Clinical dissection of childhood occipital epilepsy of Gastaut and prognostic implication.

BACKGROUND AND PURPOSE: Our aim was to describe the clinical and electrical features and the long-term evolution of childhood occipital epilepsy of Gastaut (COE-G) in a cohort of patients and to compare long-term prognosis between patients with and without other epileptic syndromes. METHODS: This was a retrospective analysis of the long-term outcome of epilepsy in 129 patients with COE-G who were referred to 23 Italian epilepsy centres and one in Austria between 1991 and 2004. Patients were evaluated clinically and with electroencephalograms for 10.1-23.0 years. The following clinical characteristics were evaluated: gender, patient age at seizure onset, history of febrile seizures and migraine, family history of epilepsy, duration and seizure manifestations, circadian distribution and frequency of seizures, history of medications including the number of drugs, therapeutic response and final outcome. RESULTS: Visual hallucinations were the first symptom in 62% and the only manifestation in 38.8% of patients. Patients were subdivided into two groups: group A with isolated COE-G; group B with other epileptic syndromes associated with COE-G. The most significant (P < 0.05) difference concerned antiepileptic therapy: in group A, 45 children responded to monotherapy; in group B only 15 children responded to monotherapy. At the end of follow-up, the percentage of seizure-free patients was significantly higher in group A than in group B. CONCLUSIONS: Childhood occipital epilepsy of Gastaut has an overall favourable prognosis and a good response to antiepileptic therapy with resolution of seizures and of electroencephalogram abnormalities. The association of typical COE-G symptoms with other types of seizure could be related to a poor epilepsy outcome.

Rufinamide in refractory childhood epileptic encephalopathies other than Lennox-Gastaut syndrome.

BACKGROUND: To report on the first multicenter Italian experience with rufinamide as adjunctive drug in children, adolescents and young adults with refractory childhood-onset epileptic encephalopathies other than Lennox-Gastaut syndrome. METHODS: Thirty-eight patients (19 males, 19 females), aged between 4 and 34 (mean 13.7 ± 8.3, median 12.5), all affected by different types of childhood-onset refractory epileptic encephalopathies other than Lennox-Gastaut syndrome, were treated with rufinamide as adjunctive drug for a mean period of 11.4 months (range 3-26 months). RESULTS: Fifteen of 38 patients (39.5%) had a ≥ 50% seizure reduction in countable seizures. Complete seizure freedom was achieved in one of these patients (2.6%). Three patients (7.9%) had a 25-49% seizure reduction, whilst seizure frequency remained unchanged in 15 (39.5%) and increased in five patients (13.1%). Eleven patients (28.9%) reported adverse side effects. Vomiting was reported in five patients (13.1%); drowsiness, decreased appetite and irritability with migraine manifested in other four patients. They were transient and mild in all cases. CONCLUSION: Rufinamide may be an effective and well-tolerated adjunctive drug for the treatment of refractory childhood-onset epileptic encephalopathies other than Lennox-Gastaut syndrome. Rufinamide was most effective in patients with drop-attacks and (bi)frontal spike-wave discharges.

Deep brain stimulation in patients with long history of drug resistant epilepsy and poor functional status: Outcomes based on the different targets.

BACKGROUND: Deep brain stimulation (DBS) is a widely used surgical procedure for the treatment of patients with drug resistant epilepsy (DRE) and several anatomical target have been described. Indications for DBS includes patients with focal, partial seizure and those for which resective or disconnective surgery are contraindicated, such as involvement of eloquent cortex or significant comorbidities. Despite the SANTE trial has clearly indicated the efficacy of DBS of anterior nucleus of the thalamus (ANT), specific indications regarding the best anatomical target and outcome in patients with severe disability are lacking. Here we described our case series of patients underwent DBS of three different target including ANT, centromedian thalamic nucleus (CMN) and subthalamic nucleus (STN). METHOD: Six patients with DRE have been treated with DBS of ANT (n = 3), STN (n = 2) and CMN (n = 1). Outcome has been expressed as seizures frequency reduction and patients functional status after surgery with a follow-up of 5-11 years. RESULTS: Four out of six patients show no reduction of seizures frequency after DBS implant with one case of increasing atypical absence. Two cases, one ANT and one CMN, show a significant reduction of seizures frequency of 50-60%. No patients improve relative to functional outcome and one showed psychiatric symptoms worsening. CONCLUSIONS: For patients with DRE and severe functional disability, DBS may reduce seizure frequency in some cases, but it does not improve functional outcome.

