>>> Posting number 3603, dated 31 Jan 1997 13:18:37
                  Febrile seizures, amygdala, autism (text, 1 of 3)

The following paper was posted in 3 text-sections and 3 reference- sections to the
bit.listserv.autism newsgroup and is copyrighted 1997 by Teresa C. Binstock. Persons
wishing to share this paper may do so in its entirety. Persons wishing to cite the
paper in correspondence or in academic papers may use the following internet
protocol citation:
      Binstock T. Hypothesis: Febrile seizures and the amygdala: a causal
      mechanism in autism and related disorders. Bit.listserv.autism January
      31, 1997.

.....PRELUDE.....
Although vaccinations are considered a major milestone in medical history (1), they
are not without risk (2-11). This paper sets forth a rationale whose purpose is not
to assert "all vaccinations are inappropriate" but instead is to delineate a
mechanism by which negative vaccination-reactions may be occurring in some
individuals; for if substrates of such processes are understood, then better
pre-vaccination screening may allow highly susceptible children to be more
accurately identified and thus exempted from mandatory vaccinations. Furthermore,
this paper offers a rationale in which febrile seizures induced by other
physiological processes other than vaccinations may also be causally significant in
some cases of autism, including but not limited to such syndromes as tuberous
sclerosis, Lennox-Gastaut and Landau-Kleffner.

.....ABSTRACT.....
During childhood, febrile seizures (FS) have a variety of causes, of which
vaccinations are but one; and some children with FS progress to status epilepticus
(SE). A recent article by Tuunanen et al (Eur J Neurosci 8:2711-2725 1996) documents
that, in the rat, artifically induced SE causes neurons to die in certain subregions
of the amygdala. A survey of amygdala and autism literatures indicates that the
areas identified by Tuunanen and colleagues participate in several autistic traits
(eg, eye-contact avoidance). The idea is offered and preliminarily explicated that
the work of Tuunanen et al may have identified both a causal mechanism and neural
substrates central to pathogenesis in autism.

.....INTRODUCTION.....
A primary causal factor in many cases of autism may have been identified in the work
of Jarkko Tuunanen and colleagues, who describe neuronal death within specific
amygdala subregions (12). The demise of these amygdaloid neurons was a direct result
of artifically induced status epilepticus (SE) which, when occurring in humans, is
associated with febrile seizures (13-16) that may arise from from infection,
vaccination, or other possible causes (9-10, 17-21).
     With strongly deleterious effects upon amygdaloid GABAergic neurons (12), the
areas wherein SE-induced neuronal death occurred are documented in studies of higher
primates as centrally involved in such processes as eye contact and responses to the
faces of others, social behaviors, emotional regulation, sensory processing, etc
(22). This localization within certain amygdaloid sub-areas is not suprising, for
a number of autism researchers have suggested amygdala participation (eg, 23-35),
especially since amygdala atypicalities were reported in the 1985 Bauman and Kemper
autopsy study (23). Additionally, (i) SE-induced amygdala damage in humans often
leads to permanent damage within the hippocampus (13-14), thereby suggesting
impairments in memory among autistics having SE-induced pathogenesis, and (ii)
status epilepticus is associated with reduced cerebellar sizes, particularly among
Purkinje cells, where gliosis-like scarring is not always evident (36-38).
     Aside from theoretical constructs wherein unusual combinations of primary,
secondary, and tertiary genes are hypothesized to account for at least some cases
of autism, my readings have suggested three major categories likely to be causes of
many and perhaps most cases of autism (discussion in 38a): (i) infections with CNS
edema (38b), (iii) febrile seizures (summarized in this essay), and (iv) subacute,
ongoing infections of the GI-tract (38c,38d). Furthermore, at least one kind of
genetic predisposition (Complement 4b immunodeficiency) has been identified by Reed
Warren and colleagues (38e-38h). From person to person, various and diverse
combinations of i,ii, and iii, can occur.
     Given the consistency between certain autistic traits and various
neuroanatomical studies of the amygdala, the sub-areas and neuronal- death processes
identified by Tuunanen et al appear to be significant for understanding etiologies
in many cases of autism -- including but not limited to specific instances linked
with tuberous sclerosis, Lennox-Gastaut and Landau-Kleffner syndromes (38i), as well
as infectious encephalopathies and the occasional adverse reaction prompted by
vaccinations (10,15). With regard to autism, the common factor among these seemingly
diverse processes may be amygdaloid damage induced by a prolonged incident of status
epilepticus during early childhood, a process often but not necessarily preceeded
by febrile seizures. Consideration of various medical literatures suggests that the
data from Tuunanen et al may have identified both a primary substrate and cause in
many cases of autism.

