Early-onset absence epilepsy: SLC2A1 gene analysis and treatment evolution.

BACKGROUND AND PURPOSES: To determine the prevalence of SLC2A1 mutations in children with early-onset absence epilepsy (EOAE) and to investigate whether there were differences in demographic and electroclinical data between patients who became seizure-free with anti-epileptic drug (AED) monotherapy (group I) and those who needed add-on treatment of a second AED (group II). METHODS: We reviewed children with EOAE attending different Italian epilepsy centers. All participants had onset of absence seizures within the first 3 years of life but otherwise conformed to a strict definition of childhood absence epilepsy. Mutation analysis of SLC2A1 was performed in each patient. RESULTS: Eighty-four children (57 in group I, 27 in group II) fulfilled the inclusion criteria. No mutation in SLC2A1 was found. There were no statistical differences between the two groups with regard to F/M ratio, age at onset of EOAE, early history of febrile seizures, first-degree family history for genetic generalized epilepsy, duration of AED therapy at 3 years after enrollment, use of AEDs at 3 years, failed withdrawals at 3 years, terminal remission of EOAE at 3 years, and 6-month follow-up EEG data. Mean duration of seizures/active epilepsy was significantly shorter in group I than in group II (P = 0.008). CONCLUSIONS: We demonstrate that in a large series of children with rigorous diagnosis of EOAE, no mutations in SLC2A1 gene are detected. Except for duration of seizures/active epilepsy, no significant differences in demographic and electroclinical aspects are observed between children with EOAE who responded well to AED monotherapy and those who became seizure-free with add-on treatment of a second AED.

Intravesical chemo-immunotherapy in non muscle invasive bladder cancer.

Non-Muscle-Invasive-Bladder-Cancer represents 75-85% of the new bladder cancer cases per year. Trans-uretral vesical resection is the milestone for diagnosis and therapy. After primary treatment, recurrence is frequent depending on the presence of several established risk factors: multiplicity, T dimension, prior recurrence. In some patients disease progress to an advanced stage. Adjuvant chemo-immunotherapy has been widely used depending on the risk category assigned on the basis of the risk factors for recurrence. In low risk categories a one shot treatment with chemotherapy is considered the standard treatment without any maintenance therapy. In intermediate risk patients, adjuvant induction therapy and maintenance chemotherapy or immunotherapy for at least one year is recommended. In high risk patients adjuvant induction and maintenance immunotherapy until 3 years is considered the best strategy. In this review data on the different drugs used in this setting will be discussed.

Flexible dosing of adjunctive zonisamide in the treatment of adult partial-onset seizures: a non-comparative, open-label study (ZEUS).

OBJECTIVES: To assess the efficacy and tolerability of zonisamide in a study allowing flexible dosing in a more diverse and less refractory population than assessed in randomized controlled trials. METHODS: This 19-week, non-comparative study of adjunctive zonisamide included 281 adults who had at least four partial-onset seizures within 8 weeks on one or two antiepileptic drugs. Alterations to zonisamide doses were allowed after titration, except during two fixed-dose periods (weeks 10-13 and 16-19). RESULTS: At the end of the second fixed-dose period (median dose 300 mg/day), the median reduction in monthly seizure frequency was 33.3-41.1%; > or =50% responder rate was 40.9-44.2%; and seizure freedom rate was 15.0-15.9%, depending on the analysis used. The most common adverse events were fatigue (16.7%) and somnolence (15.3%). CONCLUSIONS: Zonisamide demonstrated efficacy in a setting more reflective of clinical practice and was generally well tolerated.

The clinical response on bone metastasis from breast and lung cancer during treatment with zoledronic acid is inversely correlated to skeletal related events (SRE).

Current management of bone metastases involves a multimodal approach. Aminobisphosphonates (BPs) are a valid weapon in the treatment of skeletal localization of tumour disease. Patients with bone metastases from breast and lung cancer were enrolled in order to evaluate the impact of the addition of bisphosphonates therapy to standard treatments in terms of (i) pain control, (ii) quality of life (QoL) and (iii) toxicity and to evaluate (iv) any relations between clinical activity and the occurrence of SREs. A total of 60 patients were included in the study. Median age was 76 years (range 40-83). The majority of patients were treated with chemotherapy or hormonal therapy. All patients received zoledronic acid (ZOL) (4 mg) every 3-4 weeks for at least 3 cycles. No significant improvement in Performance Status of patients after 12 cycles of ZOL (p = 0.1672) was recorded. A statistically significant early and long-lasting amelioration of both pain, narcotic scores and QoL was found. Twenty-one patients (48%) experienced at least one SRE during the study. The most common SRE was radiation to bone (30% of patients). An inverse correlation between bone tumour response and SREs was also found (p = 0.019). ZOL addition induces a clinical benefit and improves QoL of patients with bone metastases. Moreover, the occurrence of bone clinical response is related to a reduced risk of SREs.

