>>> Posting number 17059, 
                                          dated 1 Jul 1997 17:13:27

I.    SUBOPTIMALITY: IgA & OTITIS, CELIAC, GASTROINTESTINAL

.....Introduction.....
IgA occurs in two primary forms, serum IgA and secretory IgA. In many studies by
various researchers, IgA immunodeficiencies are strongly linked with recurrent
otitis media, with ongoing gastrointestinal problems, and with celiac disease (cites
and quotes follow new autism/IgA cite).
      Recently, Warren RP et al reported IgA-deficiencies in a subset of autistics.
These IgA deficiencies were not primary IgA deficiencies (ie, via mutations of
specific IgA-component genes, wherein no IgA would be produced) but were linked to
reduced IgA levels. Relatedly, there were strong associations between IgA
deficiencies in the autistic subjects, and (i) certain MHC haplotypes and/or with
(ii) complement C4b null alleles. I have included this posting in the Suboptimality
series because reduced IgA is so associated with adverse-events that could occur
during the pre-, peri-, and neonatal periods as well as during the time a child is
an infant or toddler. Much of the following has some statistics (for which I
apologize), yet those statistics help point the way toward susceptibility factors
(decreased IgA levels, certain MHC haplotypes, C4b null alleles) and thereby towards
certain kinds of causality factors indentified in the various adverse-events,
suboptimality/autism studies.


Here are some quotes from Warren et al (1):

"Overall the 40 subjects with autism had a mean serum IgA level... which was
significantly (p = .006) lower than that found in the age- and sex-
matched controls..."

"... all of the normal subjects had values which were within the normal range... In
contrast, 8 (20%) of the 40 autistic subjects had IgA levels that were below the
normal range..."

"Of the 40 autistic subjects, 17 (40%) had one of the three...[MHC]... haplotypes...
associated with IgA deficiency; 7 of these subjects had decreased IgA levels."

In the next to last paragraph, Warren et al mention how the IgA findings relate to
infections and report a fascinating double susceptibility in that 6 of 8 autistic
kids with low IgA levels also had null alleles of the complement C4b:

"...IgA is also important in protection against pathogenic infections and
participates in the clearance of pathogens via the alternative complement pathway.
C4 proteins [eg, from the C4a and C4b genes] are involved in the other complement
pathway, the classical complement pathway. Therefore, it is interesting that of the
eight autistic subjects with decreased IgA levels, all but two also had a C4b null
allele suggesting that, in these patients, both pathways of complement activation
[and response to infections] are probably operating at less than optimal level."

                                  *****

Let us keep in mind that Warren et al's C4b findings and the IgA findings point
toward susceptibility factors and not towards actual causes. In contrast, the
various suboptimality studies are pointing towards actual causes in a large subgroup
of autistics; and the Warren et al findings are illustrating how immunodeficiencies
are a primary type of susceptibility factor that is causally related to a number of
the adverse events in suboptimality/autism studies.

1. Warren RP et al. Brief report: Immunoglobulin A deficiency in a subset of
autistic subjects. J Autism Developmental Disorders 27.2.187-192 1997.


                  >>> Posting number 17060, dated 1 Jul 1997 17:21:14
                  5b Suboptimality: IgA & (celiac and/or gastrointestinal)

Many autism parents report (i) celiac disease, gluten sensitivity, and/or behavioral
improvements via gluten-free diets, and/or (ii) various gastrointestinal problems
-- eg, a period of severe diarrhea, ongoing colonization (eg, by Candida albicans),
etc.
      The IgA\autism findings of Reed Warren et al (1) acquire enhanced significance
when placed along side numerous articles linking celiac disease and/or other
gastrointestinal problems and IgA deficiencies.
      Let us keep in mind that Warren et al's C4b findings and the IgA findings
point toward susceptibility factors and not towards actual causes. In contrast, the
various suboptimality studies are pointing towards actual causes in a large subgroup
of autistics, and the Warren et al findings are illustrating how immunodeficiencies
are a primary type of susceptibility factor that appears to be causally related to
a number of the post-natal factors reported by many parents of autistic children.
      Following the Warren et al citation and a quote therefrom are medical
literature tidbits illustrating the link between IgA deficiencies and celiac disease
and/or other gastrointestinal problems.

1. Warren RP et al. Brief report: Immunoglobulin A deficiency in a subset of
autistic subjects. J Autism Developmental Disorders 27.2.187-192 1997.