                  >>> Posting number 3610, dated 31 Jan 1997 13:20:45
                  Febrile seizures, amygdala, autism (text, 2 of 3)

.....FEBRILE SEIZURES & STATUS EPILEPTICUS.....
Estimated to occur in 3-5% of all children (39), febrile seizures (FS) are often
described as benign (40-41); yet approximately 30% of children (among the 3 to 5%)
will have a second FS, and half of those 30% will have "two or more recurrences"
(42). Despite the often repeated assurances that FS are "benign", a level of seizure
known as Status Epilepticus (SE) occurs in approximately 5% of individuals who
experience FS (43); and the fact that febrile seizures are associated with status
epilepticus suggests that, in some cases, damage to various regions of the amygdala
may occur (12-16). Causes of FS are diverse, and the most common factors associated
with FS were fever and rate of fever development, regardless of the underlying cause
of fever (17).
     Although febrile seizures have long been associated with vaccinations (reviewed
in 20-21), the idea of a causal relationship is often refuted; and instead, the
notion "temporal association" is offered as an explanatory model which rejects
causal connection between vaccinations and subsequent FS (reviewed in and endorsed
by O'Donohoe NV 1994; see Ch 4 in ref 44).
     Whether the relationship between between FS and vaccinations is causal or
merely that of temporal association has special importance to autism, wherein a
subgroup of parents report that a previously normal child's onset of autism occurred
soon after a vaccination whose response in the child included fever and febrile
convulsions (21-22, 45). Thus, regarding vaccinations and FS, perusing the validity
of the two models is important with regard to seemingly dichotomous alternatives:
merely temporal-association or causal relationship.
     In his excellent 1994 book, drawing upon extensive personal experience and
citing the work of GS Golden, O'Donohoe wrote: "Consistent neuropathological
findings have never been produced to support such a specific pathophysiological
process [of vaccinations causing febrile seizures], nor has any acceptable animal
model been found (44, 46). However, by 1996 the reservations expressed by Golden and
O'Donohoe appear to have been addressed, because the work of Tuunanen and colleagues
may have provided (i) a animal model of specific neural substrates, and (ii)
identification of neurological processes occurring not only in the animal model but
also in humans.
     Utilizing several methods of inducing status epilepticus phenomena in rats, the
brain-areas primarily affected by SE have been identified. These areas are certain
neuronal clusters within traditional amygdala sub-areas and, as a result of status
epilepticus (SE) events, some amygdala neurons in those areas actually die. These
areas are known to have significance to social interactions, eye contact, emotions,
and motivation, etc (discussions and cites below).
     The Tuunanen et al findings may also account for the fact that some autistic
children have ongoing seizures and some do not. The rationale is as follows: whereas
status epilepticus may be a causal factor in autisms of infants and children in whom
amygdaloid neurons die, the very fact of those neurons dying may actually disincline
many such children from having further seizures. Such a sequence of causality
(albeit *hypothtical*) would account for how (i) SE may be a primary cause in
autism, even though (ii) many autistics do not have seizures, ie, because in some
individuals a sufficiently large number of dead amygdaloid neurons might not
contribute to hyper-excitability within primary seizure-prone neuronal groups, eg
the amygdala (13-15).
     Let us review: 3-5% of children have one or more noticable FS. Among those
children, approximatey 5% will have one or more SE events, which evidence now shows
can lead to neuronal death within specific amygdaloid sub-areas whose neurons
participate in traits directly linked with autism.

.....AMYGDALA.....
For more than a decade, the amygdala has been identified as a substrate whose
dysregulation is likely to contribute to some aspects of autism (eg, 23-35). Via
artificially induced status epilepticus (SE), Tuunanen et al identified a number of
amygdaloid regions experiencing SE-induced neuronal damage, most sensitive to damage
were neurons within the accessory basal, lateral, basal, medial, and anterior
cortical nuclei (12). Based upon neuroanatomical studies of the amygdala in higher
primates including humans, the sub-areas identified by Tuunanen et al are linked
with certain traits in autism.

A. Eyes and faces: Atypical, avoidant eye contact is a trait occurring in a high
percentage of autistic children (47-48) and is often reported by parents of some
autistic children as one of the earliest traits seen the post-vaccination period
(21-22,45), a time some individuals have their first recognized FS (10). Let us now
compare these events with primate and human amygdaloid data and with the Tuunanen
et al findings regarding status epilepticus.
     A relatively small number of single neurons within the primate amygdala are
known to be responsive to faces; and these neurons have been identified within the
basal-lateral and basal accessory nuclei (49- 50), areas functionally similar to
those described in rats and other sub-primates (see discussion in 52), ie, areas
damaged by SE (12). Furthermore, some of these neurons are responsive to variations
in facial direction, to direction of gaze of the face being perceived, as well as
to eye contact (51); and processes similar to these occur in human amygdala (53-54).
     That Tuunanen et al identified SE-induced neuronal damage in amygdaloid regions
wherein face- and eye-contact neurons are located suggests, in regard to eye-related
traits in autism, that a neural substrate and type of causality may have been
identified.

