Electroencephalographic changes in pyridoxine‐dependant epilepsy: new observations

Electroencephalographic Cerebral Dysrhythmic Abnormalities in the Trinity of Nonepileptic General Population, Neuropsychiatric, and Neurobehavioral Disorders

V11 Poster location 011 Seizures in infants with pyridoxine-dependent epilepsy and pyridoxine phosphate oxidase deficiency

Electroclinical variability of pyridoxine-dependent epilepsy caused by ALDH7A1 gene mutations in four Taiwanese children

EFFECTS OF BARBITURATES AND ETHER ON SPONTANEOUS ELECTRICAL ACTIVITY OF DOG BRAIN

Inborn errors of metabolism are a diverse group of genetic disorders including many that cause neonatal-onset epilepsy such as pyridoxine-dependent epilepsy (PDE). PDE occurs secondary to biallelic pathogenic variants in ALDH7A1 and can present with refractory neonatal seizures and status epilepticus. Neonatal seizures and encephalopathy are modifiable with pyridoxine (vitamin B6) supplementation. However, the clinical response to pyridoxine supplementation can be delayed. We present the case of a full-term neonate with PDE in which seizure cessation was seen a few hours after intravenous pyridoxine load, but the improvement in EEG background and level of clinical encephalopathy occurred 5 days later. We share this case to provide an example in which clinical improvement in PDE was gradual and required continuation of treatment for several days illustrating the necessity of continuing vitamin B6 supplementation in suspected cases until confirmatory genetic testing is obtained or an alternate cause is found.

The occurrence of sharp waves, spikes and fast activity in supratentorial tumours

Objective: To analyze the clinical feature, treatment, and prognosis of epileptic spasms (ES) in vitamin B6–dependent epilepsy, including patients with pyridoxine-dependent epilepsy (PDE) caused by ALDH7A1 mutation, pyridox(am)ine-5′-phosphate oxidase (PNPO) deficiency, and PLPBP deficiency.Methods: We analyzed data from a cohort of 54 cases with PDE, 13 cases with PNPO deficiency, and 2 cases with PLPBP deficiency and looked for the presentation of ES among them.Results: A total of 11 patients with the seizure presentation of ES have been collected. Among them, four patients carried mutations in ALDH7A1, six carried mutations in PNPO, and the remaining one carried mutation in PLPBP. The analysis of this cohort identified nine cases presenting as infantile spasms distributed in the three diseases and two cases presenting as Ohtahara syndrome diagnosed with PDE and PNPO deficiency, respectively. In the PDE and PLPBP deficiency groups, seizures were controlled by pyridoxine monotherapy, and the remaining one had refractory seizures due to secondary brain atrophy. In the groups with PNPO deficiency, one patient showed seizure-free when treated by PLP combined with valproic acid, three still had infrequent seizures treated by PLP monotherapy or pyridoxine or PLP combined with other antiseizure medications, and two died. In two cases presenting as Ohtahara syndrome, after regular treatment, one showed seizure-free, the others showed a marked decrease in seizure frequency, and they both showed an improvement in EEG.Significance: ES might be a common form of seizures in PNPO deficiency, and EEG presented as hypsarrhythmia or a burst suppression pattern. It is difficult for pyridoxine to control frequent seizures caused by secondary brain injury. In our PNPO deficiency cohort, patients with infantile spasms did not respond better to PLP than pyridoxine. Timely and correct treatment could prevent the transformation of the child’s disease from Ohtahara syndrome and infantile spasms to subsequent epileptic encephalopathy or refractory epilepsy.