"...IgA is also important in protection against pathogenic infections and
participates in the clearance of pathogens via the alternative complement pathway.
C4 proteins [eg, from the C4a and C4b genes] are involved in the other complement
pathway, the classical complement pathway. Therefore, it is interesting that of the
eight autistic subjects with decreased IgA levels, all but two also had a C4b null
allele suggesting that, in these patients, both pathways of complement activation
[and response to infections] are probably operating at less than optimal level."

2.  Lai Ping So A.  Mayer L. Gastrointestinal manifestations of primary
immunodeficiency disorders. Seminars in Gastrointestinal Disease 8(1):22-32, 1997
Jan.
Ab:   Because the gastrointestinal tract is the largest lymphoid organ in the body,
it is not surprising that patients with immunodeficiency would present with
pathological conditions in the intestine. Several studies have documented a high
prevalence of inflammatory, malignant, and infectious gastrointestinal (GI)
disorders in patients with common variable immunodeficiency or immunoglobulin A
(IgA) deficiency. Interestingly, it has become increasingly apparent that antibody
deficiency alone does not result in GI disease. Rather, defects in cellular immunity
appear to predispose to a sprue-like disorder, pernicious anemia, giardiasis,
nodular lymphoid hyperplasia, and even inflammatory bowel disease. In patients with
unusual inflammatory GI disorders, measurement of serum immunoglobulins should be
obtained.

3.  Meini A. Pillan NM. Villanacci V.  Monafo V.  Ugazio AG.  Plebani A.
Prevalence and diagnosis of celiac disease in IgA-deficient children.    Annals of
Allergy, Asthma, & Immunology  77(4):333-6, 1996 Oct.
Ab:   BACKGROUND: Reported frequencies of celiac disease in selective IgA deficiency
in childhood vary widely and this is probably due to the different characteristics
of the patients studied and to the different criteria used for intestinal biopsy:
all patients or only those with symptoms of malabsorption. Diagnosis of celiac
disease is of considerable importance in IgA deficiency because of its increased
frequency and also because avoidance of dietary gluten permits elimination of the
symptoms and complications of celiac disease. OBJECTIVES: To obtain a more
reliable estimate of the incidence of celiac disease in childhood IgA deficiency
jejunal biopsies were performed in 65 consecutively diagnosed IgA-deficient children
whose parents consented. Some clinical and laboratory parameters including
IgA-antigliadin and IgG-antigliadin antibodies were evaluated to predict their
usefulness in selecting IgA-deficient patients for intestinal biopsy....
CONCLUSIONS: The 7.7% frequency of celiac disease observed in these IgA-deficient
children is about 20 times higher than in the general Italian population, and the
lowest among the studies biopsying all patients; this is probably attributable to
the presence of substantial proportion of healthy children (20/65) and very few
(2/65) with autoimmune disorders. The elevated sensitivity and negative-predictive
value of IgG-antigliadin antibodies lead us to suggest that positive IgG-antigliadin
antibodies can be used to select IgA-deficient children for jejunal biopsy with a
very low probability of missing celiac disease while allowing a drastic reduction
in the number of biopsies performed.


            >>> Posting number 17061, dated 1 Jul 1997 17:26:23
            5b2 Suboptimality: IgA & (celiac and/or gastrointestinal)

Some additional citations:

4.  Catassi C et al. Coeliac disease in the year 2000: exploring the iceberg. 
Lancet 343(8891):200-3, 1994 Jan 22.
Ab:   It is now generally believed that subclinical coeliac disease is common in the
general population. We have undertaken screening for this disorder in a school
district in central Italy. Screening was divided into three levels: first, IgG and
IgA antigliadin antibody (AGA) assay on capillary blood obtained by finger prick;
second, AGA plus IgA anti-endomysium antibody (AEA) test and measurement of serum
immunoglobulins in venous blood; and third, intestinal biopsy. 3351 students (66%
of the eligible population) aged 11-15 years attended first-level screening. 71 (2%)
were recalled because of AGA positivity; 18 of these satisfied second-level criteria
and underwent intestinal biopsy. Coeliac disease was diagnosed in 11 subjects, most
of whom had no serious symptoms. Selective IgA deficiency was found in 4 subjects,
1 of whom also had coeliac disease. The prevalence of subclinical coeliac disease
in the study group was 3.28 per 1000. Coeliac disease screening is feasible and
involves only slight discomfort to the general population. Such screening can detect
large numbers of cases of coeliac disease, which can be treated with a gluten-free
diet. Many subclinical cases of coeliac disease would not be detected by screening
only a selected group of at-risk patients.