Cingulate epilepsy in a child with a low-grade glioma.

INTRODUCTION: Anterior cingulate epilepsy is a peculiar epileptic syndrome with a broad range of clinical manifestations, depending on the numerous projections of anterior cingulate into motor systems. Its diagnosis is often delayed, as seizures mostly occur during sleep and are typically misdiagnosed as parasomnias. Moreover, most focal anterior cingulate epilepsies are believed to be cryptogenic or idiopathic, even if there are some reports of anterior cingulate cortical dysplasia, while anterior cingulate neoplasms underlying epilepsy are rare. CASE REPORT: Here, we report a 30-month-old boy who developed, at the age of 20 months, cingulate epilepsy associated with a low-grade oligodendroglial tumor. It must outlined that the clinical presentation was characterized by very frequent and disabling seizures as the only symptom of the disease, while the results of several neuropsychological tests suggested intact intellectual and behavioral abilities. DISCUSSION AND CONCLUSION: Seizures disappeared completely after surgical removal of the lesion and neuropsychological child's performances remained completely normal. Long-term follow-up and observation are essential for evaluating the future clinical course.

Efficacy and safety of levetiracetam in infants and young children with refractory epilepsy.

The aim of this multicentric, retrospective, and uncontrolled study was to evaluate the efficacy and safety of levetiracetam (LEV) in 81 children younger than 4 years with refractory epilepsy. At an average follow-up period of 9 months, LEV administration was found to be effective in 30% of patients (responders showing more than a 50% decrease in seizure frequency) of whom 10 (12%) became seizure free. This efficacy was observed for focal (46%) as well as for generalized seizures (42%). In addition, in a group of 48 patients, we compared the initial efficacy (evaluated at an average of 3 months of follow-up) and the retention at a mean of 12 months of LEV, with regard to loss of efficacy (defined as the return to the baseline seizure frequency). Twenty-two patients (46%) were initial responders. After a minimum of 12 months of follow-up, 9 of 48 patients (19%) maintained the improvement, 4 (8%) of whom remained seizure free. A loss of efficacy was observed in 13 of the initial responders (59%). Maintained LEV efficacy was noted in patients with focal epilepsy and West syndrome. LEV was well tolerated. Adverse events were seen in 18 (34%) patients. The main side effects were drowsiness and nervousness. Adverse events were either tolerable or resolved in time with dosage reduction or discontinuation of the drug. We conclude that LEV is safe and effective for a wide range of epileptic seizures and epilepsy syndromes and, therefore, represents a valid therapeutic option in infants and young children affected by epilepsy.

Effectiveness and tolerability of perampanel in children and adolescents with refractory epilepsies-An Italian observational multicenter study.

PURPOSE: To evaluate the efficacy and tolerability of Perampanel (PER) in children and adolescents with refractory epilepsies in daily clinical practice conditions. PATIENTS AND METHODS: This Italian multicenter retrospective observational study was performed in 16 paediatric epilepsy centres. Inclusion criteria were: (i) ≤18 years of age, (ii) history of refractory epilepsy, (iii) a follow-up ≥5 months of PER add-on therapy. Exclusion criteria were: (i) a diagnosis of primary idiopathic generalized epilepsy, (ii) variation of concomitant AEDs during the previous 4 weeks. Response was defined as a ≥50% reduction in monthly seizure frequency compared with the baseline. RESULTS: 62 patients suffering from various refractory epilepsies were included in this study: 53% were males, the mean age was 14.2 years (range 6-18 years), 8 patients aged <12 years. Mean age at epilepsy onset was 3.4 years and the mean duration of epilepsy was 10.8 years (range 1-16), which ranged from 2 seizures per-month up to several seizures per-day (mean number=96.5). Symptomatic focal epilepsy was reported in 62.9% of cases. Mean number of AEDs used in the past was 7.1; mean number of concomitant AEDs was 2.48, with carbamazepine used in 43.5% of patients. Mean PER daily dose was 7.1mg (2-12mg). After an average of 6.6 months of follow-up (5-13 months), the retention rate was 77.4% (48/62). The response rate was 50%; 16% of patients achieved ≥75% seizure frequency reduction and 5% became completely seizure free. Seizure aggravation was observed in 9.7% of patients. Adverse events were reported in 19 patients (30.6%) and led to PER discontinuation in 4 patients (6.5%). The most common adverse events were behaviour disturbance (irritability and aggressiveness), dizziness, sedation and fatigue. CONCLUSION: PER was found to be a safe and effective treatment when used as adjunctive therapy in paediatric patients with uncontrolled epilepsy.

