Role of Vagus Nerve Stimulation in Refractory and Super Refractory Status Epilepticus: A Pediatric Case Series.

BACKGROUND: Status epilepticus is a life-threatening condition that is defined as refractory (RSE) when the seizure activity continues despite treatment with benzodiazepine and a second appropriate treatment. Super refractory status epilepticus (SRSE) is an RSE that persists or recurs for ≥24 h. Few papers have reported the outcomes of pediatric patients affected by RSE and SRSE and treated with neuromodulation therapies. Vagus nerve stimulation (VNS) is an approved treatment for drug-resistant epilepsy. We present our findings of pediatric patients treated with VNS for RSE/SRSE. METHODS: We present a case series of seven consecutive pediatric patients treated with VNS for SRSE since 2012 by a single surgeon in Monza and Padua. A rapid titration was started soon after implantation. We considered electroclinical data before and after VNS implantation and at the last follow-up. RESULTS: We achieved the resolution of SRSE in five out of seven patients in a mean time of two weeks. At the last follow-up, these patients had a significant reduction of seizure burden without any relapse of SE. DISCUSSION AND CONCLUSIONS: Based on our limited findings, we discuss the potential role of VNS therapy in similar but distinct clinical contexts. For patients with drug-resistant epilepsy and RSE/SRSE, prompt VNS consideration is suggested, offering rapid responses and potentially reducing pharmacological load. Meanwhile, in NORSE/FIRES, we suggest early neuromodulation during the acute phase if standard treatments prove ineffective or not tolerated. This approach may leverage VNS's potential anti-inflammatory effects and neuromodulation, enhancing patient-specific treatments. Expanding case studies and prolonged follow-ups are recommended to strengthen these clinical insights.

Effect of Vagus Nerve Stimulation on Blood Inflammatory Markers in Children with Drug-Resistant Epilepsy: A Pilot Study.

BACKGROUND: Since one of the suggested mechanisms of action of VNS on epilepsy is the reduction of central inflammation, we carried out a comprehensive analysis of blood inflammatory markers in children considered for VNS surgery. MATERIALS AND METHODS: Five pediatric patients were studied. An extensive analysis of blood inflammatory markers was performed before surgery (T0) and six weeks after VNS implantation (T1). An epileptological outcome was obtained according to the McHugh score. RESULTS: The variations of IgA, IgE, IgG, CD19, and PTX3 displayed a tendency toward a positive statistical correlation between T0 and T1. According to McHugh score, the patients were divided into Group 1 (i.e., Class I) and Group 2 (i.e., Classes II and III). IL-1ß and PTX-3 tended to decrease more in Group 1, while TNF-α decreased in Group 2 (-56.65%) and slightly increased (+3.61%) in Group 1 at T1 without statistical correlation. CONCLUSIONS: The variation of IL-1ß and PTX-3 seem to be related to a better outcome; thus, they do not reach statistical significance. A larger series of patients is needed to determine whether biochemical changes could relay with the clinical improvement of epilepsy.

Further delineation and long-term evolution of electroclinical phenotype in Mowat Wilson Syndrome. A longitudinal study in 40 individuals.

BACKGROUND: Epilepsy is a main feature of Mowat Wilson Syndrome (MWS), a congenital malformation syndrome caused by ZEB2 variants. The aim of this study was to investigate the long-term evolution of the electroclinical phenotype of MWS in a large population. METHODS: Forty-individuals with a genetically confirmed diagnosis were enrolled. Three age groups were identified (t1 = 0-4; t2 = 5-12; t3 = >13 years); clinical data and EEG records were collected, analyzed, and compared for age group. Video-EEG recorded seizures were reviewed. RESULTS: Thirty-six of 40 individuals had epilepsy, of whom 35/35 aged >5 years. Almost all (35/36) presented focal seizures at onset (mean age at onset 3.4 ±â€¯2.3 SD) that persisted, reduced in frequency, in 7/22 individuals after the age of 13. Absences occurred in 22/36 (mean age at onset 7.2 ±â€¯0.9 SD); no one had absences before 6 and over 16 years old. Paroxysmal interictal abnormalities in sleep also followed an age-dependent evolution with a significant increase in frequency at school age (p = 0.002) and a reduction during adolescence (p = 0.008). Electrical Status Epilepticus during Sleep occurred in 14/36 (13/14 aged 5-13 years old at onset). Seven focal seizure ictal video-EEGs were collected: all were long-lasting and more visible clinical signs were often preceded by prolonged electrical and/or subtle (erratic head and eye orientation) seizures. Valproic acid was confirmed as the most widely used and effective drug, followed by levetiracetam. CONCLUSIONS: Epilepsy is a major sign of MWS with a characteristic, age-dependent, electroclinical pattern. Improvement with adolescence/adulthood is usually observed. Our data strengthen the hypothesis of a GABAergic transmission imbalance underlying ZEB2-related epilepsy.