5.  Mochizuki S.  Smith CI.  Hallgren R.  Hammarstrom L. Systemic immunization
against IgA in immunoglobulin deficiency.  Clinical & Experimental Immunology
94(2):334-6, 1993 Nov.
Ab:   The presence of serum IgM and IgG antibodies against IgA is common among
individuals with IgA deficiency. The route of immunization is still unknown, but it
is possible that immunization occurs through the gut. We analysed anti-IgA antibody
production in gastrointestinal lavage, saliva and breast milk from patients with IgA
deficiency. In no case was there any evidence of local production of anti-IgA
antibodies. Immunization may thus be due to exposure to endogenous IgA and therefore
represent a 'true' autoimmune phenomenon which may possibly be involved in the
pathogenesis of the disease.

<5>  Brandtzaeg P. Humoral immune response patterns of human mucosae: induction and
relation to bacterial respiratory tract infections.     Journal of Infectious
Diseases.  165 Suppl 1:S167-76, 1992 Jun.
Ab:   Immunoglobulin-producing cells in mucosal tissues, quantitatively the body's
most important humoral immune system, synthesize mainly dimers and larger polymers
of IgA (poly-IgA) with incorporated J (joining) chain. Poly-IgA is actively
transported to exocrine secretions by a transmembrane epithelial glycoprotein called
secretory component. Enhancing secretory immunity by oral vaccination is an
interesting possibility, but mucosal antigen uptake and local immune regulation are
complex and only partly understood. Immunoglobulin isotype response patterns in the
upper respiratory mucosa and distal gut are strikingly different. The preferential
production of IgA1 in nasal and bronchial mucosae is intriguing in view of the
frequent synthesis of IgA1-specific proteases by Haemophilus influenzae,
Streptococcus pneumoniae, and Neisseria meningitidis. A relationship of proneness
to produce invasive disease and enzymatically induced deterioration of secretory
immunity has been proposed. Differences in mucosal immune response patterns among
patients with selective IgA deficiency or IgG subclass deficiencies also suggest
that local humoral immunity is an important variable in resistance to infections.

<6>  Schaffer FM.  Monteiro RC.  Volanakis JE.  Cooper MD. IgA deficiency.
Immunodeficiency Reviews.  3(1):15-44, 1991.
Ab:   IgA deficiency, the most common primary immunodeficiency, is a very
heterogeneous clinical disorder which may be associated with a variety of
infections, allergies, autoimmune disorders, gastrointestinal diseases, and genetic
disorders. The central phenotypic feature of this immunodeficiency is a B cell
differentiation arrest, the extent of which may determine the clinical variability.
Integrity of the immunoglobulin genes and their expression by immature B cells in
affected individuals suggests an immunoregulatory basis for the B cell arrest.
Genetic studies imply that a susceptibility gene in or near the major
histocompatibility locus may predispose homozygous individuals to a spectrum of
antibody deficiencies which may range from isolated IgA deficiency to
panhypogammaglobulinemia. Essential cofactors in the pathogenesis of IgA deficiency
include environmental factors, such as certain drugs and viral infections.

<7>  Pignata C. et al Jejunal bacterial overgrowth and intestinal permeability in
children with immunodeficiency syndromes.  Gut  31(8):879-82, 1990 Aug.
Ab:   Seventeen paediatric patients with immunodeficiency syndromes (10 with
selective IgA deficiency, four with panhypogammaglobulinaemia, and three with
selective T cell deficiency) were investigated for bacterial overgrowth of the small
intestine and gut permeability to macromolecules. These studies indicate that
bacterial overgrowth of the small intestine is a common feature in immunodeficient
patients, regardless of the immunological abnormality. Moreover, these patients have
an increased gut permeability to macromolecules.