B. Other traits. "The accessory basal nucleus is located at the interface between
the information flow from the external and internal milieus." (55). As a result,
there are numerous studies of neuronanatomy and traits related to the amygdaloid
areas identified by Tuunanen et al. Furthermore, there are numerous intra-amygdaloid
routes by which the Tuunanen-identified nuclei would exert effects via nuclei
additional to those described in reference 12 (reviewed in 22). Therefore, a
thorough delineation would be far too lengthy at this time, but the following are
examples of traits that, in some individuals, would be likely to become atypical as
a result of the sequence febrile seizures, status eptilepticus, and amygdaloid
damage:
     - processing of fear and other emotions (56-57)
     - alterations in social behavior (58-59)
     - gastrointestinal processes (60-61)
     - stimulus-reward encodings (62-63);
     - via amygdaloid/hippocampal and other interconnections, certain
       aspects of memory (13-14, 64-69).


                  >>> Posting number 3611, dated 31 Jan 1997 13:22:15
                  Febrile seizures, amygdala, autism (text, 3 of 3)

.....SEIZURES IN AUTISM.....
As reviewed in Bailey et al (70) the overlap between autism and epileptiform
activity has long been known. "Several systematic studies have shown that epilepsy
develops in about a fifth to a third of autistic individuals... What is most
distinctive about the epilepsy associated with autism, as compared with that found
in mentally retarded individuals... is the high frequency of an onset of epileptic
attacks in late adolescence or early adult life. The significance of the age of
onset is not known but it is relatively distinctive... There does not seem to be
anything particularly characteristic about the type of epilepsy in those with a late
onset."
      However, regarding the late age of onset an article by Lawrence Hudson and
colleagues may provide a clue: "Without exception, people who exhibited HS
[hippocampal sclerosis] on temporal lobe specimens had sustained an early convulsive
event; this event [if recognized] took place at a mean age of 1.7 years... and
consisted of a generalized seizure related to febrile convulsions, status
epilepticus, head injury, or meningitis (71).
     Hudson et al continue, "Subsequently there was a mean interval of 12.3 years
during which no convulsive activity was documented; following this quiescent period,
HS-positive patients went on to manifest recurrent complex partial or generalized
seizures at a mean age of approximately 14.0 years."  Furthermore, "Patients with
isolated amygdaloid sclerosis (HS-negative) did not exhibit this natural history;
with few exceptions, these patients began to experience de novo recurrent seizures
at a mean age of 17.0 years."
     That Hudson et al describe a time delay similar to what Bailey et al consider
to be a trait commonly seen in autism does not prove that the FS, SE, and autism are
pointing towards the same causal substrate, but such an inference is credible; the
validity of such an inference may even be likely.

Let us return to the Bailey et al section about epilepsy: "There is also a
substantial group in whom the epilepsy begins during the preschool years and this
is perhaps particularly characteristic of autism associated with strong mental
retardation. In this earlier onset group, infantile spasms may be particularly
associated with autism..." (70).
     Again, epilepsy literature may provide clues, for the association between
epilepsy and mental retardation has long been known (72). In 1970 Aicardi and
Chevrie wrote about a subgroup of 47 children in whom no pre-existing neurological
condition had been identified: "In the remaining 47... the child appears to have
been normal before the status [epilepticus] and no other cause other than status
epilepticus seemed to account for the neurological deterioration." And the authors
continue, "Mental retardation was conspicuous after the convulsive episode in 114
children (48%). Seventy-eight of them [had] developed normally prior to their first
status [epilepticus] (or at least were not grossly retarded)." And importantly,
"Febrile status epilepticus is quite common in our experience... In this respect
febrile status epilepticus does not differ from the more usual febrile convulsions."
A graph on p188 (72) shows that approximately 3/4 of the studied seizures occurred
prior to the age of 4.5 years, with the far greater abundance prior to age 1.5.
     Bailey et al's 1996 descriptions of infantile spasms among autistics are
remarkably similar to status epilepticus occurrences described by Aicardi and Cevrie
in 1970, with regard (i) to cognitive functions and their sudden deterioration after
prior normalcy, and (ii) to ages of onset. Again, these 1970 and 1996 descriptions
are at least consistent with the Tuunanen et al findings that status epilepticus
induces neuronal damage in crucial regions of the amygdala, regions possibly having
directly relationship to certain traits seen in autism.

