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Dernières publications d'Alexis ARZIMANOGLOU
Epilepsy Res 2003;53(3)
Topiramate: efficacy and tolerability in children according to epilepsy syndromes.
Mikaeloff Y, Saint-Martin A, Mancini J, Peudenier S, Pedespan JM, Vallée L, Motte J, Bourgeois M, Arzimanoglou A, Dulac O, Chiron C
Neuropediatric Department, Cochin-Saint-Vincent de Paul University Hospital, 82 Bd Denfert-Rochereau, 75014, Paris, France
To evaluate the efficacy and tolerability of topiramate (TPM) as add-on therapy in children less than 12 years of age with refractory epilepsy, according to epilepsy syndromes, we conducted an open, prospective, pragmatic and multicenter study in France. Efficacy was assessed, especially according to epilepsy syndromes, as well as tolerability. We included 207 children (41 of whom were less than 4 years of age). TPM was effective (responders with >50% decrease in seizure frequency) in 50% of 128 patients with partial epilepsy, and in 44% of 79 patients with generalized epilepsy. In case of generalized epilepsy, responders more frequently had generalized symptomatic epilepsy, severe myoclonic epilepsy and myoclono-astatic epilepsy, whereas response rate was mild in both infantile spasms and Lennox-Gastaut syndrome (LGS). Improvement was well maintained in all patients during the treatment period (median 5.6 months). Seizure frequency/severity increased (worsening) in 13% of patients with partial epilepsy and 17% with generalized epilepsy (particularly in those with infantile spasms), and resulted in withdrawal of TPM for 8%. The most frequently reported adverse events were moderate neurobehavioral and gastrointestinal disorders. Adverse events led to withdrawal of TPM from 13.5% of patients. Children less than 4 years of age had particularly good tolerability. Results confirm that TPM is effective and well tolerated in children under 12 years of age in a broad range of epilepsy syndromes, including refractory partial epilepsy, and symptomatic and myoclonic generalized epilepsy. Use of TPM should be considered in children under 4 years of age, and slow and progressive titration is important.
PMID: 12694931[PM]
Cancer Genet Cytogenet 2003;139(1)
Allelic imbalance in selected chromosomal regions in ovarian cancer.
Hansen LL, Jensen LL, Dimitrakakis C, Michalas S, Gilbert F, Barber HR, Overgaard J, Arzimanoglou II
Department of Human Genetics, The Bartholin Building, University of Aarhus, DK-8000 C, Aarhus, Denmark. lotte@humgen.au.dk
Ovarian cancer (OC) is often asymptomatic at the initial stage. When diagnosed, up to 75% of the patients present grade III or IV tumors with metastasis in nearby organs of the abdomen. Genetic imbalance is abundant in OC, and allelic loss (AL) of specific chromosomal regions is considered an early event. To establish association between genetic markers for early diagnosis/prognosis of OC, our target was to define narrow specific regions of AL. We analyzed 65 ovarian carcinomas by using 19 microsatellite markers located in three different chromosomes. First, a 7.6-Mb region containing the estrogen receptor (ESR1) and the tumor suppressor gene LATS1 was analyzed. Several chromosomal breakpoints flanking ESR1 affecting the region harboring LATS1 were found. Second, we found chromosomal breakpoints on 13q13.1 approximately q13.3 that defined two narrow regions flanking the BRCA2 locus. Third, our ovarian tumors exhibited a very high frequency of AL on 16q and chromosomal breakpoints defining two narrow regions within 16q22.2 approximately q24.3. In this article, we report three new polymorphic microsatellite markers and strong evidence of AL of narrow well-defined regions in hot spots on 6q, 13q, and 16q in ovarian tumors.
PMID: 12547149[PM]
Epileptic Disord 2003;4(3)
Treatment options in pediatric epilepsy syndromes.
Arzimanoglou A
Epilepsy Unit, Department of Child Neurology and Metabolic Disorders, Children's University Hôpital Robert-Debré, Paris, France. alexis.arzimanglou@rdb.ap-hop-pain.fr
Recent evidence suggests that various epilepsy syndromes respond differently to antiepileptic drugs. It follows that a more precise diagnosis, together with a better understanding of AED mechanisms of action, enables them to be used more specifically, and therefore more effectively. Patient characteristics including age of onset, seizure frequency, EEG data and the findings of imaging studies, provide diagnostic pointers which enable the physician to reach a syndrome diagnosis and to choose the most appropriate AED for the individual patient. Home videotapes of paroxysmal events are becoming increasingly available and are often of great assistance. Parents should be encouraged to record their children's attacks. Careful history-taking and correct interpretation of clinical data remain the cornerstones of accurate diagnosis and successful treatment. However, the specificity of antiepileptic drugs is relatively limited and often pharmacotherapy should start using an agent with a broad spectrum of activity appropriate for the primary seizure type. It is in fact common that several antiepileptic agents have similar or identical effectiveness for one particular form of epilepsy. Therefore, the eventual side effects and the greater or lesser difficulties in handling the drug play an essential role in the choice of a therapeutic agent. Polypharmacy should be avoided and surgery should be considered early for selected patients, particularly children, who fail to respond to an appropriate drug trial. Correct diagnosis and the first drug(s) used may have a crucial impact on the evolution of given epilepsy. One major emphasis in the management of epilepsy is on information that should be complete, adapted to the level of understanding, and objective, although given in a positive manner. The understanding and cooperation of children and their families is clearly decisive for the success of therapy, and this requires a confident relationship between the physician and the patient. Current knowledge, on antiepileptic drugs options in paediatric epilepsy syndromes, is discussed.
PMID: 12446225[PM]
Epileptic Disord 2003;4(3)
Epilepsy and neuroprotection: an illustrated review.
Arzimanoglou A, Hirsch E, Nehlig A, Castelnau P, Gressens P, Pereira de Vasconcelos A
Epilepsy Unit, Child Neurology and Metabolic Diseases Departmentand INSERM E9935, University Hospital Robert-Debré, Paris, France. alexis.arzimanoglou@rdb.ap-hop-paris.fr
Multiple types of insults, such as status epilepticus, hypoxia and trauma, may alter the central nervous system. Strategies to protect the brain against insults remain a very difficult and challenging problem. Damage to the central nervous system can be modulated via excessive excitatory and reduced inhibitory neurotransmission. In addition, increased sodium and calcium loading through impaired voltage-sensitive channels, as well as alterations in the acid-base balance can contribute to both excitotoxic and apoptotic cell death. Epilepsy treatment has always been related to neuroprotection, since it aims to reduce the duration or totally suppress seizures. Although the debate on the capacity of simple seizures to induce neuronal injury is still ongoing, no doubt persists on the disastrous effects of prolonged episodes of status. The next step would be to prevent epilepsy. Several animal models have been used to study the various aspects of the epileptogenic process. In humans, one of the most compelling examples of a series of epileptogenic events is temporal lobe epilepsy (TLE). Temporal lobe epilepsy is often attributed to prolonged febrile convulsions in childhood resulting in mesial temporal sclerosis. However, the relationship between TLE, seizures in childhood and hippocampal sclerosis may not be apparent as initially believed. Furthermore, it is well recognized that in a number of patients there is a delay from a specific insult to the onset of seizures. This "latent period" could be an opportunity for effective intervention, provided that the underlying mechanisms are understood and that appropriate means for a beneficial modification of the disease process become available. The present review discusses the various steps of temporal lobe epilepsy and provides illustrations of the various mechanisms implicated in neuronal death. Data from animal models is also presented and illustrated with video sequences. Finally, on the basis of what is known on mechanisms of action of available antiepileptic drugs, some suggestions are put forward. Basic science and research are guided by clinical queries and from ongoing dialogue. The present illustrated review deals with only a small part of the important amount of work related to epilepsy and neuroprotection. As such it is necessarily schematic or even simplistic. The review is designed to inform clinicians about the basic issues related to the subject, thus allowing them to follow the ongoing debate and participate with pertinent questions. (Published with video sequences).
PMID: 12446219[PM]
Epileptic Disord 2003;4 Suppl 2
Recent developments in treatment of status epilepticus: a review.
Rosenow F, Arzimanoglou A, Baulac M
Interdiciplinary Epilepsy Center Marburg-Dept of Neurology, Philipps-University Marburg, Germany. rosenow@post.med.uni-marburg.de
Considering that status epilepticus (SE) is a medical emergency associated with significant morbidity and mortality, there are surprisingly few evidence-based data to guide management decisions. The purpose of this review is to give an overview of the incidence and classification of SE and to summarise the recent developments in the treatment of generalized tonic clonic status epilepticus (GTCSE). These consist in two prospective randomised studies indicating that SE should be treated as soon as possible, even out-of hospital, by intravenous (IV) benzodiazepine. Lorazepam is probably the best choice for the initial therapy. However, the differences in efficacy as compared to diazepam, diazepam associated to phenytoin or phenobarbital were not significant. There is no Class I evidence to help us choose which drug to give in SE that is not responsive to the initial lorazepam. Traditionally, based on a long clinical experience, IV phenytoin is given as the second drug. Recently, phenytoin is being increasingly substituted by fosphenytoin, even though no formal, comparative tolerability studies have been performed to study this compound in GTCSE. Starting in the 1980's, the use of injectable valproic acid (IV VPA) has been reported in an increasing number of uncontrolled case series initiated by doctors, indicating relative easy use, relative good tolerability and suggesting that it may be efficacious. Finally, we have very little data concerning the treatment of SE refractory to a benzodiazepine and phenytoin. Despite this lack of data many centres today use midazolam or propofol rather than phenobarbital or pentobarbital in this setting because these compounds have short half-lives and are, therefore, easier to handle.
PMID: 12424083[PM]
Epileptic Disord 2003;4 Suppl 2
Rationale for treating epilepsy in children.
Guerrini R, Arzimanoglou A, Brouwer O
Neurosciences Unit, Great Ormond Street Hospital for Children and Institute of Child Health, The Wolfson Centre, Mecklenburgh Square, London, WC1N 2AP, UK.
Growing evidence indicates that the effects of antiepileptic drugs on childhood epilepsies are partly linked to the specific type of epilepsy or epilepsy syndrome. Most (but not all) types of epilepsy can be classified into categories that are conceptually meaningful. It is likewise logical to set treatment targets and to estimate the risks according to the main syndromic groups, as they share common, electroclinical presentations and long-term prognosis. Treatment should then be adjusted to each patient's clinical characteristics. Treatment should be started soon, whenever there is indication that delay would harm the child. However, if seizures are not disabling, treatment may be delayed, in order to acquire more knowledge about the spontaneous expression of the disorder and the plan thoughtfully explained to the parents. In children presenting with partial symptomatic or cryptogenic epilepsy, it is important to assess the patient's response to several different drugs. However, in patients regarded as having refractory epilepsy, possibilities for a surgical solution must be evaluated early in the course of the disease. In severe epileptic encephalopathies, complete seizure control is impossible and, ideally, treatment should provide as much integration and autonomy, with alleviation of frequent seizures. Again, this should be carefully explained to the parents. In children with severe epileptiform EEG abnormalities coexisting with brain dysfunction (diffuse or specific), the extent of EEG-related neurological dysfunction should be determined, and vigorous treatment should be started to abate its effects. Finally, seizures could be worsened by inappropriate drugs, paradoxical reaction or intoxication. Severe childhood epilepsies are particularly at risk and mild idiopathic epilepsies may be transformed into severe disorders, priming a vicious circle of heavy treatment, whereby the original disorder is no longer recognizable.
PMID: 12424080[PM]
Epilepsy Res 2002;49(2)
Evaluation of the positional candidate gene CHRNA7 at the juvenile myoclonic epilepsy locus (EJM2) on chromosome 15q13-14.
Taske NL, Williamson MP, Makoff A, Bate L, Curtis D, Kerr M, Kjeldsen MJ, Pang KA, Sundqvist A, Friis ML, Chadwick D, Richens A, Covanis A, Santos M, Arzimanoglou A, Panayiotopoulos CP, Whitehouse WP, Rees M, Gardiner RM
Department of Paediatrics and Child Health, Royal Free and University College Medical School, University College London, Gower Street Campus, 5 University Street, London WC1E 6JJ, UK. n.taske@ucl.ac.uk
A previous study of 34 nuclear pedigrees segregating juvenile myoclonic epilepsy (JME) gave significant evidence of linkage with heterogeneity to marker loci on chromosome 15q13-14 close to the candidate gene CHRNA7 (Hum. Mol. Genet. 6 (1997) 1329). The aim of this work was to further evaluate the putative aetiological role of CHRNA7 in JME within the 34 families originally described, and to assess the contribution of this locus to a broader phenotype of idiopathic generalised epilepsy (IGE). Multipoint linkage analysis and intrafamilial association studies were performed with microsatellite markers that encompass both CHRNA7 and its partial duplication (CHRFAM7A). A maximum HLOD of 3.45 [alpha=0.58; (Zall=2.88, P=0.0008)] was observed 8 cM distal to D15S1360, a CHRNA7 intragenic marker. Significant exclusion lod scores were obtained across the region in 12 mixed phenotype JME/IGE families. Mutation screening of the CHRNA7 gene (and consequently exons 5-10 of CHRFAM7A) and its putative promoter sequence identified a total of 13 sequence variants across 23 of 34 JME-affected families. Two variants (c.1354G>A and c.1466C>T) are predicted to result in amino acid changes and one (IVS9+5G>A) is predicted to result in aberrant transcript splicing. However, none of the variants alone appeared either necessary or sufficient to cause JME in the families in which they occurred. In conclusion, linkage analyses continue to support the existence of a locus on chromosome 15q13-14 that confers susceptibility to JME but not to a broader IGE phenotype. Causal sequence variants in the positional candidate CHRNA7 have not been identified but the presence of multiple segmental duplications in this region raises the possibility of undetected disease-causing genomic rearrangements.
