Dr. Abe and colleagues have written an important review wherein
they summarize mild convulsions associated with certain viruses
within gastrointestinal tissue (1). Table 1 of the article lists
a number of viruses, including rotavirus, adenoviridae,
caliciviridae, astroviridae, poliovirus, Coxsackie A,B viruses,
cytomegalovirus, human herpesviruses 6 & 7, as well as influenza
virus, respiratory syncytial virus, and hepatitis A virus.
The authors speculate about routes of viral entry into
the CNS but do not appear to have thought of infected-monocytes
as one entry-route (3). Also, the authors have omitted herpes
simplex virus from their Table 1. I shall be writing them with
citations about gastrointestinal HSV as well as a description of
intra-monocyte pathogens -- an observation derived from immune
panels sent me for analysis.
Despite the aforementioned nuances, the Abe et al article
is an important contribution to literature about the gut-brain
connection and may have special relevance for many
autism-spectrum children.
The whole-article would be very informative for
physicians treating ASD children with gastrointestinal pathology.
Here are some quotes from the article:
Regarding rotavirus seizures:
"Patients show no family or past history of neurological disease,
are 1 year 6 months old on average and the incidence is
equivalent between boys and girls."
"Patients show no increase of cells or protein in CSF, no
epileptic discharge in interictal EEG records, and no abnormal
imaging findings, such as brain abscess, intracranial bleeding or
severe brain edema."
Regarding small round structured virus (SRVS):
"The initial sign in most [convulsion/gastroenteritis] patients
was vomiting, which continued for a few days."
From article's discussion:
"Recently Ishiguro et al. reported that HHV-6 and HHV-7 genomes
and antigens where frequently detected in patients with exanthema
subitum who showed a convulsive seizure, bulging fontanel,
encephalitis or encephalopathy..."
"These results suggest that HHV-6 may be able to invade the CNS
of infected infants to cause neurologic involvement."
"Symptoms of mild gastroenteritis such as loose stools or
constipation due to malfunction of gut can be found in almost all
HHV-6 and HHV-7 infected patients under careful examination."
"The administration of steroids, which regulate the immune and
chemokine system of the CNS..., is effective in some of these
patients, but may worsen the symptoms of other cases."
In closing: Dr. VK Singh has documented elevated titres against
HHV6 in many ASD children, and specific ASD-children's data from
other labs confirms these findings. Other studies document
gastrointestinal CMV, EBV, and HHV6 (eg, 5). In total, these
various findings -- when combined with inter-child differences in
immunity and genomics -- suggest that subtle seizures with mild
symptoms of gastroenteritis may have other than benign neurologic
sequelae in children who eventually present with autism. A series
of studies by Pitkaanen and Tuunanen and colleagues may be
instructive (eg, 4).
A major significance of these studies is that an autistic child's
chronic gastrointestinal symptoms may be etiologically associated
with neurologic ramifications within his or her CNS.
If in its entirety, this post may be reposted into other lists
and shared in other ways.
Teresa Binstock
Researcher in Developmental & Behavioral Neuroanatomy
1: Brain Dev 2000 Aug;22(5):301-6
Infantile convulsions with mild gastroenteritis.
Abe T, Kobayashi M, Araki K, Kodama H, Fujita Y, Shinozaki T,
Ushijima H
Department of Pediatrics, Teikyo University School of Medicine
The development of sensitive new molecular genetic
techniques has led to the
detection of rotavirus in cerebrospinal fluid, stools and throat
swabs from
patients with gastroenteritis with accompanying clinical symptoms
similar to
infantile benign convulsions. Small round structured virus (SRSV)
has also been
found in stools of patients with similar clinical symptoms by a
new procedure.
However, the mechanism by which these viral infections induce
benign convulsions
remains to be elucidated. The present paper reviews recent
virological and
clinical studies of seizures probably caused by gastroenteritis
viruses
including rotavirus, SRSV and other viruses.
Publication Types: Review Review, tutorial
2: Brain Dev 1993 Nov-Dec;15(6):457-9
Detection of rotavirus in cerebrospinal fluid and blood of
patients with
convulsions and gastroenteritis by means of the reverse
transcription polymerase
chain reaction.
Nishimura S, Ushijima H, Nishimura S, Shiraishi H, Kanazawa C,
Abe T, Kaneko K,
Fukuyama Y
Rotavirus RNA was detected in the blood and cerebrospinal
fluid from eight
Japanese children with convulsions and gastroenteritis in the
acute stage by
means of the reverse transcription polymerase chain reaction.
