Cristina Petrelli

Clinical course of young patients with Dravet syndrome after vagal nerve stimulation

Medical treatment of Dravet syndrome is disappointing. Ketogenic Diet and neurostimulation procedures as Vagus Nerve Stimulation (VNS) and Deep Brain Stimulation are in ongoing evaluation. In the present study, the long-term effectiveness of VNS on seizures, cognition and behavior was retrospectively evaluated in eight young patients with DS and medically refractory epilepsy (mean age at VNS implant: 10.28 years, range: 5-25). The average duration of treatment was 54 months (range: 12-120). Compared to baseline (mean: 55; standard deviation: 83, range: 4-200), the mean number of monthly seizures after VNS implantation was 39 ± 67 at 3 months, 42 ± 67 at 6 months and 38 ± 69 at twelve months (not significant comparisons). In particular, VNS produced a mean seizure rate reduction of 12% at three months, 6% at six months, and 31% at twelve months. All patients but three experienced some reduction in seizure burden (range: 33-61%) at twelve months. Seizure outcome after one year of stimulation was rated as Mc Hugh class II (50-79% reduction in seizure frequency) in four patients, class III (<50% reduction) in one patient and class V (no improvement) in three patients. In this small case series of patients with DS, VNS therapy had a clinically significant effect in reducing seizures at twelve months in four of the eight patients. Even in patients in whom seizure reduction was not dramatic, a slight improvement in alertness and communicative skills was seen. The long-term clinical course of two selected cases is discussed.

Variable epilepsy phenotypes associated with a familial intragenic deletion of the SCN1A gene.

Deletions and duplications/amplifications of the α1‐sodium channel subunit (SCN1A) gene occur in about 12% of patients with Dravet syndrome (DS) who are otherwise mutation‐negative. Such genomic abnormalities cause loss of function, with severe phenotypes, reproductive disadvantage and, therefore, sporadic occurrence. Inherited mutations, occurring in ∼5% of patients with DS, are usually missense; transmission occurs from a mildly affected parent exhibiting febrile seizures (FS) or the generalized epilepsy with febrile seizures plus (GEFS+) spectrum. We identified an intragenic SCN1A deletion in a three‐generation, clinically heterogeneous family. Sequence analysis of SCN9A, a putative modifier, ruled out pathogenic mutations, variants, or putative disease–associated haplotype segregating with phenotype severity. Intrafamilial variability in phenotype severity indicates that SCN1A loss of function causes a phenotypic spectrum in which seizures precipitated by fever are prominent and schematic syndrome subdivisions would be inappropriate. SCN1A deletions should be ruled out even in individuals with mild phenotypes.

Vagus Nerve Stimulation for Refractory Epilepsy in Tuberous Sclerosis

The goal of the study was to assess the long-term seizure and neuropsychologic outcomes of patients with tuberous sclerosis and refractory epilepsy who received vagus nerve stimulator implantation. Eleven patients with a follow-up period of at least 12 months were studied retrospectively. The mean age at the time of implantation was 14 years (range, 2-35). Seizure outcome was rated as class I (>80% seizure frequency reduction) in 1 (9%), class II (50-79% reduction) in 7 (63%), and class III (<50% reduction) in 3 (27%). No patient experienced permanent adverse effects after the procedure. A significant increase of adaptive behaviors and quality of life was observed. Patients who had implantation during childhood exhibited a greater improvement in cognitive and neuropsychologic functioning. Vagus nerve stimulation can be considered an effective and safe therapeutic option in patients with tuberous sclerosis and refractory epilepsy who are not candidates for epilepsy surgery.

