Inherited convulsive disorders in mice.

In this chapter, we review the major inherited convulsive disorders found in mice and discuss their possible relationship to specific clinical seizure disorders in humans. These disorders in mice include audiogenic seizures, the epilepsy (El) mouse, various spontaneous seizures, the tottering/leaner syndrome, seizures associated with cerebellar abnormalities, seizures associated with myelin disorders, and alcohol withdrawal seizures. We find that for most major types of epilepsy in humans, there exists a similar counterpart in the mouse. Because human and rodent nervous systems respond similarly to seizure-provoking stimuli, it is possible that biochemical and physiological mechanisms of naturally occurring convulsive disorders are also similar in these species. The use of recombinant inbred (RI) and congenic mouse strains for genetic and biochemical studies of audiogenic seizures is presented. Using these strains, we have identified a major gene, Ias, that inhibits the spread of seizure activity. This gene was found through its close linkage with the Ah locus on chromosome 17. We also found that juvenile-onset and adult-onset audiogenic seizures are controlled by different genetic systems. The problem of juvenile-onset audiogenic seizure susceptibility is especially interesting because these seizures are genetically associated with an ecto-Ca2+-ATPase deficiency among the RI strains. This deficiency is the first neurochemical trait found to be inherited together with an idiopathic convulsive disorder, and may represent a potentially important basic mechanism of epilepsy. Because the brains of human epileptics are generally inaccessible for neurochemical research, the epileptic mouse mutants offer a convenient means of pursuing this type of research. The well-known genetic constitution of the mouse, together with the availability of numerous physiologically distinct convulsive disorders, makes the mouse ideally suited for molecular, genetic, and biochemical studies of convulsive behavior.

Focal epilepsy with mesial temporal sclerosis after acute meningitis.

Following acute meningitis associated with severe convulsions in childhood, two patients had chronic, drug-resistant, temporal lobe epilepsy. This disorder was preceded by an entirely natural development, in one case extending for nine years and in the other case for eight years. Each patient was treated with right anterior temporal lobectomy. Classic mesial temporal sclerosis (Ammon's horn sclerosis) was found in both patients. Relief of the epilepsy was associated with remission of the concomitant social and psychiatric handicaps. At least ten years of follow-up are required in the evaluation of the treatment of early brain infections. Chronic focal epilepsy after childhood meningitis with febrile convulsions merits neurosurgical consideration.

A review of mouse mutants as genetic models of epilepsy.

Here we review the major inherited convulsive disorders found in mice and discuss their possible relationship to specific clinical seizure disorders in humans. These mouse disorders include audiogenic seizures, the epilepsy (El) mutation, spontaneous seizures, the tottering/learner syndrome, cerebellar abnormalities, myelin disorders, and alcohol withdrawal seizures. Some of these disorders are symptomatic and others are idiopathic. We find that for many major types of epilepsy in humans there exists a similar counterpart in mice. Because the genetic constitution of the mouse is better known and more easily manipulated that that of other mammalian species, the mouse may serve as an excellent animal model for genetic and biochemical studies of epilepsy.

Monitoring at the West Haven VA/Yale University School of Medicine Epilepsy Center.

The Epilepsy Center of the West Haven VA Medical Center and Yale University School of Medicine was established in 1970. Nearly 2800 patients have been admitted and 130,000 h of EEG/video monitoring have been performed. Of the 300 annual admissions, over half are for diagnostic purposes and the majority of the remainder involve pre-surgical evaluation or post-surgical followup. Intensive monitoring at West Haven/Yale has been and continues to be based upon several fundamental concepts--continuous 24 h/day recording of EEG via cable telemetry, simultaneous video/audio recording of patient behavior, pen-written paper copy EEG for at least 24 h of the monitoring period, and around the clock capability for direct interaction with the patient to assess neurologic function. This maximal utilization has been possible because of a corps of specially trained nurses, who not only provide nursing care, but who can function as EEG technologists in their absence. Although pen-written EEG and multiplexed EEG recorded on video tape have been the monitoring mainstays at West Haven/Yale, ambulatory cassette and digitized computer recordings have recently been introduced. The resultant combined monitoring approach emphasizes the strengths of each technique and minimizes their weaknesses. The Epilepsy Center, its extensive patient population and a variety of talented personnel have formed a critical mass, the results of which have been numerous clinical investigations in the diagnosis and treatment of epilepsy.