<8>  Burks AW Jr.  Steele RW. Selective IgA deficiency. Annals of Allergy. 
57(1):3-13, 1986 Jul.
Ab:         Selective IgA deficiency is the most common form of immunodeficiency.
Certain select populations, including allergic individuals, patients with autoimmune
and gastrointestinal tract disease and patients with recurrent upper respiratory
tract illnesses, have an increased incidence of this disorder. These patients have
the unique ability to form various antibodies and auto-antibodies including anti-IgA
antibodies...

eof

                  >>> Posting number 17063, dated 1 Jul 1997 17:30:08
                  5c Suboptimality: IgA & recurrent otitis

Many autism parents report a long series of ear infections and antiobiotics
treatments that *seem* to be related to the onset of the child's autism. The
IgA\autism findings of Reed Warren et al (1) acquire enhanced significance when
placed along side numerous article linking recurrent otitis media and IgA
deficiencies.
      Let us keep in mind that Warren et al's C4b findings and the IgA findings
point toward susceptibility factors and not towards actual causes. In contrast, the
various suboptimality studies are pointing towards actual causes in a large subgroup
of autistics, and the Warren et al findings are illustrating how immunodeficiencies
are a primary type of susceptibility factor that is causally related to a number of
the adverse events in suboptimality/autism studies.
      Following the Warren et al citation and a quote therefrom are medical
literature tidbits illustrating the link between IgA deficiencies and recurrent
otitis media.

1. Warren RP et al. Brief report: Immunoglobulin A deficiency in a subset of
autistic subjects. J Autism Developmental Disorders 27.2.187-192 1997.

"...IgA is also important in protection against pathogenic infections and
participates in the clearance of pathogens via the alternative complement pathway.
C4 proteins [eg, from the C4a and C4b genes] are involved in the other complement
pathway, the classical complement pathway. Therefore, it is interesting that of the
eight autistic subjects with decreased IgA levels, all but two also had a C4b null
allele suggesting that, in these patients, both pathways of complement activation
[and response to infections] are probably operating at less than optimal level."

         [Reference 5 has an interesting Epstein-Barr connection.]

2.  Fujihara K.  Fujihara T.  Yamanaka N. Secretory IgA and squamous epithelization
in adenoids of children with otitis media with effusion.
Acta Oto-Laryngologica - Supplement.  523:155-7, 1996.
Ab:         Infection of adenoids has been considered a causative factor of otitis
media with effusion (OME). We believe that the deterioration in the mucosal barrier
of adenoids makes the adenoids vulnerable to bacterial infections, resulting OME.
In this study, we evaluated secretory IgA, secretory component (SC) and reticular
and squamous changes of ciliated epithelium in adenoids...   These results suggest
that the production of the secretory component is lower in the epithelium of
adenoids in children with OME. Hyperplasia, squamous epithelization and decreased
number of ciliated cells may also hamper mucosal clearance of the adenoids of
children with OME. These findings suggest that the adenoids of children with OME are
more susceptible to infections than adenoids of children without OME.

3.  Nagao AT.  Mai FH.  Pereira AB.  Carneiro-Sampaio MM. Measurement of salivary,
urinary and fecal secretory IgA levels in children with partial or total IgA
deficiency.  J Investigational Allergology & Clinical Immunol  4(5):234-7 1994.
Ab:   We measured salivary, urinary and fecal secretory IgA (sIgA) levels in 11
children with total IgA deficiency and in 6 children with partial IgA deficiency
using an ELISA technique.... No salivary or fecal sIgA, and only low levels of
urinary sIgA, were detected in the selective IgA-deficient group. The partial
IgA-deficient children presented with low levels of salivary, urinary and fecal
sIgA. Fecal sIgA levels correlated with salivary sIgA levels (p < 0.01) but not with
urinary sIgA levels (p > 0.05) in the IgA-deficient patients. We found that all the
children with partial IgA deficiency, except one, had detectable, but low values of
secretory IgA. Our data suggest that these patients also have a partial mucosal IgA
deficiency.  