Open comparative long-term study of vigabatrin vs carbamazepine in newly diagnosed partial seizures in children.

OBJECTIVE: To compare vigabatrin with carbamazepine as monotherapy in newly diagnosed children with partial epilepsy in order to evaluate the efficacy and tolerability of both drugs. DESIGN: Open and randomized with a 2-year follow-up period. SETTING: The Infantile Neuropsychiatric Division of the Regional Pediatric Hospital, Ancona, Italy. PATIENTS: Seventy children with newly diagnosed partial epilepsy were treated with vigabatrin (38 patients) or carbamazepine (32 patients). INTERVENTION: Vigabatrin, 50 to 60 mg/kg per day, or carbamazepine, 15 to 20 mg/kg per day, split into twice-a-day doses. OUTCOME MEASURES: The efficacy and tolerability of vigabatrin were compared with those of the standard treatment (carbamazepine) for this patient group. RESULTS: The efficacy of vigabatrin and carbamazepine was similar, with the suggestion of a better side effect profile with vigabatrin. CONCLUSIONS: Vigabatrin monotherapy should be considered as a monotherapeutic treatment option in patients with newly diagnosed epilepsy. However, more studies are needed to evaluate other issues of concern, such as the cognitive and behavioral adverse effects of antiepileptic drugs, to determine the most suitable therapy.

Joubert syndrome with associated corpus callosum agenesis.

In 1969, Joubert et al. studied a family where four of six children had a severe clinical condition with episodic alternate hyperpnoea and apnoea, hypotonia, ataxia, psychomotor delay, and abnormal ocular movements. Two of the four had agenesis of the posterior-inferior part of the cerebellar vermis and two had complete agenesis of the vermis. We report a 5-month-old girl with Joubert syndrome in whom MRI shows both features typical of this condition and associated corpus callosum agenesis. To our knowledge, complete callosal agenesis has been infrequently reported in children with Joubert syndrome; consequently, it might be regarded as a casual finding. Nevertheless, the hypothesis of a developmental abnormality of midline structures extended to the supratentorial compartment is rather attractive.

Hearing assessment in developmentally impaired infants: classical conditioning as a supplement to brainstem-evoked response audiometry (BERA).

The brainstem-evoked response audiometry (BERA) is probably the most common approach to hearing assessment in high-risk and developmentally handicapped infants. It is usually suggested, however, that BERA should not be the sole assessment method. In an attempt to determine an effective supplement to BERA, the present study evaluated a classical conditioning procedure with developmentally impaired babies. Within this procedure, different tones served as conditioned stimuli while an air-puff was used as the unconditioned stimulus. Results indicate that this procedure could be successfully applied with almost all of the babies.

Effectiveness of vagal nerve stimulation (VNS) in patients with drop-attacks and different epileptic syndromes.