PMID: 12049804[PM]
J Sleep Res 2002;11(2)
Heart rate variability during sleep in children with partial epilepsy.
Ferri R, Curzi-Dascalova L, Arzimanoglou A, Bourgeois M, Beaud C, Nunes ML, Elia M, Musumeci SA, Tripodi M
Sleep Research Center, Department of Neurology, Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Troina, Italy. rferri@oasi.en.it
Alterations in autonomic control of cardiac activity in epileptic patients have been reported by several studies in the past, and both ictal and interictal modifications of heart rate regulation have been described. Alterations of autonomic control of cardiac activity can play an important role in sudden unexplained death in patients with epilepsy (SUDEP). However, the presence of specific changes in heart rate variability (HRV) during sleep, not correlated with seizures, has not been assessed in children with epilepsy; for this reason, we evaluated features of cardiac autonomic function during sleep without ictal epileptiform electroencephalogram (EEG) activity in a group of children with partial epilepsy. Eleven patients (five males and six females; mean age 11.5 years, SD: 3.65 years) affected by partial epilepsy were admitted to this study; 11 normal subjects (five males and six females; mean age 12.9 years, SD: 2.72 years) served as a control group. All subjects slept in the laboratory for two consecutive nights. The data were analyzed during the second night. Sleep was polygraphically recorded [including one electrocardiography (ECG) channel] and signals were digitally stored. A series of 5-min ECG epochs were chosen from each sleep stage, during periods without evident ictal epileptiform activity in the EEG. Electrocardiography signals were analyzed for automatic detection of R-waves and, subsequently, a series of time- and frequency-domain measures were calculated. Epileptic subjects tended to show an overall lower HRV in both time- and frequency-domain parameters, principally during rapid eye movement (REM) sleep and, to a lesser extent, during sleep stage 2. Among the different bands, this decrease was most evident for the high-frequency band (HF) absolute power. For this reason, the ratio between the low-frequency band (LF) and HF was always higher in epileptic patients than in normal controls and the difference was statistically significant during sleep stages 3 and/or 4 and REM sleep. Our results indicate that during sleep, a particular condition of basal modification in autonomic characteristics occurs (mostly during REM sleep) in partial epilepsy patients. This finding might represent an important factor contributing to the complex mechanism of SUDEP which takes place most often during sleep and supports the need of studying HRV specifically during this state in subjects with seizures.
PMID: 12028480[PM]
Anticancer Res 2002;22(2A)
Frequent LOH at hMLH1, a highly variable SNP in hMSH3, and negligible coding instability in ovarian cancer.
Arzimanoglou II, Hansen LL, Chong D, Li Z, Psaroudi MC, Dimitrakakis C, Jacovina AT, Shevchuk M, Reid L, Hajjar KA, Vassilaros S, Michalas S, Gilbert F, Chervenak FA, Barber HR
Department of Obstetrics-Gynecology, Weill Medical College of Cornell University, New York, NY 10021, USA. Arziman@lycosmail.com
BACKGROUND: Molecular alterations such as DNA microsatellite instability (MSI/RER), single nucleotide polymorphism (SNP) and loss of heterozygosity (LOH) can occur throughout the genome and be associated with different types of cancer. In the present study, we aimed at detecting molecular alterations within the mismatch DNA repair genes in ovarian cancer (OC), using a sensitive, accurate and reliable protocol we have developed. MATERIALS AND METHODS: A combination of high-resolution GeneScan software analysis and automated DNA cycle sequencing was used. RESULTS: Negligible coding MSI was observed in selected sequences of mismatch DNA repair genes in our series of sixty-two ovarian tumors and matched blood DNAs. Unlike MSI, loss of one hMLH1 allele was scored in almost half (47%) of the informative cases. In addition, an SNP in hMSH3/intron 5 was found to be highly variable in OC patients. CONCLUSION: 1) Coding DNA instability is likely to be a very rare event in OC and, therefore, may not significantly contribute to the development of OC, and 2) the high frequency of LOH at hMLH1 observed in our ovarian tumors suggests that further investigation is needed to determine if such a trend exists in other mismatch DNA repair and/or critical genes.
PMID: 12014680[PM]
Epileptic Disord 2002;3(4)
Semiology of typical and atypical Rolandic epilepsy: a video-EEG analysis.
Saint-Martin AD, Carcangiu R, Arzimanoglou A, Massa R, Thomas P, Motte J, Marescaux C, Metz-Lutz MN, Hirsch E
Service de Pédiatrie 1, Hôpital de Hautepierre, 67098 Strasbourg Cedex, France. anne.desaintmartin@chru-strasbourg.fr
Since the first descriptions of Rolandic Epilepsy or benign epilepsy with centrotemporal spikes (BECTS), typical and atypical forms have been reported. Indeed, classical focal seizures are sometimes associated with various atypical ictal symptoms and cognitive or behavioural disorders. In an effort to define early clinical and EEG criteria allowing early distinction between typical and atypical forms, we recently conducted a prospective study in a cohort of children with Rolandic Epilepsy. The results of this study have been reported elsewhere. We now discuss the semiological characteristics, and comment on the video-EEG data collected during this study. Symptoms were classified into three major categories: "classical focal seizures"; "spike and wave related symptoms"; and "paraictal symptoms". Classical focal seizures constitute the electroclinical expression of the development and the propagation of a focal cortical neuronal discharge. "Spike and wave related symptoms" are brief neurological or neuropsychological phenomena having a relatively strict temporal relation with individual components of isolated focal or generalized spikes and waves. "Paraictal symptoms" consist of acquired progressive and fluctuating motor or cognitive deficits and are not directly correlated with Todd paralysis. We present detailed video-EEG material of selected cases and discuss the usefulness of such distinctions in terminology. We suggest that variability in clinical expression probably reflects the implication of different pathophysiological mechanisms, which in turn could explain differences in sensitivity to treatment. (Published with videosequences.)
PMID: 11844712[PM]
J Surg Res 2001;99(2)
Can expression of apoptosis genes, bcl-2 and bax, predict survival and responsiveness to chemotherapy in node-negative breast cancer patients?
Kymionis GD, Dimitrakakis CE, Konstadoulakis MM, Arzimanoglou I, Leandros E, Chalkiadakis G, Keramopoulos A, Michalas S
Laboratory of Surgical Research, Hippokratio Hospital, Athens, Greece. kymionis@med.uoc.gr
BACKGROUND: Although the status of the axillary lymph nodes is widely accepted to be associated with prognosis in breast cancer patients, there is a need for biomarkers to be analyzed as indicators of responsiveness to treatment. The objective of this study was to test the hypothesis that the expression of apoptosis genes, bcl-2 and bax, predicts survival and responsiveness to chemotherapy in node-negative breast cancer patients. METHODS: One hundred thirty premenopausal women with primary breast carcinoma were studied for the expression of bcl-2 and bax genes. The relationship between the expression of bcl-2 and bax proteins and a series of markers of known prognostic value [such as tumor size, nuclear grade, receptors of the steroid hormones estrogen (ER) and progesterone (PgR)].The association of these proteins with survival and responsiveness to chemotherapy was also examined. RESULTS: Sixty (46%) and sixty-four (49%) breast cancer cases were found positive for bcl-2 and bax, respectively, as indicated by immunohistochemistry. A statistically significant association was found between expression of bcl-2 and tumor size (P = 0.001), low grade (grade I) (P = 0.002), positivity of ER (P = 0.001), positivity of PR (P = 0.03), and superior disease-free survival (DFS) (P = 0.04), and superior overall survival (OS) (P = 0.03). In contrast, no similar associations were observed for the bax gene. Overall, there was a trend toward an association between adjuvant chemotherapy and DFS (P = 0.08) and OS (P = 0.07). This trend became statistically significant when the patients were analyzed by individual gene expression. In bax-positive patients, chemotherapy improves 6-year DFS (P = 0.01) and OS (P = 0.03) while similar effects were not observed in the other subgroups of patients. CONCLUSION: Our results indicated that bcl-2 expression is associated with a number of favorable prognostic factors and better clinical outcome, while bax expression seems to have positive predictive value for responsiveness to chemotherapy in lymph node-negative breast cancer patients.
PMID: 11469882[PM]
Epilepsy Res 2001;46(2)
Polymorphism analysis of JRK/JH8, the human homologue of mouse jerky, and description of a rare mutation in a case of CAE evolving to JME.
Moore T, Hecquet S, McLellann A, Ville D, Grid D, Picard F, Moulard B, Asherson P, Makoff AJ, McCormick D, Nashef L, Froguel P, Arzimanoglou A, LeGuern E, Bailleul B
Department of Biochemistry, University College Cork, Lee Maltings, Prospect Row, Cork, Ireland. t.moore@ucc.ie
Disruption of the function of the mouse jerky gene by transgene insertion causes generalized recurrent seizures reminiscent of human idiopathic generalized epilepsy (IGE). A human homologue, JRK/JH8, has been cloned, which maps to 8q24, a chromosomal region associated with several forms of IGE. JRK/JH8 is, therefore, a candidate locus for at least some forms of IGE. We report corrected cDNA sequences and extended open reading frames for the mouse jerky and human JRK/JH8 genes, which add 48 amino acids to the N-terminus of the Jerky protein and which extends the region of homology with the N-terminal DNA-binding domain of the centromere-binding protein, CENP-B. Systematic sequencing of the coding region of the extended JRK/JH8 gene identified single nucleotide polymorphisms that define three haplotypes, which were used for association studies in patients with idiopathic generalized epilepsy. We report one subject with childhood absence epilepsy (CAE) that evolved to juvenile myoclonic epilepsy (JME) that has a unique de novo mutation that results in a non-conservative amino acid change at a potential protein glycosylation site. Familial analysis supports a causal role for this mutation in the disease.
PMID: 11463517[PM]
Rev Neurol (Paris) 2001;157(5)
[Optimal use of lamotrigine in clinical practice: results of an open multicenter trial in refractory epilepsy]
Arzimanoglou A, Kulak I, Bidaut-Mazel C, Baldy-Moulinier M
Service de Neurologie Pédiatrique et des Maladies Métaboliques, Hôpital Robert Debré, Paris. alexis.arzimanoglou@rdb.ap-hop-paris.fr
The study was designed to evaluate optimal use of add-on lamotrigine in the treatment of children and adults with refractory epilepsy of any type. Because of the available evidence from controlled studies, indicating the large spectrum of action of lamotrigine, we designed this prospective study to investigate the efficacy and safety of lamotrigine in everyday clinical practice, to collect useful information on its action in specific epilepsy syndromes and on the clinical results of specific co-medications. We studied 566 patients with a diagnosis of refractory epilepsy of any type currently receiving stable conventional regimens of antiepileptic therapy. Efficacy analysis was limited to 510 patients (388 patients aged 12 years or more, 122 patients aged 2 to 12 years) for which the exact number of seizures could be evaluated. Seizure characteristics were: simple and/or complex partial seizures in 298 (58p. cent) patients, partial seizures with secondary generalisation in 85 (17p. cent), generalised seizures of any type in 226 (44 percent). Syndromic diagnosis was partial symptomatic or cryptogenic epilepsy in 302 patients (59 percent), generalised symptomatic or cryptogenic epilepsy in 116 (23 percent) and idiopathic generalised epilepsy in 50 (10 percent). The percentage of patients who achieved at least 50 percent reduction in the frequency of seizures was evaluated around 40p. cent for all epilepsy categories, and up to 61 percent in idiopathic generalised epilepsies. Response to treatment with lamotrigine was usually obtained by the end of titration (4 weeks) and remained stable at 48 weeks. Thirty-three patients (7 percent) remained seizure-free at 48 weeks. In the group of patients with partial epilepsy, 19p. cent presented a more than 75 percent reduction in seizure frequency. A more than 50 percent reduction in secondary generalisation of partial seizures was observed in 45 percent of the patients. Efficacy results were similar in both the adult and paediatric age groups. They were better for patients receiving valproate co-medication (45 percent of the responders) as compared to other co-medications (37 percent of the responders), suggesting a synergistic action. Safety has been evaluated for all the patients having received lamotrigine (n=566). The incidence of adverse events attributed to lamotrigine was similar to the results of controlled studies, with somnolence reported in 10p. cent, a cutaneous reaction in 8 percent and episodes of transitory diplopia in 8 percent. A cutaneous reaction was more frequent in patients receiving carbamazepine (10 percent) as compared to valproate comedication (5 percent). However, the adverse event was sufficiently serious to necessitate hospitalisation in 3 patients receiving valproate. Dose escalation was not respected in two. Rash was reversible in all of the patients following discontinuation of the drug. The results of this study contribute to the overall understanding of the spectrum of lamotrigine effectiveness across seizure types and epileptic syndromes. Lamotrigine was well tolerated in children and adults.
