Intravenous levetiracetam in clinical practice--Results from an independent registry.

PURPOSE: Most common clinical studies with antiepileptic drugs do not reflect medical everyday practice due to their strict in- and exclusion criteria and specifications of treatment regimens. Here we present a large non-interventional registry with the intention to evaluate the spectrum of applications in daily use and the efficacy and tolerability of intravenously given levetiracetam (LEV-iv). METHODS: In a prospective approach of 17 neurological and neuropediatric centres in Germany LEV-iv treated patients of all ages were included over a period of 10 months. The observational period was 10 days with daily documentation of LEV-iv administration, type and frequency of seizures, currently used drugs and doses, and adverse events (AEs). In addition, treatment efficacy and tolerability were assessed by patients and physicians at study end as well as practicability of LEV-iv using a five-step scale. RESULTS: In 95 patients LEV-iv was administered, 93 were included into the analysis. The median LEV-iv dose was 1500 mg (range 110-6000 mg) per day. Median age was 66 years (range 0.7-90.3 years). The majority of patients (n=70, 75%) suffered from status epilepticus (SE, n=55, 59%) and acute seizure clusters (n=15, 16%). Of those with SE, 41 patients (75%) had SE for the first time. Acute seizure clusters and SE terminated in 83% after LEV-iv administration. A total of 29 adverse events were reported in 17 of the 95 patients from the safety set. Ten of these were at least possibly related to LEV-iv treatment. Slight decrease of blood pressure during the infusion (3 patients each) was captured most frequently. No serious side effect was observed. Physicians rated the efficacy and tolerability of LEV-iv treatment as good or very good in 78% and 82% of the cases, respectively. CONCLUSION: In this large observational study of everyday practise the use of LEV-iv exhibited a remarkable good response and tolerability in patients with acute onset seizures (mostly SE). Further randomized controlled studies, like the established status epilepticus trial (ESET) are needed to confirm these findings.

Low long-term efficacy and tolerability of add-on rufinamide in patients with Dravet syndrome.

In this retrospective European multicenter study we evaluated the efficacy and tolerability of rufinamide in patients with Dravet syndrome and refractory seizures. Twenty patients were included; in 16 patients a SCN1A mutation was detected. The responder rate after 6 months was 20%, and after 34 months, 5%. The retention rate was 45% after 6 months and 5% after 34 months. Rufinamide treatment was stopped because of aggravation of seizures (30%), no effect (45%), and side effects (10%). The efficacy and long-term retention rate were low in our patients with Dravet syndrome and refractory seizures, far lower than in patients with Lennox-Gastaut syndrome; one-third of our patients experienced seizure aggravation. Therefore, rufinamide does not seem to be a suitable option for long-term treatment in patients with Dravet syndrome.

Combined EEG and MEG analysis of early somatosensory evoked activity in children and adolescents with focal epilepsies.

OBJECTIVE: The study aimed to evaluate differences between EEG and MEG analysis of early somatosensory evoked activity in patients with focal epilepsies in localizing eloquent areas of the somatosensory cortex. METHODS: Twenty-five patients (12 male, 13 female; age 4-25 years, mean 11.7 years) were included. Syndromes were classified as symptomatic in 17, idiopathic in 2 and cryptogenic in 6 cases. 10 patients presented with malformations of cortical development (MCD). 122 channel MEG and simultaneous 33-channel EEG were recorded during tactile stimulation of the thumb (sampling rate 769 Hz, band-pass 0.3-260 Hz). Forty-four hemispheres were analyzed. Hemispheres were classified as type I: normal (15), II: central structural lesion (16), III: no lesion, but central epileptic discharges (ED, 8), IV: lesion or ED outside the central region (5). Analysis of both sides including one normal and one type II or III hemisphere was possible in 15 patients. Recordings were repeated in 18 hemispheres overall. Averaged data segments were filtered (10-250 Hz) and analyzed off-line with BESA. Latencies and amplitudes of N20 and P30 were analyzed. A regional source was fitted for localizing S1 by MRI co-registration. Orientation of EEG N20 was calculated from a single dipole model. RESULTS: EEG and MEG lead to comparable good results in all normal hemispheres. Only EEG detected N20/P30 in 3 hemispheres of types II/III while MEG showed no signal. N20 dipoles had a more radial orientation in these cases. MEG added information in one hemisphere, when EEG source analysis of a clear N20 was not possible because of a low signal-to-noise ratio. Overall N20 dipoles had a more radial orientation in type II when compared to type I hemispheres (p=0.01). Further N20/P30 parameters (amplitudes, latencies, localization related to central sulcus) showed no significant differences between affected and normal hemispheres. Early somatosensory evoked activity was preserved within the visible lesion in 5 of the 10 patients with MCD. CONCLUSIONS: MEG should be combined with EEG when analyzing tactile evoked activities in hemispheres with a central structural lesion or ED focus. SIGNIFICANCE: At time, MEG analysis is frequently applied without simultaneous EEG. Our results clearly show that EEG may be superior under specific circumstances and combination is necessary when analyzing activity from anatomically altered cortex.

