Lafora disease: spectroscopy study correlated with neuropsychological findings.

PURPOSE: To evaluate the metabolic changes both in grey and white matter in Lafora disease using proton magnetic resonance spectroscopy and to determine the possible correlation with the pattern of cognitive impairment. METHODS: Five patients with Lafora disease and six healthy controls were included in the study. Patients underwent at the same time-point neuropsychological testing and 1[H]MRS, using PRESS sequences (TE=136 and 25 ms) positioned in the frontal and posterior cingulate gyrus cortexes and in the adjacent frontal and parietal white matter. RESULTS: Neuropsychological testing showed in all patients a prevalent involvement of performance abilities--with partial sparing of verbal competences--and of executive functions, suggesting a major involvement of frontal areas. Analysis of 1[H]MRS showed a statistically significant reduction in NAA/mI and NAA/Cr in grey matter of patients compared to controls, more significant in frontal regions. In white matter, a significant reduction of NAA/mI ratio was observed both in the frontal and parietal regions, associated with a reduction of the NAA/Cr only in the frontal white matter. NAA/mI was found to be the most statistically significant altered parameter in all regions studied and the only significantly altered ratio in strong correlation with all sets of neuropsychological parameters. CONCLUSIONS: Our study confirmed the predominant metabolic damage in the frontal cortex, also demonstrating NAA/mI ratio to be the most sensitive parameter to detect metabolic brain changes in Lafora disease; moreover, it evidenced frontal white matter spectroscopic changes. Both spectroscopy values and clinical features of cognitive impairment showed a prevalent frontal impairment.

A pilot study of a ketogenic diet in patients with Lafora body disease.

PURPOSE: Lafora body disease (LBD) is severe and rapidly worsening progressive myoclonus epilepsy (PME), not treatable with specific therapy. In LBD patients, typical polyglucosan accumulations result from alterations of proteins involved in the regulation of glycogen metabolism. Thus, a ketogenic regimen might reasonably be expected to counteract the disease progression. We set out to assess the feasibility and tolerability of a long-term ketogenic diet (KD) in LBD patients and to make a preliminary evaluation of its effect on the disease course. METHODS: We treated five LBD patients with KD and evaluated the changes in the clinical, neuropsychological and neurophysiological findings over 10-30 months. RESULTS: The KD was well tolerated in all the patients for the first 16 months. Nutritional measures and laboratory findings remained substantially stable. The disease progressed in all the patients, reaching an advanced stage in one. Electrophysiological findings indicated the presence of increased cortical excitability in four patients, paralleling the worsening of the myoclonus. CONCLUSION: KD was unable to stop the disease progression. However, given the considerable heterogeneity of the natural history of LBD, we cannot exclude the possibility that KD has the potential to slow down the disease progression. The application of this nutritional approach should be further evaluated in larger case series.

Motor impairment on awakening in a patient with an EEG pattern of "unilateral, continuous spikes and waves during slow sleep".

Movement disorders are rarely described in association with the "continuous spikes and waves during slow sleep (CSWS)" EEG pattern. We report the case of a young girl affected by an epileptic encephalopathy who, from the age of seven years and four months, has twice presented a movement disorder affecting the right arm, manifesting on awakening and disappearing by early afternoon. Sleep EEG during these periods showed continuous, high-amplitude, diphasic spikes and slow waves over the left hemisphere. Association of clobazam, valproic acid and, on the second occasion, ethosuccimide led to disappearance of the above-described EEG picture and associated motor symptoms. Neurophysiological investigations excluded other possible aetiologies. In view of this, and of the close relationship between the EEG picture and clinical course, we interpret the patient's impairment as "motor neglect" secondary to the continuous electrical activity recorded during sleep over the left hemisphere and involving the associative areas. This electrical activity in sleep, may be regarded as a "functional lesion" whose clinical consequences can be correlated with the site of the abnormalities.[Published with video sequences].

The ketogenic diet in children, adolescents and young adults with refractory epilepsy: an Italian multicentric experience.

PURPOSE: This collaborative study by three Italian groups of child neuropsychiatrists was carried on to evaluate the efficacy and safety of the classic 4:1 ketogenic diet as add-on treatment in refractory partial or generalized epilepsy in children, adolescents and young adults. METHODS: We performed a prospective add-on study in 56 refractory epilepsy young patients (age 1-23 years, mean 10.4 years), all with both symptomatic and cryptogenic, generalized or partial epilepsies. Child neuropsychiatrists worked with nutritional team for sample selection and patients management. The ketogenic diet was added to the baseline antiepileptic drugs and the efficacy was rated according to seizure type and frequency. During treatment, seizure frequency, side effects, urine and blood ketone levels and other parameters were systematically evaluated. RESULTS: Patients have been treated for 1-18 months (mean 5 months). A >50% reduction in seizure frequency was gained in 37.5 and 26.8% of patients after 3 and 6 months, respectively, at 12 months, this number fell by 8.9%. No significant relationship between diet efficacy and seizure or epilepsy type, age at diet onset, sex and etiology of epilepsy was noted. Nevertheless, it seems noteworthy that 64% of our patients with neuronal migration disorders improved on this diet. Adverse effects occurred, mainly in the first weeks of treatment, in 32 patients (57.1%), but were generally mild and transient. In seven patients (12.5%) it was possible to withdraw one to two AED after 3-4 months on ketogenic diet. CONCLUSION: This initial experience with the ketogenic diet was effective in difficult-to-treat patients with partial and generalized epilepsies, though its efficacy dropped significantly by 9-12 months.

