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Editorial
Molecular genetics of the idiopathic epilepsies: the next steps...
S.F. Berkovic, R. Ottman
been the case for many neurological diseases, molecular discoveries in the epilepsies depend on synergy between clinical researchers and molecular geneticists. Initial careful identification of clinically homogeneous phenotypes greatly facilitates successful linkage analysis and subsequent gene identification. The molecular discoveries can then be applied to a wider range of patients, which may result in refinement of the phenotypic spectrum, and lead to a deeper understanding of the disorder. For example, molecular discoveries have re-shaped the classification of muscular dystrophies, spino-cerebellar ataxias, hereditary neuropathies, etc. [2].
Synthèse
Prognosis in nonconvulsive status epilepticus
P.W. Kaplan
several factors: under-recognition of NCSE with its spontaneous resolution (thus decreasing the "denominator" of total cases that will have a poor outcome); incorrect diagnosis of NCSE based on misinterpretation of EEG "epileptiform" activity; mis-classification of certain EEG patterns as NCSE (e.g. PLEDs; triphasic waves); and grouping of different populations that have markedly different co-morbidities (ambulatory patients with NCSE together with comatose patients with electrographic seizure activity on EEG). There are almost no prospective studies with premorbid neuropsychometric studies, and retrospective studies typically include isolated cases, or case series that include conditions in which the cause of NCSE itself causes cognitive morbidity.
To summarize available data, absence status (ambulatory generalized non-convulsive status epilepticus) would appear to carry no lasting morbidity. Complex partial status epilepticus in ambulatory patients rarely results in measurable permanent neurologic deficit, although rarely, short or long-standing deficits may clearly occur.
Because intensive treatment with intravenous anticonvulsants (e.g. benzodiazepines or phenytoin) can confer morbidity, the equation has not yet been made as to whether the morbidity of such intensive treatment for all cases of NCSE exceeds the morbidity of the disease itself. Larger, prospective studies will be needed to truly determine the prognosis in the different types of NCSE, stratified according to associated degrees of impairment (minimally impaired, moderately obtunded, comatose).
While convulsive status epilepticus represents at one extreme, a striking example of a prolonged ictal state, there is another group of more subtle types of status epilepticus: namely nonconvulsive status epilepticus (NCSE). A growing body of information and some excellent recent reviews discuss the morbidity of convulsive status epilepticus (CSE); however, determining the morbidity of nonconvulsive states has proven more elusive and contentious [1-5]. Part of the contention resides in the fact that there are several conditions which have collectively been referred to as NCSE [3]. Other problems impairing analysis of outcome arise from an ascertainment bias almost intrinsic to NCSE: that is, that these states (particularly when subtle) evade notice, and hence diagnosis [6, 7]. It is even arguable that numbers of patients in a state of NCSE for hours, following tonic-clonic seizures, may well go unrecognized, with their seizures resolving unnoticed and spontaneously behind the veil of a "post-ictal state". The issue is further complicated by problems in classification, epitomized by what is, or is not NCSE. It might seem simple, perhaps, to formulate a definition such as: a) a behavioral or cognitive change from a patient's baseline state of functioning without convulsive moments, and b) seizure activity on the EEG. But such a broad definition would subsume "PLEDS-plus"; triphasic encephalopathy; arguably some forms of waxing and waning periodic lateralized epileptiform discharges (PLEDS), or even deeply comatose patients with incidental EEG ictal activity. Such a broad grouping would therefore include at one end of the spectrum, ambulatory patients with little cognitive impairment, and at the other, comatose patients with their attendant organ systems failure in an intensive care setting with rudimentary cortical functioning as evaluated by bedside neurologic examination. This grouping would include patients with irreversible major brain damage (e.g. from strokes or trauma), and patients with clearly reversible toxic/metabolic encephalopathies (e.g. uremia, lithium toxicity).
Clearly, when problems in the definition, diagnosis, ascertainment bias, and lack of consensus on "seizure" EEG patterns along with a widely variable patient substrate converge, there will be a significant problem in determining prognosis for this syndrome.
In this review paper, I will address several issues: 1) the evolving definition of NCSE; 2) reasons for misidentification or missed diagnosis of NCSE; 3) problems in determining outcome after NCSE (distinguishing concurrent insult with its own morbid consequences from consequent insult solely attributable to seizure activity); and 4) considerations regarding the morbidity of treatment of NCSE.