.....IN CLOSING..... 
This paper presents a sketch of how the Tuunanen et al article may be important for
understanding etiology and pathophysiology in a large subgroup of autistics and
other individuals along the PDD spectrum.
     In the article, Tuunanen et al suggest that their findings about SE-induced
neuronal damage also may apply to effects induced by febrile seizures (12), which
is reinforced by the FS/SE relationships described and cited hereinabove. In some
individuals, if by these processes certain amygdala neurons die, then numerous
autonomic, emotional, motivational, behavioral, and social processes will become
atypical. For these reasons, the Tuunanen et al findings may (i) delineate the
neuropathological substrate and (ii) provide the "acceptable animal model" that
Golden and O'Donohoe did not feel existed in 1990 and 1994 (44,46).

A.    Additive effects: 
Febrile seizures have many causes (17). FS are additive, by which I mean that a
young child who has had one FS then becomes more likely to have an additional FS
(qq-1). FS are a predisposing factor to SE (zz+3), which can destroy neurons in
specific areas of the amygdala (12). This suggests that, in some cases, several
otherwise "mild" insults over a period of months or years (eg, neonate, infant,
toddler time-span) may combine so that a later FS episode -- whether from infection,
vaccination, or other cause -- is more damaging than it otherwise would have been.
Constrastingly, the possibility remains that, in some individuals, reactions to an
single infection or a vaccination may be sufficient for inducing the sequence from
FS to SE to amygdaloid-damage.

B.    Inter-individual variations among autistics: 
The additive-effects principle may account for some cases of inter-individual
variation, even among siblings including twins. Consider the subset of children
whose autism may have come via the "FS to SE to amygdaloid-damage" route. The
medical history of each sibling, while very similar in regard to vaccination
timings, nonetheless may have been different with regard to one or more early,
severe infections. As a result, when a subsequent fever and related
cytokines-release occurred (73), the sibling with one or more extra FS in his or her
medical history would, in contrast with other siblings, have been more inclined to
have had a FS- and SE-induced neuropathy within the amygdala (74).
     Another source of inter-individual variations is presented in the Tuunanen et
al article, wherein status epilepticus stimulation led to variations in degrees of
damage within primary and secondary amygdaloid locales having neuronal death.

Epilogue:
Please keep in mind that this paper is a hypothesis. The causal sequence portrayed,
though rooted in medical literature, has not been proven. However, that the Tuunanen
et al findings identified amygdaloid regions with clear significance to various
autistic traits is either remarkably coincidental or profoundly important. This
author of this hypothesis has felt that the Tuunanen findings should be presented
with supporting discussion so that their possible applicability to autism and
related disorders can be contemplated and evaluated.

REFERENCES, QUOTES, & COMMENTS

                  >>> Posting number 3604, dated 31 Jan 1997 13:23:16
                  Febrile seizures, amygdala, autism (References, 1 of 3)
                  >>> Posting number 3605, dated 31 Jan 1997 13:24:20
                  Febrile seizures, amygdala, autism (Refs, 2 of 3)
                  >>> Posting number 3652, dated 31 Jan 1997 22:02:13
                  Febrile seizures, amygdala, autism (Refs, 3 of 3)

1. Ada GL. Vaccines. In: Paul WE, ed. Fundamental Immunology. 3rd ed.
New York: Raven Press Ltd, 1993.
2. Miller HG, Stanton JB. Neurological sequelae of prophylactic inoculation.
Quarterly Journal of Medicine, New Series 1954;XXIII:1-27.
3. Stetler HC, Orenstein WA, Bart KJ, Brink EW, Brennan JP, Hinman AR. History of
convulsions and use of pertussis vaccine. Journal of Pediatrics 1985;107:175-179.
4. Clayton EW, Hickson GB. Compensation under the National Childhood Vaccine Injury
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5. Hsu CY, Huang LM, Lee CY, Lin TY, Lee PI, Chen JM. Local massage after
vaccination enhances the immunogenicity of diptheria-tetanus- pertussis vaccine.
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     "Local massage after [DPT]... vaccination was associated with
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     "not particularly disturbing" may come to be seen as soothing
     but not particularly accurate, for some individuals.

6. Vlacha V, Forman EN, Miron D, Peter G. Recurrent thrombocytopenic purpura after
repeated measles-mumps-rubella vaccination. Pediatrics 1996:97;738-739.
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     "...the vast majority of, though not all, FS patients follow a
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8. Menkes JH, Kinsbourne M. Workshop on neurologic complications of pertussis and
pertussis vaccination. Neuropediatrics 1990;21:171-176.

9. Cherry JD, Holtzman AE, Shields WD, et al. Pertussis immunization and
characteristics related to first seizures in infants and children. Journal of
Pediatrics 1993;122:900-903.
     Having excluded children with previously known epilepsy, non-
     epilepsy children with post-vaccination febrile seizures are
     described as follows: "...the following characteristics in
     children with febrile seizures were significantly more common
     when pertussis immunization had occurred within 3 days,
     compared with more than 7 days of the [immunization] event:
     first seizure more tha 10 minutes in duration, the occurrence
     of more than one seizure, the longest seizure (when there was
     more than one) more than 10 minutes in duration, and the
     occurrence of a seizure described as focal." ** "The cause of
     increase severity of febrile seizures apparently associated
     with pertussis immunizaiton is unknown."
      