PMID: 11438772[PM]
Topiramate: efficacy and tolerability in children according to epilepsy syndromes.
Mikaeloff Y, Saint-Martin A, Mancini J, Peudenier S, Pedespan JM, Vallée L, Motte J, Bourgeois M, Arzimanoglou A, Dulac O, Chiron C
Neuropediatric Department, Cochin-Saint-Vincent de Paul University Hospital, 82 Bd Denfert-Rochereau, 75014, Paris, France
To evaluate the efficacy and tolerability of topiramate (TPM) as add-on therapy in children less than 12 years of age with refractory epilepsy, according to epilepsy syndromes, we conducted an open, prospective, pragmatic and multicenter study in France. Efficacy was assessed, especially according to epilepsy syndromes, as well as tolerability. We included 207 children (41 of whom were less than 4 years of age). TPM was effective (responders with >50% decrease in seizure frequency) in 50% of 128 patients with partial epilepsy, and in 44% of 79 patients with generalized epilepsy. In case of generalized epilepsy, responders more frequently had generalized symptomatic epilepsy, severe myoclonic epilepsy and myoclono-astatic epilepsy, whereas response rate was mild in both infantile spasms and Lennox-Gastaut syndrome (LGS). Improvement was well maintained in all patients during the treatment period (median 5.6 months). Seizure frequency/severity increased (worsening) in 13% of patients with partial epilepsy and 17% with generalized epilepsy (particularly in those with infantile spasms), and resulted in withdrawal of TPM for 8%. The most frequently reported adverse events were moderate neurobehavioral and gastrointestinal disorders. Adverse events led to withdrawal of TPM from 13.5% of patients. Children less than 4 years of age had particularly good tolerability. Results confirm that TPM is effective and well tolerated in children under 12 years of age in a broad range of epilepsy syndromes, including refractory partial epilepsy, and symptomatic and myoclonic generalized epilepsy. Use of TPM should be considered in children under 4 years of age, and slow and progressive titration is important.
PMID: 12694931[PM]
Cancer Genet Cytogenet 2003;139(1)
Allelic imbalance in selected chromosomal regions in ovarian cancer.
Hansen LL, Jensen LL, Dimitrakakis C, Michalas S, Gilbert F, Barber HR, Overgaard J, Arzimanoglou II
Department of Human Genetics, The Bartholin Building, University of Aarhus, DK-8000 C, Aarhus, Denmark. lotte@humgen.au.dk
Ovarian cancer (OC) is often asymptomatic at the initial stage. When diagnosed, up to 75% of the patients present grade III or IV tumors with metastasis in nearby organs of the abdomen. Genetic imbalance is abundant in OC, and allelic loss (AL) of specific chromosomal regions is considered an early event. To establish association between genetic markers for early diagnosis/prognosis of OC, our target was to define narrow specific regions of AL. We analyzed 65 ovarian carcinomas by using 19 microsatellite markers located in three different chromosomes. First, a 7.6-Mb region containing the estrogen receptor (ESR1) and the tumor suppressor gene LATS1 was analyzed. Several chromosomal breakpoints flanking ESR1 affecting the region harboring LATS1 were found. Second, we found chromosomal breakpoints on 13q13.1 approximately q13.3 that defined two narrow regions flanking the BRCA2 locus. Third, our ovarian tumors exhibited a very high frequency of AL on 16q and chromosomal breakpoints defining two narrow regions within 16q22.2 approximately q24.3. In this article, we report three new polymorphic microsatellite markers and strong evidence of AL of narrow well-defined regions in hot spots on 6q, 13q, and 16q in ovarian tumors.
PMID: 12547149[PM]
Epileptic Disord 2003;4(3)
Treatment options in pediatric epilepsy syndromes.
Arzimanoglou A
Epilepsy Unit, Department of Child Neurology and Metabolic Disorders, Children's University Hôpital Robert-Debré, Paris, France. alexis.arzimanglou@rdb.ap-hop-pain.fr
Recent evidence suggests that various epilepsy syndromes respond differently to antiepileptic drugs. It follows that a more precise diagnosis, together with a better understanding of AED mechanisms of action, enables them to be used more specifically, and therefore more effectively. Patient characteristics including age of onset, seizure frequency, EEG data and the findings of imaging studies, provide diagnostic pointers which enable the physician to reach a syndrome diagnosis and to choose the most appropriate AED for the individual patient. Home videotapes of paroxysmal events are becoming increasingly available and are often of great assistance. Parents should be encouraged to record their children's attacks. Careful history-taking and correct interpretation of clinical data remain the cornerstones of accurate diagnosis and successful treatment. However, the specificity of antiepileptic drugs is relatively limited and often pharmacotherapy should start using an agent with a broad spectrum of activity appropriate for the primary seizure type. It is in fact common that several antiepileptic agents have similar or identical effectiveness for one particular form of epilepsy. Therefore, the eventual side effects and the greater or lesser difficulties in handling the drug play an essential role in the choice of a therapeutic agent. Polypharmacy should be avoided and surgery should be considered early for selected patients, particularly children, who fail to respond to an appropriate drug trial. Correct diagnosis and the first drug(s) used may have a crucial impact on the evolution of given epilepsy. One major emphasis in the management of epilepsy is on information that should be complete, adapted to the level of understanding, and objective, although given in a positive manner. The understanding and cooperation of children and their families is clearly decisive for the success of therapy, and this requires a confident relationship between the physician and the patient. Current knowledge, on antiepileptic drugs options in paediatric epilepsy syndromes, is discussed.
PMID: 12446225[PM]
Epileptic Disord 2003;4(3)
Epilepsy and neuroprotection: an illustrated review.
Arzimanoglou A, Hirsch E, Nehlig A, Castelnau P, Gressens P, Pereira de Vasconcelos A
Epilepsy Unit, Child Neurology and Metabolic Diseases Departmentand INSERM E9935, University Hospital Robert-Debré, Paris, France. alexis.arzimanoglou@rdb.ap-hop-paris.fr
Multiple types of insults, such as status epilepticus, hypoxia and trauma, may alter the central nervous system. Strategies to protect the brain against insults remain a very difficult and challenging problem. Damage to the central nervous system can be modulated via excessive excitatory and reduced inhibitory neurotransmission. In addition, increased sodium and calcium loading through impaired voltage-sensitive channels, as well as alterations in the acid-base balance can contribute to both excitotoxic and apoptotic cell death. Epilepsy treatment has always been related to neuroprotection, since it aims to reduce the duration or totally suppress seizures. Although the debate on the capacity of simple seizures to induce neuronal injury is still ongoing, no doubt persists on the disastrous effects of prolonged episodes of status. The next step would be to prevent epilepsy. Several animal models have been used to study the various aspects of the epileptogenic process. In humans, one of the most compelling examples of a series of epileptogenic events is temporal lobe epilepsy (TLE). Temporal lobe epilepsy is often attributed to prolonged febrile convulsions in childhood resulting in mesial temporal sclerosis. However, the relationship between TLE, seizures in childhood and hippocampal sclerosis may not be apparent as initially believed. Furthermore, it is well recognized that in a number of patients there is a delay from a specific insult to the onset of seizures. This "latent period" could be an opportunity for effective intervention, provided that the underlying mechanisms are understood and that appropriate means for a beneficial modification of the disease process become available. The present review discusses the various steps of temporal lobe epilepsy and provides illustrations of the various mechanisms implicated in neuronal death. Data from animal models is also presented and illustrated with video sequences. Finally, on the basis of what is known on mechanisms of action of available antiepileptic drugs, some suggestions are put forward. Basic science and research are guided by clinical queries and from ongoing dialogue. The present illustrated review deals with only a small part of the important amount of work related to epilepsy and neuroprotection. As such it is necessarily schematic or even simplistic. The review is designed to inform clinicians about the basic issues related to the subject, thus allowing them to follow the ongoing debate and participate with pertinent questions. (Published with video sequences).
PMID: 12446219[PM]
Epileptic Disord 2003;4 Suppl 2
Recent developments in treatment of status epilepticus: a review.
Rosenow F, Arzimanoglou A, Baulac M
Interdiciplinary Epilepsy Center Marburg-Dept of Neurology, Philipps-University Marburg, Germany. rosenow@post.med.uni-marburg.de
Considering that status epilepticus (SE) is a medical emergency associated with significant morbidity and mortality, there are surprisingly few evidence-based data to guide management decisions. The purpose of this review is to give an overview of the incidence and classification of SE and to summarise the recent developments in the treatment of generalized tonic clonic status epilepticus (GTCSE). These consist in two prospective randomised studies indicating that SE should be treated as soon as possible, even out-of hospital, by intravenous (IV) benzodiazepine. Lorazepam is probably the best choice for the initial therapy. However, the differences in efficacy as compared to diazepam, diazepam associated to phenytoin or phenobarbital were not significant. There is no Class I evidence to help us choose which drug to give in SE that is not responsive to the initial lorazepam. Traditionally, based on a long clinical experience, IV phenytoin is given as the second drug. Recently, phenytoin is being increasingly substituted by fosphenytoin, even though no formal, comparative tolerability studies have been performed to study this compound in GTCSE. Starting in the 1980's, the use of injectable valproic acid (IV VPA) has been reported in an increasing number of uncontrolled case series initiated by doctors, indicating relative easy use, relative good tolerability and suggesting that it may be efficacious. Finally, we have very little data concerning the treatment of SE refractory to a benzodiazepine and phenytoin. Despite this lack of data many centres today use midazolam or propofol rather than phenobarbital or pentobarbital in this setting because these compounds have short half-lives and are, therefore, easier to handle.
PMID: 12424083[PM]
Epileptic Disord 2003;4 Suppl 2
Rationale for treating epilepsy in children.
Guerrini R, Arzimanoglou A, Brouwer O
Neurosciences Unit, Great Ormond Street Hospital for Children and Institute of Child Health, The Wolfson Centre, Mecklenburgh Square, London, WC1N 2AP, UK.
Growing evidence indicates that the effects of antiepileptic drugs on childhood epilepsies are partly linked to the specific type of epilepsy or epilepsy syndrome. Most (but not all) types of epilepsy can be classified into categories that are conceptually meaningful. It is likewise logical to set treatment targets and to estimate the risks according to the main syndromic groups, as they share common, electroclinical presentations and long-term prognosis. Treatment should then be adjusted to each patient's clinical characteristics. Treatment should be started soon, whenever there is indication that delay would harm the child. However, if seizures are not disabling, treatment may be delayed, in order to acquire more knowledge about the spontaneous expression of the disorder and the plan thoughtfully explained to the parents. In children presenting with partial symptomatic or cryptogenic epilepsy, it is important to assess the patient's response to several different drugs. However, in patients regarded as having refractory epilepsy, possibilities for a surgical solution must be evaluated early in the course of the disease. In severe epileptic encephalopathies, complete seizure control is impossible and, ideally, treatment should provide as much integration and autonomy, with alleviation of frequent seizures. Again, this should be carefully explained to the parents. In children with severe epileptiform EEG abnormalities coexisting with brain dysfunction (diffuse or specific), the extent of EEG-related neurological dysfunction should be determined, and vigorous treatment should be started to abate its effects. Finally, seizures could be worsened by inappropriate drugs, paradoxical reaction or intoxication. Severe childhood epilepsies are particularly at risk and mild idiopathic epilepsies may be transformed into severe disorders, priming a vicious circle of heavy treatment, whereby the original disorder is no longer recognizable.
PMID: 12424080[PM]
Epilepsy Res 2002;49(2)
Evaluation of the positional candidate gene CHRNA7 at the juvenile myoclonic epilepsy locus (EJM2) on chromosome 15q13-14.
Taske NL, Williamson MP, Makoff A, Bate L, Curtis D, Kerr M, Kjeldsen MJ, Pang KA, Sundqvist A, Friis ML, Chadwick D, Richens A, Covanis A, Santos M, Arzimanoglou A, Panayiotopoulos CP, Whitehouse WP, Rees M, Gardiner RM
Department of Paediatrics and Child Health, Royal Free and University College Medical School, University College London, Gower Street Campus, 5 University Street, London WC1E 6JJ, UK. n.taske@ucl.ac.uk
A previous study of 34 nuclear pedigrees segregating juvenile myoclonic epilepsy (JME) gave significant evidence of linkage with heterogeneity to marker loci on chromosome 15q13-14 close to the candidate gene CHRNA7 (Hum. Mol. Genet. 6 (1997) 1329). The aim of this work was to further evaluate the putative aetiological role of CHRNA7 in JME within the 34 families originally described, and to assess the contribution of this locus to a broader phenotype of idiopathic generalised epilepsy (IGE). Multipoint linkage analysis and intrafamilial association studies were performed with microsatellite markers that encompass both CHRNA7 and its partial duplication (CHRFAM7A). A maximum HLOD of 3.45 [alpha=0.58; (Zall=2.88, P=0.0008)] was observed 8 cM distal to D15S1360, a CHRNA7 intragenic marker. Significant exclusion lod scores were obtained across the region in 12 mixed phenotype JME/IGE families. Mutation screening of the CHRNA7 gene (and consequently exons 5-10 of CHRFAM7A) and its putative promoter sequence identified a total of 13 sequence variants across 23 of 34 JME-affected families. Two variants (c.1354G>A and c.1466C>T) are predicted to result in amino acid changes and one (IVS9+5G>A) is predicted to result in aberrant transcript splicing. However, none of the variants alone appeared either necessary or sufficient to cause JME in the families in which they occurred. In conclusion, linkage analyses continue to support the existence of a locus on chromosome 15q13-14 that confers susceptibility to JME but not to a broader IGE phenotype. Causal sequence variants in the positional candidate CHRNA7 have not been identified but the presence of multiple segmental duplications in this region raises the possibility of undetected disease-causing genomic rearrangements.
