramate, probably have serious adverse effects on learning. Merrit and Putman 6 introduced phenytoin in the early 1940s. Their great contribution was to develop the maximal electroshock technique in animals for screening drugs. They reasoned that compounds would exist with anti-seizure properties separate from sedative effects. The Parke Davis company provided them with 19 compounds to test: the first was phenytoin! Thousands of additional compounds have been screened in a variety of animal models with some successes. Most successes have not been the result of an understanding of epilepsy--just good luck. Carbamazepine was discovered in a search for better antipsychotic medications, z The story of valproic acid is extraordinary. Valproic acid is a well-known organic solvent. In the Berthier Laboratories in France, it was noted that a whole series of compounds had good antiepileptic properties. The brilliant deduction was that the solvent, valproic acid, was the active ingredient. 8 In our opinion, valproic acid remains the most effective drug for many childhood epilepsies despite some significant side effects such as frequent weight gain and very rare liver failure or pancreatitis. As mechanisms of neuronal excitation and inhibition became better understood, it was surmised that drugs that increased inhibition might be effective AEDs, Since gamma-aminobutyric acid had emerged as the major cortical inhibltory neurotransmitter, drugs that looked like GABA were sought. Gabapentin was synthesized as a GABA analogue; it has antl-selzure properties but apparently not through the GABA system! The only truly rational AEDs to date have been tiagabine and vigabatrln, both of which were specifically developed to interfere with GABA metabolism. Tiagabine blocks GABA reuptake and vigabatrin prevents its degradation by blocking GABA transaminase. Each has good efficacy, but neither is a 848
"blockbuster." It is surprising that drugs that enhance the brain's inhibitory system do not have more side effects.
EPILEPSY SURGERY At the turn of the century, Hughlings Jackson recognized the localized onset ' of partial seizures. The concept that epilepsy arises from an irritative lesion meant that it might be possible to remove the lesion and cure the epilepsy but not induce serious deficits. During this century, Victor Horsley performed the first successful cortical resection for epilepsy. Wilder Penfield developed and popularized the technique of localized resection while learning much about brain function. 9 Herbert Jasper was the key electroencephalographer who worked alongside Penfield at the Montreal Neurologic Hospital. Surgery is helpful for only a small number of children, but for those children, it may be miraculous. Brain imaging, particularly magnetic resonance imaging, allows much better selection of surgical candidates and guides the surgical resection. There continue to be advances in patient selection and operative technique and improved results with surgery in the very young. New techniques including vagal nerve stimulation are of interest but as yet of uncertain value.
CLASSIFICATION AND NATURAL HISTORY Not all epilepsy is the same. The first important distinction was between partial or focal epilepsy and generalized epilepsy. In 1981, the International League Against Epilepsy 10 first codified the many types of seizures--an enormous improvement all over the world. Then in 1989, came the critical classification of epilepsy syndromes. 11 When the clinician puts together all of the information about the child (seizure type, etiology, EEG, etc) then groups ofpa-
tients emerge. Syndromes have proliferated. The power of the syndromic approach is well illustrated by 2 examples: juvenile myoclonic epilepsy and benign partial epilepsy of childhood with centrotemporal spikes. Juvenile myoclonlc epilepsy starts in healthy children in early adolescence with generalized tonic-clonic seizures, myoclonus, and absence. The EEG shows fast spike and wave. The disorder is inherited in a complex fashion, is usually lifelong, and responds well to valproate but poorly to most other AEDs. Benign partial epilepsy of childhood with centrotemporal spikes begins in earlier childhood; the seizures are partial and nocturnal and start in the mouth and tongue. This disorder is always outgrown, and there is increasing evidence that treatment is not needed. The natural history of childhood epilepsy has been clarified in the past 20 years. 