Articles originaux
Multifactorial pathogenesis of neonatal seizures - relationships to the benign partial epilepsies
H. Doose, K. Kouddriavtseva, B.A. Neubauer
relationships between these conditions. Further insight into the nature of these relationships can be expected only from NS patients with long-term follow-up, which includes the age range of maximum manifestation of subsequent seizures or epilepsies (SSE), and age-dependent genetic EEG traits. A sample of such cases will necessarily be selected and thus prohibit any quantitative inferences regarding the incidence of SSE and special EEG characteristics. Nevertheless, the data provide new aspects with regard to a possibly multifactorial pathogenesis of NS and SSE. Children in the present study were selected applying the following inclusion criteria: cerebral seizures during the first 14 days of life; follow up of more than two years with at least two EEG recordings beyond the age of two. Children with metabolic NS or subsequent West syndrome were not included. Seventy-six cases were confirmed, 42 with SSE, 34 without. The incidence of EEG symptoms of a generalized genetic seizure liability (theta rhythms, generalized spikes and waves, photoparoxysmal response) was significantly elevated, equally in children with and without SSE. Beyond the age of two years, 50% of the probands had focal sharp waves foci characteristic of idiopathic partial epilepsy (e.g. rolandic epilepsy). Among SSE, febrile convulsions and partial epilepsies with benign course dominated. Idiopathic generalized epilepsies were not observed. These findings indicate that in a certain proportion of cases, NS have genetic factors in common with idiopathic partial epilepsies. Quantitative representative data cannot be obtained to determine the incidence of such pathogenetic mechanisms in NS and SSE.Neonatal seizures (NS) are usually divided into benign familial, benign non-familial, and symptomatic forms (for lit. see [1]). This classification is preliminary as up to 20% of families with benign NS also have other forms of seizures or epilepsy. EEG and clinical follow-up show relationships between NS and benign epilepsy with centrotemporal sharp waves (SHW) [2-5]. An elevated incidence of NS in children with idiopathic partial epilepsies and in children with febrile convulsions (FC) with focal SHW point in the same direction [6-9]. Taken together, these findings indicate that in addition to the 20q13 and 8q24 loci in benign familial NS [10, 11] other genetic factors are involved in the pathogenesis of NS (see also Neubauer et al. [12]). Further insight into these questions can come only from long-term clinical and EEG observations of NS children, which include the period of maximum manifestation of subsequent seizures and epilepsies (SSE), and of different age-dependent genetic EEG traits. Spikes and waves and photoparoxysmal response representing the best known markers of a genetic seizure liability, have their maximum expressivity between the 5th and 15th year of life. Thus, a retrospective study of pathogenic mechanisms and especially of a possible contribution of different genetic factors necessarily involves a selected patient sample. This, in turn precludes any quantitative inferences regarding the incidence of SSE and special pathogenic constellations in NS in general.
Melatonin and epileptic seizures in patients with acute intermittent porphyria
I. Bylesjö, L. Forsgren, I. Wetterberg
melatonin may have anti-convulsive or pro-convulsive effects in AIP.
Melatonin concentration in urine, sampled over eight hours on two consecutive nights, was analysed in eight AIP patients with epileptic seizures and in 14 AIP relatives without epilepsy. The AIP patients with epileptic seizures had a significantly lower urinary excretion of melatonin, compared with their AIP relatives without epilepsy, which may indicate that melatonin has a protective effect on seizures.
The porphyrias are inherited metabolic disorders characterized by the impairment of haem biosynthesis [1]. Acute intermittent porphyria (AIP) is the most common of the acute porphyrias diagnosed in Sweden. In AIP, the mutated enzyme porphobilinogen deaminase (PBGD), is the third enzyme in the haem biosynthetic pathway.
During acute attacks of AIP, neurological dysfunction of the peripheral, autonomic or central nervous system may occur and the excretion in urine of the haem precursors delta-5-aminolevulinic acid (ALA) and porphobilinogen (PBG) often increases [2].
Epileptic seizures may occur [3, 4] in patients with AIP, but the exact prevalence of seizures is not known. The percentage of persons with AIP who have experienced epileptic seizures has been estimated at 10-20% [3, 4]. Previous investigations of seizures in AIP appear to come from selected clinic-based studies and generally include case reports or limited comments on seizures. A population-based study has shown a lifetime prevalence of AIP-associated seizures of 2.2% for all AIP gene carriers and 5.1% for those with clinically manifested AIP symptoms [5].
The well-known functions of the pineal hormone melatonin are to modulate endocrine [6, 7] and circadian systems [8, 9]. The rate-limiting enzyme for melatonin synthesis is N-acetyltransferase (NAT) [10, 11]. The activity of NAT is influenced by the environmental light-dark cycle. The production of melatonin is under genetic control [12] and decreases with age [13, 14]. Wetterberg et al. [14] found that the correlation coefficient between age (years) and melatonin was 0.188; p < 0.001 for 165 men, and 0.193; p < 0.013 for 156 females.