PMID: 12049804[PM]
J Sleep Res 2002;11(2)
Heart rate variability during sleep in children with partial epilepsy.
Ferri R, Curzi-Dascalova L, Arzimanoglou A, Bourgeois M, Beaud C, Nunes ML, Elia M, Musumeci SA, Tripodi M
Sleep Research Center, Department of Neurology, Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Troina, Italy. rferri@oasi.en.it
Alterations in autonomic control of cardiac activity in epileptic patients have been reported by several studies in the past, and both ictal and interictal modifications of heart rate regulation have been described. Alterations of autonomic control of cardiac activity can play an important role in sudden unexplained death in patients with epilepsy (SUDEP). However, the presence of specific changes in heart rate variability (HRV) during sleep, not correlated with seizures, has not been assessed in children with epilepsy; for this reason, we evaluated features of cardiac autonomic function during sleep without ictal epileptiform electroencephalogram (EEG) activity in a group of children with partial epilepsy. Eleven patients (five males and six females; mean age 11.5 years, SD: 3.65 years) affected by partial epilepsy were admitted to this study; 11 normal subjects (five males and six females; mean age 12.9 years, SD: 2.72 years) served as a control group. All subjects slept in the laboratory for two consecutive nights. The data were analyzed during the second night. Sleep was polygraphically recorded [including one electrocardiography (ECG) channel] and signals were digitally stored. A series of 5-min ECG epochs were chosen from each sleep stage, during periods without evident ictal epileptiform activity in the EEG. Electrocardiography signals were analyzed for automatic detection of R-waves and, subsequently, a series of time- and frequency-domain measures were calculated. Epileptic subjects tended to show an overall lower HRV in both time- and frequency-domain parameters, principally during rapid eye movement (REM) sleep and, to a lesser extent, during sleep stage 2. Among the different bands, this decrease was most evident for the high-frequency band (HF) absolute power. For this reason, the ratio between the low-frequency band (LF) and HF was always higher in epileptic patients than in normal controls and the difference was statistically significant during sleep stages 3 and/or 4 and REM sleep. Our results indicate that during sleep, a particular condition of basal modification in autonomic characteristics occurs (mostly during REM sleep) in partial epilepsy patients. This finding might represent an important factor contributing to the complex mechanism of SUDEP which takes place most often during sleep and supports the need of studying HRV specifically during this state in subjects with seizures.
PMID: 12028480[PM]
Anticancer Res 2002;22(2A)
Frequent LOH at hMLH1, a highly variable SNP in hMSH3, and negligible coding instability in ovarian cancer.
Arzimanoglou II, Hansen LL, Chong D, Li Z, Psaroudi MC, Dimitrakakis C, Jacovina AT, Shevchuk M, Reid L, Hajjar KA, Vassilaros S, Michalas S, Gilbert F, Chervenak FA, Barber HR
Department of Obstetrics-Gynecology, Weill Medical College of Cornell University, New York, NY 10021, USA. Arziman@lycosmail.com
BACKGROUND: Molecular alterations such as DNA microsatellite instability (MSI/RER), single nucleotide polymorphism (SNP) and loss of heterozygosity (LOH) can occur throughout the genome and be associated with different types of cancer. In the present study, we aimed at detecting molecular alterations within the mismatch DNA repair genes in ovarian cancer (OC), using a sensitive, accurate and reliable protocol we have developed. MATERIALS AND METHODS: A combination of high-resolution GeneScan software analysis and automated DNA cycle sequencing was used. RESULTS: Negligible coding MSI was observed in selected sequences of mismatch DNA repair genes in our series of sixty-two ovarian tumors and matched blood DNAs. Unlike MSI, loss of one hMLH1 allele was scored in almost half (47%) of the informative cases. In addition, an SNP in hMSH3/intron 5 was found to be highly variable in OC patients. CONCLUSION: 1) Coding DNA instability is likely to be a very rare event in OC and, therefore, may not significantly contribute to the development of OC, and 2) the high frequency of LOH at hMLH1 observed in our ovarian tumors suggests that further investigation is needed to determine if such a trend exists in other mismatch DNA repair and/or critical genes.
PMID: 12014680[PM]
Epileptic Disord 2002;3(4)
Semiology of typical and atypical Rolandic epilepsy: a video-EEG analysis.
Saint-Martin AD, Carcangiu R, Arzimanoglou A, Massa R, Thomas P, Motte J, Marescaux C, Metz-Lutz MN, Hirsch E
Service de Pédiatrie 1, Hôpital de Hautepierre, 67098 Strasbourg Cedex, France. anne.desaintmartin@chru-strasbourg.fr
Since the first descriptions of Rolandic Epilepsy or benign epilepsy with centrotemporal spikes (BECTS), typical and atypical forms have been reported. Indeed, classical focal seizures are sometimes associated with various atypical ictal symptoms and cognitive or behavioural disorders. In an effort to define early clinical and EEG criteria allowing early distinction between typical and atypical forms, we recently conducted a prospective study in a cohort of children with Rolandic Epilepsy. The results of this study have been reported elsewhere. We now discuss the semiological characteristics, and comment on the video-EEG data collected during this study. Symptoms were classified into three major categories: "classical focal seizures"; "spike and wave related symptoms"; and "paraictal symptoms". Classical focal seizures constitute the electroclinical expression of the development and the propagation of a focal cortical neuronal discharge. "Spike and wave related symptoms" are brief neurological or neuropsychological phenomena having a relatively strict temporal relation with individual components of isolated focal or generalized spikes and waves. "Paraictal symptoms" consist of acquired progressive and fluctuating motor or cognitive deficits and are not directly correlated with Todd paralysis. We present detailed video-EEG material of selected cases and discuss the usefulness of such distinctions in terminology. We suggest that variability in clinical expression probably reflects the implication of different pathophysiological mechanisms, which in turn could explain differences in sensitivity to treatment. (Published with videosequences.)
PMID: 11844712[PM]
J Surg Res 2001;99(2)
Can expression of apoptosis genes, bcl-2 and bax, predict survival and responsiveness to chemotherapy in node-negative breast cancer patients?
Kymionis GD, Dimitrakakis CE, Konstadoulakis MM, Arzimanoglou I, Leandros E, Chalkiadakis G, Keramopoulos A, Michalas S
Laboratory of Surgical Research, Hippokratio Hospital, Athens, Greece. kymionis@med.uoc.gr
BACKGROUND: Although the status of the axillary lymph nodes is widely accepted to be associated with prognosis in breast cancer patients, there is a need for biomarkers to be analyzed as indicators of responsiveness to treatment. The objective of this study was to test the hypothesis that the expression of apoptosis genes, bcl-2 and bax, predicts survival and responsiveness to chemotherapy in node-negative breast cancer patients. METHODS: One hundred thirty premenopausal women with primary breast carcinoma were studied for the expression of bcl-2 and bax genes. The relationship between the expression of bcl-2 and bax proteins and a series of markers of known prognostic value [such as tumor size, nuclear grade, receptors of the steroid hormones estrogen (ER) and progesterone (PgR)].The association of these proteins with survival and responsiveness to chemotherapy was also examined. RESULTS: Sixty (46%) and sixty-four (49%) breast cancer cases were found positive for bcl-2 and bax, respectively, as indicated by immunohistochemistry. A statistically significant association was found between expression of bcl-2 and tumor size (P = 0.001), low grade (grade I) (P = 0.002), positivity of ER (P = 0.001), positivity of PR (P = 0.03), and superior disease-free survival (DFS) (P = 0.04), and superior overall survival (OS) (P = 0.03). In contrast, no similar associations were observed for the bax gene. Overall, there was a trend toward an association between adjuvant chemotherapy and DFS (P = 0.08) and OS (P = 0.07). This trend became statistically significant when the patients were analyzed by individual gene expression. In bax-positive patients, chemotherapy improves 6-year DFS (P = 0.01) and OS (P = 0.03) while similar effects were not observed in the other subgroups of patients. CONCLUSION: Our results indicated that bcl-2 expression is associated with a number of favorable prognostic factors and better clinical outcome, while bax expression seems to have positive predictive value for responsiveness to chemotherapy in lymph node-negative breast cancer patients.
PMID: 11469882[PM]
Epilepsy Res 2001;46(2)
Polymorphism analysis of JRK/JH8, the human homologue of mouse jerky, and description of a rare mutation in a case of CAE evolving to JME.
Moore T, Hecquet S, McLellann A, Ville D, Grid D, Picard F, Moulard B, Asherson P, Makoff AJ, McCormick D, Nashef L, Froguel P, Arzimanoglou A, LeGuern E, Bailleul B
Department of Biochemistry, University College Cork, Lee Maltings, Prospect Row, Cork, Ireland. t.moore@ucc.ie
Disruption of the function of the mouse jerky gene by transgene insertion causes generalized recurrent seizures reminiscent of human idiopathic generalized epilepsy (IGE). A human homologue, JRK/JH8, has been cloned, which maps to 8q24, a chromosomal region associated with several forms of IGE. JRK/JH8 is, therefore, a candidate locus for at least some forms of IGE. We report corrected cDNA sequences and extended open reading frames for the mouse jerky and human JRK/JH8 genes, which add 48 amino acids to the N-terminus of the Jerky protein and which extends the region of homology with the N-terminal DNA-binding domain of the centromere-binding protein, CENP-B. Systematic sequencing of the coding region of the extended JRK/JH8 gene identified single nucleotide polymorphisms that define three haplotypes, which were used for association studies in patients with idiopathic generalized epilepsy. We report one subject with childhood absence epilepsy (CAE) that evolved to juvenile myoclonic epilepsy (JME) that has a unique de novo mutation that results in a non-conservative amino acid change at a potential protein glycosylation site. Familial analysis supports a causal role for this mutation in the disease.
PMID: 11463517[PM]
Rev Neurol (Paris) 2001;157(5)
[Optimal use of lamotrigine in clinical practice: results of an open multicenter trial in refractory epilepsy]
Arzimanoglou A, Kulak I, Bidaut-Mazel C, Baldy-Moulinier M
Service de Neurologie Pédiatrique et des Maladies Métaboliques, Hôpital Robert Debré, Paris. alexis.arzimanoglou@rdb.ap-hop-paris.fr
The study was designed to evaluate optimal use of add-on lamotrigine in the treatment of children and adults with refractory epilepsy of any type. Because of the available evidence from controlled studies, indicating the large spectrum of action of lamotrigine, we designed this prospective study to investigate the efficacy and safety of lamotrigine in everyday clinical practice, to collect useful information on its action in specific epilepsy syndromes and on the clinical results of specific co-medications. We studied 566 patients with a diagnosis of refractory epilepsy of any type currently receiving stable conventional regimens of antiepileptic therapy. Efficacy analysis was limited to 510 patients (388 patients aged 12 years or more, 122 patients aged 2 to 12 years) for which the exact number of seizures could be evaluated. Seizure characteristics were: simple and/or complex partial seizures in 298 (58p. cent) patients, partial seizures with secondary generalisation in 85 (17p. cent), generalised seizures of any type in 226 (44 percent). Syndromic diagnosis was partial symptomatic or cryptogenic epilepsy in 302 patients (59 percent), generalised symptomatic or cryptogenic epilepsy in 116 (23 percent) and idiopathic generalised epilepsy in 50 (10 percent). The percentage of patients who achieved at least 50 percent reduction in the frequency of seizures was evaluated around 40p. cent for all epilepsy categories, and up to 61 percent in idiopathic generalised epilepsies. Response to treatment with lamotrigine was usually obtained by the end of titration (4 weeks) and remained stable at 48 weeks. Thirty-three patients (7 percent) remained seizure-free at 48 weeks. In the group of patients with partial epilepsy, 19p. cent presented a more than 75 percent reduction in seizure frequency. A more than 50 percent reduction in secondary generalisation of partial seizures was observed in 45 percent of the patients. Efficacy results were similar in both the adult and paediatric age groups. They were better for patients receiving valproate co-medication (45 percent of the responders) as compared to other co-medications (37 percent of the responders), suggesting a synergistic action. Safety has been evaluated for all the patients having received lamotrigine (n=566). The incidence of adverse events attributed to lamotrigine was similar to the results of controlled studies, with somnolence reported in 10p. cent, a cutaneous reaction in 8 percent and episodes of transitory diplopia in 8 percent. A cutaneous reaction was more frequent in patients receiving carbamazepine (10 percent) as compared to valproate comedication (5 percent). However, the adverse event was sufficiently serious to necessitate hospitalisation in 3 patients receiving valproate. Dose escalation was not respected in two. Rash was reversible in all of the patients following discontinuation of the drug. The results of this study contribute to the overall understanding of the spectrum of lamotrigine effectiveness across seizure types and epileptic syndromes. Lamotrigine was well tolerated in children and adults.
PMID: 11438772[PM]
©2001 Ph. Evrard
Epileptic Disord 2001;2(4)
Infantile spasms and Menkes disease.