More intense focal seizure types after callosal section: the role of inhibition.

Corpus callosum section reduces the incidence of generalized seizures associated with loss of consciousness. Minimal data are available, however, regarding the types of seizures that may be present following surgery. Five of 17 patients in our clinic who underwent partial or complete corpus callosum section developed more intense and sometimes newly patterned (but not necessarily more frequent) focal seizures postoperatively. These patients were not predictably different from the other 12 in terms of age at onset of seizures or at surgery, cause of seizures, extent of callosum sectioned, radiographically demonstrable structural lesions, or the types of preoperative seizures. All 5 patients, however, had bilateral independent frontal electroencephalographic foci. No patients without these electroencephalographic findings developed more intense focal seizures after surgery. The findings are consistent with the results of experimental animal studies and argue for a suppressive influence of the contralateral hemisphere on some types of seizures.

Genetic analysis of serum thyroxine content and audiogenic seizures in recombinant inbred and congenic strains of mice.

We previously proposed that the audiogenic seizure (AGS) susceptibility of 21 +/- 1-day-old DBA/2 (D2) mice may result from an early postnatal elevation in serum thyroxine (T4) concentration. In the present study we used seven C57 X DBA (BXD) recombinant inbred strains and the D2.B6-Iasb congenic strain to study the association between serum T4 content and susceptibility to AGS. The D2.B6-Iasb congenic mice are genetically similar to the D2 mice except for the Iasb gene, which inhibits AGS susceptibility. The total and estimated free serum T4 concentrations in these strains at 14 +/- 1 days of age were compared with the previously determined AGS susceptibilities of these strains at 21 +/- 1 days of age. We found no significant correlations between serum T4 concentration and AGS susceptibility in these strains. It is unlikely, therefore, that inherited differences in neonatal serum T4 content are directly responsible for differences in susceptibility to AGS in 21 +/- 1-day-old mice. The mechanisms by which the experimental manipulation of serum T4 content influences AGS susceptibility are discussed.

Selective memory improvement and impairment in temporal lobectomy for epilepsy.

Reexamination of 23 patients 1 year after elective anterior temporal lobectomy for intractable complex partial (psychomotor) seizures showed a reduction in certain memory functions combined with an improvement in others. Both improvement and impairment in selective memory functions were related to the degree of postoperative seizure reduction as well as to the side of the remaining temporal lobe. The results imply that uncontrolled seizures interfered with the memory functions of the temporal lobe contralateral to the epileptogenic focus.

Occupational adjustment following neurosurgical treatment of epilepsy.

Occupational adjustment was investigated in a group of 32 adult epileptic patients followed for 1 to 10 years after cortical resection for intractable seizures. An employment status rating was assigned according to the following scale: (1) employed (working 75 to 100% of full time); (2) underemployed (25 to 74%); and (3) unemployed (0 to 24%). The number of patients employed increased from 14 to 23, whereas the number of underemployed decreased from 8 to 0. The unemployed group showed little change. An improvement or maintenance of employment status was correlated directly with improved postoperative seizure control. Conversely, poor occupational adjustment was often associated with fair or poor seizure control following operation. Unemployment was also related to the presence of preoperative psychiatric disorders, a history of past unemployment, and cognitive disturbances affecting nondominant hemisphere function. Although improvement in seizure control is important, this investigation suggests it is only one of many influences on the occupational adjustment of patients following surgical treatment of epilepsy.

Psychomotor epilepsy and violence in a group of incarcerated adolescent boys.

The authors report the finding of psychomotor epilepsy in 18 of 97 incarcerated delinquent boys. Number of psychomotor symptoms was correlated with degree of violence in the members of this group. In addition, psychomotor symptoms were correlated more strongly with certain psychotic symptoms than with soft neurological signs or intellectual deficits. The relationship of violence to ictal and interictal states is explored.