The physiological production of melatonin measured in blood and urine reaches its peak when the person sleeps in darkness, between midnight and dawn [15].
In contrast, the urinary excretion of porphyrin does not display a circadian variation in healthy persons without AIP [16]. Melatonin exerts a depressive influence on brain excitability [17, 18] and has been shown to have an anti-convulsive effect in animal models [18-20] and in humans [18, 21].
On the other hand, melatonin can hypothetically have a pro-convulsive effect [22]. This hypothesis is in agreement with the fact that subgroups of epileptic patients experience seizures at night [23] when plasma melatonin levels are several times higher than they are during the day [24-27].
Melatonin is metabolized in the liver to 6-sulfatoxymelatonin (aMT6s), which is excreted in the urine and corresponds to the pineal melatonin production and secretion rate [28].
Antimyoclonic effect of levetiracetam
P. Genton, Ph. Gelisse
from 24 to 40 g/d. Levetiracetam (LEV), a new antiepileptic drug, is a structurally related compound that has a distinct pharmacological profile and appears to be efficient at much lower doses. We gave LEV, 4,000 mg/d, without titration, to three volunteers with post-anoxic myoclonus (PAM) (one case) and Unverricht-Lundborg disease (two cases), over 2, 2 and 10 weeks, respectively. LEV produced a clear abatement of myoclonus, which is demonstrated on video for the patient with post-anoxic myoclonus, without any unwanted side-effects. These preliminary findings suggest that LEV may have interesting antimyoclonic properties that deserve further investigation.Myoclonus may occur in various neurological disorders, including many forms of epilepsy, and often appears as a debilitating symptom. Piracetam (PIR) is effective in the treatment of many forms of myoclonus, especially in cortical myoclonus [1, 2], but high, impractical doses of up to 40 g/d are necessary [3]. Levetiracetam (LEV), a compound with a chemical structure that is closely related to that of PIR, has a different pharmacological profile [4] and is a potent new antiepileptic drug (AED) that is effective in human focal epilepsies and against generalized tonic-clonic seizures (GTCS) [5, 6] and has also shown promising efficacy in animal models of generalized epilepsies [7-9]. It was also shown to be effective in preventing the photoparoxysmal response in patients with photosensitive epilepsy [10], which may predict efficacy in generalized epilepsies and myoclonus. We thus decided to publish these case reports on the efficacy of LEV in the treatment of severe action myoclonus.
Clinical and EEG video-polygraphic features of epileptic spasms in a child with dihydropteridine reductase deficiency. Efficiency of hydrocortisone
Y. Mikaeloff, P. Plouin, J.L. Dhondt, G. Ponsot, O. Dulac
child with dihydropteridine reductase deficiency who developed hypsarrhythmia and infantile spasms which were documented on video-polygraphic EEG. Despite dietary restriction of phenylalanine, and oral administration of amine precursors, the initial course was unfavorable. A beneficial effect from hydrocortisone was then observed, with control of spasms and improvement of psychomotor delay.The international classification of epilepsies and epileptic syndromes considers epileptic spasms (ES) to be the typical seizures of West syndrome (WS) [1], in which they are combined with psychomotor deterioration and hypsarrhythmia. Within the wide range of inborn errors of metabolism, isolated cases of WS have been mentioned but remain poorly documented from the neurophysiological point of view [2].
In biopterin deficiency, a rare cause of hyperphenylalaninemia (HPA), an insufficient supply of endogenous tetrahydrobiopterin (BH4) cofactor impairs the function of phenylalanine (Phe), tyrosine and tryptophan hydroxylases. Symptoms result more from defective synthesis of neurotransmitters (dopamine, serotonin, noradrenalin and adrenalin), resulting in low level of homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA) in the cerebrospinal fluid (CSF), than from Phe accumulation, which may be very mild. BH4 may be deficient because of deficient BH4 synthesis caused by mutations affecting 6-pyruvoyl tetrahydropterin synthase (6-PTS) or GTP cyclohydrohydrolase (GTP-CH), or deficient recycling of BH4 mainly caused by mutations of the dihydropteridine reductase (DHPR) gene [3]. All these deficiencies are autosomal recessive. Prenatal diagnosis is possible. To date, about 150 cases of DHPR deficiency are recorded in the International Register (JL Dhondt, personal communication). This condition is twice less frequent than 6-PTS deficiency, whereas GTP-CH is very rare.
