Martina Balestri

Pontocerebellar hypoplasia type 6 caused by mutations in RARS2: definition of the clinical spectrum and molecular findings in five patients

Recessive mutations in the mitochondrial arginyl-transfer RNA synthetase (RARS2) gene have been associated with early onset encephalopathy with signs of oxidative phosphorylation defects classified as pontocerebellar hypoplasia 6. We describe clinical, neuroimaging and molecular features on five patients from three unrelated families who displayed mutations in RARS2. All patients rapidly developed a neonatal or early-infantile epileptic encephalopathy with intractable seizures. The long-term follow-up revealed a virtual absence of psychomotor development, progressive microcephaly, and feeding difficulties. Mitochondrial respiratory chain enzymes in muscle and fibroblasts were normal in two. Blood and CSF lactate was abnormally elevated in all five patients at early stages while appearing only occasionally abnormal with the progression of the disease. Cerebellar vermis hypoplasia with normal aspect of the cerebral and cerebellar hemispheres appeared within the first months of life at brain MRI. In three patients follow-up neuroimaging revealed a progressive pontocerebellar and cerebral cortical atrophy. Molecular investigations of RARS2 disclosed the c.25A>G/p.I9V and the c.1586+3A>T in family A, the c.734G>A/p.R245Q and the c.1406G>A/p.R469H in family B, and the c.721T>A/p.W241R and c.35A>G/p.Q12R in family C. Functional complementation studies in Saccharomyces cerevisiae showed that mutation MSR1-R531H (equivalent to human p.R469H) abolished respiration whereas the MSR1-R306Q strain (corresponding to p.R245Q) displayed a reduced growth on non-fermentable YPG medium. Although mutations functionally disrupted yeast we found a relatively well preserved arginine aminoacylation of mitochondrial tRNA. Clinical and neuroimaging findings are important clues to raise suspicion and to reach diagnostic accuracy for RARS2 mutations considering that biochemical abnormalities may be absent in muscle biopsy.

Intravenous levetiracetam terminates refractory status epilepticus in two patients with migrating partial seizures in infancy

OBJECTIVE To evaluate the efficacy and tolerability of intravenous (IV) levetiracetam in refractory status epilepticus of migrating partial seizures in infancy (MPSI). METHODS IV levetiracetam was infused in two infants, first as a loading dose of 60mg/kg in 30min, then at 30mg/kg twice a day. Both infants were continuously monitored with video-EEG before, during and after the drug trial. Blood count, liver enzymes, serum creatinine, ammonia and lactate blood levels were performed repeatedly before and after the IV levetiracetam administration. Follow-up was of 16 and 10 months. RESULTS EEG monitoring allowed the diagnosis of MPSI, showing the typical seizures pattern in both patients. IV levetiracetam was effective in stopping status epilepticus in both infants. Levetiracetam also prevented the recurrence of status epilepticus during follow-up. No adverse reactions were observed during the infusion phase or during follow-up. CONCLUSIONS MPSI is a newly recognized epileptic syndrome characterized by early onset of intractable partial seizures arisingly independently and sequentially from both hemispheres, migrating from one region of the brain to another and from one hemisphere to another. We report the efficacy of intravenous levetiracetam in resolving refractory status epilepticus in two infants with this new epilepsy syndrome.

Habituation to Pain in “Medication Overuse Headache”: A CO2 Laser-Evoked Potential Study

(Headache 2012;52:792‐807)

Electroencephalographic features in Dravet syndrome: Five-year follow-up study in 22 patients

The aim of the study was to evaluate interictal electroencephalogram features in 22 patients with Dravet syndrome from the onset of the disease through the next 5 years. Electroencephalogram was abnormal in 5 patients (22.7%) at onset, and in 17 (77.3%) at the end of the study. Epileptiform abnormalities (focal, multifocal, or generalized) were seen in 6 patients at the onset and in 14 (27% vs 64%) at the end of the study. Photoparoxysmal response was present in 41% of patients at the end of follow-up. No statistical differences were found between mutated and nonmutated groups regarding evolution of background activity, interictal abnormalities, and presence of photoparoxysmal response. Electroencephalogram findings seemed to be age dependent, variable among different patients, and not influenced by the presence of sodium channel, voltage-gated, type I, alpha subunit (SCN1A) mutation. The lack of specific epileptiform abnormalities contributes to the difficulty of patients’ management in Dravet syndrome.