Genetic analysis of the LGI/Epitempin gene family in sporadic and familial lateral temporal lobe epilepsy.

Mutations in the LGI1/Epitempin gene cause autosomal dominant lateral temporal lobe epilepsy (ADLTE), a partial epilepsy characterized by the presence of auditory seizures. However, not all the pedigrees with a phenotype consistent with ADLTE show mutations in LGI1/Epitempin, or evidence for linkage to the 10q24 locus. Other authors as well as ourselves have found an internal repeat (EPTP, pfam# PF03736) that allowed the identification of three other genes sharing a sequence and structural similarity with LGI1/Epitempin. In this work, we present the sequencing of these genes in a set of ADLTE families without mutations in both LGI1/Epitempin and sporadic cases. No analyzed polymorphisms modified susceptibility in either the familial or sporadic forms of this partial epilepsy.

Characterization of reproductive endocrine disorders in women with epilepsy.

An increased frequency of reproductive endocrine disorders has been reported in women with epilepsy. A possible role of the seizure disorder or, alternatively, of the use of antiepileptic drugs (AEDs) has been suggested as the pathogenic mechanism. The aim of the present study was to assess the frequency of reproductive endocrine disorders in a series of women with epilepsy, examining the possible relationships of these disturbances with different epilepsy syndromes and AED treatment. Fifty epileptic women, all of reproductive age and none pubertal, pregnant, or lactating, were submitted to clinical endocrinological evaluation, hormonal assessment, and ovarian ultrasonography. Subjects with abnormal findings in this preliminary study underwent additional evaluations. Reproductive endocrine disorders were diagnosed in 16 (32%), consisting of polycystic ovary syndrome in 13, hypothalamic amenorrhea in 2, and luteal phase deficiency in 1. There was no significant association of these disturbances with epilepsy type or AED treatment. Patients with reproductive endocrine disorders often showed delayed ovulation with shortened luteal phase. The results of this study suggest that the prevalence of disordered ovulation, in particular polycystic ovary syndrome, is increased in epilepsy, independent of antiepileptic medications or type of seizure disorder.

Abnormal pattern of luteinizing hormone pulsatility in women with epilepsy.

Dysfunction of the hypothalamic-pituitary-ovarian axis in epileptic females has been suggested in the latest years. To further elucidate this issue, we assessed reproductive endocrine function in 10 normally cycling, drug-free epileptic women and in 5 normal controls, evaluating the basal hormonal profile and luteinizing hormone (LH) pulsatility in the midfollicular phase. Luteinizing hormone pulse frequency was significantly higher in epileptic women with a consequent reduction of the LH interpulse interval. We suggest that epilepsy may interfere with the functional activity of the gonadotropin-releasing hormone pulse generator. The pathogenetic mechanisms for this phenomenon may be the spreading of paroxysmal activity within the hypothalamic areas or, alternatively, a neurotransmitter dysfunction giving rise both to the seizure disorder and to the abnormal LH pulsatile pattern.

Interictal depression in epilepsy.

The relation between depression and epilepsy was evaluated in 96 epileptic out-patients. We found that 50% of epileptic patients fulfilled the DSM-IIIR criteria for depression. The Hamilton Rating Scale for Depression, the Beck Self Depression Inventory and the Zung Anxiety Scale were also used in all patients. The patients with partial seizures with complex semiology (CPS) were more depressed than the patients with primary generalized epilepsy and with partial seizures with elementary semiology. A significant increase in the level of anxiety was also found in the group with CPS compared to the other two groups. No correlations were noted between severity of depression and duration of epilepsy, seizure frequency, socio-economic status, education, and family history of depressive illness. No relationship was observed between anticonvulsant drug levels and depression. We failed to confirm an association between side of epileptic lesion and severity of depression. We suggest that depression in epileptic patients does not represent a psychological reaction to a particular cognitive or physical impairment, but is in some way related to the type of epilepsy.

Distal hypoglycemic neuropathy. An insulinoma-associated case, misdiagnosed as temporal lobe epilepsy.

