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.

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.

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.

Familial temporal lobe epilepsy with psychic auras associated with a novel LGI1 mutation.

BACKGROUND: Autosomal dominant lateral temporal epilepsy (ADLTE) is characterized by focal seizures with auditory features or aphasia. Mutations in the LGI1 gene have been reported in up to 50% of ADLTE pedigrees. We report a family with temporal lobe epilepsy characterized by psychic symptoms associated with a novel LGI1 mutation. METHODS: All participants were personally interviewed and underwent neurologic examination and video-EEG recordings. LGI1 exons were sequenced by standard methods. Mutant cDNA was transfected into human embryonic kidney 293 cells; both cell lysates and media were analyzed by Western blot. In silico modeling of the Lgi1 protein EPTP domain was carried out using the structure of WD repeat protein and manually refined. RESULTS: Three affected family members were ascertained, 2 of whom had temporal epilepsy with psychic symptoms (déjà vu, fear) but no auditory or aphasic phenomena, while the third had complex partial seizures without any aura. In all patients, we found a novel LGI1 mutation, Arg407Cys, which did not hamper protein secretion in vitro. Mapping of the mutation on a 3-dimensional protein model showed that this mutation does not induce large structural rearrangements but could destabilize interactions of Lgi1 with target proteins. CONCLUSIONS: The Arg407Cys is the first mutation with no effect on Lgi1 protein secretion. The uncommon, isolated psychic symptoms associated with it suggests that ADLTE encompasses a wider range of auras of temporal origin than hitherto reported.

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.

Is retinal assessment useful in epileptic patients with hyperhomocysteinemia?

PURPOSE: The arteriole-to-venule ratio (AVR) is widely used for investigating subclinical cerebral microangiopathy. The possible occurrence of retinal vascular caliber changes was investigated in a population of hyperhomocysteinaemic (plasma total homocysteine (tHcy) >13 micromol/l) adult epileptic patients. METHODS: Retinal photographs of cases and controls were evaluated for generalized narrowing of the retinal arterioles, measured as AVR, by graders masked to case-control status using standardized protocols. Plasma total homocysteine (tHcy) levels were assayed by HPLC. RESULTS: Sixty-seven patients (36M/31F, 36.4+/-7.5 years of age; mean level of tHcy 22.8+/-11.4 micromol/l), and 75 control subjects (42M/33F, 35.4+/-8.5 years of age; mean level of tHcy 7.8+/-2.3 micromol/l) were enroled. No retinal caliber changes were detected in any patient and healthy subject. The analysis of retinal photographs failed to identify any difference in the venular diameters, arteriolar diameters, and AVR measurements between the two groups (P=0.98). CONCLUSIONS: We showed that adult hyperhomocysteinaemic epileptic patients do not show any changes in retinal vascular caliber assessed by the measurement of AVR.

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.

An open-label trial of levetiracetam in severe myoclonic epilepsy of infancy.

OBJECTIVE: To conduct an open-label, add-on trial on safety and efficacy of levetiracetam in severe myoclonic epilepsy of infancy (SMEI). PATIENTS AND METHODS: SMEI patients were recruited from different centers according to the following criteria: age > or =3 years; at least four tonic-clonic seizures/month during the last 8 weeks; previous use of at least two drugs. Levetiracetam was orally administrated at starting dose of approximately 10 mg/kg/day up to 50 to 60 mg/kg/day in two doses. Treatment period included a 5- to 6-week up-titration phase and a 12-week evaluation phase. Efficacy variables were responder rate by seizure type and reduction of the mean number per week of each seizure type. Analysis was performed using Fisher exact and Wilcoxon tests. RESULTS: Twenty-eight patients (mean age: 9.4 +/- 5.6 years) entered the study. Sixteen (57.1%) showed SCN1A mutations. Mean number of concomitant drugs was 2.5. Mean levetiracetam dose achieved was 2,016 mg/day. Twenty-three (82.1%) completed the trial. Responders were 64.2% for tonic-clonic, 60% for myoclonic, 60% for focal, and 44.4% for absence seizures. Number per week of tonic-clonic (median: 3 vs 1; p = 0.0001), myoclonic (median: 21 vs 3; p = 0.002), and focal seizures (median: 7.5 vs 3; p = 0.031) was significantly decreased compared to baseline. Levetiracetam effect was not related to age at onset and duration of epilepsy, genetic status, and concomitant therapy. Levetiracetam was well tolerated by subjects who completed the study. To date, follow-up ranges 6 to 36 months (mean, 16.2 +/- 13.4). CONCLUSION: Levetiracetam add-on is effective and well tolerated in severe myoclonic epilepsy of infancy. Placebo-controlled studies should confirm these findings.