The clinical course of patients with 6-PTS or DHPR is similar. Onset is around 4-5 months of age. The most severe cases exhibit microcephaly and developmental delay with progressive neurological deterioration that may lead to death. Extra-pyramidal symptoms are frequent. Patients less severely affected experience symptom stabilization or even slow developmental progress. Epileptic disorders are not systematically reported but clinical descriptions refer to myoclonus, ES and generalized seizures [4]. Epilepsy is more frequently reported in DHPR deficiency than in other biopterin deficiencies. In the International Register, EEG before 1 year of age is normal in 38% of DHPR deficient patients, and 46% have hypsarrhythmia, sharp waves or epileptic discharges [5]. Neuroimaging may show brain atrophy, leucodystrophy and intracranial calcifications. Treatment of the metabolic disorder includes control of Phe accumulation with low-Phe diet or oral BH4 (this is rarely effective in DHPR deficiency) [6-9]. Folinic acid is necessary in DHPR deficiency because gradual deficiency of folate within the central nervous system may occur. Neurotransmitter homeostasis is restored by oral administration of amine precursors L-Dopa (associated with an inhibitor of peripheral aromatic amino-acid decarboxylase) and 5-hydroxytryptophan (5HT). Some authors use monoamine oxidase inhibitors [7]. The clinical outcome of patients undergoing this treatment is variable and often disappointing, even if therapy is started early. In some cases, the treatment was given late, with some improvement of the neurological condition. A partial effect on epilepsy is reported [5, 10].
To date, there is no report of the efficacy of steroids in ES associated with inherited metabolic disorders. We describe the features of WS in a child with DHPR deficiency and where hydrocortisone was used to effectively control the ES.
Article spécial
Selection criteria and preoperative investigation of patients with focal epilepsy who lack a localized structural lesion
M. Duchowny, P. Jayakar, S. Koh
the need to localize the primary area of epileptogenesis, surgery protocols are being developed which rely on clinical semiology, EEG and functional imaging data. In selected cases, intracranial EEG monitoring may be required. While testing more often depends on the convergence of modalities, it is possible to localize seizure origin in the majority of children, and fully excise the epileptogenic region. This review presents the etiology and preoperative modalities available for children with intractable, non-lesional epilepsy.The presence of gross structural lesions greatly facilitates the preoperative evaluation of intractable seizures. While a structural lesion may not prove seizure origin, it nonetheless implicates one brain region as the source of seizure origin, and may add additional information about its underlying substrate. Furthermore, a lesion may lie adjacent to eloquent cortex, signaling that complete removal of the epileptogenic zone may be difficult or impossible. The occurrence of multiple lesions is indicative of a more diffuse process, and preoperative studies must select the primary epileptogenic abnormality and estimate potential seizure activation at other sites. Children referred for epilepsy surgery often have normal or non-specific imaging findings. These "intractable non-lesional" epilepsy (INLE) patients are extremely challenging as they typically present with severe epilepsy, and are as prone to deterioration as lesional cases. In response to the lack of structural imaging data, surgery protocols have been developed that rely on clinical semiology, EEG and functional imaging data to define the epileptogenic zone.
Compte-rendu de cas
Infantile spasms and Menkes disease
I. Sfaello, P. Castelnau, N. Blanc, H. Ogier, Ph. Evrard, A. Arzimanoglou
of infantile spasms in two patients with Menkes disease and the relation with subcutaneous administration of copper-histidine.Menkes disease is an X-linked disorder with a primary defect in copper transport resulting in growth failure, bone lesions, elongation and tortuosity of cerebral arteries, lack of keratinisation and pigmentation of hair, temperature instability, seizures and multifocal degenerative disease in early childhood [1-3].
The Menkes disease gene (MNK) was recently cloned [4, 5]. Evidence revealed that the gene encodes a highly conserved copper transporting adenosine triphosphatase (ATPase) which disturbs intracellular copper homeostasis and the functioning of copper-requiring enzymes such as cytochrome c oxidase, superoxidase dimutase, lysyl hydroxylase and dopamine b hydroxylase [6].
Biochemically, the disease is characterised by low serum, liver and brain copper levels, whereas the copper content in nearly all other organs is increased [7, 8].
Epileptic seizures are frequently associated with Menkes disease, but details of type of seizures and EEG patterns are rarely reported. We evaluated the evolution of infantile spasms in two patients with Menkes disease and the relation with copper-histidine treatment.
Lettre de l'éditeur
Spitting automatism
Ph. Kahane, L. Minotti
In a recent article, Ozkara et al. have suggested that spitting automatism could be a localizing sign to the nondominant temporal lobe [1].
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