Index of suspicion. Case 1. Hypersensitivity pneumonitis

We report a case of a 17-year-old white girl with Marfan's syndrome and generalized absence-type seizures since 11 years of age. A video EEG recording for six hours demonstrated 52 episodes of clinical generalized absence-type seizures and three-per-second spike and wave epileptiform discharges, characteristic of petit mal epilepsy. Sodium valproate therapy was successful in controlling her seizures. In this article, we review various possible causes of epilepsy in patients with Marfan's syndrome.     

Idiopathic epilepsy with generalized seizures in early childhood]

Idiopathic epilepsies with generalized seizures of early childhood are based on a genetic predisposition. The onset takes place between the first and fifth years of age, boys are affected more often than girls. Dependent on the clinical symptomatology you have to distinguish: myoclonic seizures; atonic-astatic seizures; myoclonic-astatic seizures; absences; tonic-clonic seizures. In more than half of the cases a combination of these seizures can be observed. The differentiation of epilepsies with generalized seizures of multifocal origin (infantile spasms, Lennox-Gastaut syndrome and Pseudo-Lennox syndrome [atypical benign epilepsy]) may be difficult but is essential. Therapy of choice is valproate, often in combination with ethosuximide (in children with minor seizures) or with kaliumbromide or phenobarbital (in children with tonic-clonic seizures). Generally the prognosis is more unfavourable if epilepsy starts in the first year of life with afebrile and febrile generalized tonic-clonic or clonic seizures, if children are suffering from longlasting states of seizures and if development is disturbed before beginning of epilepsy.     

Ergonomics: where have we been and where are we going: IV

The long-term prognosis of 185 children with epilepsy, who continued to attend the Clinic for Epileptic Children, the Department of Pediatrics, the University of Tokyo, beyond the age of 18 years, was reported. The length of follow-up varied from three to 20 years, but most of them were followed longer than 10 years. The presumed etiology in these children was divided into a cryptogenic group (124, 67.0%) and a symptomatic group (61). The types of seizures were classified into grand mal (86 cases), focal seizure (27), petit mal absence (4), psychomotro seizure (5), infantile spasms (7), and so on. It may be noted that the highest frequency of grand mal was demonstrated, while the incidences of infantile spasms, myoclonic seizure, and akinetic seizure were low in the series. Only 28 children (15.1%) had complications of physical and/or mental handicaps. The follow-up study revealed that 140 patients (75.7%) had been seizure-free in the last 12 months. One hundred and fifteen of them had no seizures for five years or longer. On the other hand, electroencephalographic abnormalities generally continued for a long time after disappearance of seizures. Eightly-one of well-controlled patients were gradually decreasing the doses of anticonvulsants. As for seizure types, it is noted that focal seizure, psychomotor seizure, and infantile spasms were relatively difficult to be controlled. Except for 27 patients, most of them attended normal schools, including junior colleges or universities, and engaged in various occupations. Fifteen female patients had already married, and out of 13 babies who were born from these patients, there were one with ventricular septal defect, one with mental deficiency, and one with anencephaly, while the rest were entirely normal. Additional problems on withdrawal of anticonvulsants after a long-term seizure-free period, and what a medical system should be for treatment of epilepsy in children up to their adulthood were discussed.     

Cerebral blood flow effects of sodium valproate in drug combinations in the baboon model

Sodium valproate (CAS 1069-66-5, Epilim) has been used in the management of epilepsy during the last three decades. Although important information on the pharmacological actions and efficacy of sodium valproate has accrued to date, limited research has been conducted on its effects on cerebral blood flow. In recent years, with the aid of SPECT (single photon emission computed tomography) and PET (positron emission tomography) it has been shown that marked cerebral blood flow changes occur in epileptic patients. Furthermore it was established recently that sodium valproate influences the cerebral blood flow in children by decreasing the flow significantly. The present study investigated the effects of sodium valproate on the cerebral blood flow, using 99mTc-HMPAO (hexamethylpropylene amino oxime) and SPECT, in a primate model, as well as the effects of its drug interactions with therapeutic agents that influence cerebrovascular dynamics, e.g. sumatriptan, nimodipine and acetazolamide. The current study using single dose treatment with sodium valproate did not detect a decrease or increase of the cerebral blood flow when compared with control baseline results. Drug interaction between sodium valproate and nimodipine may occur as a reduction of 25% in cerebral blood flow from the baseline control was observed in this case. The effects observed for the combinations of sodium valproate respectively with sumatriptan and acetazolamide are attributed to the influences of the sumatriptan (decrease) and acetazolamide (increase) alone. The cerebral blood flow effects of these drugs and possible interactions during an acute epileptic seizure need to be investigated.     

