Low-dose ACTH therapy for West syndrome: initial effects and long-term outcome.

BACKGROUND: Most Japanese pediatric neurologists attempt other treatments before using adrenocorticotropic hormone (ACTH) therapy for West syndrome (WS), and even then, they use only a low-dose synthetic ACTH to avoid serious adverse effects. In this multi-institutional study, the authors analyzed the initial effects, adverse effects, and long-term outcome in patients treated with low-dose synthetic ACTH in Japan. METHODS: The medical records of 138 patients with WS, who were treated with low-dose synthetic ACTH therapy for the first time at the authors' institutions between 1989 and 1998, were analyzed. RESULTS: At the end of ACTH therapy, excellent effect on seizures was noted in 106 of 138 (76%) patients, good effect in 23 (17%), and poor effect in 9 (7%). Initial effects on EEG were excellent in 53 of 138 (38%) patients, good in 76 (55%), and poor in 9 (7%). As for seizure prognosis at the time of follow-up, 51 of 99 (52%) patients were seizure-free, whereas 48 (48%) patients had seizures. Mental outcome was normal in 6 of 98 (6%) patients, mild mental retardation in 16 (16%), moderate mental retardation in 26 (27%), and severe mental retardation in 50 (51%). The initial effects of ACTH on seizures and long-term outcome were not dose dependent (daily dosage 0.005 to 0.032 mg/kg, 0.2 to 1.28 IU/kg; total dosage 0.1 to 0.87 mg/kg, 4 to 34.8 IU/kg). The severity of adverse effects correlated with total dosage of ACTH, and the severity of brain volume loss due to ACTH correlated well with the daily dosage and total dosage of ACTH. CONCLUSION: Low-dose synthetic ACTH therapy is as effective for the treatment of WS as the higher doses used in previous studies. The dosage of synthetic ACTH used in the treatment of WS can be decreased as much as possible to avoid serious adverse effects.

Refractory grand mal seizures with onset during infancy including severe myoclonic epilepsy in infancy.

In 1978, Dravet proposed a clinical entity called severe myoclonic epilepsy in infancy (SMEI). In the same year, a patient group, which was later called high voltage slow wave-grand mal syndrome (HVSW-GM), is reported in Japan. Both syndromes are very similar, except for seizure manifestation: generalized tonic-clonic convulsions (GTC) with myoclonic and other polymorphic seizures in SMEI vs. GTC only in HVSW-GM. To study the pathophysiology of these refractory epilepsies, the author formulated new clinical diagnostic criteria common to both syndromes as follows: GTC with onset before the age of 1 year as the principal seizure type; an epilepsy entity unclassifiable either as partial or generalized by all the clinical data including EEG findings; mental and motor dysfunction absent prior to seizure onset but appearing later; absence of epileptiform activities on EEG in the initial stage; stubborn refractoriness to conventional antiepileptic medication. Twenty-two patients meeting all of five clinical criteria above mentioned were recruited in the study. Detailed analysis of clinico-electrical features and long-term follow-up of these patients led the author to the conclusion that GTC in combination with seizures of other types will contribute to an unfavorable pathophysiological or prognostic conditions, and, especially when GTC exists in combination with myoclonic seizures, the severity of epilepsy will increase. The author claimed that the three clinical entities, SMEI, HVSW-GM, and their variant form, share certain characteristics in common and may constitute a unique epilepsy syndrome for which a new name of infantile refractory grand mal syndrome (IRGMS) was offered. This is a more basic concept with broader spectrum than SMEI, encompassing not only SMEI but also related borderlands like HVSW-GM. More recently, the author observed that early zonisamide medication within 1 year after seizure onset may improve seizure prognosis in IRGMS, by preventing the development of myoclonic seizures.

Surgical strategy and outcomes for epileptic patients with focal cortical dysplasia or dysembryoplastic neuroepithelial tumor.

