Petit Mal Absence Research Articles

Bioequivalence Study of Two Tablet Formulations of Clonazepam 2mg: A Randomized, Open-Label, Crossover Study in Healthy Mexican Volunteers Under Fasting Conditions.

The prevalence of neurological disorders is high among the Mexican population. Clonazepam is primarily indicated to treat panic disorders, certain kinds of epilepsy such as status epilepticus, childhood motor seizures (petit mal absence, Lennox-Gastaut syndrome, and infantile spasms), anxiety, and muscle spasm. This study was performed to compare bioequivalence between two oral tablet formulations of clonazepam 2mg in healthy Mexican volunteers under fasting conditions. This phaseI, randomized, open-label, two-treatment, crossover study included 30healthy volunteers. Subjects were randomly assigned to either test or reference formulation of clonazepam 2mg. Each study period was separated by 21-day washout period. Blood samples were collected at pre-dose and up to 72h after drug administration. Clonazepam concentrations were determined using a validated ultra-flow liquid chromatography-tandem mass spectrometric method. Pharmacokinetic parameters were determined using a non-compartmental method. Two formulations were considered bioequivalent if geometric mean ratios (test/reference) were between 80% and 125%. Safety was evaluated by recording adverse events. Pharmacokinetic parameters were comparable between test and reference formulations. The mean maximum plasma concentration (Cmax) was ≈ 13ng/mL, area under the plasma concentration-time curve from time0 to last measurable concentration (AUC0-t) was ≈ 360ngh/mL, time to reach maximum plasma concentration (Tmax) was ≈ 3h, and elimination half-life (t1/2) was ≈ 43h. Geometric mean ratios (90% confidence interval) of Cmax (99.2-115.3%), AUC0-t (100.6-110.6%), and AUC0-∞ (98.5-111.6%) were within the bioequivalence range. Seven non-serious adverse events (mostly asymptomatic hypotension) were recorded. The test and reference formulations of clonazepam 2mg were bioequivalent and well tolerated in healthy Mexican volunteers under fasting conditions. 213301410B0051 (Approved on April 13, 2021).

Ictal SPECT of Thalamocortical Coupling in a Patient with Frontal Absence

Petit mal absence has been reported with 3-Hz generalized spike-and-wave discharges induced by secondary bilateral synchrony. Absence seizure may be present in patients with frontal lobe epilepsy. The thalamic rhythmogenic mechanisms responsible for spike-and-wave discharges have been investigated, providing a better understanding of the underlying anatomico-physiological mechanisms. We report the thalamocortical coupling in a patient with frontal absence by performing synchronous ictal single photon emission computed tomography (SPECT) analysis. Ictal SPECT revealed thalamic hyperperfusion combined with ipsilateral frontal cortical hyperperfusion in the patient. Moreover, lateral indexes of cerebral blood flow in the frontal region and thalamus were higher than those from non-epileptic control subjects. Thalamocortical coupling was thus revealed by ictal SPECT. Frontal absences should be considered as a secondarily generalized epilepsy syndrome originating from the frontal regions. The thalamus may play a crucial role as a pacemaker of rhythmic electroencephalographic activities such as secondary bilateral synchronous discharges in patients with frontal absences.

So-called “Petit Mal Status”: Epileptic syndrome or seizure type?

In 1945, Lennox was the first to describe the epileptic states mainly expressed by various degrees of consciousness disturbance, which have their onset in children who present epileptic absences correlated with ictal EEG patterns of spike-wave complex discharges at about 3 Hz. As the clinical picture seemed to be similar to an uninterrupted series of absences, this led to the definition "Petit Mal Status" (PMS). Many authors have subsequently reported that PMS can occur in epileptic subjects who have never presented absences (and even in subjects without a previous history of epilepsy) and that the related EEG pictures were characterised by paroxysmal generalized activity of various morphology, but hardly ever consisted of the continuous rhythmic spike-wave or polyspike-wave complexes at 3 Hz found in petit mal absences. Finally, in reporting the onset and recurrence of this condition typically in adults and the elderly, some authors have proposed the existence of a particular form of PMS (dependent on different types of pathologic factors and characterising a specific syndrome of this age) that is different from that of the "real PMS" typical of childhood and related to petit mal absences. This paper describes fifteen patients in whom the onset of the condition occurred at different ages, and who seem to exemplify the various possible clinical expressions of PMS, with the aim of making a contribution towards the better nosographic definition of this epileptic condition. On the basis of our study, we sustain that the so-called PMS is a seizure type of Idiopathic Generalized Epilepsy which may appear at nearly all ages, and may occur in isolation or in association with other epileptic manifestations, but cannot itself be considered as characterising one or more age-dependent syndromes.