Early clinical features in Dravet syndrome patients with and without SCN1A mutations

BACKGROUND SCN1A is the most clinically relevant epilepsy gene, most mutations causing Dravet syndrome (also known as severe myoclonic epilepsy of infancy or SMEI). We evaluated clinical differences, if any, between young patients with and without a SCN1A mutations and a definite clinical diagnosis of Dravet syndrome. METHODS Twenty-five patients with a diagnosis of Dravet Syndrome (7 males, 18 females; mean age at inclusion: 10.3; median: 9±7; range: 18 months-30 years) were retrospectively studied. A clinical and genetic study focusing on SCN1A was performed, using DHPLC, gene sequencing and MLPA to detect genomic deletions/duplications. A formal cognitive and behavioral assessment was available for all patients. RESULTS Analysis revealed SCN1A mutations comprising missense, truncating mutations and genomic deletions/duplications in eighteen patients and no mutation in seven. The phenotype of mutation positive patients was characterized by a higher number of seizures/month in the first year of life, an earlier seizure onset and a higher frequency of episodes of status epilepticus. The cognitive and behavioral profile was slightly worst in mutation positive patients. CONCLUSIONS These findings confirm that SCN1A gene mutations are strongly associated to a more severe phenotype in patients with Dravet syndrome.

Clinical and genetic factors predicting Dravet syndrome in infants with SCN1A mutations

Objective: To explore the prognostic value of initial clinical and mutational findings in infants with SCN1A mutations. Methods: Combining sex, age/fever at first seizure, family history of epilepsy, EEG, and mutation type, we analyzed the accuracy of significant associations in predicting Dravet syndrome vs milder outcomes in 182 mutation carriers ascertained after seizure onset. To assess the diagnostic accuracy of all parameters, we calculated sensitivity, specificity, receiver operating characteristic (ROC) curves, diagnostic odds ratios, and positive and negative predictive values and the accuracy of combined information. We also included in the study demographic and mutational data of the healthy relatives of mutation carrier patients. Results: Ninety-seven individuals (48.5%) had Dravet syndrome, 49 (23.8%) had generalized/genetic epilepsy with febrile seizures plus, 30 (14.8%) had febrile seizures, 6 (3.5%) had focal epilepsy, and 18 (8.9%) were healthy relatives. The association study indicated that age at first seizure and frameshift mutations were associated with Dravet syndrome. The risk of Dravet syndrome was 85% in the 0- to 6-month group, 51% in the 6- to 12-month range, and 0% after the 12th month. ROC analysis identified onset within the sixth month as the diagnostic cutoff for progression to Dravet syndrome (sensitivity = 83.3%, specificity = 76.6%). Conclusions: In individuals with SCN1A mutations, age at seizure onset appears to predict outcome better than mutation type. Because outcome is not predetermined by genetic factors only, early recognition and treatment that mitigates prolonged/repeated seizures in the first year of life might also limit the progression to epileptic encephalopathy.

Obstructive Sleep Apnea Syndrome: An Emerging Risk Factor for Dementia.

Epidemiological studies have suggested that obstructive sleep apnea syndrome (OSAS) may increase the risk of developing cognitive impairment. In patients with Alzheimers disease (AD), the prevalence of OSAS is much higher than that expected in cognitively healthy subjects. A deeper knowledge of the pathophysiological link between OSAS and AD and the demonstration that OSAS may directly influence the development of cognitive alterations, would increase prevention and treatment strategies for AD patients. In this article, we discuss the evidence of the association between OSAS and dementia. Moreover, we present data about the functional and anatomic cerebral changes induced by OSAS and the possible effects on cognitive activities and on AD pathogenesis. The possibility to positively influence cognitive impairment by OSAS treatment will be also discussed.

A novel inherited SCN1A mutation associated with different neuropsychological phenotypes: Is there a common core deficit?

We report a three-generation, clinically heterogeneous family in which we identify a novel inherited splicing mutation of the SCN1A gene. Thirteen subjects were submitted to genetic analysis, clinical and instrumental examination, and neuropsychological assessment. In eight subjects, a heterozygous c.2946+5G>A donor splice site alteration in the SCN1A gene was found. Half of them had never had a seizure and showed normal EEG and cognitive profile, whereas the other half had a history of seizures and variable neuropsychological impairments ranging from moderate cognitive disabilities to mild visual-motor impairments. Different clinical phenotypes were identified, including generalized epilepsy with febrile seizure plus (GEFS+), Dravet syndrome, and partial epilepsy with febrile seizure plus (PEFS+). Remarkable clinical heterogeneity can be found among family members carrying the same SCN1A gene mutation. Variable involvement of visual-motor abilities might represent a neuropsychological feature which needs to be further explored in other familial cases.

