>>> Posting number 16585, 
                                          dated 23 Jun 1997 11:43:46

.....INFECTIONS, SEIZURES, APHASIAS, SOCIALITY.....
Seizures of various locations, severities, and durations are known to be linked to
various aphasias and, not necessarily in the same individual, to altered social
interactions. The post-1990 writings of Isabelle Rapin and Deonna Thierry (sp?) are
some of the best in setting forth the relationships between seizures, language, and
sociality. Some of the causal mechanisms are beginning to be elucidated (eg, 1-2).
      In the book "Epilepsy in Children" (3), there is a chapter about the role of
infections:  "Infections, including parasitic diseases, are the commonest associated
cause of 'status epilepticus' in children... They constitute possibly  the second
most common etiology of seizures of recent onset in any age group; but particularly
in children..."
                              Infections and postinfective causes. 
                              p79-86, Neto and de Bittencourt.

Tc: Note that status epilepticus can be non-convulsive and overlooked and may be
findable only via sleep EEGs. As a result, some seizure-related damage may occur
even in cases wherein seizures were never apparent. Many studies that look at
co-occurrences of autism and epilepsy seem to have looked primarily at epilepsies
with outwardly see-able signs -- eg, convulsions, absence seizures during waking
hours, etc. This kind of focus may have been turning researcher-attention away from
the underlying mechanisms of seizure-induced neurotoxicity, a phenomenon that seems
to occur even in some kids having "only" epileptiform activity findable during
overnight sleep-EEGs. That infections and vaccinations can induce short-term
seizures suggests that, in some cases, either and/or both can induce neurotoxic
lesions via epileptiform processes, even in cases wherein the child does not proceed
to diagnosable epilepsy.

<1>  Tuunanen J.  Halonen T.  Pitkanen A.  Decrease in somatostatin-immunoreactive
neurons in the rat amygdaloid complex in a kindling model of temporal lobe epilepsy.
Epilepsy Research.  26(2):315-327, 1997 Jan.
<2>  Tuunanen J.  Halonen T.  Pitkanen A.  Status epilepticus causes selective
regional damage and loss of gabaergic neurons in the rat amygdaloid complex.
European Journal of Neuroscience.  8(12):2711-2725, 1996 Dec.
<3> Epilepsy in Children. Sheila Wallace, ed. 1996, Chapman & Hall,
London.

                                          >>> Posting number 20312, 
                                          dated 8 Aug 1997 13:01:22

.....TEMPORAL LOBE SEIZURES, LANGUAGE, AUTISM, GLUTAMATE.....
A new study by DeLong and Heinz (1) sheds additional light upon a category of
causality in autism. Their findings and analysis are consistent with the notion
offered by several authors in the recent Seminars in Pediatric Neurology (v4#2
1997), that epileptiform activity is not merely co-occurring with something like
autism or language impairments but actually may be a primary causal mechanism, via
a glutamate-related process of neurotoxicity. In their discussion, DeLong and Heinz
mention "long febrile seizures" and status epilepticus. We remember (i) that
vaccinations and infection-related illnesses can induce febrile seizures, and (ii)
that some seizures can be as severe as "status epilepticus" and yet will be
non-convulsive and thus probably not witnessed by parents or doctors unless EEGs are
performed (primary cites in 7 and 8).

>From DeLong and Heinz:
    ab: "Four infants had bilateral hippocampal sclerosis... 2 infants... showed
isolated bilateral anterior temporal lobe hypometabolism. All had epilepsy with
episodes of status epilepticus. Despite adequate motor and sensory functions, all
failed to develop language (or lost attained language), social skills, and complex
purposive or adaptive activity, even after epilepsy was controlled... The deficits
correspond to the cognitive deficits of severe infantile autism..."

some additional quotes:
    "Bilateral hippocampal dysfunction in adults produces amnesia... We describe the
clinical evolution of isolated bilateral hippocampal sclerosis in 4 children with
onset ages of 4 to 30 months; the children lost or failed to attain language,
complex social interactions, and organized programs of activity despite normal motor
and sensory abilities. These deficits, typical of profound mental deficiency with
autism, implicate the hippocampus and related structures as necessary for complex
learning, including language acquisition, in the infant."

"Three children had perinatal insults as possible causes of epilepsy...MRI in all
4 showed bilateral hippocampal sclerosis (atrophy and increased signal). In all, the
brain, apart from the medial temporal lobes, appeared normal, with normal mass...,
cortical architecture, myelination, and appearance of the basal ganglia, brainstem,
and cerebellum."

The first MIR of [subject SP]... at 30 months [,] after the initial bout of status
epilepticus, showed hippocampal edema (swelling and increased signal) bilaterally;
a repeat MRI at 44 months showed bilateral hippocampal sclerosis..."

"The 4 children showed a consistent clinical picture of early normal development,
then onset of epilepsy with episodes of status epilepticus, followed by failure or
loss of language development and other complex cognitive functions. Other neurologic
functions  remained relatively intact. The most prominent deficit was failure to
develop language or loss of language recently acquired. The 2 children in whom
language developed and then failed clearly had initial normal language capability...
In the other children..., the onset of seizures was early (ages 4 and 6 months,
respectively) and language did not develop, so normal language potential was
unproved. However, the isolated bilateral hippocampal sclerosis and typical
language, social, and adaptive deficits suggest a causal relationship..."

"The pathogenesis of hippocampal sclerosis has been much discussed. Prolonged
febrile seizures and status epilepticus are major predisposing factors; increasing
evidence related neuronal damage to excitotoxicity of excessive neurotransmitter
release, particulary glutamate (reviewed by Holmes...)." [See also cites 3-5 and
Holmes as 6 herein].

