Cesare T. Lombroso

A Prospective Study of Infantile Spasms: Clinical and Therapeutic Correlations

Summary: Of 363 infants with infantile spasms (IS) admitted into our hospital during an 18‐year period, 286 were closely followed for at least 6 years and form the basis of this report. These patients were divided into symptomatic (165 cases) or cryptogenic (121 cases) groups. The cryptogenic group consisted of patients exhibiting no etiological clues and in whom development until the onset of the disorder was normal, even if some had mild impurities in their previous biography. We did not use the “doubtful subgroup” proposed by others for infants with no known etiology but with definite previous psychomotor delay. Close monitoring of ictal phenomena confirmed the latter variability and strengthened the view that IS should not be classified as a distinct seizure pattern. No statistically significant clues for etiology or prognosis were offered by the analysis of prevailing seizure patterns or frequency. Etiologies in the symptomatic group were subsumed within pre‐, peri‐, and post‐natal periods. Asphyctic events predominated in this series. Dysgenetic, infectious, metabolic, and hemorrhagic factors were almost equally represented, except for the first, which was found somewhat more frequently. That postimmunization reactions may be one cause of IS was not considered sufficiently documented. A gender predominance (♀: ♂= 2:1) occurred within the symptomatic group only. No significant genetic trends could be revealed after excluding those disorders that themselves carry clear genetic implications. Age of onset was earlier than in most reports because we corrected for true concep‐tional age. When this was done, onset of IS below 3 months carried a more unfavorable prognosis (p < 0.001). As expected, the presence of preceding neurological impairment resulted in worse outcome. Infants who had typical hypsarrhythmic EEG at the onset of IS fared better than those with atypical EEG (p < 0.02). While bacterial infections usually aggravated the condition, viral ones seemed to temporarily ameliorate it. On a short‐term follow‐up (10 months from onset treatment), the hypsarrhythmic pattern may disappear in both groups regardless of therapies, but on a long‐term basis (6 years), the EEG evolution showed no statistically clear correlations with early therapies. The evolution into other seizure patterns also appeared independent of therapies. In our series less than a quarter eventually developed the Lennox‐Gastaut syndrome. Controlled therapeutic protocols were adopted in an effort to resolve ongoing controversy about optimal treatment. Both groups were maintained, thoughout the therapeutic trial, on either antiepileptic drugs, on oral steroids alone, or on nonsynthetic ACTH alone, the latter followed in one subgroup by oral steroids also. Dosages were based on body surface or weight. Whenever cross‐over or a change in the initial therapeutic regimen became necessary, the case was eliminated from the study. Clinical and laboratory tests were obtained at prefixed periods of time. For the short‐term assessment both cohorts were included. No statistical difference emerged between the controlled therapeutic regimens, each of the latter causing amelioration or not, except for a trend favoring the ACTH treatment. To establish long‐term effects (6 years) it was felt that only the more homogenous cryptogenic group would allow valid conclusions. The latter indicated that cases treated with nonsynthetic ACTH fared better than those treated with antiepileptic drugs or with oral steroids alone. This more favorable outcome included a lower incidence of later epilepsy (p < 0.05) and better psychomotor status (p < 0.025 to p < 0.05). Evolution of EEG and of motor‐sensory deficits did not appear to be significantly influenced. Babies started on ACTH within a month from onset of IS fared better than those in whom ACTH therapy was delayed (p < 0.01). These results also suggest that the effects of nonsynthetic ACTH may in part be independent of Cortisol release, through some direct influence upon the CNS.

Prognostic value of background patterns in the neonatal EEG

The prognostic value of background activity in the neonatal EEG has been well established. Whereas in older children the neonatal EEG is useful in the diagnosis of seizures, in neonates the test also provides a particularly valuable assessment of cerebral functioning following a variety of insults. In this review, the prognostic significance of abnormalities of amplitude, continuity, frequency, symmetry, synchrony, sleep state, and maturation are discussed. Certain abnormalities, such as cerebral electrical inactivity or burst suppression, are highly predictive of outcome, whereas other abnormalities of background activity are associated with more variable outcomes. Since the ill neonate may have more than one abnormality, predicting outcome based on a single EEG feature is discouraged. As in older children, drugs may affect EEG background rhythms. Although abnormalities on the neonatal EEG are not specific for diagnosis, certain EEG patterns may be highly suggestive for the diagnosis of pyridoxine dependency and neonatal herpes encephalitis. In both term and preterm infants, the prognostic value of the neonatal EEG is increased by performing serial studies.