PURPOSE: The purpose of this study was to clarify and compare the influence of surgical strategy on relief from seizures in patients with focal cortical dysplasia (FCD) and those with dysembryoplastic neuroepithelial tumor (DNT). METHODS: Six patients with FCD and five patients with DNT, all of whom underwent surgical resection for medically intractable epilepsy, were compared in terms of presurgical seizure types and frequency, location of lesions, magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT) with 99mTc-ECD, scalp electroencephalogram (EEG), and long-term video-EEG recording. Prolonged subdural recordings and intraoperative electrocorticograms (ECoG) were analyzed. The influences of surgical strategies on seizure outcomes were retrospectively analyzed. RESULTS: In all the FCD patients, ictal SPECT revealed hyperperfusion in the regions where MRI showed FCD. Interictal epileptiform activity and ictal seizure onset on ECoG performed with subdural electrodes were localized on the FCD itself. In contrast, the tumors of all the DNT patients were depicted as hypoperfuse areas on interictal SPECT scans. Ictal SPECT in one DNT patient showed hyperperfusion in the area enclosing the tumor. Interictal spiking in all DNT patients and ictal seizure onset in two DNT patients were not in the lesions themselves but in an area enclosing the lesion. All but one patient with FCD who underwent total lesionectomy became seizure free. All DNT patients who underwent resection of the epileptogenic cortex associated with lesionectomy became seizure free or achieved a 90% reduction in seizures. CONCLUSIONS: FCD has intrinsic epileptogenicity, whereas DNT is encompassed by epileptogenic cortical areas. Therefore, total lesionectomy is an essential strategy for FCD, whereas resection of the epileptic focus associated with lesionectomy of a DNT lesion is necessary to control seizures.

Neuropsychological changes after surgical treatment for temporal lobe epilepsy.

PURPOSE: The effect of unilateral temporal lobectomy on seizure frequency is well recognized, but little is known about the neuropsychological changes that occur after surgical treatment. We assessed neuropsychological status in 26 patients with an average age of 35 years before and after unilateral temporal lobectomy for medically intractable TLE. METHODS: Neuropsychological examination to assess cognitive function, memory, attention, visuospatial analysis, language, and emotional functions was performed preoperatively and at 1 month and 1 year after the surgery. RESULTS: At both 1 month and 1 year after the surgery, the patients had improved scores, compared with the preoperative scores, on the Wechsler Adult Intelligence Scale-Revised (WAIS-R: verbal IQ, performance IQ, and full-scale IQ), Wechsler Memory Scale-Revised (WMS-R: verbal, general, and delayed paired associates memory), and Raven Colored Progressive Matrices. In the Minnesota Multiphasic Personality Inventory (MMPI), significant decreases were observed at 1 year after the surgery in the scores for infrequency, hypochondriasis, psychasthenia, and schizophrenia. Patients in whom the seizures had been relieved postoperatively also had improved scores on the WAIS-R, WMS-R, and Raven Colored Progressive Matrices. CONCLUSIONS: These data suggest that neuropsychological improvement postoperatively is influenced by the reduction in the frequency of seizures after surgery.

Shuddering attacks-report of four children.

Shuddering attacks are recognized as an uncommon benign disorder occurring during infancy or early childhood. It is necessary to distinguish these episodes from epileptic seizures. The attacks seem to involve shivering movements occurring daily for several seconds without impairment of consciousness. According to the criteria for benign myoclonus of early infancy, both shuddering attacks and benign myoclonus of early infancy should be regarded as having the same nosologic entity. I studied the pathophysiology of shuddering attacks in four children between 8 and 14 months of age using a video-electroencephalographic monitoring system. In one patient the frequency of shuddering movements, which was read as contamination of the electromyography on electroencephalography during attacks, seemed to be almost the same as that as of essential tremor. Shuddering attacks have decreased in number or disappeared in all four patients, but one exhibited mild abnormalities on magnetic resonance imaging and had relatives with epilepsy, and another had a flattened sella turcica. Although previous reports suggest that these movements are benign and needless investigations should be avoided, a problem related to the development of the nervous system may be present in children with shuddering attacks.

[Shuddering attacks in four children].

Shuddering attacks (SA), an uncommon benign disorder occurring during infancy or early childhood, should be distinguished from epileptic seizures. The attacks are shivering movements occurring daily for several seconds without impairment of consciousness. SA are regarded as an early premature manifestation of essential tremor (ET), and the provoking mechanism is the same between them. There are case reports of SA, but none from Japan. We studied the pathophysiology of SA in four children aged between 8 and 14 months using a video-EEG monitoring system. In one patient, the shuddering movements, as indicated by contaminating electromyogram during electroencephalography, was almost as frequent as that of ET. SA decreased in frequency or disappeared in all our patients. One of them showed immature brain development on MRI and had relatives with epilepsy. Another showed flattened sella turcica. Although previous reports suggest that SAs are benign and require no investigation, children with SA could have borderline problems related to the development of the nervous system.