Peripheral distal neuropathy associated with hypoglycemia secondary to insulinoma is quite rare. So far, less than 40 cases have been reported in literature. In this report, we describe a 50-year-old patient with insulinoma-polineuropathy and neuropsychiatric symptoms, interpreted as temporal lobe epilepsy, over the preceding 7 years. Due to the variability of the clinical presentation, diagnostic mistakes are frequent, and diagnosis of insulinoma is often delayed. Thus, the hypoglycemic nature of neuropathy can be lately recognized.

Electroencephalographic abnormalities in homocystinuria due to cystathionine synthase deficiency.

Nineteen homocystinuric patients--13 children and 6 adults--were identified in the course of a selective screening for homocystinuria due to cystathionine synthase deficiency. Treatment with high doses (300-1200 mg/day) of pyridoxine was carried out in 17 patients, of whom 15 were completely responsive. In 10 patients EEG abnormalities were observed consisting mainly of a mild diffuse non specific slowing of background activity. In two sisters, with no history of seizures, focal paroxymal activity was also recorded. EEG recordings before and after B6 treatment were available in 16 patients, one of whom was a non responder, during treatment seven normal and six abnormal EEGs showed no change whereas three previously abnormal EEGs were classified as normal.

Heterogeneous findings in four cases of cerebellar ataxia associated with hypogonadism (Holmes' type ataxia).

We report four sporadic cases of cerebellar ataxia associated with hypogonadism. All patients were female. The neurological symptoms appeared in the first three decades. Apart from ataxia, the most frequent features were nystagmus, dysarthria, mental impairment, brisk tendon reflexes, skeletal deformities, peripheral neuropathy, and tremor. Neuroimaging studies showed constant cerebellar atrophy, in some instances associated with involvement of either grey or white cerebral matter. Neurophysiological studies demonstrated an axonal neuropathy. Endocrine evaluation showed heterogeneity of the hypogonadism, which was hypogonadotrophic in one patient and hypergonadotrophic in the other three. One patient had partial deficiency of muscle cytochrome c oxidase. The syndrome appears to be a heterogeneous multisystem disorder and in some cases a mitochondrial metabolism deficiency could be suspected.

Cerebellar ataxia and hypogonadism. A clinicopathological report.

A female showed primary amenorrhea and slowly progressive ataxia of limbs and gait, that had started when she was 18 years old. Endocrine data were consistent with hypogonadotropic hypogonadism. She died at 35 years of age. Post mortem examination showed mucinous carcinoma of the lung, hypoplastic uterus, atrophic ovaries. The cerebellum was small, with the atrophy most marked in the vermis, and the pons was shrinked. There was almost complete Purkinje cell disappearance and neuronal loss in the granular layer and the inferior olives.

Bioptically demonstrated Lafora disease without EPM2A mutation: a clinical and neurophysiological study of two sisters.

Lafora disease (LD) is an autosomal recessive inherited form of progressive myoclonic epilepsy with dementia and ataxia, usually presenting in the second decade of life and inexorably progressing until death. Neuropathological hallmarks are Lafora bodies, intracytoplasmic inclusions that can be found in neurons and in other tissues. LD gene (EPM2A), mapping on chromosome 6, encodes for a tyrosine phosphatase protein called laforin. However, up to 20% cases of LD are not genetically linked to chromosome 6. We report two sisters affected from bioptically diagnosed LD but without evidence of EPM2A mutation. Although familial cases of LD are already reported in literature, our observation leads to some considerations on clinical-electrophysiological evolution as well as to remark the genetic heterogeneity of this condition. In addition, we report the good effect of the Levetiracetam for the treatment of myoclonus in these patients, also demonstrated by the electrophysiological findings.

Epilepsia arithmetices: study of four cases.

In a 12-year period, in a total of about 2000 new patients referred to our Epilepsy Centre, we observed four patients with seizures exclusively or predominantly triggered by calculation or by card and board games (epilepsia arithmetices, EA). In agreement with observations reported in the literature, all the patients suffered from idiopathic generalized epilepsy (IGE), and probably from juvenile myoclonic epilepsy of Janz. In only one patient was it possible, during arithmetic tasks of increasing difficulty and stress, to evoke electroencephalographic (EEG) paroxysmal discharges, progressively increasing to clinical seizures. In the remaining patients the diagnosis of EA was exclusively clinical, as it was not possible to record EEG interictal or ictal paroxysmal activity specifically triggered by arithmetic tasks. Consequently, it is emphasized that in some cases the diagnosis of EA in a patient with IGE may be based exclusively on clinical criteria. As reported in the literature, it is possible to observe during mathematical calculation or during games both clinical (myoclonic jerks of the right hand) and EEG (localized small spikes) focal signs, which suggest a localized activation of specific areas in a patient with IGE.