     Perhaps quite significantly, "Children who had their first
     febrile convulsion within 3 or 7 days of pertussis
     immunization were more likely to have had..." more severe
     seizures and age was not a confound. [See 2nd & 3rd paragraphs
     in Results, p901]

     "Pertussis immunization is a precipitating factor of the first
     febrile convulsion in children prone to have febrile
     convulsions..." [People should not generalize by concluding
     that only children who are 'genetically predisposed' have
     vaccination-induced febrile seizures. In a similar with more
     focused data study (6a), only 6 of 60 and 15 of 60 children
     with severe DPT reactions had personal or familial history of
     prior seizures, indicating that the majority of children with
     severe reactions had no prior personal or familial FS as
     indicators of 'genetic predispostion'.

     "Our data indicate that febrile seizures induced by pertussis
     immunization may be more severe than those induced
     collectively by other events such as otitis media and viral
     infections."

10. Blumberg DA, Lewis K, Mink CM, Christenson PD, Chatfield P, Cherry JD. Severe
reactions associated with diphtheria-tetanus-pertussis vaccine: detailed study of
children with seizures, hypotonic- hyporesponsive episodes, high fevers, and
persistent crying. Pediatrics 1993;91:1158-1165.
11. Weibel RE, Benor DE. Chronic arthropathy and musculoskeletal symptoms associated
with rubella vaccines - a review of 124 claims submitted to the national vaccine
injury compensation program. Arthritis & Rheumatism 1996;39:1529-1534.
12. Tuunanen J, Halonen T, Pitkanen A. Status epilepticus causes selective regional
damage and loss of GABAergic neurons in the rat amygdaloid complex. Eur J Neurosci
1996;8:2711-2725.
     The specific amygdaloid areas identified by Tuunanen et al
     include (i) within deep nuclei: accessory basal, lateral, and
     basal nuclei; (ii) within superficial nuclei: anterior
     cortical, medial, and posterior cortical nuclei, as well as
     lesions in the lateral olfactory tract, the bed nucleus of the
     accessory olfactory tract, and the periamygdaloid cortex; and
     (iii) within additional nuclei such as anterior amygdaloid
     area, central nucleus, amygdalohippocampal area, as well as
     the intercalated, lateral, and basal nuclei.

13. Cendes F, Andermann F, Dubeau F, et al. Early childhood prolonged febrile
convulsions, atrophy and sclerosis of mesial structures, and temporal lobe epilepsy:
an MRI volumetric study. Neurology 1993;43:1083-1087.
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with temporal lobe epilepsy: cause or consequence of repeated seizures? Annals of
Neurology 1993;34:795-801.
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amygdala and ictal fear in temporal lobe epilepsy. Brain 1994;117:739-746.
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and hippocampal sclerosis: frequent and related findings in intractable temporal
lobe epilepsy of childhood. Pediatric Neurology 1995;12:201-206.
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children with seizures, hypotonic- hyporesponsive episodes, high fevers, and
persistent crying. Pediatrics 1993;91:1158-1165.
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and mental dysfunction. New York: Wiley-Liss, 1992.
     [a very fine & thorough overview of the amygdala]

23. Bauman M, Kemper TL. Histoanatomic observations of the brain in early infantile
autism. Neurology 1985;35:866-874.
     The atypical amygdaloid areas identified by Bauman & Kemper
     are not the same as those identified by Tuunanen et al (8).
     (i) The autopsy patient's seizures were not described as
     having a febrile-seizure etiology and may not have occurred
     early in life (age of 1st reported seizure: 8+ years). Thus,
     in the autopsied individual, there may have occurred a
     pathogenesis different from that described by Tuunanen et al.
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neuropsychological model of infantile autism: Are social deficits primary? J Am Acad
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brain glucose metabolism in drug free schizophrenic patients and clinical
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Imaging 1990;8:811-816.
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model in primates. Journal of Autism & Developmental Disorders 1996;26:217-220.
34. Tuunanen J, Halonen T, Pitkanen A. Status epilepticus causes selective regional
damage and loss of GABAergic neurons in the rat amygdaloid complex. Eur J Neurosci
1996;8:2711-2725.
35. Waterhouse L, Fein D, Modahl C. Neurofunctional mechanisms in autism.
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36. Corsellis JAN, Bruton CJ. Neuropathology of status epilepticus in humans. Adv
Neurol 1983;34:129-139.
     "Insofar as the gross appearance of the brain is concerned, no
     striking abnormality is found in most cases... Evidence of
     either transtentorial or cerebellar herniation is therefore
     often absent; when present, it is seldom gross." ** In
     autopsies of who children who had died of status epilepticus,
     "Neither... showed evidence of acute neuronal or glial changes
     that could have been related to the fatal episodes of status,
     although the second child... also had evidence of scarring..."
     In other words, one child had scarring, one did not. **
     "...extensive damage of hippocampal nerve cells was seen." **
     "...classical Ammon's horn or hippocampal sclerosis is seen
     only when the patient has survived long enough for the 'scar
     tissue' and the atrophy to develop." ** "After the
     hippocampus, the next most vulnerable part of the brain is the
     cerebellar cortex, in which degeneration and destruction of
     Purkinje cells, accompanied by an acute glial reaction, can
     range from widespread and severe to no appreciable
     alternation." ** Two illustrations show the variation: "A:
     Section of cerebellar cortex from the brain... All the
     Purkinje cells have disappeared, and there is an intense glial
     reaction... B: Similar area from another infant... [wherein]
     the cerebellum has been spared." ** The 3rd to last paragraph
     of the article emphasizes that "no histological evidence of
     acute damage" is often seen in some individual cases.