[Epilepsy surgery for focal cortical dysplasia and dysembryoplastic neuroepithelial tumor].

We studied six patients with focal cortical dysplasia (CD) and four patients with dysembryoplastic neuroepithelial tumor (DNT) who had surgical resection for medically intractable epilepsy. In all CD patients, ictal single photon emission computed tomography (SPECT) using 99mTc-ECD revealed hyperperfusion in the regions where magnetic resonance (MR) imaging showed CD abnormalities. Interictal epileptiform activity and ictal seizure onset on electrocorticography using subdural strip or grid electrodes were demonstrated in the CD itself. In contrast, in all DNT patients, interictal SPECT disclosed hypoperfusion in the area of the lesions. Ictal SPECT in one DNT patient disclosed hyperperfusion in the superior area of the region where MR imaging showed cystic abnormalities. Interictal spiking in all DNT patients and ictal seizure onset in two DNT patients were demonstrated not in the lesions themselves but in the distinct zone from the region of the tumor-involved brain. All CD patients who underwent lesionectomy became seizure-free with a mean follow-up period of 33.5 months. All DNT patients who underwent lesionectomy and resection of the epileptogenic cortex became seizure-free or had their seizure significantly reduced a mean follow-up period of 41.5 months. We conclude that CDs have intrinsic epileptogenicity, while DNTs have epileptogenicity not intrinsically but in encompassed cortical surface areas.

Valproate lowered the amplitude of visual and somatosensory evoked potentials in two cases of untreated juvenile myoclonic epilepsy.

The amplitude of flash visual evoked potential (F-VEP) and somatosensory evoked potential (SEP) was found to be initially slightly higher in two untreated patients with juvenile myoclonic epilepsy (JME). Patients were studied before and after complete control of seizures with valproate. In both patients valproate prolonged the latencies of the waves IV and V and lowered the amplitudes of waves V and VI of the F-VEP. The N20-P25 amplitude in SEP in both parties was also lowered by valproate. These results may suggest that slightly higher cortical excitability in untreated JME was controlled by valproate.

Tracheal, circulatory, and respiratory responses to femoral nerve stimulation.

Tracheal, circulatory, and respiratory responses to electrical stimulation of the afferent nerve from the hindlimb were analyzed in decerebrate, paralyzed, and mechanically ventilated dogs. Tension of the tracheal smooth muscle (TSM), arterial blood pressure, and phrenic nerve activity (PNA) were measured during stimulation of the proximal end of the transected femoral nerve (FNS) with train pulses (duration; 0.5 ms, frequency; 40 Hz). With low intensity (e.g., 0.62 V) FNS, TSM exhibited relaxation, arterial pressure decreased, and neural respiratory output (NRO) was reduced (3 of 8 dogs) or unchanged (5 of 8 dogs). With increases in stimulus intensity, TSM always exhibited relaxation while arterial pressure and NRO exhibited excitatory responses almost at the same thresholds (approximately 5 V). The TSM relaxation and the excitatory NRO and arterial responses augmented with increases in stimulus intensity up to 16 times of threshold of the excitatory NRO response. TSM response was blocked by intravenous atropine but pressor response and phrenic response were not. The arterial response disappeared after administration of a ganglionic blocker. These findings suggest that TSM, arterial pressure, and PNA may be controlled by one neuronal mechanism during high intensity FNS, but that arterial pressure and PNA may be modified by another mechanism in an inhibitory direction when the stimulus intensity is low. This study suggested the existence of a neural mechanism which controls the airway and cardiorespiratory systems properly to execute exercise. Physiological significance of the responses to low intensity femoral nerve stimulation was uncertain.

Significance of spikes at temporal lobe electrocorticography.

Among 87 consecutive patients operated on under local anesthesia, few aspects of pre- and posttemporal lobe resection electrocorticograms (ECoG) yielded prognostic data. Preresection spikes were most common in the hippocampus, followed in order of frequency by the anterior temporal convexity and the inferior temporal surface. Moderately frequent (>10 spikes/100 s) preresection spikes appeared beyond the subsequent resection line in the posterior temporal region in 16 of 87 (18%) and in orbital frontal cortex in 12 of 87 (14%). Although many hippocampus spikes portended a favorable outcome and rare spikes an unfavorable one, preresection spike quantity otherwise failed to distinguish outcome groups. Absolute quantity of postresection spikes and change from preresectrion quantity in any region did not correlate with outcome except for the insula, where relatively abundant spikes portended favorable outcomes. Postresection electrographic seizures were rare but occurred equally in all outcome groups. No significant change in spike incidence occurred between the first and last 10-min epoch of the 30-min postresection recording.