12 The benign nature of febrile seizures was clearly understood for the first time with the pioneering study by Nelson and Ellenberg 13 in 1976. Several population-based studies have verified that more than half of the children with epilepsy will outgrow it, an optimistic statement in comparison with that of Gowers, who noted at the turn of the century "the spontaneous resolution of this disease is an event too rare to be reasonably anticipated in any given case. ''2 Predictors of outcome of epilepsy have come into focus: younger age at onset, idiopathic or cryptogenle etiology, normal neurologic function and intelligence, and early seizure control. It is now clear that AEDs do not alter the natural history: the epilepsy resolves on its own. AEDs hide the symptoms until brain maturation somehow solves the problem.t4
GENETICS AND MOLECULAR BIOLOGY The most exciting advance in the past decade has been the understand-
CAMFIELDAND CAMFIELD
THE JOURNALOF PEDIATRICS
VOLUME 136, NUMBER6
ing of the biochemical mechanism for some inherited epilepsies.15 At least 3 are now clear. Benign familial neonatal convulsions is an autosomal dominant disorder with neonatal seizures that are eventually outgrown. The disorder results from a defect in membrane potassium channels. Nocturnal dominant frontal lobe epilepsy is also dominantlY inherited and caused by a defect in the acetylcholine receptor. Generalized Epilepsy with Febrile Seizures Plus is a more complex clinical disorder with febrile seizures that persist beyond 5 years of age that are followed by generalized epilepsy in adolescence. The disorder may be quite common and appears to result from a defect in the sodium channel. These 3 discoveries and others are important because they clearly indicate that genetically based, structural defects in neuronal cell m e m b r a n e ion channels are the causes of some forms of epilepsy.
WHAT COMES NEXT? The stage is now set for more rational treatment. We predict very specific treatment for well-defined epilepsy
syndromes. There has been some documented improvement in the public's understanding and acceptance of epilepsy, an understanding that must grow as better treatments are designed.
8.
9.
REFERENCES 10. 1. Goldensohn E. Historical perspectives. In: Engel J, Pedley TA, editors. Epilepsy: a comprehensive textbook. Philadelphia: Lippincott-Raven; 1997. p. 15-40. 2. Gowers WR. Epilepsy and other chronic convulsive disorders. London: T and A Churchill; 1881. 3. Gibbs FA, Davis H, Lennox WG. The EEG in epilepsy and in the impaired states of consciousness. Arch Neurol Psychiatry 1935;34:1133-42. 4. Petersen O, Eeg-Olofsson O. Paroxysmal activity in EEG of normal children. In: Kelleway P, Petersen I, editors. Clinical electroencephalography of children. New York: Grune & Stratton; 1968. p. 167-88. 5. Hauptman A. Luminal bei epilepsie. Munch Med Wochenschr 1907. 6. Merritt HH, Putman TJ. A new series of anticonvulsant drugs tested by experiments in animals. Arch Neurol Psychiatry 1938;39:1003-15. 7. Sillanpaa NI. Carbamazepine. In: Wyllie E, editor. The treatment of epilepsy: principles and practice. 2rid
11.
12.
13.
14.
15.
ed. Baltimore: Williams and Wilkins; 1997. p. 808-23. Dean JC. Valproate. In: Wyllie E, editor. The treatment of epilepsy: principles and practice. 2nd ed. Baltimore: Williams and Wilkins; 1997. p. 824-32. Penfield W, Jasper H. Epilepsy and the functional anatomy of the human brain. Boston: Little Brown & Co; 1954. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:489-501. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389-99. Camfield PR, Camfield CS. Prognosis of childhood epilepsy. Semin Pediatr Neurol 1994;1:90-110. Nelson KB, Ellenberg JH. Prediction of epilepsy in children who have experienced febrile seizures. N Engl J Med 1976;295:1029-33. Shlnnar S, Berg AT. Does antiepileptic drug therapy alter the prognosis of childhood seizures and prevent the development of chronic epilepsy? Semin Pediatr Neurol 1994; 1:111-7. Prasad AN, Prasad C, Stafstrom. Recent advances in the genetics of epilepsy: insights from human and animal studies. Epilepsia 1999;40:1329-54.
849