Comparative efficacy of terfenadine, loratadine, and astemizole in perennial allergic rhinitis

BACKGROUND: It is not known how many children with epilepsy may not need treatment with antiepileptic drugs (AEDs), how many respond unsatisfactorily to subsequent treatment regimens, and how many achieve "acceptable control" despite lack of remission. METHODS: In a prospective multicenter hospital-based study, 494 children with a broad range of seizure types and types of epilepsy were followed up for at least 2 years. There was no standard treatment protocol. We describe the treatment strategies applied to these children by the neurologists in charge and outcome with respect to remission from seizures. RESULTS: Treatment was initially withheld in 29% of the children, and after 2 years 17% still had not received any AEDs. There were no serious complications caused by withholding treatment. Of the children treated with AEDs, 60% were still using the first AED after 2 years; 80% received monotherapy and 20%, polytherapy. Children with severe symptomatic epilepsies, such as the West or Lennox-Gastaut syndrome, received polytherapy early on in the course of treatment. When 3 regimens had failed, the chance of achieving a remission of more than 1 year with subsequent regimens was 10%. Nevertheless, 15 of 50 children receiving AEDs in whom the "longest remission ever" was less than 6 months did achieve acceptable seizure control according to the neurologist in charge of treatment. Hence, of 494 children, only 35 (7%) developed an intractable form of epilepsy, defined as failure to bring seizures under acceptable control. CONCLUSIONS: A substantial percentage of children with new-onset epilepsy did not need treatment with AEDs. Chances of achieving a good outcome declined with subsequent treatment regimens. Not all children with recurrent seizures were suffering from intractable epilepsy; some had achieved acceptable control of seizures.     

Complexities of primary generalized epilepsy

Abnormal arousal responses paired with paroxysmal discharges and photosensitivity are the principal mechanisms in the precipitation of seizures in primary generalized epilepsy. The abnormal arousal responses show a consistent maximum over the frontal midline region. An exception from this rule was found in two children with primary generalized epilepsy (petit mal absences, one also with grand mal) with a strongly positive family history. In these patients, the generalized-synchronous bursts showed a maximum over the vertex (Cz electrode). Both of these children also had single spikes over the Rolandic region. A relationship between primary generalized and benign Rolandic epilepsy is demonstrated. Both forms of seizure disorder are based on dysfunction (hyperexcitability) rather than on a structural epileptogenic lesion. A dichotomy of dysfunctional and structural epilepsies is presented but gray zones of overlap indubitably exist. The limitations of the dichotomy concept are pointed out.     

Carbamazepine-10,11-epoxide in therapeutic drug monitoring

Carbamazepine (CBZ) is widely used in the treatment of epilepsy, frequently in combination with other anticonvulsants. Its metabolite, carbamazepine-10,11-epoxide, is pharmacologically active and is increased with concurrent use of valproate and other anticonvulsants. This pharmacokinetic interaction may be particularly important because CBZ, its epoxide, phenytoin, and lamotrigine all act on fast voltage-dependent sodium channels. Over a 2-month period, routine serum requests for CBZ (n=47) (excluding known cases of overdose) were also analyzed for CBZ epoxide, phenytoin, and lamotrigine using a simultaneous high performance liquid chromatographic (HPLC) method. Valproate was measured using fluorescence polarization immunoassay (FPIA). With concurrent phenytoin and lamotrigine administration, there was a relative increase in CBZ epoxide and a significant decrease in the ratio of CBZ to epoxide (from more than 5 to 3). If valproate was also present, the concentration of parent and metabolite increased significantly, causing potential toxicity. Two patients in this latter group had significant clinical toxicity, with parent CBZ concentrations in the reference range; a third patient suffered from poor control of seizures. This study illustrates the importance of awareness of the contribution of active metabolites in therapeutic drug monitoring and raises questions about the role of the routine monitoring of such metabolites.     