4. Harabuchi Y.  Faden H.  Yamanaka N.  Duffy L.  Wolf J.  Krystofik D.
Nasopharyngeal colonization with nontypeable Haemophilus influenzae and recurrent
otitis media. Tonawanda/Williamsville Pediatrics.      Journal of Infectious
Diseases.  170(4):862-6, 1994 Oct. 
Ab:   The relationship between nasopharyngeal colonization with nontypeable H.
influenzae and recurrent otitis media was assessed in 157 children followed
prospectively from birth through 12 months of age. Forty-nine (31%) became
colonized. Nasopharyngeal secretory IgA (sIgA) reactive with the P6 outer membrane
protein was detected in all colonized children. Reduction or elimination of the
organism was associated with a better mucosal immune response (560 +/- 864
units/ng/mL of sIgA) than was persistence in the nasopharynx (121 +/- 81; P = .04).
Forty colonized children (82%) and 61 noncolonized children (56%) developed otitis
media (P = .004); colonized children were four times more likely to be classified
as otitis prone (P = .003). The frequency of otitis media episodes was directly
related to the frequency of colonization (r = .42, P < .01). These results
demonstrate a strong relationship between nasopharyngeal colonization patterns and
otitis media. The mucosal immune response may be important in elimination of
potential pathogens from the respiratory tract. 

5.  Stenfors LE.  Raisanen S.  Secretory IgA-, IgG- and C3b-coated bacteria in the
nasopharynx of otitis-prone and non-otitis-prone children.
Acta Oto-Laryngologica.  113(2):191-5, 1993 Mar.
Ab:   The proportions of secretory IgA (SIgA)-, IgG- and C3b-coated bacteria
obtained from a well-defined area on the posterior wall of the nasopharynx (NPH)
close to the Eustachian tube were determined. Samples taken from 25 otitis-prone
(OP) and 25 non-otitis-prone (NOP) children with normal serum levels of IgA and IgG
were evaluated using an immunofluorescence assay.... Deficiency in SIgA coating of
the nasopharyngeal bacteria may contribute to the otitis-prone condition.

<5>  Stenfors LE.  Raisanen S.  [Bacterial adhesion to epithelial cells of the
nasopharynx essential in the development of otitis media]. [Swedish]
Nordisk Medicin.  107(11):278-9, 1992.
Ab:   Otitis media develops when certain bacterial pathogens gain access to the
middle ear cavity from the nasopharynx through the eustachian tube. Adhesion of
bacteria, in particular Streptococcus pneumoniae and Haemophilus influenzae, to the
non-ciliated epithelial cells of the nasopharynx, close to the opening of the
eustachian tube, is significantly correlated to the otitis-prone condition in
children. Otitis-prone children have significantly fewer bacteria in the nasopharynx
coated with the immunoglobulin secretory IgA (SigA) then healthy children have.
Adhesion and occurrence of middle ear pathogens in the nasopharynx decreases with
advancing age. Epstein-Barr virus, causative agent of infectious mononucleosis,
causes a remarkable increase in bacterial adhesion to epithelial cells.


                                          >>> Posting number 17312, 
                                          dated 5 Jul 1997 16:06:40
II.   SUBOPTIMALITY: IgA & DILANTIN

.....Introduction.....
In a series of recent postings, I presented a rationale and citations linking Reed
Warren et al's IgA/autism findings and various anecdotal tales often shared by
autism parents -- eg, otitis/antibiotics, gluten sensitivity and other
gastrointestinal phenomena:
      However, the Warren et al findings do *not* mean that all or even most cases
of autism are linked to IgA deficiency; but what does seem important is that the
IgA/autism connection is pointing towards etiologal mechanisms also suggested by
anecdotal information from a large number of parents.
      While roaming about Medline and various articles, I encountered articles that
describe Dilantin (aka phenytoin) as capable of inducing IgA deficiencies in some
individuals. Dilantin/IgA citations will follow this commentary.


.....Possible links among Suboptimality, IgA, & Dilantin.....
Suboptimality is a concept several autism-research groups have used to demonstrate
that the number of adverse-events during the pre-, peri-, and neonatal periods is
strongly associated with autism and points towards a number of likely etiologies.
      A perinate, neonate, infant, or toddler who has seizures may be given
Dilantin. In some such kids given Dilantin, if Dilantin-induced IgA deficiency
occurs (usually during prolonged useage), then that child would be likelier to have
recurrent otitis, celiac disease, and other gastroinestinal problems.
      If that child's medical history includes recurrent otitis, then (as a result
of antibiotic-induced deflorastation of beneficial GI-tract flora) he or she would
be likelier to acquire gastrointestinal pathogens that would change gut
permeability, thereby increasing the likelihood of gluten- and/or casein
hypersensitivities, etc.