خلفية البحث: الأشخاص الذين يعانون من اضطراب طيف التوحد لديهم معدل انتشار مرتفع للنوبات الصرعية مقارنة بالأشخاص العامة وفقا لمجموعة كبيرة من الابحاث أيضا تم العثور على مرضى طيف التوحد الذين لا يعانون من نوبات صرعية لديهم معدلات عالية من موجات صرعية. ومع ذلك، لا يزال من غير المعروف كيف ترتبط هذه الموجات الصرعية بين أعراض التوحد. الأهداف: استخدمت هذه الدراسة تخطيط كهربية الدماغ للتحقيق في العلاقة بين موجات الصرع البيني وشدة التوحد عند الأطفال. المواد وطرق العمل: أجريت دراسة مقطعية على 30 طفلا مصابا بالتوحد، (23) ذكورا، و (7) إناث. تراوحت أعمار الأطفال بين (2 سنة و12 سنة). استوفى أطفال التوحد معاييرالدليل التشخيصي والإحصائي للاضطرابات العقلية، الإصدار الخامس وتم استخدام مقياس تصنيف التوحد في مرحلة الطفولة لتحديد شدة التوحد. النتائج: اكتشفنا أن 33.4٪ من الأطفال المصابين بالتوحد لديهم نتائج تخطيط كهربية الدماغ غير طبيعية. كانت شدة التوحد وتشوهات تخطيط كهربية الدماغ مرتبطة احصائيا بشكل كبير. الإستنتاجات: وفقا للنتائج هناك علاقة بين تشوهات مخطط كهربية الدماغ ودرجة شدة التوحد. وفقا للننتائج هناك علاقة بين تشوهات مخطط كهربية الدماغ ودرجة التوحد.

Current theories and models of brain rhythm generation are based on (1) the excitability of individual neurons and whole networks, (2) the structural and functional connectivity of neuronal ensembles, (3) the dynamic interaction of excitatory and inhibitory network components, and (4) the importance of transient local and global states. From the interplay of the above, systemic network properties arise which account for activity overdrive or suppression, and critical-level synchronization. Under certain conditions or states, small-to-large scale neuronal networks can be entrained into excessive and/or hypersynchronous electrical brain activity (epileptogenesis). In this chapter we demonstrate with artificial neuronal network simulations how physiological brain oscillations (delta, theta, alpha, beta and gamma range, and transients thereof, including sleep spindles and larger sleep waves) are generated and how epileptiform phenomena can potentially emerge, as observed at a macroscopic scale on scalp and intracranial EEG recordings or manifested with focal and generalized, aware and unaware, motor and nonmotor or absence seizures in man. Fast oscillations, ripples and sharp waves, spike and slow wave discharges, sharp and rhythmical slow waves, paroxysmal depolarization and DC shifts or attenuation and electrodecremental responses seem to underlie key mechanisms of epileptogenesis across different scales of neural organization and bear clinical implications for the pharmacological and surgical treatment of the various types of epilepsy.

Investigation of Sleep Patterns and Electroencephalographic Characteristics in Children With Microcephaly Associated With Congenital Zika Syndrome and Severe Cerebral Palsy.

Aim Cyclin-dependent kinase-like 5 (CDKL5) gene abnormalities cause an early-onset epileptic encephalopathy. We performed video-electroencephalography (video-EEG) monitoring early in the course of CDKL5-related epileptic encephalopathy in order to examine the early electroclinical characteristics of the condition. Method We used video-EEG to monitor six infants (five females, one male) with CDKL5-related epileptic encephalopathy (five mutations; one deletion), at ages 45 days to 12 months and followed them up to the ages of 14 months to 5 years (mean age 23mo). We focused our analysis on the first year of life. The results were evaluated against those of a comparison group of nine infants (aged below 1y) with epileptic encephalography who had tested negative for CDKL5 mutations and deletions. Results One infant exhibited normal background activity, three exhibited moderate slowing, and two exhibited a suppression burst pattern. Two participants had epileptic spasms and four had a stereotyped complex seizure pattern, which we defined as a ‘prolonged’ generalized tonic–clonic event consisting of a tonic–tonic/vibratory contraction, followed by a clonic phase with series of spasms, gradually translating into repetitive distal myoclonic jerks. Seizure duration ranged from 2 to 4 minutes. The EEG correlate of each clinical phase included an initial electrodecremental event (tonic vibratory phase), irregular series of sharp waves and spike slow waves (clonic phase with series of spasms), and bilateral rhythmic sharp waves (time locked with myoclonus). Interpretation Infants with CDKL5-related early epileptic encephalopathy can present in the first year of life with an unusual electroclinical pattern of ‘prolonged’ generalized tonic–clonic seizures.