Combined spike-related functional MRI and multiple source analysis in the non-invasive spike localization of benign rolandic epilepsy.

OBJECTIVE: To localize the irritative zone in children by combined spike-related fMRI and EEG multiple source analysis (MSA) in children with benign rolandic epilepsy. METHODS: Interictal spikes were averaged and localized using MSA, and source locations were displayed in the anatomical 3D-MRI in 11 patients (5-12 yrs, median 10). Interictal spikes were additionally recorded during the fMRI acquisition (EEG-fMRI), and the fMRI sequences were correlated off-line with the EEG spikes. RESULTS: MSA revealed an initial central dipole in all patients, including the face or hand area. A second dipolar source was mostly consistent with propagated activity. BOLD activations from EEG-fMRI, consistent with the locations of the initial dipoles, were found in four patients. We found additional large areas of BOLD activations in 3 of these subjects extending into the sylvian fissure and the insula. These were identified as propagated activity by MSA using the short time differences in the source waveforms. CONCLUSIONS: MSA provided reliable localization of the spike onset zone in all children with benign rolandic epilepsy. Using the combination of EEG-fMRI and MSA we were able to discriminate the spike onset zone from propagated epileptiform source activity, using the spatial resolution of the EEG-fMRI technique and the temporal resolution of the MSA. However, the sensitivity of the EEG-fMRI technique was low and further improvements of the technique are warranted. SIGNIFICANCE: This study shows that a combination of EEG-fMRI and MSA may be a powerful tool to describe the irritative zone of patients with idiopathic focal epilepsies. Clinical studies in patients with non-idiopathic focal epilepsies may clarify whether both techniques can be used as complementary clinical tools to localize the onset of interictal epileptic activity in focal epilepsies.

Cervical spinal cord atrophy in the atraumatically born neonate: one form of prenatal or perinatal ischaemic insult?

After atraumatic birth, three neonates presented with muscle hypotonia and weakness. Flaccid paresis of the upper extremities, spasticity of the lower extremities, dissociate sensory loss and autonomic dysfunction developed later. This ruled out the initial, tentative diagnoses of cerebral palsy, spinal muscular atrophy or hereditary neuropathy. Diagnostic imaging revealed marked thinning of the cervical spinal cord in all patients. The possible aetiology of these lesions is considered. In all cases, an antenatal or perinatal infarction is thought to be the most probable cause. Different clinical pictures following intrauterine spinal cord ischemia are discussed. Spinal cord lesion must be considered even after atraumatic birth.

Assessment of brainstem function in Chiari II malformation utilizing brainstem auditory evoked potentials (BAEP), blink reflex and masseter reflex.

Brainstem dysfunction was evaluated in 67 patients with myelomeningocele and Chiari II malformation using brainstem auditory evoked potentials (BAEP), blink reflex (BR) and masseter reflex (MR). Signs and symptoms related to Chiari II malformation were observed in 18 patients while 49 patients had normal brainstem findings. BAEP and BR showed a higher sensitivity of brainstem involvement than MR (BAEP=1.0, BR=0.83, MR=0.50). BR, and in particular, MR were of higher accuracy (BR=0.52, MR=0.72) than BAEP (0.39) in separating patients with brainstem signs and symptoms related to Chiari II malformation. We feel that this is due to anatomic and physiologic peculiarities of the brainstem structures mediating BR and MR. Our results suggest that brainstem reflexes can support the decision of further treatment.