37. Meldrum BS. Metabolic factors during prolonged seizures and their relation to
nerve cell death. Adv Neurol 1983;34:261-275.
     "...purely focal seizures can be followed by hippocampal
     lesions." ** "Hyperthermia [associated with prolonged
     seizures]... is associated with a less favorable outcome and
     is a known independent cause of cerebellar damage in humans."
     ** "...the symmetrical involvement of the cerebellum and of
     particular nuclear groups in the amygdala and thalamus are
     common features."  ** "Kainic acid is a structural analogue of
     glutamic acid... [and]... shows selectivity for particular
     cell types. Thus, in the cerebellum, Purkinje and basket cells
     are more vulnerable than granule cells."

38. Dam M. Number of Purkinje cells in patients with grand mal epilepsy treated with
diphenylhydantoin. Epilepsia 1970;11:313-320.
     his study focused upon adults with grand mal and therefore is
     not directly applicable to children with status epilepticus,
     although the findings are consistent with similar descriptions
     in young children. For instance, despite reduced numbers of
     Purkinje cells, "There was no proliferation of glial cells...
     Eight of the patients had fewer Purkinje cells in the creast
     of the folia, 10 had fewer in the depths of the sulci..." **
     "Loss of Purkinje cells and proliferation of glial cells were
     prominent in children who died of status epilepticus...", and
     here we note the difference between M. Dam's comment the
     observations of Corsellin & Bruton.

     [Comment regarding refs 36-38]: In Bauman and Kemper (19),
     only minimal explanation is offered regarding conditions for
     selection and for exclusion of patients to be autopsied.
     Therefore, the diverse gliosis-findings in references 31 to 33
     and their apparent difference from that in reference 19 need
     further comparison.

38a. Le Couteur A, Bailey A, Goode S, Picles A, Robertson S, Gottesman I, Rutter M.
A broader phenotype of autism: the clinical spectrum in twins. J Child Psychol
Psychiat 1996:37;785-801.
     [Given the findings of Reed Warren & colleagues, I question
     the validity of any mathematical model that does not include
     ramifications of complement 4b and other immunodeficiency
     processes in autism. Le Couteur et al do not cite any of the
     Warren et al studies.]

38b. Binstock TC. Hypothesis: Infection, antibiotics, vaccination- induced
neuropathies: Mechanisms of pathogenesis in some cases of autism, ADHD, Tourette's,
OCD, and other neurological disorders. Bit.listserv.autism (4 January 1997).
38c. Bolte ER. Clostridium tetani and autism: a hypothesis. 1996,
Manuscript submitted.
     [a thorougly documented paper presenting a convincingly argued
     hypothesis that some cases of autism may be due to ongoing,
     subacute intestinal colonizations by C. tetani.]
38d. Binstock TC. Hypothesis: Intestinal microflora and CD5+ B cells: their possible
significance in some cases of autism. Bit.Listserv.Autism (14 January 1997).
38e. Warren RP, Singh VK, Cole P, Odell JD, Pingree CB, Warren WL, White E.
Increased frequency of the null allele at the complement C4b locus in Autism. Clin
Exp Immunol 1991:83;438-440.
38f. Warren RP, Burger RA, Odell D, Torres AR, Warren L. Decreased plasma
concentrations of the C4b complement protein in autism. Arch Pediatr Adolesc Med
1994;148;180-183.
38g. Warren RP, Yonk J, Burger RW, Odell D, Warren WL. DR-positive T cells in
autism: association with decreased plasma levels of the complement C4b protein.
Neuropsychobiology 1995:31;53-57.
38h. Warren RP, Singh VK. Elevated serotonin levels in autism: association with the
major histocompatibility complex. Neuropsychobiology 1996:34;72-75.
38i. [The relationship between epileptiform activities and these several syndromes
is delineated in Naill V. O'Donohoe's book, ref 44.]
39. Al-Eissa YA. Febrile seizures: Rate and risk factors of recurrence. J Child
Neurol 1995;10;315-319.