Complex partial status epilepticus in a patient with leptomeningeal carcinomatosis

Complex partial status epilepticus (CPSE) is rare and can be difficult to recognize. It is less common than petit mal (absence) status, and the EEG findings are less striking. The clinical findings include prolonged confusion, aphasia, automatic behavior, and amnesia without convulsive activity. A case of CPSE in a patient with a rare form of leptomeningeal cancer has been reported. In this paper we report a 2nd case in a patient with meningeal carcinomatosis

Reflex Petit Mal Absence?

The importance of tactile somatosensory stimuli as a triggering mechanism in provoking epileptic seizures is widely acknowledged. These seizures are mostly partial ones with secondary generalization, but may also be, rarely, primary generalized seizures. Up to now, no case of petit mal absence, triggered by somatosensory stimuli, has been described. The subject of this report is a 15-month-old girl, who for a period of 3 months presented absence induced by finger tapping on her forehead or in the parietal region; the duration of the attacks ranged from 6 to 12 seconds. The EEG showed a characteristic pattern of diffuse discharges of 3 Hz/sec spike and wave complexes. During this critical period, the child was well, except for the seizures. Possible mechanisms for triggering this type of seizure are discussed.

Study of asymmetric and focalized spike-wave paroxysms in generalized idiopathic epilepsies with petit mal absences

Study of asymmetric and focalized spike-wave paroxysms in generalized idiopathic epilepsies with petit mal absences

Cerebral electrical fields during petit mal absences

The electrical fields of spike-wave complexes were plotted with the aid of a microcomputer in patients suffering from petit mal absences. The maximum positivity as well as negativity of the individual complexes was mainly in the frontal areas. While this observation was quite constant among different patients and different seizures within the same patient, the way in which these maxima were reached varied markedly. Even in the most regular patterns, succesive spike-wave complexes within one seizure could show different origins and different spread of the field. Positive and negative components of the wave and occasionally of the spike could show different areas of onset. The earliest positive change was frequently in one occipital area or at Pz while negativity could be initiated in frontal or posterior head regions. The variability of onset and spread tended to be somewhat more marked for the positive rather than negative component. The spread of the field over the scalp was at times somewhat discontinuous and one or more preliminary peaks could occur which either disappeared or coalesced before the maximum was reached. The findings suggest that several intracortical generators contribute to the formation of the spike-wave complex but the frontal areas play the most crucial role and medial as well as lateral portions appear to be involved.

A model of chronic spontaneous petit mal-like seizures in the rat: comparison with pentylenetetrazol-induced seizures.

Of 100 randomly chosen, adult male Wistar rats in the breeding colony at the Centre de Neurochimie , Strasbourg, 31 presented spontaneous, nonconvulsive epileptic seizures: wave-and-spike discharges, 7-11 cycles/s, 200-600 microV, accompanied by behavioral arrest and myoclony of the vibrissae and of the facial and cervical muscles. Pentylenetetrazol (PTZ) 10 and 20 mg/kg increased the duration and number of seizures by 100-150% in these spontaneously epileptic animals, and caused identical seizures in apparently normal rats. Sodium valproate, diazepam, trimethadione, and ethosuximide suppressed the spontaneous seizures and protected against PTZ-induced seizures in a dose-dependent fashion. Carbamazepine and diphenylhydantoin were inefficacious or aggravative in the two cases. The clinical, EEG, and pharmacological observations suggest that the Wistar rats displaying spontaneous seizures constitute a valid physiological and pharmacological model of petit mal absences, presenting advantages compared to the usual models in which seizures are induced by injected epileptogenic drugs.