Efficacy of levetiracetam in the treatment of drug-resistant Rett syndrome

Rett syndrome (RTT) is a progressive neurological disorder characterized by a wide spectrum of phenotypes. Epilepsy is reported to occur in 50-90% of patients with RTT; some develop medically refractory epilepsy. The aim of this study is to investigate the efficacy of levetiracetam (LEV) in drug-resistant patients with RTT. This prospective, pragmatic, open-label study consisted of an 8-week baseline period and a 6-month evaluation period. Efficacy variable was the mean frequency of monthly seizures before, and after 3 and 6 months of treatment with LEV. Eight female patients, aged 7.5-19 years (M12.8+/-5) entered the study. Mean age at epilepsy onset was 25.8+/-14.1 months. All patients showed MeCP2 mutation. Patients had been treated with a mean of 3.4 AEDs (2-7) before LEV. The mean LEV dose was 44.84+/-18.02mg/kg/day. The mean monthly seizure frequency for all types of seizures during the baseline period was 21.3+/-8.1 (range 10-35); after 3 months it was 3.3+/-4.1 (range 0-9) and after 6 months of LEV treatment it was 1.5+/-2 (range 0-4), p<0.0001. The mean follow-up period was 20.2+/-13 months. Mild sleepiness occurred in two patients, one reported intermittent agitation. Levetiracetam appeared effective in our series of drug-resistant RTT patients. All reported a reduction in seizure frequency and consequently a better quality of life.

Infantile Childhood Onset of Spinocerebellar Ataxia Type 2

Spinocerebellar ataxia type 2 (SCA2) is a late-onset autosomal dominant cerebellar ataxia caused by triplet CAG/CTG expansion in the ATX2 gene. The initial symptoms usually appear when subjects are in their 30s. Pediatric onset is less common and usually associated with larger triplet expansions. We here report the case of a 1-year-old girl who presented with facial dysmorphism, dystonic features, developmental delay, and retinitis pigmentosa. She was diagnosed as carrying an expanded CAG/CTG tract (92 repeats) before a molecular diagnosis of SCA2 was made in her father. Facial dysmorphism associated with developmental delay and retinitis pigmentosa in early childhood should prompt a careful family investigation for ataxia and study of ATX2.

Rapid and safe response to low-dose carbamazepine in neonatal epilepsy.

To evaluate treatment responses in benign familial neonatal epilepsy (BFNE).

Role of the Attachment Style in Determining the Association Between Headache Features and Psychological Symptoms in Migraine Children and Adolescents. An Analytical Observational Case–Control Study

We aimed to study the role of attachment style on headache severity and psychological symptoms in migraineurs children/adolescents. Moreover, we investigated the association between attachment style, migraine severity, and psychological symptoms.

Features of aura in paediatric migraine diagnosed using the ICHD 3 beta criteria

Background In children and adolescents, the prevalence rate of migraine with aura is 1.6%. Few studies concerning migraine with aura features in paediatric population have been reported. Aim The aim of our study was to investigate clinical features of aura in a retrospective cohort of children with migraine with aura. Furthermore, we studied whether the International Classification of Headache Disorder (ICHD) 3 beta version criteria could efficiently detect migraine with aura in a paediatric population. Results We included 164 patients who experienced aura associated with headache (mean age 9.92 ± 2.64 years). When the ICHD-II criteria were used, a final diagnosis of migraine with typical aura was obtained in 15.3% of patients, probable migraine with typical aura in 13.4%, and typical aura with headache in 61.8%, while in in 9.5% of patients the diagnosis was undetermined. According to ICHD-3 beta, we diagnosed migraine with typical aura in 77.7% of patients, probable migraine with typical aura in 13.4%, and an undetermined diagnosis in 9.5% (less than two attacks). Conclusion Aura features did not depend on age and were similar to those of adults. However, the headache could be difficult to classify if headache duration was considered. In this view, the ICHD-3 beta offers the advantage of not considering headache features, including pain duration, for the diagnosis of migraine with typical aura, thus making this diagnosis easier in children and adolescents.

Mild hypothermia and hemorrhagic lesions in neonates with hypoxic-ischemic encephalopathy: experience in an outborn center

Abstract Objective: Therapeutic hypothermia (TH) started within six hours from birth has been shown to improve neurodevelopmental outcomes in newborns with moderate-to-severe hypoxic-ischemic encephalopathy. Methods: Twenty-nine consecutive newborns treated with whole body cooling at the Bambino Gesú Childrens Hospital between March 2011 and December 2012 were included in this study. All infants were out-born neonates. Passive cooling was always started at the birth center and continued during transportation. Pre- and post-transport risk index of physiological stability (TRIPS) scores were calculated for each patient to evaluate the impact of the transportation. Magnetic resonance imaging (MRI) was performed within 10 days of life to investigate the presence of brain injury. Results: Among the 26 survivors, 14 had no detectable lesions and 12 presented with brain injury on MRI. Four babies presented with cerebral bleeding. Babies with cerebral hemorrhage had a worse pre-transport TRIPS score, but among these neonates no worsening between pre and post-transport score was registered. Conclusion: The presence of cerebral hemorrhagic lesions seemed to be related to the initial clinical conditions of the baby rather than to the transport itself. Our data confirm that TH performed in an out-born center is efficient and safe.