Age-dependent changes in long-term seizure susceptibility and behavior after hypoxia in rats.

Summary: We showed that hypoxia is acutely epileptogenic in immature but not in adult rats. In the present study, we evaluated whether hypoxia results in an in‐crease in long‐term seizure susceptibility to flurothyl and whether this is associated with impaired performance on behavioral tests. We also determined whether these long‐term outcomes are dependent on age at time of O2, deprivation. Long Evans hooded rats were rendered hypoxic on either postnatal day (P)5, P10, or P60. Sixty to 75 days after hypoxia, rats were tested for performance in water maze, open field, and handling tests and for seizure susceptibility to flurothyl. Hypoxia at P10 significantly in‐creased seizure susceptibility to fluorothyl, whereas hypoxia at P5 and P60 induced no long‐term changes in seizure threshold. At P10, greater seizure severity during hypoxia and more prolonged exposure to hypoxia significantly increased long‐term seizure susceptibility. This long‐term change in seizure susceptibility appeared to be dissociated from any long‐term neurobehavioral consequences, because only animals rendered hypoxic as adults (P60) had impaired behavioral performance. The results suggest that hypoxia‐induced seizures can alter long‐term seizure susceptibility and that this long‐term effect is dependent on age and on severity of seizure activity at the time of previous hypoxia.

Consistent EEG Focalities Detected in Subjects with Primary Generalized Epilepsies Monitored for Two Decades

Summary: Purpose: To describe the evolution of interictal findings in serial EEGs from patients with primary generalized epilepsy.

Ctenoids in healthy youths Controlled study of 14‐ and 6‐per‐second positive spiking

SINCE 1951, when Gibbs and Gibbsl first published their description of the electroencephalographic (EEG) phenomenon which they designated as 14and 6-per-second positive spiking, there has been growing interest in this finding. It appears to be most prevalent in the 5to 15-year-age group and seldom appears outside of the stages of drowsiness and light sleep. Typical examples are shown in Figures 1, 2, 3, and 4. It is possible that much of the interest in these bursts may derive from their striking appearance and rather complex morphology, for which we have proposed the name “ctenoids,” from the Greek KTEN6S = comb, as a snbstitute for the more unwieldy and only illusorily precise phrase “14 & 6/second positive spikes.” Equally remarkable are the uniformity of their distribution and ease of identification. According to Gibbs and Gibbs? a rather broad spectrum of clinical manifestations was associated with the occurrence of ctenoids. Almost as puzzling as the congeries of clinically unrelated symptoms has been the diversity of presumed etiologies. Subsequent workers, while in earlier years denying either the reality or the significance of these complexes, gradually began to take them more and more seriously, variously stressing their association with complaints of vegetative dysfunction or of behavioral disturbances, both notorious sonrces of perplexing diagnostic problems. Perhaps the most complete paper dealing with the association between ctenoids and the autonomic nervous system is that of Kellaway and associates,3 who formulated a specific electroclinical syndrome in 459 children with primary complaints of headache or abdominal pain associated with other auto-

Treatment of status epilepticus with diazepam

STATUS EPILEPTICUS constitutes a medical emergency, as well as a difficult problem of therapy. This statement has been made authoritatively and sufficiently frequent so that to belabor the point further is unnecessary (Gowers,l Clark,2 Turner,3 Wilson,4 and the more recent review of the problem by Hunter”. Two features of the problem seem worthy of stress here, as they do not seem to have received much attention in the literature. The first concerns the possible iatrogenic effects attributable to excessive treatment. In the emergency presented by status epilepticus, the tendency is often to overdose. A patient in status is likely to have dissipated much of his vital reserves and may more easily become a victim of the depressant effects characteristic for most, if not all, antiepileptic agents. The cardiac and respiratory centers and functions, already overburdened, are particularly vulnerable. In the course of an analysis concerned in establishing the immediate cause of death in patients that succumbed in status epilepticus at the Children’s Hospital Medical Center over a ten-year period, just short of a quarter of the total number was found to have had cardiac or respiratory arrest, or both, closely following the intravenous administration of a hypnotic agent.6 Further, there are some disquieting reports dealing with central nervous system lesions attributable to other nonbarbituric drugs, when administered parentally and in the large doses often used in status.?-9 It would seem, therefore, that a need still exists for drugs that would interrupt the vicious state of “continuous epilepsy” but would not be the source of equally dangerous iatrogenic effects. Such need has been obviously felt by many, as shown by the proposal to use intravenous urea, as advocated by Carter,lo or the intracarotid injections of amylobarbital, as advocated by Bladin.ll The other point needing clarification in a