PURPOSE: The effectiveness of VNS was evaluated in thirty-nine encephalopatic patients with drug-resistant epilepsy characterized by multiple seizures and drop attacks. Twenty-five patients were affected by severe epilepsy with multiple independent spike foci (SE-MISF) and fourteen patients by Lennox-Gastaut syndrome (LGS). METHOD: Changes in seizure frequency, cognition, adaptive behaviour and quality of life were assessed before and after VNS implant until three years. Outcome assessment for all seizure types included the number of seizures/month and the reduction in seizure frequency rate at each follow-up. Moreover, the effect of VNS on frequency, duration and intensity of drop attacks was separately addressed by a modification of McHugh scale. RESULTS: VNS produced a mean seizure rate reduction of 41% at six months, 50% at twelve months, and 54% at thirty-six months. After one year of stimulation, thirteen patients with SE-MISF (52%) and three patients with LGS (21%) showed a reduction above 50% in all seizures' frequency rate. As for drop attacks, eight patients (20%) gained a reduction above 50%, while seven patients (17%) showed a reduction only in intensity and duration. Cognitive level and adaptive behaviour were unchanged, while a better quality of life was reported in half out of the patients. CONCLUSIONS: VNS had a greater effect in reducing seizures frequency and drop attacks' intensity and duration in SE-MISF patients than LGS patients. An improved quality of life was observed also in those patients who only reduced the intensity and duration of drop attacks.

Diagnosing Sjögren-Larsson syndrome in a 7-year-old Moroccan boy.

Sjögren-Larsson syndrome (SLS) is an autosomal recessively inherited neurocutaneous disorder characterized by the triad of congenital ichthyosis, mental deficiency, and spastic diplegia or tetraplegia. Less common features are retinal changes, short stature, kyphoscoliosis, preterm birth, photophobia, reduction of visual acuity, seizures, and delayed speech. SLS is characterized by a genetic block in the oxidation of fatty alcohol to fatty acid because of deficient activity of fatty aldehyde dehydrogenase (FALDH), a component of the fatty alcohol: NAD oxidoreductase enzyme complex. As in other rare multisystem diseases, the diagnosis of SLS is often delayed. The definitive test for SLS is considered the measurement of FALDH or fatty alcohol: NAD oxidoreductase in cultured skin fibroblasts. Nevertheless, if specific FALDH activity test or DNA FALDH gene mutation tests are not available (as in our country), a reliable diagnosis of SLS is also possible when it is based on the matching of peculiar clinical, histologic and ultrastructural, laboratoristic, and imaging features. The simultaneous presence of cutaneous histologic features including hyperkeratosis, orthokeratosis, thickening of granular layer, abnormal lamellar inclusions in the cytoplasm of granular and horny cells (demonstrated by light and electron microscopy) in a child with ichthyosis, and typical neurologic abnormalities is highly suggestive of SLS. We describe the case of a young Moroccan boy presenting with ichthyosis, mental retardation, spastic diplegia, and peculiar skin histologic findings.

Atypical Clinical Picture in a Patient with Benign Occipital Epilepsy: Diagnostic Contribution of Morpho-Functional MR. A Case Report.

Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is a maternally inherited disease due to mitochondrial DNA (mtDNA) point mutations. The clinical phenotype varies in relation to the systems affected, age at onset and disease severity. The characteristic signs of MELAS are nausea and vomiting due to acidosis, headache, epilepsy, ataxia or generalized weakness, ophthalmoplegia, motor and sensory focal neurological deficits. The clinical course may improve due to partial regression of the typical lesions, but the prognosis is usually adverse. A 19-year-old man with a diagnosis of benign occipital epilepsy and resumption of seizure activity with focal occipital attacks since the age of 14 years came to our attention for the recent onset of drug-resistant electroclinical seizures of long duration with complex symptoms, where the dominant clinical feature was an intense, persistent bilateral periorbital migraine with nausea and vomiting, scintillation scotomata and blurring of vision. MR studies were performed at our institution in the immediate post-seizure phase and then at one week, three and six months. The acute-phase morphological scans showed a right cortical-subcortical area with altered signal in the occipitopolar region that was hypointense on T1 and hyperintense on T2 and FLAIR, with cortical thickening and effacement of the sulci. Contrast-enhanced scans did not demonstrate BBB alterations. The DWI scans showed a right temporo-occipital cortical area with higher signal intensity. In the subsequent examinations the area with altered signal shrank gradually and significantly in parallel with improvement in clinical conditions. The diagnostic hypothesis of benign occipital epilepsy was consistent neither with the clinical course, characterized by persistent headache, visual disturbance and refractoriness to antiepileptic drugs, nor with the temporal-occipital cortical MR findings, which resembled ischemic lesions but displayed a non-territorial pattern as well as reversibility over time. These elements guided in the diagnosis of MELAS, which was subsequently confirmed by identification of the typical gene mutation. On DWI the stroke-like lesions of MELAS are seen more frequently as focal hyperintense areas compared with healthy parenchyma. Such high signal intensity likely corresponds to T2 shine-through rather than cytotoxic edema. Indeed, several studies have demonstrated that in acute-phase scans of MELAS stroke-like lesions DWI hyperintensity is associated with increased ADC values that are not associated with restricted water diffusivity, reflecting the metabolic rather than anoxic-ischemic nature of these changes. In the present case, morphological MR associated with DWI was very helpful in guiding the diagnosis by demonstrating some pathognomonic features of MELAS stroke-like lesions such as cortical-subcortical involvement of the posterior hemispheres, the non-territorial pattern, lesion reversibility and the pathophysiological role of vasogenic edema in inducing an increase in extracellular water and thus in diffusion values.