Topiramate efficacy in an infant with partial seizures refractory to conventional antiepileptic drugs.

Many studies showed that Topiramate (TPM) may be a useful drug in a wide spectrum of childhood epilepsies. We report a 3-month-old female with stormy onset of secondarily generalized partial seizures. She showed a high seizure frequency and a progressive worsening electroencephalogram (EEG), despite standard antiepileptic drugs administration. TPM succeeded in controlling seizures, even after the other drugs were discontinued. This case suggests that TPM may represent a good choice for the treatment of partial seizures refractory to conventional drugs in infants.

Familial severe myoclonic epilepsy of infancy: truncation of Nav1.1 and genetic heterogeneity.

BACKGROUND: Severe myoclonic epilepsy of infancy (SMEI) or Dravet syndrome has been long suspected of having a genetic origin. Recently, mutations in SCN1A and GABRG2 have been described in SMEI patients. The sporadic nature of the SMEI syndrome and the occurrence of SCN1A and GABRG2 mutations in a mild familial phenotype, termed generalized epilepsy with febrile seizure plus complicates genotype-phenotype correlations. In order to further investigate the role of SCN1A and GABRG2 in the pathogenesis of SMEI we have screened for mutations three families with at least two members affected by Dravet syndrome. METHODS: Clinical criteria followed the international classification of epileptic syndromes. Mutational screening of SCN1A and GABRG2 genes was performed by denaturing high performance liquid chromatography (DHPLC) and direct sequencing of DNA fragments showing a variant chromatogram. RESULTS: Thirty-eight fragments spanning 26 exons of SCN1A and nine exons of GABRG2 were analysed in three probands. Five variant chromatograms were identified; four corresponded to known polymorphisms, one to a novel dinucleotide insertion on exon 26 of SCN1A. The mutation leads to a frameshift and a premature stop codon at amino acid 1 779 of the protein. The mutation was present in the affected sibling and was inherited from the mother who had experienced a single febrile seizure in childhood. CONCLUSIONS: Among three families analysed, a single family was mutant for SCN1A. Our study suggests that the syndrome is genetically heterogeneous. The variable expressivity we observed for the c5240insAA mutation suggests that other factors are needed for the development of the full SMEI phenotype.

[Nutritional status and bone mineral mass in children treated with ketogenic diet]. / Stato nutrizionale e mineralizzazione ossea durante trattamento con dieta chetogenica.

Ketogenic diet (KD) is a high fat (90%), low carbohydrate (3%) diet used to treat refractory seizures in child. This highly unbalance diet could damage nutritional status. The aim of this study is to evaluate if KD can affect on growth and on mineral status in child. Seven child (1 females and 6 males) age between 3-16 years were retrospectively studied to assess nutritional status during KD; we evaluated anthropometric measurements (weight, height, skinfold and circumferences), bone mineral content and bone mineral density, using x-ray energy absorptiometry (DXA) and some biochemical parameters. We have not found any short term modifications (six months) concerning growth, and biochemical parameters studied. KD could worsen bone mineral status.

Cryptogenic epileptic syndromes related to SCN1A: twelve novel mutations identified.

BACKGROUND: Sodium channel alpha 1 subunit gene, SCN1A, is the gene encoding the neuronal voltage-gated sodium channel alpha 1 subunit (Na(v)1.1) and is mutated in different forms of epilepsy. Mutations in this gene were observed in more than 70% of patients with severe myoclonic epilepsy of infancy (SMEI) and were also found in different types of infantile epileptic encephalopathy. OBJECTIVE: To search for disease-causing mutations in SCN1A in patients with cryptogenic epileptic syndromes (ie, syndromes with an unknown cause). DESIGN: Clinical characterization and molecular genetic analysis of a cohort of patients. SETTING: University hospitals, rehabilitation centers, and molecular biology laboratories. PATIENTS: Sixty unrelated patients with cryptogenic epileptic syndromes. MAIN OUTCOME MEASURES: Samples of DNA were analyzed for mutations and for large heterozygous deletions encompassing the SCN1A gene. A search for microdeletions in the SCN1A gene was also performed in the subset of patients with SMEI/SMEI-borderland who had negative results at the point mutation screening. RESULTS: No large deletions at the SCN1A locus were found in any of the patients analyzed. In contrast, 13 different point mutations were identified in 12 patients: 10 with SMEI, 1 with generalized epilepsy with febrile seizures plus, and 1 with cryptogenic focal epilepsy. An additional search for SCN1A intragenic microdeletions in the remaining patients with SMEI/SMEI-borderland and no point mutations was also negative. CONCLUSIONS: These results confirm the role of the SCN1A gene in different types of epilepsy, including cryptogenic epileptic syndromes. However, large deletions encompassing SCN1A were not common disease-causing rearrangements in this group of epilepsies.