The use of positron emission tomographic scanning in epilepsy

Positron emission tomography (PET) with fluorine-18-labeled fluorodeoxyglucose (18FDG) has demonstrated the epileptogenic lesion in partial epilepsy to be hypometabolic interictally . This finding is useful for localizing the area of resection when surgical therapy is contemplated. 18FDG scans during partial seizures show increased metabolism in areas of ictal onset and spread and in other regions of decreased metabolism that could reflect postictal effects. In the generalized epilepsies, petit mal absences and generalized convulsions induced by electroconvulsive shock therapy (ECT) are associated with global hypermetabolism, while global hypometabolism is seen in the postictal period following ECT. More information about the factors that influence the interictal hypometabolic zone in partial epilepsy should improve the diagnostic value of this finding for presurgical localization and perhaps also for the evaluation of other therapeutic regimens. New techniques for more dynamic PET studies with improved resolution, combined with computerized electroencephalographic analysis, should allow more accurate interpretation of ictal, as well as interictal, phenomena. Application of PET technology to other paroxysmal disorders may provide a basis for new diagnostic classifications that have therapeutic and prognostic value and may allow clearer differentiation among epileptic phenomena, myoclonus, and movement disorders. More clinical and animal research is needed, however, before we can delineate fundamental mechanisms of human epilepsy from PET data. To this end, it is now possible to use combined multidisciplinary parallel approaches in patients and animals to define specific aspects of epileptic disorders clinically, to intensively investigate them with experimental models in the animal laboratory, and to verify the relevance of these experimental results by returning to clinical studies.

Therapy of Petit Mal (Absence) Seizures

Although petit mal or typical absence seizures are not life threatening, it is important for the pediatrician to recognize the disorder because untreated they can affect school performance, increase the risk of accidental injury, and lead to the victim's being ridiculed by classmates for being "spacey." CLASSIFICATION Unfortunately, petit mal is probably the most misused term in epileptology. In 1969, The International League Against Epilepsy published a classification of epileptic seizures entitled The International Classification of Epilepsy. This classification, which has recently undergone revision, categorizes seizures into two groups: partial, seizures in which the first clinical and electroencephalographic changes indicate initial activation of a system of neurons limited to a part of one cerebral hemisphere, and generalized, those in which the first clinical changes indicate initial involvement of both hemispheres. In absence seizures, as in all primary generalized seizures, the ictal EEG patterns are bilateral and reflect neuronal discharge which is widespread. Absence seizures can be further subdivided into typical and atypical absences (Table 1). Although the term petit mal has been eliminated from the revised International Classification of Seizures, the term is still widely used by physicians. Most physicians use it to describe a simple absence with impairment of consciousness only, and with a rhythmic, three cycles per second, spike and wave discharge on the electroencephalogram in a child between age 3 years and puberty who has normal intelligence and in whom a neurologic examination prduces normal findings.

Patterns of human local cerebral glucose metabolism during epileptic seizures.

Ictal patterns of local cerebral metabolic rate have been studied in epileptic patients by positron computed tomography with 18F-labeled 2-fluoro-2-deoxy-D-glucose. Partial seizures were associated with activation of anatomic structures unique to each patient studied. Ictal increases and decreases in local cerebral metabolism were observed. Scans performed during generalized convulsions induced by electroshock demonstrated a diffuse ictal increase and postictal decrease in cerebral metabolism. Petit mal absences were associated with a diffuse increase in cerebral metabolic rate. The ictal fluorodeoxyglucose patterns obtained from patients do not resemble autoradiographic patterns obtained from common experimental animal models of epilepsy.

GIANT AXONAL NEUROPATHY: REPORT OF TWO SIBLINGS WITH ENDOCRINOLOGICAL AND HISTOLOGICAL STUDIES

Giant axonal neuropathy in two siblings was reported. The fact that two cases are found in the same family supports this disorder is genetically determined and recessively inherited. These two cases, similar to the cases reported in literature, had chronic peripheral neuropathy and CNS symptoms, and also petit mal absence and mental retardation in elder sister (case 1) and precocious puberty in younger sister (case 2). Sural nerve biopsies in both cases disclosed axonal swellings or giant axons filled with aggregated neurofilaments, and that aggregated intermediate-sized filaments were found within cytoplasm of Schwann cells, endothelial cells of intra and extra-neurial capillaries and of extra-neurial arterioles, perineurial cells and endoneurial fibroblasts. Skin biopsies in both cases disclosed that aggregated intermediate-sized filaments were also found within cytoplasm of fibroblasts, Langerhans' cells, melanocytes and endothelial cells of capillaries, lymphatic vessels and arterioles. The diagnosis of giant axonal neuropathy can be made only by the findings in skin biopsy.

A clinical and electroencephalographical follow-up study for more than 10 years in patients with epilepsy.