Abnormal somatosensory evoked potentials indicate compressive cervical myelopathy in mucopolysaccharidoses.

Compressive myelopathy at the cranio-cervical junction is a complication of mucopolysaccharidoses (MPS). To detect cervical myelopathy we recorded median and posterior tibial nerve SEPs in 15 patients aged 2.4-33.4 years (median 8.8 years) with MPS I-S (n = 3), MPS IVA (n = 8) and MPS VI (n = 4). In addition to the cortical waveforms we recorded the subcortical median nerve SEPs N13b and P13 generated near the cranio-cervical junction and the lemniscal P30 after posterior tibial nerve stimulation. MRI studies in 13 subjects revealed spinal cord compression at the cranio-cervical junction in 10 patients; 5 patients had an increased signal intensity on the T2-weighted initial MRI indicating high cervical myelomalacia and 4 patients had clinical signs of cervical myelopathy. We did not find a relationship between the SEPs and spinal cord compression. Abnormal SEPs were found in the patients with MRI evidence of myelomalacia (sensitivity 1.0, specificity 1.0) and correspondingly in the patients with clinical signs (sensitivity 1.0, specificity 0.91). The SEPs consequently deteriorated in 2 subjects of 7.3 and 10.3 years of age. Abnormal SEPs indicated subclinical cervical myelopathy in 3 subjects. Cervical cord compression may be present before occurrence of clinical or electrophysiological evidence of myelopathy. However, we feel that the SEP analysis is useful to detect functional impairment of the cervical cord in patients with MPS.

Clinical and molecular genetic spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations of the lamin A/C gene.

Emery-Dreifuss muscular dystrophy (EDMD) is characterized by early contractures of the elbows and Achilles tendons, slowly progressive muscle wasting and weakness, and life-threatening cardiomyopathy with conduction blocks. We recently identified LMNA encoding two nuclear envelope proteins, lamins A and C, to be implicated in the autosomal dominant form of EDMD. Here, we report on the variability of the phenotype and spectrum of LMNA mutations in 53 autosomal dominant EDMD patients (36 members of 6 families and 17 sporadic cases). Twelve of the 53 patients showed cardiac involvement exclusively, although the remaining 41 all showed muscle weakness and contractures. We were able to identify a common phenotype among the patients with skeletal muscle involvement, consisting of humeroperoneal wasting and weakness, scapular winging, rigidity of the spine, and elbow and Achilles tendon contractures. The disease course was generally slow, but we observed either a milder phenotype characterized by late onset and a mild degree of weakness and contractures or a more severe phenotype with early presentation and a rapidly progressive course in a few cases. Mutation analysis identified 18 mutations in LMNA (i.e., 1 nonsense mutation, 2 deletions of a codon, and 15 missense mutations). All the mutations were distributed between exons 1 and 9 in the region of LMNA that is common to lamins A and C. LMNA mutations arose de novo in 76% of the cases; 2 of these de novo mutations were typical hot spots, and 2 others were identified in 2 unrelated cases. There was no clear correlation between the phenotype and type or localization of the mutations within the gene. Moreover, a marked inter- and intra-familial variability in the clinical expression of LMNA mutations exists, ranging from patients expressing the full clinical picture of EDMD to those characterized only by cardiac involvement, which points toward a significant role of possible modifier genes in the course of this disease. In conclusion, the high proportion of de novo mutations together with the large spectrum of both LMNA mutations and the expression of the disease should now prompt screening for LMNA in familial and sporadic cases of both EDMD and dilated cardiomyopathy associated with conduction system disease.

Complex long-segment intestinal dysganglionosis.