Anticonvulsant combination therapy: rational concepts versus real effectiveness

Primary drug treatment of epilepsies is usually a monotherapy with an antiepileptic drug. This procedure causes less side effects as polytherapy and probably shows the same efficacy. Two third of patients with focal epilepsies are sufficiently treated with a single antiepileptic drug: 60% of patients with Grand mal and 22-30% of patients with complex focal seizures remain seizures free. An alternative monotherapy will suppress seizures in another 30% of patients. With polytherapy this is achieved in only 12% of the remaining patients, furthermore, side effects increase in polytherapy. Generalized epilepsies are usually treated with valproate monotherapy. Patients remain seizure free from absence in 60-90%, from myoclonic-impulsive seizures in 75-97% and from Grand mal in about 85%. Alternative monotherapy is less common because of the limited efficacy and possible side effects of drugs: ethosuximide does not control Grand mal and phenobarbitone may cause sedation. Thus, polytherapy is commonly initiated when monotherapy fails to control seizures (lamotrigine is often chosen as comedication). Rational polypharmacy is a term suggesting rational concepts in planning antiepileptic polytherapy leading to a superior anticonvulsant effect. However, this consideration is not based on or supported by clinical data. Yet, a combination of drugs which have no or little pharmacokinetic interactions seems to be a clinically relevant recommendation. Thus, newly developed drugs such as vigabatrin, lamotrigine or gabapentin are more frequently used as comedication with standard antiepileptic drugs.     

Effect of carbamazepine and valproate on bone mineral density

OBJECTIVE: To examine the effect of carbamazepine and valproate monotherapy on bone mineral density in children. METHODS: Axial (second, third, and fourth lumbar vertebrae) and appendicular (distal third of radius) bone mineral density was measured by dual-energy x-ray absorptiometry in 27 healthy children and 26 children with uncomplicated idiopathic epilepsy treated with either carbamazepine (n = 13) or valproate (n = 13) for more than 18 months. Control subjects and patients were similar with respect to age, race (all white), and geographic area, and had no dietary restrictions, neurologic impairment, or physical handicaps. RESULTS: Subjects were seizure-free for more than 6 months on a regimen of carbamazepine or valproate therapy, and had mean serum trough levels of 6.88 +/- 2 micrograms/ml and 72.04 +/- 45.6 micrograms/ml, respectively. Dietary calcium intake was similar in control and treated groups. After correction for gender and age, children treated with valproate had a 14% (p = 0.003) and 10% (p = 0.005) reduction in bone mineral density at the axial and appendicular sites, respectively. The reduction in bone mineral density increased with the duration of valproate therapy. Carbamazepine did not significantly reduce bone mineral density. CONCLUSION: Valproate montherapy, but not carbamazepine therapy, significantly reduces axial and appendicular bone mineral density in children with idiopathic epilepsy and may increase their risk of osteoporotic fractures.     

A meta-analytic review of the preventive treatment of recurrences of febrile seizures

OBJECTIVE: To assess the efficacy of various medications in the prevention of recurrent febrile seizures. STUDY DESIGN: A meta-analysis of all published randomized, placebo-controlled trials of the preventive treatment of febrile seizures published in English; 45 articles were found, but only 9 trials were randomized and placebo-controlled--4 using phenobarbital; 3, diazepam; 1, pyridoxine; and 1, phenytoin. In one of the phenobarbital trials, valproate was also compared with placebo. RESULTS: The risk of recurrences was significantly lower in children receiving continuous phenobarbital therapy than placebo (odds ratio 0.54, 95% confidence intervals 0.33 to 0.90, p = 0.017). The odds ratio for recurrences in the valproate group was 0.09, 95% CI 0.01 to 0.78, p = 0.011. No difference in the risk was found for recurrences between children receiving intermittent diazepam and placebo (odds ratio 0.81, 95% CI 0.54 to 1.22, p = 0.31). The risk for recurrences in children receiving pyridoxine or phenytoin did not differ from the risk among children receiving placebo. Four children would have to be treated with valproate (95% CI 2 to 11) or eight children would have to be treated with phenobarbital (95% CI 5 to 27), continuously, to prevent one febrile seizure. CONCLUSIONS: Because both agents found to be effective in prevention of recurrent febrile seizures have known adverse effects, prophylaxis of febrile seizures cannot be recommended.     