40. Bergman DA et al as "Provisional Committee on Quality Improvement, Subcommitte
on Febrile Seizures". Practice parameter: The neurodiagnostic evaluation of the
child with a first simple febrile seizure. Pediatrics 1996;97;769-772.
41. Powers JH, Scheld WM. The clinical significance of fever patterns. Infect Dis
Clin NA 1996;10;45-66.
42. van Esch A, Steyerberg EW, Berger MY, Offringa M, Derksen-Lubsen G, Habbema JDF.
Family history and recurrence of febrile seizures. Arch Dis Child 1994;70;395-99.
43. van Esch A, Ramlal IR, van Steensel-Moll HA, Steyerberg EW, Derksen- Lubsen G.
Oucome after febrile status epilepticus. Dev Med Child Neurol 1996:38;19-24.
44. O'Donohoe NV. Epilepsies of Childhood. 3rd ed. Oxford: Butterworth- Heinemann
Ltd, 1994.

45. Baker SM, Pangborn J. Clinical Assessment Options for Children with Autism and
Related Disorders: A biomedical approach. San Diego, California: Autism Research
Institute, 1996.
46. Golden GS. Pertussis vaccine and injury to the brain. J Pediatr
1990:116;854-861.
47. Volkmar FR. Social development. Chapter 3 p41-60 in Handbook of Autism and
Pervasive Developmental Disorders 1987 Cohen DJ, Donnellan AM, Paul R editors; V.H.
Winston & Sons, Silver Spring; John WIley & Sons, New York.
     Table 3.1 on p45 shows that the "avoided eye contact" trait is
     nearly but not quite universal among the autistic children
     evaluated prior to age 6. Also, there were gradations, with
     "very often" and "almost always" the most common pattern.
48. Cohen IL, Vietze PM, Sudhalter V, Jenkins EC, Brown WT. Parent-child dyadic gaze
patterns in fragile X males and non-fragile X males with autistic disorder. J Child
Psychol Psychiat 1989:30;845-856.
49. Rolls ET. Neurons in the cortex of the temporal lobe and in the amygdala of the
monkey with responses selective for faces. Human Neurobiology 1984:3;209-222.

50. Leonard CM, Rolls ET, Wilson FAW, Baylis GC. Neurons in the amygdala of the
monkey with responses selective for faces. Behavioural Brain Research
1985:15;159-76.
51. Heywood CA, Cowey A. The role of the 'face-cell' area in the discrimination and
recognition of faces by monkeys. Phil Trans R Soc Lon B 1992:335;34-38.
52. Amaral DG, Price JL, Pitkanen A, Carmichael ST. Anatomical organization of the
primate amydaloid complex. 1992 Chapter 1, p1-66, in reference 18.
53. Seeck M, Schomer D, Mainwaring N, Ives J, Dubuisson D, Blume H, Cosgrove R,
Ransil BJ, Mesulam MM. Selectively distributed processing of visual object
recognition in the temporal and frontal lobes of the human brain. Ann Neurol
1995:37;538-545.
54. Breiter HC, Etcoff NL, Whalen PJ, Kennedy WA, Rauch SL, Buckner RL, Strauss, MM,
Hyman SE, Rosen BR. Response and habituation of the human amygdala during visual
processing of facial expression. Neuron 1996:17;875-887.

55. Savander V, Go CG, Ledoux JE, Pitkanen A. Intrinsic connections of the rat
amygdaloid complex: Projections originating in the accessory basal nucleus. J Comp
Neurol 1996:374;291-313.
56. LeDoux JE, Cicchetti P, Xagoraris A, Romanski LM. The lateral amygdaloid
nucleus: Sensory interface of the amygdala in fear conditioning. J Neurosci
1990:10;1062-1069.
57. LeDoux JE. Emotional memory systems in the brain. Behavioral Brain Research.
1993:58;69-79.
58. Kling AS, Brothers LA. The amygdala and social behavior. 1992 Chapter 13,
p353-377 in reference 18.
59. Brothers LA, Ring B. Mesial temporal neurons in the macaque monkey with
responses selective for aspects of social stimuli. Behavioural Brain Research
1993:57;53-61.