Emergency room access for recurring seizures: when and why

To develop a hypothetical model identifying potentially modifiable predictive factors of Emergency Room (ER) visits by patients suffering from drug resistant epilepsy.

Sleep Apnea, Cognitive Profile, and Vascular Changes: An Intriguing Relationship

BACKGROUND Sleep breathing disorders can affect cognitive performances through complex brain anatomical and functional changes. OBJECTIVE Our aim was to evaluate the correlations between cognitive performances and obstructive sleep apnea syndrome (OSAS), as well as the possible influence of vascular factors. METHODS Thirty-four non-demented OSAS patients and 34 controls were submitted to a neuropsychological evaluation and to a vascular screening including the study of cerebrovascular reactivity by means of the breath-holding index (BHI) calculation. After 6 months, polisomnographic, neuropsychologic, and hemodynamics assessment was repeated in patients. RESULTS At baseline, some cognitive performances involved in executive and memory functions were significantly lower in patients with respect to controls. Significantly lower values in mean BHI were also detected in patients with respect to controls (p < 0.0001). At the 6-month evaluation, 18 patients had a reduction in OSAS severity (group 1) and 16 remained stable (group 2). Group 1 patients had a significant improvement in left and mean BHI (p < 0.001) and in short-term (p = 0.02) and long-term Rey Auditory Verbal Learning Test (p < 0.001). No change in cerebrovascular reactivity and cognitive profile was detected in group 2 patients. CONCLUSIONS Patients with OSAS may experience a reduced cognitive efficiency. Improvement of OSAS was associated to favorable hemodynamic changes and increased level of performances in verbal memory tasks so suggesting an involvement of vascular underlying mechanisms in sustaining cognitive dysfunctions in OSAS. Our preliminary data suggest the need for further studies to deepen the knowledge about the relationships between OSAS, cerebral hemodynamic compromise, and cognitive impairment risk.

Impact of sleep disorders on the risk of seizure recurrence in juvenile myoclonic epilepsy

OBJECTIVE The aim of this study was to investigate the presence of sleep disturbances in patients with juvenile myoclonic epilepsy (JME) using sleep questionnaires. Further, we tried to evaluate whether alterations in sleep quality may influence the clinical expression of JME. METHODS Sixty-two patients with JME treated with levetiracetam were included. Demographic and clinical variables were collected. Moreover, all patients submitted the Pittsburgh Sleep Quality index (PSQI) and the Epworth Sleepiness Scale (ESS) in order to respectively assess sleep quality during the last month and daytime sleepiness. All patients were followed up for a 6-month period and divided in two groups: seizure-free (Group 1) and seizure recurrence (Group 2). The PSQI and ESS scores were synthesized as binary variables <5/≥5 and <10/≥10, respectively. A comprehensive analysis was performed to evaluate the independent effect of the sleep quality and daytime sleepiness on the risk of having seizures during the follow-up. RESULTS Both reduced sleep quality during the last month and daytime sleepiness were associated with an increased risk of suffering from seizures during the follow-up period. In fact, a PSQI score<5 or an ESS score<10 resulted significantly associated with the absence of seizure recurrence (p<0.004 and p<0.001, respectively). Increasing age had a significantly protective effect in the risk of seizure relapse. CONCLUSIONS Our findings show that reduced sleep quality and daytime sleepiness in patients with JME increase the risk of seizure occurrence in spite of an appropriate pharmacological treatment. This negative effect seems to be more relevant in younger patients. Sleep disorders and their specific correction should be taken into consideration for the management of patients with JME.