Abdominal epilepsy in an adolescent with bilateral perisylvian polymicrogyria

PURPOSE: We report a patient with recurrent episodes of severe periumbilical pain accompanied by headache, pallor, dizziness, and visual hallucinations who was subsequently diagnosed as having abdominal epilepsy and a bilateral sylvian cortical malformation. METHODS AND RESULTS: During an EEG examination, the patient had a simple partial seizure, manifested as intense abdominal pain. The ictal EEG showed a focal electrographic seizure arising from the left frontotemporal region. Computed tomography scan was normal; however, magnetic resonance imaging (MRI) revealed asymmetric lesions involving both sylvian fissures compatible with polymicrogyria. Onset of treatment with sodium valproate was followed by a significant reduction of seizures. CONCLUSIONS: Abdominal epilepsy should be suspected in adolescents or adults with paroxysmal episodes of abdominal pain associated with migraine-like symptoms. EEG and MRI investigations are indicated. A developmental brain disorder should be considered as a possible etiology.     

Predictors of epilepsy in children who have experienced febrile seizures

We examined the frequency of development of afebrile seizures in 1706 children who had experienced at least one febrile seizure and were followed to the age of seven years. Epilepsy developed by seven years of age in 20 per 1000 (2 per cent), and another 10 per 1000 had at least one afebrile seizure that did not meet our definition of epilepsy. In children whose neurologic or developmental status was suspect or abnormal before any seizure and whose first seizure was complex (longer than 15 minutes, multiple or focal) epilepsy developed at a rate 18 times higher than in children with no febrile seizures (92 vs. 5 per 1000; P less than 0.001). In the largest group with febrile seizures, those previously normal with noncomplex first febrile seizures, epilepsy developed in 11 per 1000; this rate, although moderate, was greater than that for children with no febrile seizures (P = 0.027). Prior neurologic and developmental status and characteristics of the first febrile seizure are important predictors of epilepsy after febrile seizures.     

A registry for European biologists: why create it?]

BACKGROUND: Pathological laughter can be a sign of epilepsy, psychiatric illness, effect of toxins or psychotropic drugs or of structural brain disease. METHOD: Case Studies. RESULT: Two patients developed inappropriate uncontrollable laughter following intravenous sodium valproate for treatment of epilepsy. CONCLUSION: Pathological laughter can be a side effect of intravenous sodium valproate.     

Convulsant-specific architecture of the postictal behavior syndrome in the rat

The postictal immobility syndrome was examined in five experimental grand mal epilepsy models in an attempt to analyze separately the behavioral and underlying neurochemical aspects of the rigid-catatonic and flaccid-cataleptic states. Catalepsy and analgesia were found in varying degrees after maximal electroshock (MES), metrazol, picrotoxin, and Ro 5-3663 activated seizures. Signs of rigidity were noticed after the MES and picrotoxin seizures. Kindled seizures were followed by explosive behavior without signs of rigidity, catalepsy, and analgesia. Naloxone reduced the duration but not the score (intensity) of catalepsy and failed to selectively antagonize analgesia. The relative representation of the tonic stage of convulsions seemed to be the major determinant of the development of catatonic-cataleptic symptomatology. It is suggested that more than a single neurotransmitter system is involved in the postictal immobility syndrome and each epilepsy model has its unique neurochemical profile.     

Primary therapy with OKT3 for biopsy-proven acute renal allograft rejection

Our patient underwent right anteromesial temporal resection at 17 years of age for intractable complex partial seizures due to hippocampal sclerosis, and then developed juvenile myoclonic epilepsy after a change in medication. Postoperative seizures ceased after a change to valproate monotherapy. Our patient reminds us to remain aware that generalized and focal epilepsy may coexist as an unusual cause for surgical failure. We feel that these patients may still be favorable candidates for epileptic surgery, as long as the focal epileptogenic zone is amenable to resection and the generalized epilepsy appears to be readily controllable.     