Leigh Syndrome: an MR Study of Three Cases.

Leigh syndrome (LS), or subacute necrotizing encephalomyelopathy, is the most common childhood mitochondrial encephalopathy, accounting for more than 50% of cases in this age group. Its estimated incidence is 1:40,000 - 1:77,000 liveborn infants a year. LS is a rare progressive multisystem fatal disorder inherited by autosomal recessive, X-linked and maternal transmission. Clinical onset is predominantly in the first two years of life (average: six months); 50% of patients die within a year, even though there are later- and even adult-onset forms with a more protracted evolution. LS is due to a deficit of various respiratory chain and Krebs cycle enzymes resulting in insufficient production of adenosine triphosphate (ATP), in particular cytochrome-c-oxidase (COX), pyruvate carboxylase, pyruvate dehydrogenase complex and complex I of the respiratory chain, which share an autosomal recessive and X-linked mode of transmission. Cases with maternal inheritance (MILS) are due to a mitochondrial DNA (mtDNA) point mutation. LS is clinically heterogeneous in relation to the severity of the metabolic dysfunction and is characterized by muscle involvement and especially CNS disorders, particularly psychomotor retardation, ocular symptoms, hypotonia and pyramidal signs. Death is most commonly due to respiratory failure, status epilepticus and sudden coma. The major neuropathological findings, first described by Leigh in 1951, are symmetrical foci of spongy necrosis associated with vessel proliferation and reactive gliosis in basal nuclei, brainstem and thalamus grey matter. The neuronal metabolic alteration can also affect the white matter, resulting in delayed myelination or hypomyelination. The diagnosis rests on clinical signs, elevated CSF lactate, pyruvate and alanine, and biochemical and neuroradiological data. We describe two patients with LS studied with morphological MR associated with diffusion and spectroscopy techniques to assess the diagnostic potential of standard MR imaging and establish whether the association of functional MR methods can improve its diagnostic accuracy. A case of LS with a post-mortem MR study is also described. Three patients with a diagnosis of LS based on clinical, CSF and laboratory data were studied on a GE SIGNA EXCITE 1.5 T unit using an eight-channel phased-array head coil to acquire standard sequences (SE T1; TSE DP T2; FLAIR) and echo-planar diffusion-weighted sequences (DWI; b= 1000 s/mm2) with calculation of ADC maps. The spectroscopic study used single-voxel (TE/TR ms = 144/1500) and multi-voxel techniques (TE/TR ms = 144/1000) at the level of the basal nuclei. Bilateral and symmetrical involvement of basal nuclei grey matter with T2 hyperintensity was a consistent finding in the morphological MR study. In one patient, associated white matter involvement with T2 hyperintensity in periventricular and retrotrigonal areas reflected delayed myelination or hypomyelination. The deep grey matter changes, sometimes associated with white matter lesions, suggested a diagnosis of subacute necrotizing encephalomyelopathy, in line with the literature. Acute-phase ADC values in affected areas were lower than those of normal grey and white matter and displayed signal hyperintensity on DWI. Reduced ADC values are associated with restricted water diffusivity typical of cytotoxic edema. Spectroscopy showed a high lactate peak, reflecting altered anaerobic glycolysis, and a reduced NAA peak in affected areas, which are however non-specific findings. The most informative study in these patients is standard MR associated with functional techniques, which can confirm the diagnosis obtained with morphological imaging.

