Giulia Prato

Type 1 diabetes and epilepsy: more than a casual association?

To the Editors: In 2006, McCorry et al. reported a strong epidemiologic association between type 1 diabetes mellitus (T1DM) and idiopathic generalized epilepsy (IGE) and claimed that this link would support an autoimmune pathogenesis for IGE (McCorry et al., 2006). However, O’Connel and coworkers did not confirm an increased risk of epilepsy among a series of patients with T1DM (O’Connell et al., 2008). We reviewed 249 T1DM patients (145 male; mean age 16.3 € 7.02 years, range 1.7–34.5 years; mean age at disease onset 7.7 € 6.9 years; range 0.8–18 years) attending the Diabetes Clinic at G. Gaslini Institute, Genoa, where a collaborative network provides epidemiologic data by an active surveillance model (Cotellessa et al., 2003). Extensive research was undertaken through the electronic database and subjects not followed up during the previous year were excluded. Epilepsy was diagnosed when ‡2 unprovoked euglycemic seizures (blood glucose >3.9 and <11.1 mmol/L) and syndromic classification (Commission on Classification and Terminology of the ILAE, 1989) was confirmed by reviewing clinical (family history, seizures type onset and frequency, response to treatment) and instrumental [electroencephalography (EEG), neuroimaging] data. Among 249 T1DM patients, 6 showed the electroclinical features of idiopathic epilepsy (4 IGE, 2 focal idiopathic epilepsy) (Table 1). In this group, mean age of T1DM onset was 4.6 € 2.7 years; mean age at first seizure was 6.7 € 4.4 years. None of these patients had a family history of epilepsy in firstand second-degree relatives. In all patients but one (case 4), T1DM preceded epilepsy onset, with a mean of 2.8 years (range 0.7–6.9 years). Patient 1 had concomitant celiac disease. Dosage of glutamic-acid decarboxylase antibodies (GADA) was available in two patients at T1DM diagnosis and in all cases at the last follow-up (Table 1). The high proportion of IGE observed in our series (4 of 249, 1.6%) (Hauser & Banerjee, 2008) confirms the data reported by McCorry et al. (McCorry et al., 2006). In all patients but one, T1DM manifested years before epilepsy. This may simply reflect different age of onset of the two conditions. Alternatively, it could support an autoimmune mechanism starting with T1DM and then affecting the central nervous system (McCorry et al., 2006). We did not perform GADA evaluation methodically at epilepsy onset in our patients, so that no definitive conclusion can be drawn about the existence of a pathogenetic link between GADA and epilepsy in T1DM patients (Striano et al., 2008). Interestingly, the patient with partial response to antiepileptic therapy (case 4) is the only one with recent GADA positivity. Because of the retrospective analysis, epilepsy could be underrecognized or overestimated in our T1DM population, but this is unlikely to explain the higher than expected degree of the association. Because both epilepsy and T1DM are serious worldwide problems with high medical and social management costs, this possible association deserves further investigation by prospective studies involving multiple centers.

Epileptic Encephalopathy With Continuous Spike and Wave During Sleep Associated to Periventricular Leukomalacia

Periventricular leukomalacia is the most common type of brain injury in premature infants. Our aim is to describe the frequency and the features of epilepsy in a single-center population of 137 children with periventricular leukomalacia. Forty-two of the 137 (31%) patients presented epilepsy. Twelve percent of these patients presented West syndrome, whereas 19% showed a pattern of continuous spike-waves during slow sleep syndrome. In the latter group, outcome was frequently unfavorable, with a greater number of seizures and more drug resistance. A significant association was found between epilepsy and neonatal seizures, spastic tetraplegia, and mental retardation. Although less common than in other forms of brain injury, epilepsy is nevertheless a significant complication in children with periventricular leukomalacia. The fairly frequent association with continuous spike-waves during slow sleep syndrome deserves particular attention: electroencephalographic sleep monitoring is important in order to provide early treatment and prevent further neurologic deterioration.

Magnetic resonance imaging "tigroid pattern" in Alexander disease.

Alexander disease (AD) is a rare white matter disorder resulting from mutations in the gene encoding for the glial fibrillary acidic protein. Diffuse white matter involvement with frontal predominance is typical of infantile AD that is clinically characterized by progressive motor and mental retardation, seizures, and megaloencephaly. We describe the case of a 10-year-old patient harboring a de novo missense mutation c.235C > T (p.R79C) in the GFAP gene, showing a relatively slow clinical and neuroradiologic progression of disease associated with a previously unreported magnetic resonance imaging (MRI) finding consistent with the so-called tigroid pattern. This pattern has been previously described in only a few different neurologic conditions, including Pelizaeus-Merzbacher disease and some lysosomal disorders. This report expands the spectrum of MRI features in AD.