Outcome and life prospects after surgical management of medically intractable epilepsy in patients under 18 years of age

A retrospective analysis of seizure outcome and quality of life assessment was done in 64 patients under 18 years of age with medically refractory epilepsy who underwent 64 primary and 16 repeat operative procedures in an attempt to control their epilepsy. At least 2 years' follow-up data were available for each patient. Operative procedures were 44 temporal lobe resections; 16 extratemporal resections; and 4 hemispherectomies. Effective control of previously intractable seizures was obtained in most patients: 55%, 11%, and 17% achieved Engel class I, II, and III status, respectively. Successful seizure control was thus obtained in 83%, while 17% (Engel class IV) failed to improve significantly after operation. Quality-of-life measures parallelled the improvements in seizures control, being highest in Engel I, outcome group and lowest in Engel IV outcome group. In appropriately selected pediatric and adolescent patients with medical refractory epilepsy, surgical management can offer a safe and effective adjunct to medication.     

Epilepsy in children with shunted hydrocephalus

OBJECT: The incidence of epilepsy among children with hydrocephalus and its relation to shunts and their complications, raised intracranial pressure (ICP), and developmental outcome are explored in a retrospective study. METHODS: The authors studied a series of 802 children with hydrocephalus due to varying causes, who were treated by ventriculoperitoneal shunt placement between 1980 and 1990, with a mean follow-up period of 8 years. Patients who had tumoral hydrocephalus and those whose files lacked significant data were excluded. Data extracted from medical records, including history of the hydrocephalus and history of seizures, if any, were analyzed. Thirty-two percent of the children had epilepsy, the onset of which frequently occurred at approximately the same time that the diagnosis of hydrocephalus was made. The majority of the affected children had severe uncontrolled epilepsy. The incidence of epilepsy was significantly affected by the original cause of the hydrocephalus. The presence of radiological abnormalities was also found to be a significant predictor of epilepsy. Similarly, shunt complications predisposed to epilepsy. Episodes of raised ICP related to hydrocephalus or in association with shunt malfunction may also predispose to epileptic seizures. Furthermore, the presence of a shunt by itself seems able to promote an epileptogenic focus. Finally, epilepsy appears to be an important predictor of poor intellectual outcome in hydrocephalic children with shunts. CONCLUSIONS: A prospective study is needed to identify clearly and confirm avoidable factors predisposing to seizures in these children so that we can strive to reduce the incidence of these seizures and, subsequently, improve these children's quality of life.     

Treatment of epilepsy: where are we today?

The modern treatment of epilepsy has improved considerably in all three pillars. More than a century has passed, however, since Sir Charles Locock introduced the bromides in 1857 and Sir Victor Horsely pioneered epilepsy surgery in 1886 (18). In drug therapy, the 'classic AED' of the last decades, i.e. phenobarbital (Hauptmann, 1912) and phenytoin (Putnam and Merrit, 1938) are being largely displaced by valproate (Meunir, 1963) and carbamazepine (Lorge, 1963). Only ethosuximide (Zimmermann, 1951) has continued to maintain its position in 3/s spikewave-absence epilepsy, in particular in the USA (28, 29). Although it is an excellent drug against absences, it has the unpleasant property that it may induce GM seizures and should therefore be combined with a so-called 'GM protector' (mostly phenobarbital). For this reason ethosuximide has been relegated to second place in Europe by valproate. Thus, the decision as to which AED should be employed at the outset has been simplified considerably: actually, with valproate as the drug of first choice, which displays a very broad spectrum of action, we are on the right track for virtually all forms of epilepsy, perhaps with the exception of focal epilepsy (11). Especially in the event of focal epilepsy of temporal origin we employ carbamazepine as the preparation of first choice. In some countries (Denmark), because of the less severe side effects, oxcarbazepine is already preferred (Mogens Dam, personal communication). Considerable experience and knowledge are still required, however, when resistance has developed to traditionally applied classic monotherapy. Here, the range of further treatment can also be greatly extended by the availability of the 'new AED'. A generally accepted protocol for the replacement of one preparation with another first- or second-choice drug and, above all, for the 'right' combination with third-choice preparations can as yet not be compiled. What we need here is the expert epileptologist who has experience with 'theoretically useful' combinations and has an insight into the interactions occurring with such combinations. For several specific epileptic syndromes the 'K?nigsteiner Working Group of German-Speaking Epileptologists' has given clear and binding recommendations for AED therapy (e.g. for benign juvenile myoclonic epilepsy--Janz syndrome). This working group has also made recommendations for the necessary clinical and laboratory controls in AED therapy with potentially severe side effects (e.g. valproate therapy in high-risk children), which were published and/or are being published and discussed in the 'Epilepsie-Bl?tter' of the German League against Epilepsy (4). Despite all advances in drug therapy, the number of epilepsy patients not satisfactorily treatable with drug therapy has not been dramatically reduced statistically, so that the other two pillars of epilepsy therapy, i.e. epileptic surgery and behavioural therapy, continue to be very important.     