[Clinical characteristics and outcome of 508 patients with hyperventilation syndrome].

The characteristics of hyperventilation syndrome (HVS) were studied in 508 patients who visited our hospital over 11 years. Information regarding symptoms and laboratory data was collected from the clinical records, and outcome was surveyed with a questionnaire mailed to all patients. Patients with acute HVS ranged in age from 5-85 years, and acute HVS was particularly prevalent among women in their late teens. Triggers of HVS included anxiety, nausea & vomiting, and fever due to the common cold. The primary symptoms were dyspnea and numbness, but these differed from the symptoms that appeared during a provoked attack, Half of the patients had no underlying disorder, but the others were suffering from neurosis, cardiovascular disorders, or other diseases. These characteristics of acute HVS did not differ from those seen in patients in whom the diagnosis of HVS was confirmed with arterial blood gas analysis. Half of the patients recovered without treatment, and the others underwent paper-bag rebreathing or intravenous infusion of sedatives. The prevalence of chronic HVS was 2% and almost all those patients were middle-aged women. In contrast, the questionnaire revealed that half of the patients had repeated HVS attacks. In 10% of the patients, these attacks persisted for more than 3 years. Many of these patients reported that they sighed frequently and felt air hunger while in remission. These findings were compatible with the criteria for chronic HVS. Therefore, it may be possible to diagnose HVS from symptoms alone, without hyperventilation provocation tests. In conclusion, these data underscore the importance of clinical symptoms in the diagnosis of HVS.

[Neural control of tracheal smooth muscle during cough].

Contraction of tracheal smooth muscle during mechanically induced coughing was studied in dogs. Recordings of smooth muscle tension were obtained from the cervical trachea, which is not influenced by intrathoracic pressure. We observed that during breathing at rest, tracheal smooth muscle contracts and relaxes in synchrony with phrenic nerve activity. When cough occurs, the tracheal smooth muscle contracts continuously and tonically with no rhythmic correlation to phrenic nerve activity. Sometimes the contraction starts before the phrenic nerve activity increases. A neuromuscular blocking agent caused a significant decrease in phrenic nerve activity in response to mechanical stimulation. The correlation between phrenic nerve activity and tracheal smooth muscle tension during normal breathing was also observed after afferent inputs from pulmonary mechanoreceptors were interrupted. During coughing, however, this correlation was lost. From these results we conclude that the neural control of tracheal smooth muscle is at least partially independent of phrenic nerve activity during coughing. Because coughing was attenuated by neuromuscular blocking agents, we speculate that there is a positive feedback mechanism from receptors in the chest wall or airway, which increases the magnitude of coughing.

Diaphragmatic electrical activity during controlled and assisted mechanical ventilation in conscious human subjects.

Breathing during mechanical ventilation was analyzed in 8 conscious healthy volunteers by application of intermittent positive pressure ventilation through a mouthpiece. In controlled mechanical ventilation (CMV), the respiratory rate and tidal volume were fixed at 110 and 120% of the subject's corresponding spontaneous breathing parameters. The diaphragmatic electromyogram (EMGdi) decreased significantly but become synchronous with the rhythm of the CMV. In assisted mechanical ventilation (AMV), the EMGdi response developed prior to and during the inspiratory phase of AMV. Application of an unexpected mechanical breath elicited the EMGdi. As the triggering sensitivity was decreased, the EMGdi prior to and during a mechanical breath was augmented, however, its rate of rise was unaffected. Our results suggest that the EMGdi during mechanical ventilation in conscious subjects is initiated by the respiratory center, however, this activity is modulated strongly by input from the pulmonary afferents and from the cerebral cortex.

[99mTc-HMPAO SPECT in epileptic disorders in childhood].

