Claudia Passamonti

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.

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.

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.

New Association Between Ring Chromosome 20 Syndrome and Hypomelanosis of Ito

Hypomelanosis of Ito is an uncommon neuroectodermal disease associated with a wide range of cytogenetic abnormalities. Ring chromosome 20 is a rare chromosomal disorder characterized by severe, refractory epilepsy, cognitive delay, and unspecific dysmorphic traits. An association between the hypomelanosis of Ito and ring chromosome 20 syndrome was never reported peviously. We describe a young girl who has ring chromosome 20 and who also has clinical symptoms of hypomelanosis of Ito. After her diagnosis of epilepsy, she was submitted to neurologic and genetic testing, a skin biopsy, and repeated neuropsychologic examinations. Karyotyping revealed a 46 XX, r(20) with mosaicism in 34% of peripheral blood lymphocytes and 8% of skin fibroblasts. A severe, progressive cognitive deterioration was evident. The epilepsy was refractory to antiepileptic drugs, in apparent contrast with the evidence that both telomeric regions were preserved. The percentage of mosaicism seems unrelated to the severity of the clinical phenotype.

Vagus nerve stimulation during pregnancy: an instructive case

BackgroundLittle is known about the safety of vagus nerve stimulation during pregnancy.Case ReportHerein we report the case of a young woman affected by childhood-onset partial epilepsy, obesity, and depression in which a malfunctioning of VNS was detected during pregnancy. Although device functioning was not optimal during the critical period of organogenesis, no morphological abnormalities of the fetus were detected.ConclusionA confirmation of VNS safety may increase its use during pregnancy, thus reducing possible systemic effects of antiepileptic drugs and antidepressants on the women and the baby.

Fourth ventricle hamartoma presenting with progressive myoclonus and hemifacial spasms: case report and review of literature

Cerebral hamartomas are rare tumor-like lesions composed of disorganized but mature cells, mostly a combination of neuronal or ganglion cells [1]. These lesions are commonly located in the cortex of temporal and frontal lobes, where may determine chronic or medically intractable epilepsy [2]. Hypothalamic hamartomas represent a rare but important model of subcortical epilepsy. Recent clinical studies, primarily based on intracranial seizure recordings, have established that the hypothalamic hamartoma is intrinsically epileptogenic. In some patients, however, the hamartoma contributes to secondary epileptogenesis affecting the neocortex [3]. Hamartomas of the floor of fourth ventricle (HFFV) are extremely rare. To date, only five cases have been reported in literature [4–7]. Common clinical signs are hemifacial spasms, eye blinking, nystagmic eye movements, and autonomic manifestations. It has been suggested that such signs represent a rare form of cerebellar epilepsy [5–7]. In the present work, we describe a new case of HFFV in a child with progressive myoclonus associated with hemifacial spasms. Other cases reported in literature are reviewed and discussed.

Microsurgical endoscopy-assisted anterior corpus callosotomy for drug-resistant epilepsy in an adult unresponsive to vagus nerve stimulation

Because most of the corpus callosotomy (CC) series available in literature were published before the advent of vagus nerve stimulation (VNS), the efficacy of CC in patients with inadequate response to VNS remains unclear, especially in adult patients. We present the case of a 21-year-old female with medically refractory drop attacks that began at the age of 8 years, which resulted in the patient being progressively unresponsive to vagus nerve stimulation implanted at the age of 14 years. Corpus callosotomy was recommended to reduce the number of drop attacks. However, the patient had only mild cognitive impairments and no neurological deficits. For this reason, we were forced to plan a surgical approach able to maximize the disconnection for good seizure control while, at the same time, minimizing sequelae from disconnection syndromes and neurosurgical complications because in such cases of long-lasting epilepsy the gyri cinguli and the arteries can be tenaciously adherent and dislocated with all the normal anatomy altered. In this scenario, we opted for a microsurgical endoscopy-assisted anterior two-thirds corpus callosotomy. The endoscopic minimally invasive approach proved to be quite adequate in this technically demanding case and confirmed that CC may offer advantages, with good results, even in adult patients with drop attacks who have had inadequate response to VNS.