<1> DeLong GR, Heinz ER. The clinical syndrome of early-life bilateral hippocampal
sclerosis. Annals of Neurology 42.11-17 1997.
<2> [10 of 14 autistic in this study, similar to DeLong & Heinz] Chugani HT.  Da
Silva E.  Chugani DC. Infantile spasms: III. Prognostic implications of bitemporal
hypometabolism on positron emission tomography. Annals of Neurology.  39(5):643-9,
1996 May.
  Positron emission tomography (PET) of brain glucose utilization is highly
sensitive in detecting focal cortical abnormalities in patients with infantile
spasms even when the computed tomographic (CT) and magnetic resonance imaging (MRI)
scans are normal. Of 110 infants with spasms evaluated for potential surgical
intervention during an 8-year period, we encountered 18 infants (7 males, 11
females; age range, 10 mo to 5 yr) with a common metabolic pattern on positron
emission tomography (PET) consisting of bilateral hypometabolism in the temporal
lobes. CT and MRI scans did not reveal any focal abnormalities in the 18 infants.
Video-electroencephalographic monitoring indicated either bilateral or multifocal
epileptogenicity, or failed to show any epileptic focus, so that none of the 18
infants were considered candidates for resective surgery. These patients were then
enrolled in a prospective study aimed at determining long-term outcome in the
presence of bilateral temporal PET hypometabolism. Analysis of outcome in 14 of the
18 subjects (follow-up period, 10 mo to 10 yr 5 mo; mean, 3 yr 11 mo +/- 2 yr 4 mo
[SD]) revealed the following: (1) all had severe developmental delay and had failed
to gain significant milestones; (2) language development had been minimal or absent;
(3) 10 of the 14 met the DSM-IV criteria for autistic disorder. Our findings
indicate that patients with infantile spasms and bitemporal glucose hypometabolism
on PET comprise a relatively homogeneous group and are typically not candidates for
cortical resection. The long-term outcome of these infants is particularly poor and
the majority are autistic.  

<3>  Tuunanen J.  Halonen T.  Pitkanen A. Decrease in somatostatin-immunoreactive
neurons in the rat amygdaloid complex in a kindling model of temporal lobe epilepsy.
Epilepsy Research.  26(2):315-27, 1997 Jan.
  In human temporal lobe epilepsy, seizures can begin in the hippocampus, amygdala,
or surrounding cortical areas. Histologically, the seizure-induced selective
neuronal damage and synaptic reorganization are best documented in the hippocampus.
Little information is available about the damage in the other temporal lobe
structures or whether the distribution of damage depends on the location of the
primary seizure focus. We used an amygdala-kindling model of temporal lobe epilepsy
to study whether seizures of amygdaloid origin cause damage to the amygdala and
hippocampus...  Such decrease in SOM-ir neurons which form one subpopulation of
GABAergic inhibitory interneurons may increase the local excitability in the
amygdala and, therefore, contribute to epileptogenesis.

<4>  Tuunanen J.  Halonen T.  Pitkanen A. Status epilepticus causes selective
regional damage and loss of GABAergic neurons in the rat amygdaloid complex. Eur J
of Neuroscience.  8(12):2711-25, 1996 Dec.
  In human epilepsy, the amygdala is often a primary focus for seizures. To analyse
the status epilepticus-induced alterations in the amygdaloid circuitries which may
later underlie epileptogenesis, we studied the amygdaloid damage in kainic acid and
perforant pathway stimulation models of status epilepticus in the rat... According
to our data, the initial insult, such as status epilepticus, selectively damages
amygdaloid nuclei. The loss of inhibition may underlie the spontaneous generation
of seizures and epileptogenesis. On the other hand, many amygdaloid output nuclei
(magnocellular and intermediate division of the basal nucleus, the central nucleus)
remained relatively undamaged, providing pathways for seizures spread and generation
of seizure-related behavioural manifestations such as motor convulsions and fear
response.

<5>  Pitkanen A et al. Vigabatrin and carbamazepine have different efficacies in the
prevention of status epilepticus induced neuronal damage in the hippocampus and
amygdala. Epilepsy Research.  24(1):29-45 1996.
  The present study compares the efficacy of carbamazepine (20 mg/kg/day) and
vigabatrin (250 mg/kg/day) in preventing hippocampal and amygdaloid damage in the
perforant pathway stimulation model of status epilepticus in the rat... The
amygdaloid neurons were not protected by any of the treatments. Our results show
that even though vigabatrin and carbamazepine treatments had similar anticonvulsant
efficacy during the perforant pathway stimulation, only vigabatrin but not
carbamazepine decreased seizure-induced neuronal damage. Vigabatrin decreased
neuronal damage in the hippocampus but not in the amygdala. These results
demonstrate that different brain regions and neuronal networks may be protected
unequally by different anticonvulsants.

<6> Holmes GL. Case records of the Massachusetts General Hospiatl, case 7-1996. New
Eng J Med 334.586-92 1996.
<7> Binstock T. Hypothesis: Febrile seizures and the amygdala: a causal mechanism
in autism and related disorders. Bit.listserv.autism (31 January 1997)
<8> Binstock T. 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 (3 January 1997)       

POSTING HISTORY:

>>> Posting number 16585, dated 23 Jun 1997 11:43:46
Sender:       SJU Autism and Developmental Disablities List
              
From:         Teresa Binstock 
Subject:      Infections, Seizures, Aphasias, Sociality

>>> Posting number 20312, dated 8 Aug 1997 13:01:22
Sender:       SJU Autism and Developmental Disablities List
              
From:         Teresa Binstock 
Subject:      Temporal lobe seizures.language.autism.glutamate.febrile