Sfaello I, Castelnau P, Blanc N, Ogier H, Evrard P, Arzimanoglou A
Service de Neurologie Pédiatrique et des Maladies Métaboliques, Hôpital Robert-Debré, 48, boulevard Sérurier, 75019 Paris, France. isfaello@wanadoo.fr
Epileptic seizures are a common feature in Menkes disease, an X-linked genetic disorder of copper metabolism. Details of type of seizures are rarely reported. We report the evolution of infantile spasms in two patients with Menkes disease and the relation with subcutaneous administration of copper-histidine.
PMID: 11174154[PM]
Neurology 2001;55(10)
Sturge-Weber syndrome: indications and results of surgery in 20 patients.
Arzimanoglou AA, Andermann F, Aicardi J, Sainte-Rose C, Beaulieu MA, Villemure JG, Olivier A, Rasmussen T
Service of Child Neurology and Metabolic Disorders, University Hospital Robert Debré, University Hospital Enfants Malades, Paris, France. alexis.arzimanoglou@rdb.ap-hop-paris.fr
OBJECTIVE: To discuss the indications and timing for resective surgery in patients with Sturge-Weber syndrome (SWS) and medication-resistant epilepsy. BACKGROUND: SWS that causes epilepsy severe enough to merit surgery is rare. Because of the variable natural history of the disease, it is difficult to establish clear-cut indications for surgery and prospective studies are not feasible. Attitudes of clinicians and surgeons remain variable. METHODS: The authors assessed the presurgical epilepsy profile, criteria for surgery, monitoring techniques, and the postoperative outcome of epilepsy in all patients with SWS consecutively admitted between 1972 and 1990 to two referral centers (Paris and Montreal) and underwent surgery for intractable seizures. RESULTS: All 20 patients had a minimal postoperative follow-up of 4 years and all but one are still followed by one of the authors. One patient had a callosotomy, five underwent hemispherectomy, and 14 had cortical resection. Despite variability in the age at onset of seizures (range: 2 months to 12 years), age at operation (range: 8 months to 34 years) and surgical methods, almost all patients benefited from surgery. Visually guided complete resection of the pial angioma and underlying cortex, whenever possible, seemed sufficient; results were no better with intraoperative corticography. In children with previous hemiparesis, hemispherectomy proved particularly effective: all five became seizure free. None of the patients showed any aggravation of cognitive impairment following surgery; none of those who were operated on early presented with severe mental retardation, and 13 of 20 became seizure free. CONCLUSION: Although the natural history of SWS is imperfectly known, increasing duration of seizures and of postictal deficits, increase in atrophy or of calcified lesions or both, are indicative of its progressive nature. Despite the expected heterogeneity that renders formal comparison of the various approaches difficult, the current study provides new evidence to support early surgery in patients with SWS and drug-resistant epilepsy. The authors' results suggest that lesionectomy is a good approach, provided that the pial angioma is unilateral and the resection can be complete.
PMID: 11094100[PM]
Epilepsia 2001;41 Suppl 5
New insights into the clinical management of partial epilepsies.
Hirsch E, de Saint-Martin A, Arzimanoglou A
Service de Neurologie, Neuropsychologie et Explorations Fonctionnelles des Epilepsies, Hôpitaux Universitaires de Strasbourg, France.
The diagnosis, treatment, and prognosis of seizure disorders depend on the correct identification of epileptic syndromes. Partial epilepsies are heterogeneous and can be divided into idiopathic, cryptogenic, and symptomatic epilepsies. The most common of the idiopathic localization-related epilepsies is benign epilepsy with rolandic or centrotemporal spikes (BECTS). Seizures remain rare and the use of antiepileptic drug (AED) treatment in all patients does not appear justified. Children who present with some of the electroclinical characteristics of BECTS may also display severe unusual neurologic, neuropsychological, or atypical symptoms. In some cases, carbamazepine has been implicated as a triggering factor. Primary reading epilepsy and idiopathic occipital lobe epilepsies with photosensitivity are examples of an overlap between idiopathic localization-related and generalized epilepsies and respond well to sodium valproate. Autosomal dominant nocturnal frontal lobe epilepsy and benign familial infantile convulsions are recently described syndromes, differing in several ways from classical idiopathic localization-related epileptic syndromes. In cryptogenic or symptomatic epilepsy, the topography of the epileptogenic zone might influence drug efficacy. An individualized approach to AED selection, tailored to each patient's needs, should be used. Resistance of seizures to antiepileptic therapy may be due to diagnostic and/or treatment error or may be the result of noncompliance. Increasing the dosage, discontinuation or replacement of a drug, or addition of a second drug is indicated in truly resistant cases. The use of more than two AEDs rarely optimizes seizure control, and in some cases reduction of treatment may improve seizure control while lessening side effects. EEG-video assessment of patients with refractory epilepsy is important. Indications for and timing of epilepsy surgery should be reconsidered. Surgical therapy should probably be used more often and earlier than it is at present.
PMID: 11045435[PM]
Epileptic Disord 2000;1(2)
Hemifacial spasm or subcortical epilepsy?
Arzimanoglou AA, Salefranque F, Goutières F, Aicardi J
Child Neurology and Metabolic Diseases Dpt., Hôpital Robert-Debré, Paris, France. alexis.arzimanoglou@rdb.ap-hop-paris.fr
A child with Goldenhar's syndrome presented at about one week of age with stereotyped, repetitive paroxysmal episodes of hemifacial contraction, suggestive of partial seizures or hemifacial spasm. Later in life he also developed independent, permanent abnormal eye and chin movements identical in rhythm to those seen in myorhythmias, suggesting involvement of the dentato-olivary pathway. MRI demonstrated a hamartomatous lesion at the level of the pontomedullary junction. We speculate that the nature of the lesion could be responsible for the partial seizures mimicking hemifacial spasm and that because of its location, this same lesion could also be implicated in the genesis of myorhythmias. The presence of a hamartomatous lesion in a region affected by the abnormal development of the first and second branchial arches is not fortuitous.
PMID: 10937142[PM]
Hum Mol Genet 2000;9(9)
MECP2 mutations account for most cases of typical forms of Rett syndrome.
Bienvenu T, Carrié A, de Roux N, Vinet MC, Jonveaux P, Couvert P, Villard L, Arzimanoglou A, Beldjord C, Fontes M, Tardieu M, Chelly J
Laboratoire de Génétique et Physiopathologie des retards mentaux-ICGM, Faculté de Médecine Cochin, 24 rue du Faubourg Saint Jacques, 75014 Paris, France,
Rett syndrome (RTT) is a severe progressive neurological disorder that affects almost exclusively females, with an estimated prevalence of approximately one in 10 000-15 000 female births. Most cases are sporadic, but several reports about familial recurrence support X-linked dominant inheritance with male lethality. The gene responsible for this disorder, MECP2, was recently identified by candidate gene strategy. Mutations were detected in <25% of RTT cases in this first report. To characterize the spectrum of mutations in the MECP2 gene in RTT patients, we selected 46 typical RTT patients and performed mutation screening by denaturing gradient gel electrophoresis combined with direct sequencing. We identified 30 mutations, accounting for 65% of RTT patients. They include 12 novel mutations (11 located in exon 3 and one in exon 2). Mutations, such as R270X and frameshift deletions in a (CCACC) (n) rich region, have been found with multiple recurrences. Most of the mutations were de novo, except in one family where the non-affected transmitter mother exhibited a bias of X inactivation. Although this study showed that MECP2 mutations account for most cases of typical forms of RTT (65%) and mutations in non-coding regions cannot be excluded for the remaining cases, an alternative hypothesis that takes into account the homogeneous phenotype and exclusive involvement of females, could be the implication in RTT of a putative second X-linked gene.
PMID: 10814719[PM]
Rev Neurol 2000;29(4)
[Landau-Kleffner sydnrome]
Aicardi J
Institute of Child Health, University College, Londres, Gran Bretaña. alexis.arzimanoglou@rdb.aphopparis.fr
The Landau-Kleffner syndrome consists of the association of paroxysmal EEG abnormalities, more marked during sleep, acquired aphasia usually of receptive type, and epileptic seizures in three quarters of cases. Additional features include behavioral disturbances that may even present with autistic features, cognitive regression of variable degree, and sometimes motor difficulties, indicating the pervasive nature of the disorder. The epileptic activity, as manifested by the EEG, seems responsible for the pervasive dysfunction. Treatment with antiepileptic drugs is often ineffective. ACTH and corticosteroids are currently regarded as the best therapy but surgical treatment by subpial transection is being actively studied.
PMID: 10797930[PM]
J Neurol 1998;245(12)
Gilles de la Tourette syndrome.
Arzimanoglou AA
Department of Child Neurology and Metabolic Disorders, Hôpital Robert Debré, Paris, France. alexis.arzimanoglou@rdb.ap-hop-paris.fr
The study of childhood movement disorders is still in an early stage. Tics and related disorders are recognized as one of the most common movement disorders. This contribution reviews the main clinical, epidemiological, pathophysiological, and treatment issues on tics and Gilles de la Tourette syndrome. Although these disorders are not life threatening, they may be psychologically or functionally disabling. Early diagnosis and special management permit the alleviation of symptoms.
PMID: 9840347[PM]
Neurology 1998;51(5)
Is the underlying cause of epilepsy a major prognostic factor for recurrence?
Semah F, Picot MC, Adam C, Broglin D, Arzimanoglou A, Bazin B, Cavalcanti D, Baulac M
Epilepsy Unit, Clinique P. Castaigne, Hôpital de la Salpêtrière, Paris, France.
BACKGROUND: We investigated the prognostic value of the type of epilepsies and epileptic syndromes for seizure recurrence. In patients with partial epilepsy, we focused on the prognostic value of any structural brain abnormality and of the location of the epileptogenic region. METHODS: A total of 2,200 adult outpatients were included in a hospital-based observational survey, with a follow-up of 1 to 7 years. Twenty-two percent of the patients exhibited generalized epilepsy, 62% partial epilepsy, and 16% undetermined epilepsy. RESULTS: Seizure control (>1 year without seizure) was achieved in 82% of patients who had idiopathic generalized epilepsy, 35% of those with symptomatic partial epilepsy, 45% of those with cryptogenic partial epilepsy, and 11% of those with partial epilepsy associated with hippocampal sclerosis (HS). Temporal lobe epilepsy (TLE) was the most refractory partial epilepsy, with only 20% of such patients remaining seizure free, compared with 36% of extra-TLE patients. In partial epilepsy, HS, cerebral dysgenesis, and dual pathology (HS and another lesion) were associated with a low rate of seizure-free patients (11%, 24%, and 3%, respectively). No significant difference in seizure control was found between patients with extra-TLE and those with TLE and no HS. CONCLUSIONS: In adults, partial epilepsy is more difficult to treat than idiopathic generalized epilepsy. In patients who have partial epilepsy, the location of the epileptogenic zone does not seem to be a determining factor. Brain abnormalities--especially HS, either alone or associated with another lesion--are a major prognostic factor.
PMID: 9818842[PM]
Ann Neurol 1998;44(2)
Hippocampal developmental changes in patients with partial epilepsy: magnetic resonance imaging and clinical aspects.
Baulac M, De Grissac N, Hasboun D, Oppenheim C, Adam C, Arzimanoglou A, Semah F, Lehéricy S, Clémenceau S, Berger B
Clinique P. Castaigne, Höpital de la Pitié-Salpêtrière, Paris, France.
Developmental disorders of the hippocampal formation (HF) have been described in epileptic syndromes associated with lissencephaly, but HF malformations can be found without widespread cortical changes. We report 19 patients with partial epilepsy and abnormal HF patterns on magnetic resonance imaging (MRI). The changes consisted of incomplete folding with abnormal medial location along the choroid fissure, globular shape and/or verticalization, and were observed in the following three contexts: (1) diffuse disorder of neuronal migration (n=1); (2) temporal lobe malformation (n=5), including heterotopia, abnormal gyration, and, in 2 cases, reduced HF volume; and (3) apparently isolated HF changes (n=13, bilateral in 3 cases). The clinical features were heterogeneous in terms of severity of epilepsy and, when the focus could be determined, in localization (temporal or extratemporal). In 4 patients with apparently isolated HF changes, MRI was suggestive of both abnormal development and hippocampal sclerosis. In these patients, presurgical investigation and postoperative results suggested multiple epileptogenic foci, involving the frontal lobes in 2 cases. One HF specimen was large enough for the observation of developmental abnormalities corresponding to the changes seen on MRI. HF changes in shape and/or position should be included among the structural abnormalities associated with partial epilepsies. They may represent the visible part of a more extensive or more distant disorder of brain development.
PMID: 9708545[PM]
Seizure 1998;7(1)
Gabapentin add-on therapy with adaptable dosages in 610 patients with partial epilepsy: an open, observational study. The French Gabapentin Collaborative Group.
Baulac M, Cavalcanti D, Semah F, Arzimanoglou A, Portal JJ
Epilepsy Unit, Hôpital de la Pitié-Salpêtrière, Paris, France.