Anticonvulsant drug effects in the direct cortical ramp-stimulation model in rats: comparison with conventional seizure models

A modified cortical ramp stimulation (CRS) model has been developed allowing repeated determinations of seizure threshold at short time intervals in individual rats without inducing postictal threshold increases. Anticonvulsant potency of the standard antiepileptic drugs carbamazepine, phenytoin, phenobarbital, valproate, diazepam and ethosuximide in the CRS model was compared with respective drug potencies in two more traditional seizure models with transcorneal stimulus application, i.e., the minimal electroshock seizure threshold (minEST) and the maximal electroshock seizure threshold (maxEST). In the CRS model, two different types of threshold were determined, the threshold for localized seizures (TLS) and the threshold for generalized seizures (TGS). When screw electrodes were implanted over the primary motor cortex, TLS was characterized by unilateral forelimb clonus, tonic abduction of contralateral forelimb, and head adversion. When ramp-shaped stimulation was continued above the TLS current, bilateral clonic forelimb seizures with loss of posture developed, which was defined as TGS. In contrast to TLS, TGS could not be repeatedly determined at short time intervals because of postictal threshold increase. TLS was dose-dependently increased by carbamazepine, phenobarbital, valproate and diazepam, although phenytoin showed a truncated dose-response, and ethosuximide was ineffective. In comparison to TLS, drug-induced increases in TGS were more marked. All drugs dose-dependently increased minEST and, except ethosuximide, maxEST. For comparison of drug potencies, doses increasing seizure thresholds by 20 or 50% were calculated from dose-response curves. Respective comparisons showed marked differences in drug potencies between models, indicating that the CRS method presents a model of another, more pharmacoresistant seizure type than seizure types induced in traditional models, such as transcorneal electroshock. Based on the location of electrodes in the frontal neocortex, the characteristic seizure pattern, and the low pharmacological sensitivity of the seizures to standard antiepileptics, the modified CRS model most likely represents a new model of localization-related seizures occurring in frontal lobe epilepsy and may thus be used in the search for novel drugs with higher efficacy against this difficult-to-treat type of epilepsy.     

Seizures involving the supplementary sensorimotor area in children: a video-EEG analysis

Most reports of supplementary sensorimotor seizures have been of adults with medically refractory epilepsy. Typically, supplementary sensorimotor seizures have onset in childhood. We describe the electroclinical features in 12 children. Cases were selected from an EEG laboratory population in whom video-EEG was performed routinely on all children. Supplementary sensorimotor seizures were diagnosed when there was bilateral tonic posturing of the upper or lower extremities, preserved consciousness, and lack of postictal confusion. Sensory auras were reported by 8 of 9 children aged > 3 years who had daytime seizures. Speech arrest occurred in all patients in whom it could be assessed, and abnormal vocalization was observed in 7 children. Interictal EEGs were often normal (49% of recordings), and ictal EEG changes could be subtle. An etiology was demonstrated in only 2 children, and brain imaging studies were normal in the other 10 patients. Seizures were controlled with antiepileptic drugs (AEDs) in 6 of the 12 children. The clinical manifestations of supplementary sensorimotor seizures in children are similar to those reported in adults; misdiagnosis is common at all ages.