Patterns of care of brain tumor-related epilepsy. A cohort study done in Italian Epilepsy Center

Epilepsy is the most common comorbidity in patients with brain tumors. Study Aims: To define characteristics of brain tumor-related epilepsy (BTRE) patients and identify patterns of care. Nationwide, multicenter retrospective cohort study. Medical records of BTRE patients seen from 1/1/2010 to 12/31/2011, followed for at least one month were examined. Information included age, sex, tumor type/treatments, epilepsy characteristics, antiepileptic drugs (AEDs). Time to modify first AED due to inefficacy and/or toxicity was assessed with the Kaplan-Meier method and Cox proportional hazard models were used to identify predictors of treatment outcome. Enrolled were 808 patients (447 men, 361 women) from 26 epilepsy centers. Follow-up ranged 1 to 423 months (median 18 months). 732 patients underwent surgery, 483 chemotherapy (CT), 508 radiotherapy. All patients were treated with AEDs. Levetiracetam was the most common drug. 377 patients (46.7%) were still on first drug at end of follow-up, 338 (41.8%) needed treatment modifications (uncontrolled seizures, 229; side effects, 101; poor compliance, 22). Treatment discontinuation for lack of efficacy was associated with younger age, chemotherapy, and center with <20 cases. Treatment discontinuation for side effects was associated with female sex, enzyme-inducing drugs and center with > 20 cases. About one-half of patients with BTRE were on first AED at end of follow-up. Levetiracetam was the most common drug. A non enzyme-inducing AED was followed by a lower risk of drug discontinuation for SE.

Reversible cerebral vasoconstriction complicating cerebral atherosclerotic vascular disease in Schimke immuno-osseous dysplasia

Dear Editor-in-Chief, Schimke immuno-osseous dysplasia (SIOD) is an uncommon autosomal-recessive multisystem disease caused by mutations in SMARCAL1, a gene encoding a chromatin-remodeling enzyme that stabilizes stalled replication forks and prevents replication-associated DNA damage (OMIM 242900) [1]. The disease is characterized by spondyloepiphyseal dysplasia, nephropathy, immunodeficiency, and growth failure. Several neurologic manifestations have been described, including microcephaly, intellectual disability, seizures, stroke, transient neurological attack, and migraine-like headache [1]. Cerebrovascular pathology in SIOD may result from several predisposing factors, such as renal disease and immune dysfunction, leading to occlusive disease and early atherosclerosis [2]. Recently, Morimoto et al. demonstrated that vascular complications may also arise from impaired vascular elastogenesis, showing decreased elastin expression in vascular tissues, leading to disorganized internal elastic lamina and medial/intimal hyperplasia [3]. In this letter, we describe reversible cerebral vasoconstriction syndrome (RCVS) in a pediatric patient with SIOD and intracranial atherosclerotic vascular disease, proposing RCVS as a novel mechanism for cerebrovascular complications in this rare condition. A 9-year-old girl with SIOD on peritoneal dialysis secondary to end-stage renal disease presented during febrile infection with severe headache followed by drowsiness, seizures, acute aphasia, and right hemiparesis. On admission, the blood pressure was 144/82 mmHg. Her previous medical history was characterized by several episodes of myoclonic seizures and milder migraine-like events, starting from the age of 5 years, with evidence of progressive cerebral atherosclerotic vasculopathy and small vessel disease (Fig. 1). These migraine-like episodes were similarly triggered by hypertensive peaks and/or fever and were resistant to common analgesic therapy. Brain MRI and MRA studies performed at clinical onset (Fig. 2a–c), and after 1 week, revealed severe diffuse vasoconstriction of the circle of Willis and left fronto-temporoparietal ischemic lesion. Cerebral perfusion assessed by arterial spin labeling (ASL) revealed decreased perfusion in both hemispheres (Fig. 2d). Cerebrospinal fluid analysis and serological tests were normal. The patient was treated with carvedilol and dual antiplatelet therapy (aspirin plus clopidogrel). Her symptoms slowly improved in the following weeks. Brain MRI and MRA performed 1 month later demonstrated resolution of intracranial vasoconstriction with marked improvement of the ASL perfusion signal, except in the infarcted area (Fig. 2e–h). Clinical-neuroradiological features were suggestive of reversible cerebral vasoconstriction syndrome (RCVS). Six months later, she presented with headache, drowsiness and left hemiparesis, and neuroimaging features consistent with another RCVS episode (Fig. 2i–l). RCVS is a rare often underrecognized condition, characterized by ‘thunderclap’ headaches and reversible segmental vasoconstriction of cerebral arteries, occasionally complicated by ischemic or hemorrhagic stroke [4, 5]. The syndrome is mostly described in adult women, usually triggered by pregnancy, serotonin agonist medications, or illicit drug use. Hypertension is commonly observed but it is not clear if as a trigger factor or as a consequence of sympathetic tone disturbances. Only few pediatric cases have been described so far, with higher male prevalence [4]. The exact mechanisms of RCVS remain unknown. Indeed, it likely represents a common end point of different disease processes, in which alterations in cerebral vascular tone, * Mariasavina Severino mariasavinaseverino@gaslini.org

CNNM2 homozygous mutations cause severe refractory hypomagnesemia, epileptic encephalopathy and brain malformations

Magnesium (Mg2+) plays a crucial role in many biological processes especially in the brain, heart and skeletal muscle. Mg2+ homeostasis is regulated by intestinal absorption and renal reabsorption, involving a combination of different epithelial transport pathways. Mutations in any of these transporters result in hypomagnesemia with variable clinical presentations. Among these, CNNM2 is found along the basolateral membrane of distal tubular segments where it is involved in Mg2+ reabsorption. To date, heterozygous mutations in CNNM2 have been associated with a variable phenotype, ranging from isolated hypomagnesemia to intellectual disability and epilepsy. The only homozygous mutation reported so far, is responsible for hypomagnesemia associated with a severe neurological phenotype characterized by refractory epilepsy, microcephaly, severe global developmental delay and intellectual disability. Here, we report the second homozygous CNNM2 mutation (c.1642G > A,p.Val548Met) in a Moroccan patient, presenting with hypomagnesemia and severe epileptic encephalopathy. Thus, we review and discuss the phenotypic spectrum associated with CNNM2 mutations.