This may suggest
that rotavirus invades the central nervous system through blood
vessels.
3. Binstock T. Intra-monocyte pathogens delineate autism
subgroups. In press.
4. Neuroscience 1999;94(2):473-95
Status epilepticus-induced neuronal damage in the rat amygdaloid
complex:
distribution, time-course and mechanisms.
Tuunanen J, Lukasiuk K, Halonen T, Pitkanen A
The present study was designed to elucidate the
distribution, time-course and
mechanism(s) of status epilepticus-induced neuronal damage in the
rat amygdaloid
complex. Status epilepticus was induced with kainate (9 mg/kg,
i.p.), and the
behavioral and electrographic seizure activity of each rat was
monitored via
cortical electrodes attached to a continuous video
electrocorticogram system.
Rats were subsequently perfused 1, 2, 4, 8, 16, 24 or 48 h after
kainate
injection. The first signs of amygdaloid damage were seen in rats
perfused 4 h
after kainate injection, though the severity and temporal
appearance of damage
varied substantially between the different amygdaloid nuclei and
their
subdivisions. Second, terminal transferase dUTP nick-end labeling
(TUNEL)-positive nuclei and laddering of DNA in gel
electrophoresis appeared in
the amygdala 8 and 16 h after kainate, respectively. The
distribution and
density of TUNEL-positive nuclei in the different amygdaloid
nuclei correlated
with the distribution of neuronal damage in Thionin- and
silver-stained
sections. Third, the immunoreactivity of Bax protein, a promoter
of apoptotic
neuronal death, increased in the vulnerable medial division of
the lateral
nucleus prior to the appearance of argyrophilic neurons and
TUNEL-positive
nuclei. Fourth, the severity of neuronal damage progressed in
some, but not all,
amygdaloid regions throughout the 48-h follow-up, even though the
occurrence of
high-amplitude and frequency discharges, which are typically
associated with
behavioral seizure activity, extinguished after 7 h. These data
show that status
epilepticus-induced neuronal damage in the amygdala is a dynamic
region-specific
process, the severity of which depends on the duration of seizure
activity. At
least one mechanism underlying the damage involves apoptosis,
which continues
long after the behavioral and electrographic seizures have
subsided.
5. J Med Virol 1992 Nov;38(3):183-90
Detection of herpesvirus DNA in the large intestine of patients
with ulcerative
colitis and Crohn's disease using the nested polymerase chain
reaction.
Wakefield AJ, Fox JD, Sawyerr AM, Taylor JE, Sweenie CH, Smith M,
Emery VC,
Hudson M, Tedder RS, Pounder RE
The prevalence of herpesvirus DNA was examined in
inflammatory bowel disease
tissue. DNA was extracted from resection and biopsy specimens of
the large
intestine from patients with ulcerative colitis (n = 21),
patients with Crohn's
disease (n = 29), and patients with noninflammatory bowel disease
(controls) (n
= 21). The nested polymerase chain reaction was used to detect
viral DNA using
primer pairs specific for either cytomegalovirus (CMV), herpes
simplex virus 1
(HSV1), human herpesvirus 6 (HHV6), varicella zoster virus (VZV),
or Epstein
Barr virus (EBV). HSV1 and VZV DNA were not detected in any of
tissue samples.
There was a high prevalence of CMV (81%), HHV6 (76%), and EBV
(76%) DNA in
ulcerative colitis tissue compared to Crohn's disease tissues
(CMV 66%, HHV6
45%, EBV 55%). Control tissue had a relatively low frequency of
CMV (29%) and
EBV (19%) DNA but a prevalence of HHV6 DNA similar to that of
ulcerative colitis
(86%). However, the simultaneous presence of HHV6 and CMV and/or
EBV DNA in
ulcerative colitis tissue (76%) was much greater than in either
Crohn's disease
tissues (38%) or control tissue (29%) (P < 0.05). There was a low
prevalence of
CMV, HHV6, and EBV DNA in peripheral blood mononuclear cells from
all patient
groups. CMV and EBV are capable of reactivating HHV6: the high
prevalence of
coexistent HHV6 infection with either or both of these two
viruses in ulcerative
colitis tissue suggests that they may play a synergistic role in
the
pathogenesis of this disease.