The objectives were to evaluate gabapentin add-on therapy in a large population under conditions close to real practice and to determine the therapeutic doses as reached with adaptable dosages. A 6-month multicentre, open-label study, involved addition of gabapentin to pre-existing treatment at the initial dosage of 1200 mg and subsequent adjustment between 900 and 2400 mg/day according to efficacy and tolerability. A study group of 610 adult patients, with partial epilepsy, persistent seizures and a median seizure frequency with a baseline of 7.2 per month were recruited; one-third had less than four seizures per month. Polypharmacy was frequent, with a mean of 2.3 concomitant drugs. After 6 months, 368 patients (62%) continued on gabapentin, at a mean dosage of 1739 mg/day with 44% of responders. On an intention-to-treat basis, median reduction in frequency was 21.2%, and the responder rate was 33.9%. The responder rate increased to 40.7% in the less severe subgroup receiving only one concomitant drug. Seventy-nine patients (13.4%) remained without seizures during the last evaluation period, versus nine (1.5%) during the baseline. Most of them had initially less than four seizures per month. The most frequent adverse effects, somnolence (29.3%), asthenia (14.6%), nausea (7.9%), ataxia (7.7%) and vertigo (7.2%), occurred rapidly after initial titration to 1200 mg/day, and were usually transitory. Weight gain (8.8%) seemed to be related to gabapentin dose. The combination of two recent drugs, vigabatrin and gabapentin, in 190 patients led to similar efficacy levels, with a tendency for more frequent somnolence and asthenia.
PMID: 9548227[PM]
Infantile spasms and Menkes disease.
Sfaello I, Castelnau P, Blanc N, Ogier H, Evrard P, Arzimanoglou A
Service de Neurologie Pédiatrique et des Maladies Métaboliques, Hôpital Robert-Debré, 48, boulevard Sérurier, 75019 Paris, France. isfaello@wanadoo.fr
Epileptic seizures are a common feature in Menkes disease, an X-linked genetic disorder of copper metabolism. Details of type of seizures are rarely reported. We report the evolution of infantile spasms in two patients with Menkes disease and the relation with subcutaneous administration of copper-histidine.
PMID: 11174154[PM]
Neurology 2001;55(10)
Sturge-Weber syndrome: indications and results of surgery in 20 patients.
Arzimanoglou AA, Andermann F, Aicardi J, Sainte-Rose C, Beaulieu MA, Villemure JG, Olivier A, Rasmussen T
Service of Child Neurology and Metabolic Disorders, University Hospital Robert Debré, University Hospital Enfants Malades, Paris, France. alexis.arzimanoglou@rdb.ap-hop-paris.fr
OBJECTIVE: To discuss the indications and timing for resective surgery in patients with Sturge-Weber syndrome (SWS) and medication-resistant epilepsy. BACKGROUND: SWS that causes epilepsy severe enough to merit surgery is rare. Because of the variable natural history of the disease, it is difficult to establish clear-cut indications for surgery and prospective studies are not feasible. Attitudes of clinicians and surgeons remain variable. METHODS: The authors assessed the presurgical epilepsy profile, criteria for surgery, monitoring techniques, and the postoperative outcome of epilepsy in all patients with SWS consecutively admitted between 1972 and 1990 to two referral centers (Paris and Montreal) and underwent surgery for intractable seizures. RESULTS: All 20 patients had a minimal postoperative follow-up of 4 years and all but one are still followed by one of the authors. One patient had a callosotomy, five underwent hemispherectomy, and 14 had cortical resection. Despite variability in the age at onset of seizures (range: 2 months to 12 years), age at operation (range: 8 months to 34 years) and surgical methods, almost all patients benefited from surgery. Visually guided complete resection of the pial angioma and underlying cortex, whenever possible, seemed sufficient; results were no better with intraoperative corticography. In children with previous hemiparesis, hemispherectomy proved particularly effective: all five became seizure free. None of the patients showed any aggravation of cognitive impairment following surgery; none of those who were operated on early presented with severe mental retardation, and 13 of 20 became seizure free. CONCLUSION: Although the natural history of SWS is imperfectly known, increasing duration of seizures and of postictal deficits, increase in atrophy or of calcified lesions or both, are indicative of its progressive nature. Despite the expected heterogeneity that renders formal comparison of the various approaches difficult, the current study provides new evidence to support early surgery in patients with SWS and drug-resistant epilepsy. The authors' results suggest that lesionectomy is a good approach, provided that the pial angioma is unilateral and the resection can be complete.
PMID: 11094100[PM]
Epilepsia 2001;41 Suppl 5
New insights into the clinical management of partial epilepsies.
Hirsch E, de Saint-Martin A, Arzimanoglou A
Service de Neurologie, Neuropsychologie et Explorations Fonctionnelles des Epilepsies, Hôpitaux Universitaires de Strasbourg, France.
The diagnosis, treatment, and prognosis of seizure disorders depend on the correct identification of epileptic syndromes. Partial epilepsies are heterogeneous and can be divided into idiopathic, cryptogenic, and symptomatic epilepsies. The most common of the idiopathic localization-related epilepsies is benign epilepsy with rolandic or centrotemporal spikes (BECTS). Seizures remain rare and the use of antiepileptic drug (AED) treatment in all patients does not appear justified. Children who present with some of the electroclinical characteristics of BECTS may also display severe unusual neurologic, neuropsychological, or atypical symptoms. In some cases, carbamazepine has been implicated as a triggering factor. Primary reading epilepsy and idiopathic occipital lobe epilepsies with photosensitivity are examples of an overlap between idiopathic localization-related and generalized epilepsies and respond well to sodium valproate. Autosomal dominant nocturnal frontal lobe epilepsy and benign familial infantile convulsions are recently described syndromes, differing in several ways from classical idiopathic localization-related epileptic syndromes. In cryptogenic or symptomatic epilepsy, the topography of the epileptogenic zone might influence drug efficacy. An individualized approach to AED selection, tailored to each patient's needs, should be used. Resistance of seizures to antiepileptic therapy may be due to diagnostic and/or treatment error or may be the result of noncompliance. Increasing the dosage, discontinuation or replacement of a drug, or addition of a second drug is indicated in truly resistant cases. The use of more than two AEDs rarely optimizes seizure control, and in some cases reduction of treatment may improve seizure control while lessening side effects. EEG-video assessment of patients with refractory epilepsy is important. Indications for and timing of epilepsy surgery should be reconsidered. Surgical therapy should probably be used more often and earlier than it is at present.
PMID: 11045435[PM]
Epileptic Disord 2000;1(2)
Hemifacial spasm or subcortical epilepsy?
Arzimanoglou AA, Salefranque F, Goutières F, Aicardi J
Child Neurology and Metabolic Diseases Dpt., Hôpital Robert-Debré, Paris, France. alexis.arzimanoglou@rdb.ap-hop-paris.fr
A child with Goldenhar's syndrome presented at about one week of age with stereotyped, repetitive paroxysmal episodes of hemifacial contraction, suggestive of partial seizures or hemifacial spasm. Later in life he also developed independent, permanent abnormal eye and chin movements identical in rhythm to those seen in myorhythmias, suggesting involvement of the dentato-olivary pathway. MRI demonstrated a hamartomatous lesion at the level of the pontomedullary junction. We speculate that the nature of the lesion could be responsible for the partial seizures mimicking hemifacial spasm and that because of its location, this same lesion could also be implicated in the genesis of myorhythmias. The presence of a hamartomatous lesion in a region affected by the abnormal development of the first and second branchial arches is not fortuitous.
PMID: 10937142[PM]
Hum Mol Genet 2000;9(9)
MECP2 mutations account for most cases of typical forms of Rett syndrome.
Bienvenu T, Carrié A, de Roux N, Vinet MC, Jonveaux P, Couvert P, Villard L, Arzimanoglou A, Beldjord C, Fontes M, Tardieu M, Chelly J
Laboratoire de Génétique et Physiopathologie des retards mentaux-ICGM, Faculté de Médecine Cochin, 24 rue du Faubourg Saint Jacques, 75014 Paris, France,
Rett syndrome (RTT) is a severe progressive neurological disorder that affects almost exclusively females, with an estimated prevalence of approximately one in 10 000-15 000 female births. Most cases are sporadic, but several reports about familial recurrence support X-linked dominant inheritance with male lethality. The gene responsible for this disorder, MECP2, was recently identified by candidate gene strategy. Mutations were detected in <25% of RTT cases in this first report. To characterize the spectrum of mutations in the MECP2 gene in RTT patients, we selected 46 typical RTT patients and performed mutation screening by denaturing gradient gel electrophoresis combined with direct sequencing. We identified 30 mutations, accounting for 65% of RTT patients. They include 12 novel mutations (11 located in exon 3 and one in exon 2). Mutations, such as R270X and frameshift deletions in a (CCACC) (n) rich region, have been found with multiple recurrences. Most of the mutations were de novo, except in one family where the non-affected transmitter mother exhibited a bias of X inactivation. Although this study showed that MECP2 mutations account for most cases of typical forms of RTT (65%) and mutations in non-coding regions cannot be excluded for the remaining cases, an alternative hypothesis that takes into account the homogeneous phenotype and exclusive involvement of females, could be the implication in RTT of a putative second X-linked gene.
PMID: 10814719[PM]
Rev Neurol 2000;29(4)
[Landau-Kleffner sydnrome]
Aicardi J
Institute of Child Health, University College, Londres, Gran Bretaña. alexis.arzimanoglou@rdb.aphopparis.fr
The Landau-Kleffner syndrome consists of the association of paroxysmal EEG abnormalities, more marked during sleep, acquired aphasia usually of receptive type, and epileptic seizures in three quarters of cases. Additional features include behavioral disturbances that may even present with autistic features, cognitive regression of variable degree, and sometimes motor difficulties, indicating the pervasive nature of the disorder. The epileptic activity, as manifested by the EEG, seems responsible for the pervasive dysfunction. Treatment with antiepileptic drugs is often ineffective. ACTH and corticosteroids are currently regarded as the best therapy but surgical treatment by subpial transection is being actively studied.
PMID: 10797930[PM]
J Neurol 1998;245(12)
Gilles de la Tourette syndrome.
Arzimanoglou AA
Department of Child Neurology and Metabolic Disorders, Hôpital Robert Debré, Paris, France. alexis.arzimanoglou@rdb.ap-hop-paris.fr
The study of childhood movement disorders is still in an early stage. Tics and related disorders are recognized as one of the most common movement disorders. This contribution reviews the main clinical, epidemiological, pathophysiological, and treatment issues on tics and Gilles de la Tourette syndrome. Although these disorders are not life threatening, they may be psychologically or functionally disabling. Early diagnosis and special management permit the alleviation of symptoms.
PMID: 9840347[PM]
Neurology 1998;51(5)
Is the underlying cause of epilepsy a major prognostic factor for recurrence?
Semah F, Picot MC, Adam C, Broglin D, Arzimanoglou A, Bazin B, Cavalcanti D, Baulac M
Epilepsy Unit, Clinique P. Castaigne, Hôpital de la Salpêtrière, Paris, France.
BACKGROUND: We investigated the prognostic value of the type of epilepsies and epileptic syndromes for seizure recurrence. In patients with partial epilepsy, we focused on the prognostic value of any structural brain abnormality and of the location of the epileptogenic region. METHODS: A total of 2,200 adult outpatients were included in a hospital-based observational survey, with a follow-up of 1 to 7 years. Twenty-two percent of the patients exhibited generalized epilepsy, 62% partial epilepsy, and 16% undetermined epilepsy. RESULTS: Seizure control (>1 year without seizure) was achieved in 82% of patients who had idiopathic generalized epilepsy, 35% of those with symptomatic partial epilepsy, 45% of those with cryptogenic partial epilepsy, and 11% of those with partial epilepsy associated with hippocampal sclerosis (HS). Temporal lobe epilepsy (TLE) was the most refractory partial epilepsy, with only 20% of such patients remaining seizure free, compared with 36% of extra-TLE patients. In partial epilepsy, HS, cerebral dysgenesis, and dual pathology (HS and another lesion) were associated with a low rate of seizure-free patients (11%, 24%, and 3%, respectively). No significant difference in seizure control was found between patients with extra-TLE and those with TLE and no HS. CONCLUSIONS: In adults, partial epilepsy is more difficult to treat than idiopathic generalized epilepsy. In patients who have partial epilepsy, the location of the epileptogenic zone does not seem to be a determining factor. Brain abnormalities--especially HS, either alone or associated with another lesion--are a major prognostic factor.
PMID: 9818842[PM]
Ann Neurol 1998;44(2)
Hippocampal developmental changes in patients with partial epilepsy: magnetic resonance imaging and clinical aspects.
Baulac M, De Grissac N, Hasboun D, Oppenheim C, Adam C, Arzimanoglou A, Semah F, Lehéricy S, Clémenceau S, Berger B
Clinique P. Castaigne, Höpital de la Pitié-Salpêtrière, Paris, France.
Developmental disorders of the hippocampal formation (HF) have been described in epileptic syndromes associated with lissencephaly, but HF malformations can be found without widespread cortical changes. We report 19 patients with partial epilepsy and abnormal HF patterns on magnetic resonance imaging (MRI). The changes consisted of incomplete folding with abnormal medial location along the choroid fissure, globular shape and/or verticalization, and were observed in the following three contexts: (1) diffuse disorder of neuronal migration (n=1); (2) temporal lobe malformation (n=5), including heterotopia, abnormal gyration, and, in 2 cases, reduced HF volume; and (3) apparently isolated HF changes (n=13, bilateral in 3 cases). The clinical features were heterogeneous in terms of severity of epilepsy and, when the focus could be determined, in localization (temporal or extratemporal). In 4 patients with apparently isolated HF changes, MRI was suggestive of both abnormal development and hippocampal sclerosis. In these patients, presurgical investigation and postoperative results suggested multiple epileptogenic foci, involving the frontal lobes in 2 cases. One HF specimen was large enough for the observation of developmental abnormalities corresponding to the changes seen on MRI. HF changes in shape and/or position should be included among the structural abnormalities associated with partial epilepsies. They may represent the visible part of a more extensive or more distant disorder of brain development.