The concept of suboptimality applies because a newborn, infant, or toddler with
seizures (thus the possibility of receiving Dilantin) already is likely to have had
one or several adverse-events whose sequelae include the seizures. In this context,
receiving Dilantin and thereby (in some cases) inducing IgA deficiencies could lead
(in some such children) to the additional adverse- events described above re:
recurrent otitis, gluten and/or casein sensitivity, and/or other GI-tract problems.
      We note that two factors in the sequence described above are medical
treatments -- the prescribing of Dilantin and/or of an ongoing series of antibiotics
treatments.


1.  Kondo N et al.  Suppression of IgA production by lymphocytes induced by
diphenylhydantoin.  J Investigational Allergology & Clin Immunol 4(5):255-7 1994
Sep-Oct.

2.  Aarli JA. Immunological aspects of epilepsy.  Brain & Development.  15(1):41-9,
1993 Jan-Feb.

3.  Porter SR.  Scully C.  Orofacial manifestations in primary immunodeficiencies
involving IgA deficiency.  Journal of Oral Pathology & Medicine.  22(3):117-9, 1993
Mar.
ab:   The orofacial manifestations of 39 patients with primary IgA deficiency are
reported. Aphthous-like oral ulceration was observed in 61% while candidosis and
recurrent herpes labialis were each present in 25%. Only 4   (9%) patients had no
orofacial lesions.

4.  Talesnik E.  Rivero SJ.  Gonzalez B.  Serum IgA deficiency induced by prolonged
phenytoin treatment.  Revista de Investigacion Clinica.  41(4):331-5, 1989 Oct-Dec.
ab:         In a longitudinal study we have evaluated several immunological
parameters in thirty three epileptic children and adolescents 4 to 14 years old
treated with phenytoin, and matched normal controls. The patients had significantly
lower levels than normal controls of IgA (153 +/- 89 vs 236 +/- 128 mg/dL p less
than 0.001) and IgM (155 +/- 58 vs 217 +/- 105 mg/dL p less than 0.01). The decrease
in serum IgA levels correlated with the length of treatment (r = 0.44, p less than
0.03). Eight of the patients had IgA deficiency...


                                          >>> Posting number 17313, 
                                          dated 5 Jul 1997 16:11:25
III.  Suboptimality: IgA & Dilantin

5.  Ray A.  Arora S.  Plaut AG.  Rocklin RE. Sustained B-lymphocyte immunodeficiency
attributed to phenytoin therapy.  Journal of Allergy & Clinical Immunology. 
80(5):752-3, 1987 Nov.

6.  Guerra IC et al.  Permanent intrinsic B cell immunodeficiency caused by
phenytoin hypersensitivity.  Journal of Allergy & Clinical Immunology.  77(4):603-7,
1986 Apr.
ab:         We report a patient who, 3 weeks after initiation of therapy,
experienced a hypersensitivity reaction to phenytoin... No reversal of this
patient's immunodeficiency has occurred 3 years after phenytoin withdrawal.

7.  Wangel AG.  Arvilommi H.  Jokinen I.  The effect of phenytoin in vitro on normal
human mononuclear cells and on human lymphoblastoid B cell lines of different Ig
isotype specificities.  Immunobiology 170(3):232-8 1985.
ab:         The anticonvulsant drug phenytoin, in less than cytotoxic
concentrations, caused significant reductions in Ig secretion by unstimulated or
EBV-stimulated normal MNC, as measured by PFC or secretion of Ig into the culture
medium. Isotype-specific LBL varied in their sensitivity, the secretion of IgA (1
line) and IgG (3 lines) being reduced by phenytoin near therapeutic concentrations,
whereas that of IgM (1 line) was resistant. Six-day exposure of MNC to phenytoin
caused no selective depletion of or enrichment for B cells, monocytes or T cell
subsets. The results suggest that the reduction in serum Ig levels reported in
phenytoin-treated epileptic patients is, at least in part, due to a direct effect
of the drug on the B lymphocyte. However, among EBV-activated normal MNC, those
secreting IgA were no more sensitive to the drug than those secreting IgG or IgM,
and other factors may, therefore, operate to cause the preferential reduction in
serum IgA in phenytoin-treated patients.