Sleep in Mowat-Wilson Syndrome: a clinical and video-polysomnographic study.

OBJECTIVE: Sleep disturbances are frequently reported in Mowat-Wilson Syndrome (MWS). The current study aimed to evaluate clinical and video-polysomnographic (VPSG) characteristics of the sleep architecture and abnormal electroencephalogram (EEG) patterns during sleep in MWS. METHODS: Sixteen individuals with MWS (range 16 months-25 years), attending the Department of Child Neurology and Psychiatry of the University of Bologna, were included. The "Sleep Disturbances Scale for Children (SDSC)" questionnaire was administered to all parents of MWS patients, and all patients underwent a VPSG recording. RESULTS: The analysis of the SDSC questionnaire revealed disturbances mainly at the sleep-wake transition and in initiating and maintaining sleep. Evaluation of sleep structure in MWS patients showed a significant reduction of total sleep time, an increase of wake after sleep onset and arousal index as compared to normal controls. An EEG pattern characterized by slowing of background activity and poverty of physiological sleep characterisitcs was observed in all patients. Moreover, in patients aged >7 years, anteriorly predominant spike and waves were observed, markedly activated by sleep configuring a sub-continuous or continuous activity. CONCLUSION: Our data (both clinical and VPSG) documented the presence of significant and clinically relevant sleep disturbances in MWS patients. Moreover, we identified a characteristic age-dependent sleep EEG pattern that could provide a new element to assist in the management of MWS.

Does emergent implantation of a vagal nerve stimulator stop refractory status epilepticus in children?

PURPOSE: Status Epilepticus can be a serious life threatening event in epileptic patients. The definition of refractory or super-refractory Status Epilepticus was based on the therapeutic response to anti-epileptic and anesthetic drugs. Vagal Nerve Stimulation showed efficacy in treating drug-resistant epilepsy but there are only few reports on emergentplacement of Vagal Nerve Stimulator for refractory or super-refractory Status Epilepticus. METHODS: Among 49 children implanted at our Institution with Vagal Nerve Stimulation for drug-resistant epilepsy, the authors retrospectively identified those implanted for refractory or super-refractory Status Epilepticus, according with the current definitions. RESULTS: 4 patients were operated upon at ages ranging 7 to 17 months and reached the programmed output current of 1 mA over a time ranging from 24 to 36 h (fast ramping-up). In 3 out of 4 patient we observed the abrupt of Status Epilepticus; one patient was refractory both to drugs and Vagal Nerve Stimulation and later died, without recovering from SE. At follow up, ranging from 24 to 45 months, the remaining 3 patients showed a decrease of the seizures frequency >80% without relapse of Status Epilepticus; in all the patients, output current and/or Duty Cycle were increased later. CONCLUSION: VNS can be effective in treating refractory or super-refractory Status Epilepticus.

Should Posterior Reversible Encephalopathy Syndrome Be Mainly Considered an Epileptic Disorder? Results of a Sequential Neurophysiological Study in a Pediatric Cohort.