PMID: 9708545[PM]
Seizure 1998;7(1)
Gabapentin add-on therapy with adaptable dosages in 610 patients with partial epilepsy: an open, observational study. The French Gabapentin Collaborative Group.
Baulac M, Cavalcanti D, Semah F, Arzimanoglou A, Portal JJ
Epilepsy Unit, Hôpital de la Pitié-Salpêtrière, Paris, France.
The objectives were to evaluate gabapentin add-on therapy in a large population under conditions close to real practice and to determine the therapeutic doses as reached with adaptable dosages. A 6-month multicentre, open-label study, involved addition of gabapentin to pre-existing treatment at the initial dosage of 1200 mg and subsequent adjustment between 900 and 2400 mg/day according to efficacy and tolerability. A study group of 610 adult patients, with partial epilepsy, persistent seizures and a median seizure frequency with a baseline of 7.2 per month were recruited; one-third had less than four seizures per month. Polypharmacy was frequent, with a mean of 2.3 concomitant drugs. After 6 months, 368 patients (62%) continued on gabapentin, at a mean dosage of 1739 mg/day with 44% of responders. On an intention-to-treat basis, median reduction in frequency was 21.2%, and the responder rate was 33.9%. The responder rate increased to 40.7% in the less severe subgroup receiving only one concomitant drug. Seventy-nine patients (13.4%) remained without seizures during the last evaluation period, versus nine (1.5%) during the baseline. Most of them had initially less than four seizures per month. The most frequent adverse effects, somnolence (29.3%), asthenia (14.6%), nausea (7.9%), ataxia (7.7%) and vertigo (7.2%), occurred rapidly after initial titration to 1200 mg/day, and were usually transitory. Weight gain (8.8%) seemed to be related to gabapentin dose. The combination of two recent drugs, vigabatrin and gabapentin, in 190 patients led to similar efficacy levels, with a tendency for more frequent somnolence and asthenia.
PMID: 9548227[PM]
Rev Neurol (Paris) 1997;155(1)
[Therapeutic options provided by new antiepileptic drugs]
Baulac M, Arzimanoglou A, Semah F, Cavalcanti D
Clinique P. Castaigne, Hôpital de la Pitié-Salpêtrière, Paris.
The introduction on the French market of vigabatrin, gabapentin and lamotrigine has considerably diversified our conventional therapeutical schemes in epilepsies, as will be as amplified by the arrivals of topiramate, tiagabine and oxcarbazepine. Compared to the conventional drugs, these new products present more favorable pharmacokinetics, no or very weak interactions and a better tolerability, specially regarding the cognitive field. They should be used according to their spectrum of activity, function of their modes of action. In add-on trials on partial epilepsy patients all these new products have shown efficacy on partial and secondarily generalized seizures. Seizure frequency is reduced by at least 50 p. 100 in 30 to 50 p. 100 of the patients. A substantial number of patients can be rendered seizure-free with vigabatrin. Lamotrigine has a broader spectrum, as it is also efficacious on the different seizure types of generalized, symptomatic or idiopathic epilepsies. Main adverse events are non-specific central nervous system disturbances such as dizziness, drowsiness, ataxia, tremor or diplopia. More specifically, vigabatrin may induce weight gain and requires closer supervision in case of psychiatric history; lamotrigine which has also probable antidepressant properties, may induce skin rashs, rarely severe. Further data are needed for gabapentin which is now used at daily dosages which are two to three times those used in the initial studies. Gabamimetic agents may be worsening in some cases of generalized epilepsies, more specially on absence and myoclonic seizures. The most obvious benefits, some patients becoming seizure-free, are obtained in cases of intermediate severity, with a bitherapy including one of these new drugs. Developments in children are often delayed. Nevertheless the prognosis, including cognitive outcome, is considerably improved in infantile spasms with vigabatrin and in Lennox-Gastaut syndrome with lamotrigine and felbamate, the latter being highly toxic. For the moment in France, authorities have limited the use of all these new antiepileptic drugs to adjunctive therapy in epilepsies resisting to conventional drugs. But recent monotherapy data show similar efficacy with better tolerability. Once the pivotal, controlled studies have enabled to obtain regulatory approval, all these compounds must undergo a large-scale evaluation phase in order to better define dosages, long-term tolerability, indications and eventual contra-indications in the various epileptic syndromes, including children.
PMID: 9296153[PM]
Hum Mol Genet 1997;6(8)
Genetic mapping of a major susceptibility locus for juvenile myoclonic epilepsy on chromosome 15q.
Elmslie FV, Rees M, Williamson MP, Kerr M, Kjeldsen MJ, Pang KA, Sundqvist A, Friis ML, Chadwick D, Richens A, Covanis A, Santos M, Arzimanoglou A, Panayiotopoulos CP, Curtis D, Whitehouse WP, Gardiner RM
Department of Paediatrics, University College London Medical School, The Rayne Institute, UK.
The epilepsies are a group of disorders characterised by recurrent seizures caused by episodes of abnormal neuronal hyperexcitability involving the brain. Up to 60 million people are affected worldwide and genetic factors may contribute to the aetiology in up to 40% of patients. The most common human genetic epilepsies display a complex pattern of inheritance. These are categorised as idiopathic in the absence of detectable structural or metabolic abnormalities. Juvenile myoclonic epilepsy (JME) is a distinctive and common variety of familial idiopathic generalised epilepsy (IGE) with a prevalence of 0.5-1.0 per 1000 and a ratio of sibling risk to population prevalence (lambda(s)) of 42. The molecular genetic basis of these familial idiopathic epilepsies is entirely unknown, but a mutation in the gene CHRNA4, encoding the alpha4 subunit of the neuronal nicotinic acetylcholine receptor (nAChR), was recently identified in a rare Mendelian variety of idiopathic epilepsy. Chromosomal regions harbouring genes for nAChR subunits were therefore tested for linkage to the JME trait in 34 pedigrees. Significant evidence for linkage with heterogeneity was found to polymorphic loci encompassing the region in which the gene encoding the alpha7 subunit of nAChR (CHRNA7) maps on chromosome 15q14 (HLOD = 4.4 at alpha = 0.65; Z(all) = 2.94, P = 0.0005). This major locus contributes to genetic susceptibility to JME in a majority of the families studied.
PMID: 9259280[PM]
Seizure 1997;6(3)
Multicentre clinical evaluation of vigabatrin (Sabril) in mild to moderate partial epilepsies. French Neurologists Sabril Study Group.
Arzimanoglou AA, Dumas C, Ghirardi L
Child Neurology Unit, Hôpital Salpêtrière, Paris, France.
Vigabatrin (VGB) has been shown through several studies to be safe and effective as add-on therapy, particularly for the treatment of partial seizures in patients with severe epilepsies followed for years in hospital-based clinics. We now report additional clinical experience with VGB arising from an open trial of add-on VGB therapy in patients with relatively few seizures followed by qualified neurologists in private practice (the French Neurologists Sabril Study Group). VGB was administered to 397 patients aged 12-74 years (mean age = 37.5 +/- 13.8 years) who presented with no more than seven partial seizures of any type per month during a 3-month baseline period (mean number of seizures = 3.7 +/- 1.9/month). Simple partial seizures were reported in 121 (30.5%) patients, complex partial seizures in 282 (71.0%) and seizures with secondary generalization were reported in 111 (28.0%). The mean number of associated antiepileptic drugs (AEDs) was 1.9 +/- 0.9 and the mean dose of VGB was 2.21 +/- 0.64 g/day. Following introduction of VGB, 53 (13.4%) became seizure-free and remained so during the whole trial. During the fourth month of treatment, 158 patients (39.8%) had no seizures at all and a further 69 (17.4%) had their seizure frequency reduced by more than 50%. Secondary generalization was controlled during the whole period of treatment in 55 out of 97 patients (56.7%), 17 of which remained free of all types of partial seizures. VGB showed a good tolerability profile; adverse experiences more frequently reported were drowsiness and sleep disturbances. No action was necessary in the great majority of cases; the dose was reduced in 26 (6.5%) and VGB was discontinued in 32 (8%) patients. These data provide additional evidence that VGB can be used safely early on to treat patients with mild to moderate partial epilepsies. Secondary generalization was controlled in the majority of patients. Factors associated with the everyday clinical use of VGB, that resulted from a series of organized meetings with the investigators, are discussed.
PMID: 9203252[PM]
Rev Prat 1991;41(20)
[Rett syndrome. A well defined but mysterious encephalopathy]
Arzimanoglou A
Service de pédiatrie, hôpital de la Salpêtrière, Paris.
The Rett syndrome is characterized by a progressive development of loss of intellectual functions and of motricity, including abnormal stereotypic hand movements and reduction of the motor skill. This syndrome is exclusively observed in girls. Its typical evolution is characterized by a normal initial development (until 6 to 18 months after birth) followed by a progressive installation of the clinical signs in 4 steps. There is currently no biological marker for the Rett syndrome and therefore the diagnosis is only based on clinical criteria. The most common erroneous diagnosis is infantile autism. In this review, the current status of clinical, genetic and pathogenetic knowledge of the Rett syndrome is presented.
PMID: 1925380[PM]
Arch Fr Pediatr 1990;47(10)
[Rendu Osler disease revealed by ruptured cerebral arterial aneurysm in an infant]
Roy C, Noseda G, Arzimanoglou A, Harpey JP, Binet MH, Vaur C, Caille B
Service de Pédiatrie, Höpital de la Salpëtrière, Paris.
A 6 week-old boy whose mother and sister present with hereditary hemorrhagic telangiectasia (HHT) presented suddenly with listlessness, hypotonia, and acute anemia. Cerebrospinal fluid was grossly hemorrhagic. Brain CT scan was compatible with subarachnoid and intracerebral hemorrhage. Operative investigation diagnosed a ruptured aneurysm of one branch of the right middle cerebral artery. A large clot was removed from the right frontal lobe. The ruptured artery was clipped. Further cerebral and abdominal angiographies did not show other aneurysms. The infant died 18 days later, with bilateral subdural hematoma. The family history and review of the literature suggest that the rupture of a cerebral aneurysm in this infant may have been an early manifestation of HHT. Brain CT scan study seems mandatory in every infant born to a mother with HHT.
PMID: 2082850[PM]
Stroke 1989;20(5)
Spontaneous calcific cerebral embolus from a calcific aortic stenosis in a middle cerebral artery infarct.
Rancurel G, Marelle L, Vincent D, Catala M, Arzimanoglou A, Vacheron A
Clinique Neurologique, Hôpital de La Salpétrière, Paris, France.
Calcific emboli from a calcific aortic stenosis is an uncommon event, usually following local trauma, as from cardiac surgery or left heart catheterization or as a sequel to bacterial endocarditis. We report what we believe to be the first case of a spontaneous calcareous emboli demonstrated by cranial computed tomography. In this patient, systemic hypertension and mild aortic insufficiency may have caused increasing mechanical forces acting on the aortic cusps and may have precipitated embolism.
PMID: 2655188[PM]
Br J Clin Pharmacol 1989;27 Suppl 1
Vigabatrin in the treatment of epilepsy in children.
Livingston JH, Beaumont D, Arzimanoglou A, Aicardi J
Hopital Necker - Enfants Malades, Paris, France.
1. This study presents the results of the preliminary screening of vigabatrin as add-on therapy in an open, non-controlled multicentre study in children with refractory epilepsy. 2. There were 135 children, with an age range of 2 months-12 years. Main seizure type was partial in 42%, generalized in 29%, Lennox-Gastaut syndrome in 19% and West syndrome in 10%. 3. Vigabatrin was added onto current antiepileptic treatment in an initially recommended dose of 40-80 mg kg-1 day-1. However, the doses were frequently increased when tolerance allowed it, and the final mean dose used was 87 mg kg-1 day-1 (27-600). 4. A 75% to 100% reduction in seizure frequency was observed in 25% of patients (11 patients became seizure free) and 50 to 75% decrease in a further 13%. Efficacy was better in partial seizures, with good to excellent results in 49% of patients. The use of high doses, above 100 mg kg-1 day, was not associated with greater efficacy in this preliminary study. 5. No side effects were reported in 79% of patients. Agitation and insomnia were observed in 8.8% and somnolence in 6%. Other adverse events included ataxia (2.2%), nausea (2.2%) and increased appetite (1%). A moderate and transient decrease in haemoglobin was reported in six patients from the same centre; these patients were all receiving very high doses of vigabatrin (250 to 600 mg kg-1 day-1). 6. Vigabatrin thus appears to be a safe antiepileptic drug that may be effective in the treatment of severe epilepsy in children.
PMID: 2757901[PM]
Acta Radiol Suppl 1986;369
Aneurysm of the circle of Willis. Comparison between computed tomography and angiography.