8.  Iivanainen M.  Savolainen H. Side effects of phenobarbital and phenytoin during
long-term treatment of epilepsy.  Acta Neurologica Scandinavica.  Supplementum. 
97:49-67, 1983.
ab:         Phenobarbital and phenytoin have good antiepileptic effect, but
clinically significant untoward effects occur during their long-term use.
Phenobarbital may cause hyperactivity, behavioral problems, sedation, and even
dementia; these effects are dose related to some extent. Side effects of phenytoin
include sedation, a cerebellar syndrome, phenytoin encephalopathy, psychosis,
locomotor dysfunction, hyperkinesia, megaloblastic anemia, decreased serum folate
level, decreased bone mineral content, liver disease, IgA deficiency, gingival
hyperplasia, and a lupus-like hypersensitivity syndrome. Especially susceptible to
the neurotoxic effects of phenytoin are epileptic children with severe brain damage
who are on multiple drugs. In those children, balance disturbance may develop and
be followed by gradual loss of locomotion. Among 131 mentally retarded epileptic
patients, phenytoin intoxication occurred in 73 (56%), of whom 18 experienced
persistent loss of locomotion. There is experimental evidence that the toxic action
of phenytoin lies at the cellular level, predominantly in the cerebellum. Many
experts avoid the long-term use of phenytoin because of its insidious and
potentially dangerous side effects.

9.  Gilhus NE.  Aarli JA. The reversibility of phenytoin-induced IgA deficiency.  
Journal of Neurology.  226(1):53-61, 1981.
ab:         Phenytoin has been shown to induce serum IgA deficiency in patients with
epilepsy. We have followed 37 phenytoin-treated patients with reduced serum IgA
concentrations for 2-7 years. All anti-epileptic drug treatment was withdrawn in 8
patients. Phenytoin was substituted by other anti-epileptic drugs in 13 patients.
Sixteen patients received phenytoin unchanged. The mean serum IgA concentration
increased from 0.14 g/l to 0.71 g/l in the patients off drug treatment, and from
0.20 g/l to 0.84 g/l in the patients changing to other drugs. The mean IgA
concentration increased from 0.21 g/l to 0.37 g/l in the patients with phenytoin
unchanged, due to the increase of the IgA levels in a few patients who initially
showed a slightly depressed IgA concentration. The overall increase of IgA
concentrations was significant. When tested separately in each patient group, the
difference was significant for the patients off all drugs, and for those changing
from phenytoin to other drugs. The IgM concentration increased significantly when
all patients were considered together. This was due to the increase of IgM in the
patients no longer receiving phenytoin therapy. Withdrawal of phenytoin did not
influence the IgG concentrations.

10.  Shakir RA.  Behan PO.  Dick H.  Lambie DG.  Metabolism of immunoglobulin A,
lymphocyte function, and histocompatibility antigens in patients on anticonvulsants.

Journal of Neurology, Neurosurgery & Psychiatry.  41(4):307-11 1978.
ab:         Low serum IgA levels were found in patients taking phenytoin, together
with evidence of depressed T cell function. There was no correlation between the
dose or the serum level. A correlation was found, however, with HL-A status,
patients with a low IgA showing increased frequency of HL-A2. It is suggested that
epileptic patients with HL-A2 status are likely to develop IgA deficiency when given
phenytoin.

11.  Joubert PH.  Aucamp AK.  Potgieter GM.  Verster F.  Epilepsy and IgA
deficiency--the effect of sodium valproate.  South African Medical Journal. 
52(16):642-4, 1977 Oct 8.
ab:         IgA deficiency (less than 80 IU/ml serum) occurred in 29% of 41
epileptic patients on anticonvulsant therapy. Sodium valproate users had
significantly lower mean IgA levels (102 IU/ml) than non-users (151 IU/ml) and had
a significantly higher incidence of IgA deficiency (50%) than non-users (16%). The
occurrence of IgA deficiency did not appear to be related to age, sex, number of
drugs used or to serum anticonvulsant levels.

12.  Fontana A.  Grob PJ.  Sauter R.  Joller H.  IgA deficiency, epilepsy, and
hydantoin medication.  Lancet  2(7979):228-31, 1976.
ab:         Serum-immunoglobulin concentrations were measured in 364 patients with
epilepsy. On dividing the patients into those treated with or without hydantoins,
and according to possible aetiological factors, a characteristic pattern emerged.
Irrespective of the treatment given, the mean values of IgA were significantly
reduced in patients in whom constitutional factors were apparent, including those
with familial prevalence of seizures. While IgA was rarely found below 0-6 mg/ml,
a limit chosen to define IgA deficiency in patients not treated with hydantoins, the
IgA level was subnormal in 20-25% of the patients treated with such drugs. In
contrast, the mean concentration of IgA was normal and no individual subnormal
values were observed in epileptic patients treated with or without hydantoins whose
disease was thought to be secondary to traumatic or infectious events or to
metabolic disturbances. The data suggest that epilepsy with constitutional
characteristics might predispose to low IgA, but that IgA deficiency only occurs
when hydantoins are given. Whether this postulated predisposition is relevant to the
aetiology or pathogenesis of epilepsy remained unresolved.