Facilitation of Infantile Spasms by Partial Seizures

Summary: We report 16 patients with infantile spasms in whom onset of the clusters of spasms appeared to be triggered by close temporal association with partial seizures. Common features included the presence of focal cerebral lesions in 12 infants (3 were classifiable as cryptogenic); all had partial seizures with EEG localization, clusters of bilateral spasms always preceded by partial seizures, and response to adrenocorticotropic hormone (ACTH) and traditional antiepileptic drugs (AEDs) generally was poor. Three had complete agenesis of the corpus callosum, which argues against interhemispheric callosal spread of focal discharges resulting in the generalized spasms. Surgical cortical resections were performed in 6 of the infants, with good outcomes. This group of patients supports a model in which the spasms, although probably generated at a subcortical level, are facilitated or possibly induced by focal discharges from cortical pathology.

Epileptic (Gelastic) Laughter

In the last decade we have encoutered 10 cases in whom we considered laughter to represent either the only or one of several peripheral expressions of an abnormal cerebral electrical discharge. We have distinguished between pathological laughter that may occur in the course of diffuse neurological diseases or as an expression of a dementing process, from that which can be properly called epileptic in nature. We have also distinguished between ictal and postictal laughter. Finally, we have speculated upon the functional implications of epileptic outbursts of laughing, in terms of the possible anatomic substrate and interconnections subserving this fairly unique human expression of emotion, and have pointed out differences in clinical and EEG characteristics that seem to correlate with the different location of the lesions responsible for the discharges.

Pyridoxine-dependent epilepsy: EEG investigations and long-term follow-up ☆

The EEG features and clinical correlates were investigated before, directly after, and on long-term follow-up after initiation of pyridoxine therapy in 6 patients with B6-dependent epilepsy. At each phase, the EEG provided important diagnostic and prognostic information. Pre-B6 3 neonates manifested a unique EEG pattern of generalized bursts of 1-4 Hz sharp and slow activity. This pattern has not been previously described in neonates with B6 dependency and in this age group appears to be highly suggestive of the diagnosis. Five patients experienced an apparent initial response to traditional antiepileptics. The parenteral pyridoxine test, performed in all 5, and repeated in 3, proved to be a highly reliable and reproducible diagnostic test. After 50-100 mg of B6 there was cessation of clinical seizures within minutes and of paroxysmal discharges within hours. On long-term follow-up (3-28 years) all 6 patients were seizure free on B6 (10-100 mg/day) monotherapy. Recurrences of seizures and of specific sequential EEG changes (background slowing, photoparoxysmal response, spontaneous discharges, stimulus-induced myoclonus, generalized seizures) occurred upon B6 withdrawal. Long-term prognosis correlated with the EEG. Two patients had persistently abnormal EEG backgrounds and were moderately to severely retarded, while 4 had normal EEGs with normal or near normal development.

Left and Right Temporal Lobe Epileptics: A Controlled Investigation of Some Psychological Differences

Twenty‐two young adults with clinically and electroencephalographically diagnosed temporal lobe epilepsy were selected from an outpatient neurology source; 11 with focal epileptic activity in the right temporal lobe and 11 with left temporal lobe involvement were included. All patients had normal intelligence and comparable educational and socioeconomic backgrounds. Matched nonepileptic controls were also tested. Subjects were given psychological tests assessing differences in cognitive style and affect communication. Greater reliance on the ear ipsilateral to discharge focus in a dichotic listening paradigm was discovered, confirming appropriate lateralization assignment. Left lateralized patients exhibited a more reflective cognitive style than controls; right lateralized patients were more impulsive. Previously confirmed associations between impulsivity and externalized aggressive responses suggest the hypothesis that externalization of aggressive responses may occur more often among right lateralized patients. Left lateralized patients made more atypical assignments of affect labels to emotionally evocative descriptions. Right lateralized patients tended to assign affect labels as controls. A greater potential for disturbance in the verbal communication of affect among left lateralized patients is suggested.