Single photon emission tomography (SPECT) using Tc-99m-d,1-hexamethylpropylenamine oxime (HMPAO) was performed in two children with epileptic disorders during both sleeping and waking diurnal stages. Immediate postictal and interictal SPECT scans were obtained for a child with partial epilepsy. They demonstrated an interictal decrease in the regional cerebral blood flow (rCBF) and a more remarkable immediately postictal decrease in rCBF. The focus was in the same region of the SPECT for both interictal and postictal spikes. Another patient was diagnosed as having continuous spike-waves during slow sleep without epileptic seizures. Although SPECT during wakefulness showed no asymmetry, SPECT during sleep revealed decreased rCBF at the same location as the predominant area of diffuse epileptic discharges. We conclude that HMPAO SPECT is useful in investigation of the etiological mechanisms of seizures and epileptic discharges in epileptic disorders in childhood.

Epileptic seizures in the 4p- syndrome: report of two cases.

We report ictal phenomena in two patients with the 4p- syndrome captured on simultaneous video-EEG monitor. One patient, diagnosed as having partial epilepsy, had complex partial seizures and hemiconvulsive status epilepticus. This was associated with more severe mental retardation. The second patient was diagnosed as having the West syndrome and exhibited tonic spasms with a cluster formation. We conclude that various types of epileptic seizures may occur in patients with the 4p- syndrome, including grand mal and myoclonic seizures.

Ictal 99mTc-HMPAO SPECT in alternating hemiplegia.

99mTc-hexamethylpropylenamine oxime (99mTc-HMPAO) single-photon emission computed tomography (SPECT) was performed in a patient with alternating hemiplegia during 2 episodes of the disease. The regional cerebral blood flow patterns correlated with the clinical manifestations during both episodes. Hyperperfusion of the contralateral hemisphere was suggested by asymmetric 99mTc-HMPAO uptake, whereas symmetric 123I-N-isopropyl-p-iodoamphetamine uptake was detected during the interictal period. The results suggested that alternating hemiplegia in infants represents an atypical manifestation of epilepsy, despite the lack of paroxysmal electroencephalographic abnormalities during the episodes. 99mTc-HMPAO SPECT appears to be a useful method for detecting transient regional cerebral blood flow alterations during paroxysmal events because the tracer is rapidly available for emergencies and retains a fixed distribution for 5-8 hours, sufficient time to allow for SPECT acquisition.

Status epilepticus characterized by repetitive asymmetrical atonia: two cases accompanied by partial seizures.

Two cases of discontinuous status epilepticus (SE) characterized by repetitive asymmetrical atonic episodes associated with diffuse but asymmetrical spike waves are reported. Both patients also had partial seizures and interictal rolandic discharges. Dynamic EEG topography was performed to investigate the location or propagation of each ictal discharge overlying the scalp during status and showed immediate bilateral spread of discharges originating from a primary epileptogenic focus from a rolandic area.

Visual cognitive disturbance during spike-wave discharges.

Cognitive functions of patients showing slow spike-wave discharge in EEG without obvious absence seizures were investigated using tachistoscopic stimuli triggered by spike-waves. Response times obtained during spike-waves and during non-spike-waves were compared for three tests (tapping, simple reaction, and morphological discrimination). We present one case of Lennox-Gastaut syndrome in which the test results could be statistically confirmed. The tapping test was interrupted by the occurrence of spike-waves. Response times during spike-waves were more delayed than during non-spike-waves in both the simple reaction tests and morphological discrimination tests. The differences in response times measured during spike-waves and during non-spike-waves were significantly greater in the morphological discrimination test than in the simple reaction test. The positive correlation between the length of spike-waves and response time in the discrimination test was significantly more pronounced than in the reaction test. These results were also confirmed in two other patients with Lennox-Gastaut syndrome. We conclude that spike-wave discharges may impair cognitive processing more intrinsically than motor functions.

[A case of 18 q-syndrome associated with status epilepticus].

A 15-year-old boy with 18 q-syndrome manifesting a status epilepticus is reported. He has been already diagnosed as epilepsy because of grand mal seizures at six months earlier, and abnormal EEG findings. Unilateral status epilepticus developed at 15 years of age, which were characterized by alternative repetition of horizontal nystagmus to the right and clonic convulsion of the right (mainly upper) extremities every several minutes. Ictal EEG showed continuous 2 Hz high voltage slow waves superimposed by spikes and polyspikes which transformed to localized, irregular spike discharges in the left occipital region at the end of the status. The chromosomal study revealed a partial deletion of the long arm of No. 18. He had severe mental retardation, and a typical karyotype for 18 q-syndrome with reduced prominence of the midface region, short stature and whorls on all finger tips. The immaturity of the brain probably relates to this kind of unilateral status epilepticus.