13.  Yabuki S.  Nakaya K.  Immunoglobulin abnormalities in epileptic patients
treated with diphenylhydantoin.  Folia Psychiatrica et Neurologica Japonica. 
30(2):93-109, 1976.

14.  Aarli JA.  Drug-induced IgA deficiency in epileptic patients.      Archives of
Neurology.  33(4):296-9, 1976 Apr.
ab:         Serum concentrations of IgA, IgG, and IgM were determined by
immunodiffusion technique in 184 epileptic patients and 95 healthy individuals.
Twenty-one percent of adult and 42% of children patients receiving anticonvulsants
had serum IgA levels below 0.6 mg/ml (the lowest value detected in normal sera).
Serum concentrations in non-drug-taking epileptic patients were normal. Deviations
in IgG/IgM concentrations were smaller and less consistent. Serum IgA level was
determined at intervals before and during phenytoin treatments. A fall in the IgA
level occurred in several patients. In two patients, IgA deficiency developed within
two to three months of treatment. Low IgA-responders were more frequent among men
and children. The IgA anomaly was not specific for any type of epilepsy.

15.  Seager J, Jamison DL, Wilson J, Hayward AR, Soothill JF. IgA deficiency,
epilepsy, and phenytoin treatment. Lancet 2(7936):632-5 1975.  ab:            In a
prospective study of thirty-two children with seizures treated with phenytoin
(diphenylhydantoin), five had low levels of serum-IgA before treatment. All of these
were among the fifteen who had had febrile convulsions in infancy. IgA levels fell
significantly during 6 months treatment in the fourteen patients studied
sequentially. Treated children with low serum-IgA had normal numbers of lymphocytes
with surface IgA. This suggests that phenytoin causes failure of terminal
differentiation of B lymphocytes, and is the first known cause of this, the
commonest mechanism of immunoglobulin deficiency.                    POSTING HISTORY FOR "IgA/GUT SUBOPTIMALITY" 

>>> Posting number 17059, dated 1 Jul 1997 17:13:27
Date:         Tue, 1 Jul 1997 17:13:27 -0600
Sender:       SJU Autism and Developmental Disablities List
              
From:         Teresa Binstock 
Subject:      5a Suboptimality: IgA & otitis, celiac, gastrointestinal

>>> Posting number 17060, dated 1 Jul 1997 17:21:14
Date:         Tue, 1 Jul 1997 17:21:14 -0600
Sender:       SJU Autism and Developmental Disablities List
              
From:         Teresa Binstock 
Subject:      5b Suboptimality: IgA & (celiac and/or gastrointestinal)

>>> Posting number 17061, dated 1 Jul 1997 17:26:23
Date:         Tue, 1 Jul 1997 17:26:23 -0600
Sender:       SJU Autism and Developmental Disablities List
              
From:         Teresa Binstock 
Subject:      5b2 Suboptimality: IgA & (celiac and/or gastrointestinal)

>>> Posting number 17063, dated 1 Jul 1997 17:30:08
Date:         Tue, 1 Jul 1997 17:30:08 -0600
Sender:       SJU Autism and Developmental Disablities List
              
From:         Teresa Binstock 
Subject:      5c Suboptimality: IgA & recurrent otitis

>>> Posting number 17312, dated 5 Jul 1997 16:06:40
Date:         Sat, 5 Jul 1997 16:06:40 -0600
Reply-To:     SJU Autism and Developmental Disablities List
              
Sender:       SJU Autism and Developmental Disablities List
              
From:         Teresa Binstock 
Subject:      5d1 Suboptimality: IgA & Dilantin

>>> Posting number 17313, dated 5 Jul 1997 16:11:25
Date:         Sat, 5 Jul 1997 16:11:25 -0600
Sender:       SJU Autism and Developmental Disablities List
              
From:         Teresa Binstock
Subject:      5d2 Suboptimality: IgA & Dilantin