A case is reported with aganglionosis of the rectum, sigma, and descending colon; dysganglionosis with heterotopic ganglionic cells in the muscularis propria of the hypoganglionic transverse colon; and extreme hypoganglionosis (without detection of ganglionic cells) of the ascending colon and distal ileum. The ileum showed a transition zone with hypoganglionosis and intestinal neuronal dysplasia (IND) type B. As to the etiology of such complex intestinal innervation defects, pre- and perinatal perfusion deficits must be considered because their localization seems to be linked to the vascular anatomy of the colon. Early diagnosis may be difficult, causing a delay in operative treatment and multiple operations. Different manifestations of dysganglionosis may be found in the same patient. The classical continuum of distal aganglionosis followed by proximal hypo- or dysganglionosis and then normally innervated bowel may not always be present. Therefore, in children with recurrent (sub-)ileus after resection of an aganglionic bowel segment, additional dysganglionosis such as IND or hypoganglionosis or even complex intestinal dysganglionosis should be excluded by full-thickness colon and small bowel biopsies.

Maturation of near-field and far-field somatosensory evoked potentials after median nerve stimulation in children under 4 years of age.

OBJECTIVES: The maturation of subcortical SEPs in young children. METHODS: Median nerve SEPs were recorded during sleep in 42 subjects aged 0-48 months. Active electrodes were at the ipsilateral Erb's point, the lower and upper dorsal neck, and the frontal and contralateral centroparietal scalp; reference electrodes were at the contralateral Erb's point, the ipsilateral earlobe and the frontal scalp; bandpass was 10-3000 Hz. The peaks were labelled by their latencies in adults. RESULTS: The peak latencies of N9 (brachial plexus potential) decreased exponentially with age during the first year, but increased with height thereafter. The interpeak latencies (IPLs) N9-N11, which measure conduction between brachial plexus and dorsal column, decreased with age (linear regression). The IPLs N11-P13 and N11-N13b, which measure conduction between the dorsal column and approximately the cervico-medullary junction, did not change across this age range. The IPLs N13a-N20, N13b-N20 and P13-N20, which measure central conduction, showed negative exponential regressions with rapidly decreasing latencies during the first year of life and slowly decreasing latencies thereafter. CONCLUSIONS: Maturation of the peripheral segments of the somatosensory pathway progresses more rapidly than that of the central segments. The maturation of central conduction is not completed within the first 4 years of age. Our maturational data may serve as a reference source for subsequent developmental and clinical studies.

Ischemic stroke and migraine in childhood: coincidence or causal relation?

Although migraine is an accepted cause of cerebral infarction in adults, this association is less well recognized in children. We present two children with migraine and cerebral infarction, which we regard as migrainous stroke, though neither patient fulfills all criteria of the International Headache Society for the diagnosis of migrainous infarction. Review of the literature concerning examples of migraine-associated stroke in childhood suggests that these criteria are too restrictive to comprise the majority of migrainous strokes, especially in this age group.

Abnormal subcortical somatosensory evoked potentials indicate high cervical myelopathy in achondroplasia.

UNLABELLED: Children with achondroplasia may have high cervical myelopathy due to stenosis of the cranio-cervical junction resulting in neurological disability and an increased rate of sudden death. To detect myelopathy we recorded somatosensory evoked potentials (SEPs) after median nerve stimulation in 30 patients with achondroplasia aged 13 months to 18 years (mean 6 years). In addition to the conventional technique of recording the cortical N20 and the central conduction time (CCT), we employed a noncephalic reference electrode recording the subcortical waveforms N13b and P13. generated near the cranio-cervical junction. The findings were related to the clinical status and MRI results. Eighteen patients had MRI evidence of spinal cord compression with indentation or narrowing of the upper cervical cord, and 13 showed signs of myelomalacia. Seven patients had neurological abnormalities. The sensitivities of the SEPs were 0.89 for cervical cord compression, 0.92 for myelomalacia and 1.0 for the clinically symptomatic patients. There were no false-positive results. The subcortical SEPs were more sensitive than the conventional recordings. However, the conventional SEPs were highly specific in the most severely affected patients; here the specificity was 1.0 for patients with myelomalacia and 0.96 for symptomatic patients. Postoperative SEPs improved after occipital decompression in two children. CONCLUSION: The analysis of somatosensory evoked potentials, in particular of subcortical tracings, is useful in the detection of early cervical myelopathy in children with achondroplasia. Early neurosurgical decompression may prevent irreversible damage.