Despite a wide number of studies trying to define clinical, physiopathological, and neuroradiological features of posterior reversible encephalopathy syndrome (PRES), the true nature of symptoms is still not fully understood. We studied a standard cohort of 24 pediatric patients, affected by hemato-oncological diseases, with a neuroradiological diagnosis consistent with PRES identified from 2006 to 2013. Ten of them developed PRES after hematopoietic stem cell transplantation. We analyzed the sequence of clinical, radiological, and electrophysiological data. In all the patients who were recorded at the onset of the first symptoms, electroencephalograms showed focal nonconvulsive seizures or status epilepticus (SE). We found a sensitivity of 100% for electroencephalogram (EEG) with a good correlation between clinical signs and the localization of seizures, whereas computed tomography scans showed a sensitivity of 50% only. Following prompt treatment, intensive care unit admission rate was only 8%. PRES is a multifactorial neurologic event with focal nonconvulsive seizures or SE as the main feature in pediatric patients. Clinical manifestations are epileptic in nature, and prompt EEG recording is useful for diagnosis and supports an earlier treatment, potentially preventing the appearance of complications such as generalized seizures or refractory SE.

Vagal Nerve Stimulation in the Treatment of Drug-Resistant Epileptic Encephalopathies in Inborn Errors of Metabolism: Report of 2 Cases.

Patients affected by inborn errors of metabolism can develop catastrophic epilepsies ineligible for resective surgery. Few reports concerning vagal nerve stimulation in patients with epileptic encephalopathy in the context of metabolic diseases have been published in the literature. Drug-resistant epilepsies in metabolic disease could be a specific target for vagal nerve stimulation, although the efficacy of this technique in these patients still needs to be proved. The authors report our experience in treating refractory epilepsy with vagal nerve stimulation in 2 patients affected by inborn errors of metabolism. The first patient is a 23-year-old patient affected by glutaric aciduria type II, the other one is a 16-month-old child with nonketotic hyperglycinemia. Vagal nerve stimulation reduced seizures up to 50% in the first case and up to 90% in the second one.

Enzymatic replacement therapy for Hunter disease: Up to 9 years experience with 17 patients.

Hunter disease is an X-linked lysosomal storage disorder characterized by progressive storage of glycosaminoglycans (GAGs) and multi-organ impairment. The central nervous system (CNS) is involved in at least 50% of cases. Since 2006, the enzymatic replacement therapy (ERT) is available but with no effect on the cognitive impairment, as the present formulation does not cross the blood-brain barrier. Here we report the outcome of 17 Hunter patients treated in a single center. Most of them (11) started ERT in 2006, 3 had started it earlier in 2004, enrolled in the phase III trial, and 3 after 2006, as soon as the diagnosis was made. The liver and spleen sizes and urinary GAGs significantly decreased and normalized throughout the treatment. Heart parameters improved, in particular the left ventricular mass index/m(2) decreased significantly. Amelioration of hearing was seen in many patients. Joint range of motion improved in all patients. However, no improvement on respiratory function, eye, skeletal and CNS disease was found. The developmental quotient of patients with a CNS involvement showed a fast decline. These patients were no more testable after 6 years of age and, albeit the benefits drawn from ERT, their quality of life worsened throughout the years. The whole group of patients showed a consistent residual disease burden mainly represented by persistent skeletal disease and frequent need of surgery. This study suggests that early diagnosis and treatment and other different therapies which are able to cross the blood-brain barrier, might in the future improve the MPS II outcome.

Epilepsy in Mowat-Wilson syndrome: delineation of the electroclinical phenotype.

Mowat-Wilson syndrome (MWS) is a genetic disease caused by heterozygous mutations or deletions of the ZEB2 gene and is characterized by distinctive facial features, epilepsy, moderate to severe intellectual disability, corpus callosum abnormalities and other congenital malformations. Epilepsy is considered a main manifestation of the syndrome, with a prevalence of about 70-75%. In order to delineate the electroclinical phenotype of epilepsy in MWS, we investigated epilepsy onset and evolution, including seizure types, EEG features, and response to anti-epileptic therapies in 22 patients with genetically confirmed MWS. Onset of seizures occurred at a median age of 14.5 months (range: 1-108 months). The main seizure types were focal and atypical absence seizures. In all patients the first seizure was a focal seizure, often precipitated by fever. The semiology was variable, including hypomotor, versive, or focal clonic manifestations; frequency ranged from daily to sporadic. Focal seizures were more frequent during drowsiness and sleep. In 13 patients, atypical absence seizures appeared later in the course of the disease, usually after the age of 4 years. Epilepsy was usually quite difficult to treat: seizure freedom was achieved in nine out of the 20 treated patients. At epilepsy onset, the EEGs were normal or showed only mild slowing of background activity. During follow-up, irregular, diffuse frontally dominant and occasionally asymmetric spike and waves discharges were seen in most patients. Sleep markedly activated these abnormalities, resulting in continuous or near-to-continuous spike and wave activity during slow wave sleep. Slowing of background activity and poverty of physiological sleep features were seen in most patients. Our data suggest that a distinct electroclinical phenotype, characterized by focal and atypical absence seizures, often preceded by febrile seizures, and age-dependent EEG changes, can be recognized in most patients with MWS.