Transient global amnesia of epileptic origin accompanied by fever.

The case of a previously healthy 69-year-old female patient is described who presented, in a period of 6 months, 3 long-lasting (from 2 hour- to 10 hour-duration) episodes of transient global amnesia accompanied by a temperature rise. During one of these episodes an EEG was obtained, showing a diffuse alteration, focal slowing, and bitemporal asynchronous paroxysmal activity giving rise to electrical ictal discharges. Interictal EEGs were normal. Cerebral computed tomography was normal. Carbamazepine was given with complete control of the attacks. These episodes may be interpreted as complex partial status with unusual semeiology.

Derangement of the hypothalamic GnRH pulse generator in women with epilepsy.

An increased frequency of reproductive endocrine diseases has been described in women with epilepsy and a subclinical reproductive dysfunction has been suggested in normally menstruating epileptic women. We assessed the reproductive endocrine function in 11 normally menstruating, drug-free epileptic women, evaluating the basal hormonal profile and LH pulsatile secretion during continuous EEG monitoring. A significant LH hyperpulsatility was observed in epileptic women compared with controls; moreover, a significant increase of gonadotropin basal secretions was observed when inter-ictal paroxysmal activity increased. The derangement of the hypothalamic GnRH pulse generator may represent a subclinical condition associated with epilepsy, not necessarily affecting the regularity of menstrual function. However, it is possible that the alteration of LH pulsatile pattern might eventually cause reproductive endocrine diseases. Paroxysmal activity seems to be an important additional factor in the derangement of gonadotropin secretion.

Eating epilepsy. Heterogeneity of ictal semiology: the role of video-EEG monitoring.

In this paper, three more cases of eating-induced seizures are reported. We have obtained ictal video-electroencephalogram (EEG) recordings for two patients, which confirm the heterogeneity of ictal semiology of these seizures. However, in all the cases the inclusion of this kind of reflex epilepsy (RE) among the localization-related epilepsies (LRE) is confirmed. The usefulness of video EEG monitoring in studying these seizures and reflex epilepsy in general (RE) is stressed.

[Atopy, environmental pollution and respiratory function. Study of 1000 children from 2 areas of the city of Naples]. / Atopia, inquinamento ambientale e funzionalità respiratoria. Studio su 1000 bambini di due zone della città di Napoli.

The aim of this study was to observe the chronic respiratory deficiency in childhood caused by two possible motives: allergy and ambiental pollution. We executed aerial samples in two zones of Naples, one (USL 45) with heavy pollution because many factories present and other with slight pollution (USL 40). The authors calculated the PEF (Peak Expiratory Flow at the first second) and in a group of subject also the spirometric values, in two groups of subjects, one of atopic children and in the other of non atopic children. The study showed a greater number of atopic subjects with abnormal PEF in the zone with heavy pollution; in non atopic children the abnormal PEF was greater in the zone with heavy pollution (35.2%) in comparison with slight pollution zone (3%).

LGI1 microdeletion in autosomal dominant lateral temporal epilepsy.

OBJECTIVES: To characterize clinically and genetically a family with autosomal dominant lateral temporal epilepsy (ADLTE) negative to LGI1 exon sequencing test. METHODS: All participants were personally interviewed and underwent neurologic examination. Most affected subjects underwent EEG and neuroradiologic examinations (CT/MRI). Available family members were genotyped with the HumanOmni1-Quad v1.0 single nucleotide polymorphism (SNP) array beadchip and copy number variations (CNVs) were analyzed in each subject. LGI1 gene dosage was performed by real-time quantitative PCR (qPCR). RESULTS: The family had 8 affected members (2 deceased) over 3 generations. All of them showed GTC seizures, with focal onset in 6 and unknown onset in 2. Four patients had focal seizures with auditory features. EEG showed only minor sharp abnormalities in 3 patients and MRI was unremarkable in all the patients examined. Three family members presented major depression and anxiety symptoms. Routine LGI1 exon sequencing revealed no point mutation. High-density SNP array CNV analysis identified a genomic microdeletion about 81 kb in size encompassing the first 4 exons of LGI1 in all available affected members and in 2 nonaffected carriers, which was confirmed by qPCR analysis. CONCLUSIONS: This is the first microdeletion affecting LGI1 identified in ADLTE. Families with ADLTE in which no point mutations are revealed by direct exon sequencing should be screened for possible genomic deletion mutations by CNV analysis or other appropriate methods. Overall, CNV analysis of multiplex families may be useful for identifying microdeletions in novel disease genes.