Subcortical somatosensory evoked potentials after median nerve stimulation in children.

We report our normative data of subcortical somatosensory evoked potentials (SEPs) after median nerve stimulation from a group of 55 children 4-15 years of age and 18 young adults 18-29 years of age. We recorded near-field potentials from the brachial plexus, the cervical cord and the somatosensory cortex. The far-field potentials P13, P14 and N18 from the brainstem were recorded from the scalp electrodes, when a non-cephalic reference at the contralateral Erb's point or an ear reference was used. The N9 (brachial plexus), N13a (dorsal horn), P13 (caudal medulla oblongata), N18 (medulla oblongata) and N20 (somatosensory cortex) were present in all subjects. The N13b (dorsal column near the foramen magnum or cuneate nucleus) was observed in all children and in 16 adults, P14 (medial lemniscus) in 52 children and 17 adults. The median nerve SEPs provide reliable information about the function of the somatosensory pathway from the upper limb. The subcortical median nerve SEPs should be particularly useful to detect lesions of the upper cervical cord and the cervicomedullary junction. The subcortical SEPs remain unchanged during sleep and facilitate reliable SEP recordings, when sedation is necessary in infants and children.

Somatosensory evoked potentials after posterior tibial nerve stimulation--normative data in children.

We report normative data of somatosensory evoked potentials to posterior tibial nerve stimulation from 47 children 4-15 years of age. We recorded near-field potentials from the peripheral nerve, the cauda equina, the lumbar spinal cord and the somatosensory cortex. Far-field potentials were recorded from the scalp electrodes with a reference at Erb's point and on the earlobe. The near-field potentials N8 (peripheral nerve) and P40 (cortex) were present in all children. N20 (near-field from the cauda equina) was recorded in 38 subjects. N22 (near-field from the lumbar spinal cord), P30 and N37 ( both far-field waveforms probably generated in the brainstem) were recorded in 46 subjects each. The latencies and the peripheral conduction time (N8-N22) increased with age, while the central conduction time (N22-P40) and the intracranial conduction time (P30-P40) both decreased with age (up to about 10 years of age). The spinal conduction time (N22-P30) was relatively independent of age. The interpeak latencies allow the assessment of specific portions of this pathway. The subcortical posterior tibial nerve-somatosensory evoked potentials are of particular interest in children when the cortical peaks are influenced by sedation and sleep, or by anaesthesia.

[Cataplexy in type C Niemann-Pick disease]. / Kataplexie bei Morbus Niemann-Pick Typ C.

Cataplexy usually occurs as a part of the tetrad of clinical phenomena of idiopathic narcolepsy. Symptomatic cases are rare. A 4 years old girl from consangineous parents had recurrent loss of muscle tone and fell to the ground, when she laughed. The EEG was normal. Prolonged neonatal jaundice with cholestasis, hepatosplenomegaly, mental regression, supranuclear ophthalmoplegia, and foam cells led to the diagnosis of Niemann-Pick disease type C with symptomatic cataplexy. Symptomatic forms of the narcolepsy-cataplexy complex should be considered, when there is an early onset before puberty, cataplectic attacks predominate the narcoleptic attacks, and when additional neurological symptoms occur. Symptomatic cataplexy occurs in Niemann-Pick disease type C. It is considered to be the result of lesions of the pontine reticular formation.

Preterm maturation of the somatosensory evoked potential.