60. Mogenson GJ, Wu M. Electrophysiological and behavioral evidence of interaction
of dopaminergic and gustatory afferents in the amygdala. Brain Research Bulletin
1982:8;685-691.
61. Henke PG. Stomach pathology and the amygdala. 1992 Chapter 11, p323- 337 in
reference 18.
62. Spiegler BJ, Mishkin M. Evidence for the sequential participation of inferior
temporal cortex and amygdala in the acquisition of stimulus- reward associations.
Behavioral Brain Research 1981:3;303-317.
63. Gaffan D. Amygdala and the memory of reward. 1992 Chapter 18, p471- 483 in
reference 18.
64. Aggleton JP. A description of the amygdalo-hippocampal inter- connections in the
macaque monkey. Experimental Brain Research 1986:64;517-526.

65. Involvement of the amygdaloid complex in neuromodulatory influences on memory
storage. Neuroscience & Biobehavioural Reviews 1990:14;425-31.
66. McGaugh JL, Introini-Collison IB, Cahill L, Kim M, Liang KC. Involvement of the
amygdala in neuromodulatory influences on memory storage. 1992 Chapter 16, p431-451
in reference 18. (See also Ch. 17)
66a. Amaral DG, Insausti R, Cowan WM. The entorhinal cortex of the monkey: I.
Cytoarchitectonic organization. J Comp Neurol 1987:264;326- 355.         [Parts II
and III, ibid pp356-395 & 396-408]
67. Harvey AS, Grattan-Smith JD, Desmond PM, Chow CW, Berkovic SF. Febrile seizures
and hippocampal sclerosis: Frequent and related findings in intractable temporal
lobe epilepsy. Pediatr Neurol 1995:12;201-206.
68. DeLong GR. Autism, amnesia, hippocampus, and learning. Neuroscience &
Biobehavioural Reviews 1992:16;63-70.
69. Amaral DG, Insausti R. Hippocampal formation. 1990 Chapter 21, p711- 755, in The
Human Nervous System, Paxinos G, editor; Academic Press Inc San Diego.

70. Bailey A, Phillips W, Rutter M. Autism: Towards an integration of clinical,
genetic, neuropsychological, and neurobiological perspectives. J Child Psychol
Psychiat 1996;37.89-126.
71. Hudson LP, Munoz DG, Miller L, McLachlan RS, Girvin JP, Blume WT. Amygdaloid
sclerosis in temporal lobe epilepsy. Ann Neurol 1993;33.622- 631.
     "We identified unequivocal evidence of amygdaloid cell loss
     and gliosis in a series of 8 patients with temporal lobe
     epilepsy, in the absence of significant hippocampal neuronal
     loss or gliosis." ** [This study]... reproduced the finding
     reported by numerous investigators that HS is consistently
     associated with a history of early brain injury or
     convulsions... This early event is typically followed by a
     clinically silent interval preceding the development of a
     regular pattern of complex partial seizures, usually during
     adolescence."
          [These non-autistic epileptics scored lower on word
          tests and on facial recognition.]
72. Aicardi J, Chevrie JJ. Convulsive status epilepticus in infants and children:
A study of 239 cases. Epilepsia 1970;11.187-197.
     "The incidence of convulsions, neurological signs and mental
     retardation, alone or in combination, following status
     [epilepticus] is high, and in a large proportion of cases
     these abnormalities appear to have been acquired at the time
     of status epilepticus." ** "Among cases without demonstrable
     etiology, fever is commonly present at the onset of fits and
     the clinical picture is indistinguishable from common 'simple'
     febrile convulsions of childhood, except for the long duration
     of fits and for the ensuing brain damage."  ** "...prolonged
     convulsions seem more devastating in young babies."
73. Luheshi G, Rothwell N. Cytokines and fever. 1996 Int Arch Allergy Immunol
1996:109;301-307.
74. Verity CM, Ross EM, Golding J. Infantile febrile status epilepticus: risk
factors and outcome. Brit Med J 1993:307;225-228.
                    [End of References, part 3 of 3]
                            Teresa C. Binstock
                                  Denver
                                (c)  1997

POSTING HISTORY OF "FEBRILE SEIZURES & THE AMYGDALA"

>>> Posting number 3603, dated 31 Jan 1997 13:18:37
Date:         Fri, 31 Jan 1997 13:18:37 -0700
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From:         Teresa Binstock
Subject:      Febrile seizures, amygdala, autism (text, 1 of 3)

>>> Posting number 3610, dated 31 Jan 1997 13:20:45
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Subject:      Febrile seizures, amygdala, autism (text, 2 of 3)

>>> Posting number 3611, dated 31 Jan 1997 13:22:15
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>>> Posting number 3604, dated 31 Jan 1997 13:23:16
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From:         Teresa Binstock
Subject:      Febrile seizures, amygdala, autism (References, 1 of 3)

>>> Posting number 3605, dated 31 Jan 1997 13:24:20
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>>> Posting number 3652, dated 31 Jan 1997 22:02:13
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From:         Teresa Binstock
Subject:      Febrile seizures, amygdala, autism (Refs, 3 of 3)