Genetic linkage between the AH locus and a major gene that inhibits susceptibility to audiogenic seizures in mice.

Mice of the DBA/2 (D2) strain are highly susceptible to sound-induced seizures at 21 days of age; whereas, mice of the C57BL/6 (B6) strain are resistant to these seizures. Although the difference in susceptibility to audiogenic seizures (ASs) between these two strains is inherited as a multiple-factor trait, an association was observed between susceptibility to ASs and the Ah locus. The Ah locus controls the inducibility of aryl hydrocarbon hydroxylase (AHH) activity by a number of aromatic hydrocarbons. B6 mice carry the Ahb allele and have inducible AHH activity; whereas, D2 mice carry the Ahd allele and have noninducible activity. Inducibility is inherited as a Mendelian dominant trait in crosses between these strains. Mice carrying the Ahb allele are generally less susceptible to ASs sat 21 days of age than are mice carrying the Ahd allele. The combined results from B6 X D2 recombinant inbred strains, congenic strains (where the Ahb allele was placed into the D2 genome and the Ahd allele placed into the B6 genome), the B6D2F1 X D2 backcross generation, and a random survey of various inbred strains, suggest that the association between these two traits is due to genetic linkage, rather than to pleiotrophy or to chance. A major gene that inhibits susceptibility to ASs appears to be closely linked to the Ah locus. This gene has been designated Ias, for inhibition of ASs. A large portion of the genetic variability of AS susceptibility may be due to the segregation of Ias.

Treatment of intractable temporal lobe-limbic epilepsy (complex partial seizures) by temporal lobectomy.

The results of lobectomy in carefully selected patients with intractable epilepsy now are realized as worth the risk, for complete seizure relief can be achieved in up to 50% of such cases, and moderate to good seizure control in at least an additional 25%, with reduction in the drug requirement. Along with seizure relief often comes improvement in behavior and in social and personality development and life adjustments. Temporal lobectomy for treatment of temporal lobe-limbic epilepsy therefore also has preventive value, especially if performed as early as the criteria indicate in appropriately selected patients. The resected tissue allows careful morphological studies that can enhance our knowledge of the pathogenesis of this disorder.

Genetic analysis of audiogenic seizure susceptibility in C57BL/6J X DBA/2J recombinant inbred strains of mice.

The inheritance of susceptibility to audiogenic seizures (ASs) was studied in the C57BL/6J (B6) and DBA/2J (D2) progenitor strains, their reciprocal F(1) hybrids, backcross generations and in 21 B6 x D2 recombinant inbred (RI) strains of mice at 21 days of age. All of the D2 mice tested experienced ASs, whereas none of the B6 mice responded to the sound. Although 23% of the F(1) mice experienced wild running, they were generally as resistant to ASs as their B6 parents. Mice of the F(1)x B6 backcross generation were also resistant to ASs. In the F(1)x D2 backcross generation, however, a significant preponderance (72%) of AS-susceptible mice was found. No significant association was observed between any of the four coat-color phenotypes that were segregating in this generation and susceptibility to ASs. A continuous distribution of mean seizure severity scores and several new audiogenic response phenotypes, distinctly different from the phenotypes of either progenitor strain, were found among the 21 RI strains. These and the results from the F(1)x D2 backcross generation suggest that the difference in AS susceptibility between 21-day-old B6 and D2 mice cannot be under the control of a single locus. In addition, no association was found between AS susceptibility and the chromosome 4 markers Lyb-2, Mup-1 and b among the 21 RI strains. An association was observed, however, between AS susceptibility and the Ah locus. Several of the RI strains that were AS resistant at 21 days of age became AS susceptible as adults. One RI strain was susceptible to ASs at both young and adult ages. The B6, D2 and F(1) mice were completely resistant to ASs at adult ages. Genetic differences were found among the RI strains for the incidence, onset, duration, and type of severity of ASs. A remarkable amount of phenotypic variability in the audiogenic response, which can be attributed only to the influence of environmental factors, occurred within several of the RI strains. A multiple-factor mode of inheritance involving a physiological threshold can account for our observations.