This study investigated the maturational pattern of the cortical somatosensory evoked potential (SEP) in the preterm period. SEPs were recorded in 22 preterm neonates (27-32 weeks gestational age (g.a.), mean age 28.4 weeks g.a.; total of 46 studies). The infants were first tested at an average of 5 days. At birth, all of the infants had normal neurological examinations and normal cranial ultrasounds. On follow-up the infants were assessed regularly by a multidisciplinary team and all those included in this series, at follow-up periods of 6-25 months corrected age (mean 14.8 months), had normal neuro-developmental examinations. SEPs were recorded in all of the infants. The waveform consisted of triphasic positive, negative components (at 75 ms, 125 ms and 178 ms, respectively at 27 weeks g.a.). Latencies of these components decreased rapidly over the preterm period, such that by 32 weeks g.a. they were at 41, 72 and 112 ms, respectively. There appeared to be no differences in the maturational changes as a function of gestational age at birth.

Brainstem auditory and visual evoked potentials in infants with myelomeningocele.

Brainstem auditory evoked potentials (BAEPs) and visual evoked potentials (VEPs) were recorded in 47 infants with myelomeningocele to determine if the evoked potentials reflected the early neurological status, and if they had prognostic value as to the children's neurological outcome. The infants were tested between 1 day and 3 months of age (mean 24 days), while still in hospital after the myelomeningocele repair. Outcome was assessed at a mean of 2 years of age. Normal BAEPs were found in 41% and normal VEPs in 62% of the patients. BAEPs were abnormal in all infants studied who had symptomatic Arnold-Chiari (AC) malformation (n = 9); VEPs were abnormal in only 55% of symptomatic infants. Of the infants who did not have symptomatic AC malformation, 53% had normal BAEPs, 69% had normal VEPs. Of the patients with normal BAEPs, 81% had normal cerebral function on follow-up. Of the patients with abnormal BAEPs, 87% had central neurological abnormalities on follow-up. Of the patients with normal VEPs, 63% were normal on follow-up; of the patients with abnormal VEPs, 71% were abnormal on follow-up. Thus, the VEPs studied early in the neonatal course do not appear to be sufficiently sensitive to be valuable prognostically in these infants. However, the BAEPs were consistently abnormal in symptomatic AC malformation and showed a positive predictive value of 88% and an accuracy in predicting central neurological sequelae of 84%.

Mechanical disruption of Escherichia coli for plasmid recovery.

Five different mechanical cell disruption processes were evaluated as methods to extract plasmids from bacterial cells. The methods used were sonication, nebulization homogenization, microfluidization, and bead milling. The recovery yields of intact plasmids from the various methods were measured by quantitative gel electrophoresis. Bead milling and microfluidization were found to have the highest potential for large scale extraction with total intact recoveries of over 90% and around 50%, respectively. Other methods resulted in substantial plasmid degradation, with recoveries no greater than 20% of the total intact plasmid.

Etoposide treatment in recurrent medulloblastoma.

Five consecutive patients with recurrent medulloblastoma received etoposide 120 mg/m2 for 5 to 7 days at 2 to 4-week intervals. Three patients with neuroaxis dissemination received additional intrathecal chemotherapy with methotrexate, cytosine arabinoside and prednisone. Toxicity consisted of alopecia and mild neutropenia. Complete response was registered in two patients, partial response in one. Median survival was 19 months with the 3 responders living 6, 30 and 60+ months. Etoposide seems to be an active agent in medulloblastoma.

Tethered cord after spina bifida aperta: a longitudinal study of somatosensory evoked potentials.

Progressive neurological deterioration may occur after meningomyelocele repair. Magnetic resonance imaging almost invariably demonstrates a conus medullaris in an abnormally low position, whether neurological symptoms develop or not. Surgery of a secondary tethered cord is indicated when progression of neurological symptoms is documented. We performed a longitudinal study of posterior tibial nerve somatosensory evoked potentials (SSEPs) in children and adolescents after neonatal meningomyelocele repair. All patients were able to walk. Declining or negative posterior tibial nerve SSEPs were recorded in 15 patients; 14 of these had clinical signs of a secondary tethered cord. After surgery of the tethered cord, the SSEPs improved in 8 of 10 patients. Posterior tibial nerve SSEPs may contribute to the diagnosis of secondary tethered cord. After untethering, the evoked potentials demonstrate recovery of spinal cord function and might help to delineate prognosis.