A clinical and electroencephalographical follow-up study of 10 to 18 years was conducted on 147 patients with epilepsy. Generalized epilepsy was prognostically favorable, but petit mal absence with grand mal was not always good clinically and electroencephalographically as generally accepted. Paroxysmal discharges found in the initial EEGs tended to become more localized in the final EEGs recorded at least more than 10 years later. The migration of spike foci and bilateral independent spikes were found in many patients. Prognostically the EEG background was more important. Fourteen and six-per-second positive spikes and 6Hz spike and wave phantoms had an age dependence as well as 3 Hz spike and wave complexes and these discharges were regarded as prognostically the favorable patterns.

Prognosis of Petit Mal Absence A follow-up study of more than three years

Prognosis of Petit Mal Absence A follow-up study of more than three years

Immediate changes of the electroencephalograms after intravenous injection of clonazepam and their relation to its effect on clinical fits in children with minor seizures.

Immediate EEG changes after intravenous administration of clonazepam and a correlation between the EEG changes and the effect of oral administration of the drug were studied in 21 children with minor seizures whose interictal EEG showed a paroxysmal abnormality. In 13 cases of infantile spasms whose EEG showed hypasrhythmia, paroxysmal discharges were completely or remarkably suppressed in 4 cases, partially suppressed in 3 cases, but not improved in 6 cases. Suppression bursts pattern was less improved. In 5 cases of Lennox syndrome, paroxysmal discharges were markedly improved in 3 cases. In a case of petit mal absence, parxoxysmal discharges were completely suppressed. In all 5 cases whose EEGs were completely improved, paroxysmal discharges reappeared 7 to 30 min after the intravenous injection. In 2 out of the 5 cases, paroxysmal discharges became severer at reappearance than before the injection. Among 12 cases whose EEG showed an improvement after the intravenous injection, their clinical seizures were improved in 9 cases, but the clinical effect was mostly transient. In the majority of the cases whose EEGs were not improved, no clinical effect was observed. There was a highly significant correlation between immediate EEG changes and clinical effect of clonazepam (p less than 0.02 by the chi-square test).

THE ANTICONVULSANT ACTION OF SODIUM VALPROATE (EPILIM) IN 100 PATIENTS WITH VARIOUS FORMS OF EPILEPSY

Sodium valproate (Epilim) has been used in the management of 100 patients with previously uncontrolled epilepsy for periods up to 2 years. If all manifestations of epilepsy are considered together, 75% to 100% control of seizures was achieved in 43% of patients, 25% to 74% control in 26%, and no improvement occurred in 31% of patients. Control of 75% to 100% was achieved in 57% of patients with a spike and wave electroencephalogram (EEG) disturbance but only in 35% of those with focal abnormalities, excessive slow activity, or normal records. When the various manifestations of epilepsy were considered individually, the greatest improvement was found among the patients with the minor forms of generalized epilepsy (petit mal absences, myoclonus and atonic attacks) in whom 75% to 100% control was obtained in 67%, compared with 43% of those with major generalized seizures (grand mal) and 30% of those with temporal lobe attacks and other forms of focal epilepsy. Gastrointestinal disturbances and drowsiness were noted as side effects in the early stages of treatment, but the majority of patients tolerated the drug well and many commented on increased mental alertness while taking it. Two patients were over-stimulated and some noticed tremor or twitching as side effects. Some minor abnormalities in blood coagulation studies were noted, but these were transient and did not appear to be of clinical significance. Regular blood counts and biochemical studies have not shown any significant changes. Sodium valproate appears to be a safe and useful anticonvulsant with the advantage that it usually makes patients brighter rather than drowsier. Abnormalities of platelet function have been described in some overseas reports, so that any unexplained bruising or bleeding in a patient taking valproate is an indication for a platelet count and coagulation studies.

Sodium Valproate and Clonazepam in the Treatment of Intractable Epilepsy

Of 88 patients with intractable epilepsy, 60 have been treated with clonazepam for up to three years and 60 have been treated with sodium valproate for up to 18 months. Each agent was used sequentially in an overlapping group of 32 patients. Both agents have proven effective in the control of petit mal absences and myoclonic jerks, although some patients responded to one and not to the other. Clonazepam has given better results than valproate in temporal lobe and other partial (focal) epilepsies, while valproate has given better results in grand mal seizures and atonic attacks. Both preparations were more effective in patients with spike and wave paroxysms in their EEG recordings, the correlation being more conspicuous with valproate. Both medications appear to be safe and useful additions to anticonvulsant therapy.