Twenty-six (41%) of 63 consecutive patients with triphasic waves had various types of metabolic encephalopathies while 37 patients (59%) had non-metabolic encephalopathies, usually senile dementia. Triphasic waves were not found to be specific for any single type of metabolic encephalopathy. Etiology was more closely linked to conscious level at recording than any morphological or distributional feature of the triphasic waves themselves. Thus, all 31 alert patients had non-metabolic encephalopathies while all 13 comatose patients had metabolic encephalopathies. The second, positive, component (Wave II) most often had the highest voltage while equally maximal Waves I and II occurred next most commonly. Triphasic waves were most often maximally expressed anteriorly. Among patients with metabolic encephalopathies, a posterior-anterior delay or lag of the wave II peak occurred more commonly than did the better known anterior-posterior lag. Lags occurred with both metabolic and non-metabolic conditions, but were more common with the former. No difference in quantity or mode of appearance existed between the metabolic and non-metabolic groups when matched for conscious level. Prognosis for patients with either metabolic or non-metabolic encephalopathies was unfavourable. Only 4 of 24 metabolic and one of 35 non-metabolic patients were well at follow-up over 2 years later. Forty percent of EEGs with sharp and slow wave complexes (slow spike waves) had sporadically-appearing triphasic waves. The relative amplitudes of the 3 components differed from triphasic waves in other conditions: equally maximal Waves II and III were the most usual form.

The evolution of electroencephalographic features in lissencephaly syndrome

Pyridoxine-dependent epilepsy (PDE) is a recessive genetic disease characterized by epileptic encephalopathy with therapeutic response to pharmacological doses of pyridoxine and resistance to anti-epileptic treatments. The recent discovery in 2006 of the genetic defect antiquitin (ALDH7A1, OMIM #266100) has helped to understand the underlying mechanism, which is the accumulation of neurotoxic intermediates in the lysine catabolic pathway. The goal of the new therapeutic approach, termed triple therapy (TT) (pyridoxine, lysine-restricted diet and arginine supplementation), is to improve epilepsy control and neurocognitive development in patients with PDE. We present the 3-year treatment outcome for a child with PDE on pyridoxine treatment (started at age 5months), lysine-restricted diet (started at age 17months) and arginine supplementation therapy (started at age 19months). The TT was well-tolerated with good compliance. No adverse events were reported. We observed a neurodevelopmental improvement, significantly fewer seizures, and a reduction of pipecolic acid (PA) as a biomarker of the illness. Our results show an improving clinical evolution, supporting and extending previous studies reporting efficacy of TT.

Animal functional magnetic resonance imaging (fMRI) has provided key insights into the physiological mechanisms underlying healthy and diseased brain states. In non-human primates, resting-state fMRI studies are commonly conducted under isoflurane anesthesia, where anesthetic concentration is used to roughly infer anesthesia depth. However, within the recommended isoflurane concentration range (1.00–1.50%), the brain state can switch from moderate anesthesia characterized by stable slow wave (SW) electroencephalogram (EEG) signals to deep anesthesia characterized by burst suppression (BS), which is electrophysiologically distinct from the resting state. To confirm the occurrence rate of BS activity in common setting of animal fMRI study, we conducted simultaneous resting-state EEG and fMRI experiments on 16 monkeys anesthetized using 0.80–1.30% isoflurane, and detected BS activity in two of them. Datasets either featured with BS or SW activity from these two monkeys were analyzed to investigate the intrinsic functional connectivity (FC) patterns during BS. In datasets with BS activity, we observed robust coupling between the BS pattern (the binary alternation between burst and suppression activity in EEG signal) and filtered BOLD signals in most brain areas, which was associated with a non-specific enhancement in whole brain connectivity. After eliminating the BS coupling effect by regressing out the BS pattern, we detected an overall increase in FC with a few decreased connectivity compared to datasets with SW activity. These affected connections were preferentially distributed within orbitofrontal cortex, between orbitofrontal and prefrontal/cingulate/occipital cortex, and between temporal and parietal cortex. Persistence of the default mode network and recovery of thalamocortical connections were also detected under deep anesthesia with BS activity. Taken together, the observed spatially specific alterations in BS activity induced by isoflurane not only highlight the necessity of EEG monitoring and careful data preprocessing in fMRI studies on anesthetized animals, but also advance our understanding of the underlying multi-phased mechanisms of anesthesia.