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.

Autosomal dominant cortical tremor, myoclonus and epilepsy: many syndromes, one phenotype.

The association of cortical tremor, myoclonus and epileptic seizures has been reported in many Japanese and European families with different acronyms. We reviewed the familial cases presenting the clinical picture of autosomal dominant cortical tremor, myoclonus and epilepsy and analysed the phenotypic differences between the pedigrees, according to the recent genetic acquisitions. We concluded that BAFME, FAME, FEME, FCTE and ADCME are the same clinical entity even if genetically heterogeneous, with Japanese families linked to 8q24 and Italian ones to 2p11.1-q12. A third locus could also be involved. Further studies should better clarify the electrophysiological features of this condition and identify the underlying molecular defects.

Idiopathic partial epilepsy with auditory features (IPEAF): a clinical and genetic study of 53 sporadic cases.

The purpose of our study was to describe the clinical characteristics of sporadic (S) cases of partial epilepsy with auditory features (PEAF) and pinpoint clinical, prognostic and genetic differences with respect to previously reported familial (F) cases of autosomal dominant partial epilepsy with auditory features (ADPEAF). We analysed 53 patients (24 females and 29 males) with PEAF diagnosed according to the following criteria: partial epilepsy with auditory symptoms, negative family history for epilepsy and absence of cerebral lesions on NMR study. All patients underwent a full clinical, neuroradiological and neurophysiological examination. Forty patients were screened for mutations in LGI1/epitempin, which is involved in ADPEAF. Age at onset ranged from 6 to 39 years (average 19 years). Secondarily generalized seizures were the most common type of seizures at onset (79%). Auditory auras occurred either in isolation (53%) or associated with visual, psychic or aphasic symptoms. Low seizure frequency at onset and good drug responsiveness were common, with 51% of patients seizure-free. Seizures tended to recur after drug withdrawal. Clinically, no major differences were found between S and F patients with respect to age at onset, seizure frequency and response to therapy. Analysis of LGI1/epitempin exons failed to disclose mutations. Our data support the existence of a peculiar form of non-lesional temporal lobe epilepsy closely related to ADPEAF but without a positive family history. This syndrome, here named IPEAF, has a benign course in the majority of patients and could be diagnosed by the presence of auditory aura. Although LGI1 mutations have been excluded, genetic factors may play an aetiopathogenetic role in at least some of these S cases.

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.

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.

Benign adult familial myoclonic epilepsy: genetic heterogeneity and allelism with ADCME.

Benign adult familial myoclonic epilepsy (BAFME) has been mapped to chromosome 8q24; however, genetic heterogeneity has been recently suggested. The authors report a clinical and electrophysiologic study of two Italian BAFME families showing linkage to chromosome 2p11.1-q12.2. Their report supports the evidence of non-Japanese families with BAFME and suggests a possible allelism with the recently described autosomal dominant cortical myoclonus and epilepsy syndrome.

Epilepsia partialis continua as a first symptom of multiple sclerosis: electrophysiological study of one case.

RATIONALE: The prevalence of epilepsy in people with multiple sclerosis (MS) is higher than in the general population. Sometimes seizures are among the first symptoms and can be unusual in their semiology. In rare cases a long-lasting focal somatomotor status [i.e., epilepsia partialis continua (EPC)] has been reported. CASE REPORT: A 21-year-old male patient presented with a clinical picture of EPC as a first symptom of MS at age of 19. A neurophysiological study agreed with a cortical origin of myoclonic jerks. CONCLUSIONS: MS should be considered a rare but possible aetiology of EPC in adults.