Clonazepam

Clonazepam or 5-(2-chlorphenyl)-1, 3-dihydro-7-nitro-2H-1,4benzodiazepin-2-one, is a close structural and pharmacological relative of nitrazepam. It has a broad spectrum of activity against the various types of epilepsy, and is effective in many patients whose condition has proved resistant to other antiepileptic drugs. Its chief uses are in status epilepticus, in which intravenous clonazepam may replace diazepam as the drug of first choice, and in the minor motor seizures of childhood, particularly petit mal absences, the Lennox-Gastaut syndrome and infantile spasms. Clonazepam is also at least as effective as current treatment in psychomotor and myoclonic epilepsies, but seems unlikely to replace phenytoin and the barbiturates in the treatment of grand mal or focal motor seizures except in patients resistant to standard therapy. Initial success with clonazepam can be followed by loss of effect, but benefit can often be restored, at least initially, by temporary interruption and re-institution of treatment. Side-effects are common with clonazepam. Most patients experience drowsiness and fatigue, which are frequent causes of withdrawal, together with lesser incidences of ataxia, dystonia, hypotonia, and hyperactivity. These effects usually disappear with continued therapy, and are minimised by gradual introduction of the drug over 2-4 weeks. Hypersalivation and excessive bronchial secretion may be a problem in children and infants.

The distinction between absence petit mal and psychomotor seizures

A brief discussion of the manifestations of limbic lobe discharge as opposed to discharge in neocortical temporal lobe structures is given. The opinion is expressed that, apart from certain characteristic limbic auras, the manifestations of psychomotor epilepsy are those of inactivation of brain stem mechanisms subserving consciousness. A brief discussion of other manifestations of inactivation of brain stem mechanisms subserving various other functions, as seen in other clinical patterns of epileptic discharge, follows. Hippocampal sclerosis is put forth as the cause rather than the result of seizures in both the juvenile and the adult age groups. It is proposed that limbic lobe structures have a low threshold for initiating epileptic discharge when injured, are predisposed to injury and give rise to discharge which has preferential access to brain stem structures. It is stated that petit mal absences and psychomotor attacks are clinically indistinguishable. The further opinion is expressed that the 3 per second wave and spike EEG pattern associated with petit mal is an epiphenomenon dependent upon the maturational stage of development of the brain at the time when the causative lesion responsible for epilepsy is acquired. The view that the 3 per second wave and spike pattern is a direct correlate of the clinical manifestations of epilepsy, in those patients who show this pattern, is challenged. It is concluded that the pattern is the result of rostral brain stem discharge acting upon the cortex. The view is offered that two factors are necessary for the development of epilepsy: (1) an adequate pathological basis in the form of a cerebral lesion and (2) a greater or lesser predisposition toward inadequate biochemical mechanisms tending to check or control the spread of seizure discharge, the latter being in all probability at least partially genetically determined. It is concluded that triggering cortical foci exist in nearly all cases of epilepsy, though the participation of brain stem structures is essential to explain many of the clinical and EEG manifestations of the attack.

Long-term prognosis of epilepsy in children--a follow-up report beyond 18 years of age.

The long-term prognosis of 185 children with epilepsy, who continued to attend the Clinic for Epileptic Children, the Department of Pediatrics, the University of Tokyo, beyond the age of 18 years, was reported. The length of follow-up varied from three to 20 years, but most of them were followed longer than 10 years. The presumed etiology in these children was divided into a cryptogenic group (124, 67.0%) and a symptomatic group (61). The types of seizures were classified into grand mal (86 cases), focal seizure (27), petit mal absence (4), psychomotro seizure (5), infantile spasms (7), and so on. It may be noted that the highest frequency of grand mal was demonstrated, while the incidences of infantile spasms, myoclonic seizure, and akinetic seizure were low in the series. Only 28 children (15.1%) had complications of physical and/or mental handicaps. The follow-up study revealed that 140 patients (75.7%) had been seizure-free in the last 12 months. One hundred and fifteen of them had no seizures for five years or longer. On the other hand, electroencephalographic abnormalities generally continued for a long time after disappearance of seizures. Eightly-one of well-controlled patients were gradually decreasing the doses of anticonvulsants. As for seizure types, it is noted that focal seizure, psychomotor seizure, and infantile spasms were relatively difficult to be controlled. Except for 27 patients, most of them attended normal schools, including junior colleges or universities, and engaged in various occupations. Fifteen female patients had already married, and out of 13 babies who were born from these patients, there were one with ventricular septal defect, one with mental deficiency, and one with anencephaly, while the rest were entirely normal. Additional problems on withdrawal of anticonvulsants after a long-term seizure-free period, and what a medical system should be for treatment of epilepsy in children up to their adulthood were discussed.