A rescuable folding defective Nav1.1 (SCN1A) sodium channel mutant causes GEFS+: common mechanism in Nav1.1 related epilepsies?

Mutations of voltage-gated Na(+) channels are the most common known cause of genetically determined epilepsy; Na(v)1.1 (SCN1A) is the most frequent target. They can cause both mild and severe forms, also in patients harboring the same mutation. We have recently characterized in a family with extreme phenotypes the first epileptogenic folding-defective Na(+) channel mutant (Na(v)1.1-M1841T), whose loss of function is attenuated by interactions with associated proteins and drugs. We hypothesized that in vivo variability of the interactions may modulate the functional effect and thus the phenotype (Rusconi et al., 2007). Here we characterize another Na(v)1.1 folding-defective mutant (Na(v)1.1-R1916G) that, however, has been identified in a GEFS+ family with relatively mild phenotypes. This novel mutant shows a number of specific characteristics, but, similarly to Na(v)1.1-M1841T, it can be rescued by interactions with associated proteins and drugs. Thus, loss of function caused by folding defects that can be attenuated by molecular interactions may be a common pathogenic mechanism for Na(v)1.1 epileptogenic mutants. Folding defects can be present also in families showing only mild phenotypes in which, however, severe phenotypes could emerge within a permissive genetic background.

Clinical and genetic familial study of a large cohort of Italian children with idiopathic epilepsy.

Epilepsies are characterized by genetic heterogeneity and by the possible coexistence of different phenotypes in one family. Moreover, in different epilepsies, mutations in the same gene have been reported. We aimed to collect data in a large Italian cohort of 81 families with children affected by partial or generalized epilepsies and to evaluate the prevalence of several ion channel mutations. In particular, a clinical and genetic survey was performed and DNA regions known to be associated with several epilepsies were analysed by sequencing. We observed genetic complexity in all phenotype groups: any epileptic type may be transmitted as either autosomal dominant or recessive. No significant phenotype identity among generations and no differences among genders could be observed. Two missense mutations in SCN1A were identified in two GEFS+ probands confirming the importance of this channel for this epilepsy. Moreover, a previously unreported CLCN2 mutation was detected in a proband showing CAE. In conclusion, even in this highly heterogeneous cohort, the complexity of the epileptic condition was highlighted and mutations in the analysed candidate region of ion channel genes appear to explain only a minority of cases.

Encephalopathy syndrome in children with hemato-oncological disorders is not always posterior and reversible.

BACKGROUND: Posterior reversible leukoencephalopathy (PRES) is a clinical-radiological event that can affect children undergoing chemotherapy regimen. Studies have shown that it is not always reversible, in spite of its original definition. We analyzed PRES cases which occurred during the last 10 years at our institute to focus on their clinical, radiological and EEG follow-up. PROCEDURES: We analyzed 12 cases of PRES in children who underwent intensive chemotherapy regimens, detailing the acute neurological presentation of the syndrome, their neuro-imaging characteristics (MRI) and EEG findings, in both an acute phase and during follow-up. RESULTS: All patients survived the acute event, showing a clinical recovery of the acute neurological signs in 1-3 days and normalization of the EEG pattern in a period ranging from 1 to 8 months. During long term follow-up, four patients developed either clinical impairment or EEG-MRI anomalies. CONCLUSIONS: We suggest that a long term follow-up is necessary to determine the reversibility of the neurological events. Clinical observation, as well as EEG and MRI should be included in follow-up evaluations.