Complications of vagal nerve stimulation for epilepsy in children.

Vagal nerve stimulation (VNS) is a surgical option to treat drug-resistant epilepsy. A few side effects have been described, mainly as anecdotal reports. We analysed our material concerning a juvenile population to identify the most common and most important complications, discussing them with the literature. Thirty-six patients were studied (18 months-18 years old). The children were assessed before the VNS implant and 3, 6, 12, 24 and 36 months after surgery. The mean follow-up was 30 months. Four patients required a second surgery: two for changing the device 3 years after implant; one for revision of an imperfect implant; one for removing a non-functioning device. In one patient a transient vocal cord paralysis was observed. Hoarseness was the main complaint (38.8%). More infrequent was mild sleep apnoea (8.3%), sternocleidomastoid muscle spasm, drooling and snoring in one patient each. Skin scars were reported with a different frequency according to the surgical technique. At variance with the literature reports, we did not observe infections. Side effects of VNS can be minimised, but not avoided completely, with a correct technical procedure, which in turn depends upon a thorough knowledge of vagus nerve anatomy.

Central pattern generators for a common semiology in fronto-limbic seizures and in parasomnias. A neuroethologic approach.

Central pattern generators (CPGs) are genetically determined neuronal aggregates in the mesencephalon, pons and spinal cord subserving innate motor behaviours essential for survival (feeding, locomotion, reproduction etc.). In higher primates CPGs are largely under neocortical control. We describe how certain motor events observed in parasomnias and epileptic seizures could have similar features and resemble motor behaviours, which can be the expression of the same CPG. Both epilepsy and sleep can lead to a temporary loss of control of neomammalian cortex that facilitates through a common platform (arousal) the emergences of stereotyped inborn fixed action patterns. Therefore we suggest that, independently from the nature of the trigger, be it a seizure or a parasomnia, the same CPGs can be involved, "caught up", leading to a common motor semiology (the "Carillon theory").

Spielmeyer-Vogt disease: clinical and neurophysiological aspects.

Recent neurophysiological studies have identified a characteristic profile in the case of certain progressive infantile encephalopathies which, together with clinical data, may assist with the diagnosis. The authors report a case of juvenile ceroid lipofuscinosis (Spielmeyer-Vogt disease) and stress the importance of carrying out neurophysiological investigations for diagnostic purposes and for controlling the progression of the disease. The effect of antioxidant therapy (sodium selenite and vitamin E) on these investigations and on the natural evolution of the disease is also discussed.

Endocranial calcifications, infantile celiac disease, and epilepsy.

The authors report on five patients (three female, two male) with multiple brain calcifications, infantile celiac disease, and epilepsy. The clinical, neuroradiological, neurophysiological, EEG and evolutional aspects are assessed. The authors propose that all patients with brain calcifications which cannot be traced to other known pathologies should undergo diagnostic tests for a malabsorption syndrome; analogously, patients affected with infantile celiac disease should undergo EEG, followed by a neuroradiological examination if the EEG pattern is found to be altered.

Chronic neuroborreliosis in infancy.

Lyme disease is a polymorphic and multisystemic disease caused by Borrelia burgdorferi. Neurological manifestations are found in 10%-50% of cases. We present 2 cases followed for 5 and 6 years of chronic relapsing-remitting neuroborreliosis. Diagnosis of neuroborreliosis in these cases was based on serum and cerebrospinal fluid findings. We discuss clinical, neurophysiological, laboratory and instrumental aspects regarding the difficulties of reaching a correct diagnosis. Further studies, especially in the field of immunology, should help identify the mechanisms responsible for the disease becoming chronic. With this knowledge, it may be possible to design immunological therapies for relapses, and to prevent the evolution of the disease.