Zouaoui A, Metzger J, Villanueva A, Feldman L, Arzimanoglou A, Kikhya F, Pertuiset B
Department of Neuroradiology, Hôpital de la Pitie-Salpetriere, Paris, France.
The authors report their experience in 13 patients with unruptured non-giant aneurysms diagnosed at computed tomography (CT), who were without clinical deficits but who complained of chronic headache or cranial nerve palsy and had other members in their families with a cerebral vascular malformation. Screening with contrast-enhanced CT is discussed with respect to certain social groups. Surgical management before rupture of aneurysms could be envisaged in view of the bad prognosis when rupture has occurred.
PMID: 2980429[PM]
Presse Med 1985;14(38)
[Hurst-type acute leukoencephalitis with complete recovery in a child]
Renault F, Arzimanoglou A, Rancurel G, Roy C, Harpey JP
A case of acute haemorrhagic leukoencephalitis in an 11-year old girl demonstrates the usefulness of computerized tomography which shows large, asymmetric hypodense areas in the white matter and diffuse oedema. The causative role of a Mycoplasma pneumoniae infection is suggested by positive serology and by a high level of cold anti-l agglutinins. Treatment with corticosteroids in massive doses combined with a tetracycline resulted in complete cure without sequelae.
PMID: 2933708[PM]
...
[Therapeutic options provided by new antiepileptic drugs]
Baulac M, Arzimanoglou A, Semah F, Cavalcanti D
Clinique P. Castaigne, Hôpital de la Pitié-Salpêtrière, Paris.
The introduction on the French market of vigabatrin, gabapentin and lamotrigine has considerably diversified our conventional therapeutical schemes in epilepsies, as will be as amplified by the arrivals of topiramate, tiagabine and oxcarbazepine. Compared to the conventional drugs, these new products present more favorable pharmacokinetics, no or very weak interactions and a better tolerability, specially regarding the cognitive field. They should be used according to their spectrum of activity, function of their modes of action. In add-on trials on partial epilepsy patients all these new products have shown efficacy on partial and secondarily generalized seizures. Seizure frequency is reduced by at least 50 p. 100 in 30 to 50 p. 100 of the patients. A substantial number of patients can be rendered seizure-free with vigabatrin. Lamotrigine has a broader spectrum, as it is also efficacious on the different seizure types of generalized, symptomatic or idiopathic epilepsies. Main adverse events are non-specific central nervous system disturbances such as dizziness, drowsiness, ataxia, tremor or diplopia. More specifically, vigabatrin may induce weight gain and requires closer supervision in case of psychiatric history; lamotrigine which has also probable antidepressant properties, may induce skin rashs, rarely severe. Further data are needed for gabapentin which is now used at daily dosages which are two to three times those used in the initial studies. Gabamimetic agents may be worsening in some cases of generalized epilepsies, more specially on absence and myoclonic seizures. The most obvious benefits, some patients becoming seizure-free, are obtained in cases of intermediate severity, with a bitherapy including one of these new drugs. Developments in children are often delayed. Nevertheless the prognosis, including cognitive outcome, is considerably improved in infantile spasms with vigabatrin and in Lennox-Gastaut syndrome with lamotrigine and felbamate, the latter being highly toxic. For the moment in France, authorities have limited the use of all these new antiepileptic drugs to adjunctive therapy in epilepsies resisting to conventional drugs. But recent monotherapy data show similar efficacy with better tolerability. Once the pivotal, controlled studies have enabled to obtain regulatory approval, all these compounds must undergo a large-scale evaluation phase in order to better define dosages, long-term tolerability, indications and eventual contra-indications in the various epileptic syndromes, including children.
PMID: 9296153[PM]
Hum Mol Genet 1997;6(8)
Genetic mapping of a major susceptibility locus for juvenile myoclonic epilepsy on chromosome 15q.
Elmslie FV, Rees M, Williamson MP, Kerr M, Kjeldsen MJ, Pang KA, Sundqvist A, Friis ML, Chadwick D, Richens A, Covanis A, Santos M, Arzimanoglou A, Panayiotopoulos CP, Curtis D, Whitehouse WP, Gardiner RM
Department of Paediatrics, University College London Medical School, The Rayne Institute, UK.
The epilepsies are a group of disorders characterised by recurrent seizures caused by episodes of abnormal neuronal hyperexcitability involving the brain. Up to 60 million people are affected worldwide and genetic factors may contribute to the aetiology in up to 40% of patients. The most common human genetic epilepsies display a complex pattern of inheritance. These are categorised as idiopathic in the absence of detectable structural or metabolic abnormalities. Juvenile myoclonic epilepsy (JME) is a distinctive and common variety of familial idiopathic generalised epilepsy (IGE) with a prevalence of 0.5-1.0 per 1000 and a ratio of sibling risk to population prevalence (lambda(s)) of 42. The molecular genetic basis of these familial idiopathic epilepsies is entirely unknown, but a mutation in the gene CHRNA4, encoding the alpha4 subunit of the neuronal nicotinic acetylcholine receptor (nAChR), was recently identified in a rare Mendelian variety of idiopathic epilepsy. Chromosomal regions harbouring genes for nAChR subunits were therefore tested for linkage to the JME trait in 34 pedigrees. Significant evidence for linkage with heterogeneity was found to polymorphic loci encompassing the region in which the gene encoding the alpha7 subunit of nAChR (CHRNA7) maps on chromosome 15q14 (HLOD = 4.4 at alpha = 0.65; Z(all) = 2.94, P = 0.0005). This major locus contributes to genetic susceptibility to JME in a majority of the families studied.
PMID: 9259280[PM]
Seizure 1997;6(3)
Multicentre clinical evaluation of vigabatrin (Sabril) in mild to moderate partial epilepsies. French Neurologists Sabril Study Group.
Arzimanoglou AA, Dumas C, Ghirardi L
Child Neurology Unit, Hôpital Salpêtrière, Paris, France.
Vigabatrin (VGB) has been shown through several studies to be safe and effective as add-on therapy, particularly for the treatment of partial seizures in patients with severe epilepsies followed for years in hospital-based clinics. We now report additional clinical experience with VGB arising from an open trial of add-on VGB therapy in patients with relatively few seizures followed by qualified neurologists in private practice (the French Neurologists Sabril Study Group). VGB was administered to 397 patients aged 12-74 years (mean age = 37.5 +/- 13.8 years) who presented with no more than seven partial seizures of any type per month during a 3-month baseline period (mean number of seizures = 3.7 +/- 1.9/month). Simple partial seizures were reported in 121 (30.5%) patients, complex partial seizures in 282 (71.0%) and seizures with secondary generalization were reported in 111 (28.0%). The mean number of associated antiepileptic drugs (AEDs) was 1.9 +/- 0.9 and the mean dose of VGB was 2.21 +/- 0.64 g/day. Following introduction of VGB, 53 (13.4%) became seizure-free and remained so during the whole trial. During the fourth month of treatment, 158 patients (39.8%) had no seizures at all and a further 69 (17.4%) had their seizure frequency reduced by more than 50%. Secondary generalization was controlled during the whole period of treatment in 55 out of 97 patients (56.7%), 17 of which remained free of all types of partial seizures. VGB showed a good tolerability profile; adverse experiences more frequently reported were drowsiness and sleep disturbances. No action was necessary in the great majority of cases; the dose was reduced in 26 (6.5%) and VGB was discontinued in 32 (8%) patients. These data provide additional evidence that VGB can be used safely early on to treat patients with mild to moderate partial epilepsies. Secondary generalization was controlled in the majority of patients. Factors associated with the everyday clinical use of VGB, that resulted from a series of organized meetings with the investigators, are discussed.
PMID: 9203252[PM]
Rev Prat 1991;41(20)
[Rett syndrome. A well defined but mysterious encephalopathy]
Arzimanoglou A
Service de pédiatrie, hôpital de la Salpêtrière, Paris.
The Rett syndrome is characterized by a progressive development of loss of intellectual functions and of motricity, including abnormal stereotypic hand movements and reduction of the motor skill. This syndrome is exclusively observed in girls. Its typical evolution is characterized by a normal initial development (until 6 to 18 months after birth) followed by a progressive installation of the clinical signs in 4 steps. There is currently no biological marker for the Rett syndrome and therefore the diagnosis is only based on clinical criteria. The most common erroneous diagnosis is infantile autism. In this review, the current status of clinical, genetic and pathogenetic knowledge of the Rett syndrome is presented.
PMID: 1925380[PM]
Arch Fr Pediatr 1990;47(10)
[Rendu Osler disease revealed by ruptured cerebral arterial aneurysm in an infant]
Roy C, Noseda G, Arzimanoglou A, Harpey JP, Binet MH, Vaur C, Caille B
Service de Pédiatrie, Höpital de la Salpëtrière, Paris.
A 6 week-old boy whose mother and sister present with hereditary hemorrhagic telangiectasia (HHT) presented suddenly with listlessness, hypotonia, and acute anemia. Cerebrospinal fluid was grossly hemorrhagic. Brain CT scan was compatible with subarachnoid and intracerebral hemorrhage. Operative investigation diagnosed a ruptured aneurysm of one branch of the right middle cerebral artery. A large clot was removed from the right frontal lobe. The ruptured artery was clipped. Further cerebral and abdominal angiographies did not show other aneurysms. The infant died 18 days later, with bilateral subdural hematoma. The family history and review of the literature suggest that the rupture of a cerebral aneurysm in this infant may have been an early manifestation of HHT. Brain CT scan study seems mandatory in every infant born to a mother with HHT.
PMID: 2082850[PM]
Stroke 1989;20(5)
Spontaneous calcific cerebral embolus from a calcific aortic stenosis in a middle cerebral artery infarct.
Rancurel G, Marelle L, Vincent D, Catala M, Arzimanoglou A, Vacheron A
Clinique Neurologique, Hôpital de La Salpétrière, Paris, France.
Calcific emboli from a calcific aortic stenosis is an uncommon event, usually following local trauma, as from cardiac surgery or left heart catheterization or as a sequel to bacterial endocarditis. We report what we believe to be the first case of a spontaneous calcareous emboli demonstrated by cranial computed tomography. In this patient, systemic hypertension and mild aortic insufficiency may have caused increasing mechanical forces acting on the aortic cusps and may have precipitated embolism.
PMID: 2655188[PM]
Br J Clin Pharmacol 1989;27 Suppl 1
Vigabatrin in the treatment of epilepsy in children.
Livingston JH, Beaumont D, Arzimanoglou A, Aicardi J
Hopital Necker - Enfants Malades, Paris, France.
1. This study presents the results of the preliminary screening of vigabatrin as add-on therapy in an open, non-controlled multicentre study in children with refractory epilepsy. 2. There were 135 children, with an age range of 2 months-12 years. Main seizure type was partial in 42%, generalized in 29%, Lennox-Gastaut syndrome in 19% and West syndrome in 10%. 3. Vigabatrin was added onto current antiepileptic treatment in an initially recommended dose of 40-80 mg kg-1 day-1. However, the doses were frequently increased when tolerance allowed it, and the final mean dose used was 87 mg kg-1 day-1 (27-600). 4. A 75% to 100% reduction in seizure frequency was observed in 25% of patients (11 patients became seizure free) and 50 to 75% decrease in a further 13%. Efficacy was better in partial seizures, with good to excellent results in 49% of patients. The use of high doses, above 100 mg kg-1 day, was not associated with greater efficacy in this preliminary study. 5. No side effects were reported in 79% of patients. Agitation and insomnia were observed in 8.8% and somnolence in 6%. Other adverse events included ataxia (2.2%), nausea (2.2%) and increased appetite (1%). A moderate and transient decrease in haemoglobin was reported in six patients from the same centre; these patients were all receiving very high doses of vigabatrin (250 to 600 mg kg-1 day-1). 6. Vigabatrin thus appears to be a safe antiepileptic drug that may be effective in the treatment of severe epilepsy in children.
PMID: 2757901[PM]
Acta Radiol Suppl 1986;369
Aneurysm of the circle of Willis. Comparison between computed tomography and angiography.
Zouaoui A, Metzger J, Villanueva A, Feldman L, Arzimanoglou A, Kikhya F, Pertuiset B
Department of Neuroradiology, Hôpital de la Pitie-Salpetriere, Paris, France.
The authors report their experience in 13 patients with unruptured non-giant aneurysms diagnosed at computed tomography (CT), who were without clinical deficits but who complained of chronic headache or cranial nerve palsy and had other members in their families with a cerebral vascular malformation. Screening with contrast-enhanced CT is discussed with respect to certain social groups. Surgical management before rupture of aneurysms could be envisaged in view of the bad prognosis when rupture has occurred.
PMID: 2980429[PM]
Presse Med 1985;14(38)
[Hurst-type acute leukoencephalitis with complete recovery in a child]
Renault F, Arzimanoglou A, Rancurel G, Roy C, Harpey JP
A case of acute haemorrhagic leukoencephalitis in an 11-year old girl demonstrates the usefulness of computerized tomography which shows large, asymmetric hypodense areas in the white matter and diffuse oedema. The causative role of a Mycoplasma pneumoniae infection is suggested by positive serology and by a high level of cold anti-l agglutinins. Treatment with corticosteroids in massive doses combined with a tetracycline resulted in complete cure without sequelae.
PMID: 2933708[PM]
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