Focus
This webpage asserts that, whereas Prednisone therapy may be indicated for *some* autism spectrum children, an increasing amount of immunologic and infection-related evidence indicates that some autism-spectrum children are likely to be harmed by Prednisone therapy. Furthermore, so as to determine a child's likelihood of tolerating or being injured by Prednisone, this webpage recommends that parents and their child's physicians obtain and peruse medical data based upon a *thorough* immune panel, infection-related lab tests, and hematopoietic-function tests prior to administering Predisone or similar steroids.
Background
A parent recently (a) wrote me about his son's success with Prednisone, (b)
mentioned that he is familiar with and disagrees with my webpage that urges
caution in administering steroids to autism-spectrum children in the absence of
thorough medical testing, and (c) stated that he is recommending Prednisone
therapy as a general guideline for autism-spectrum children.
Whereas I admit that Prednisone therapy may be appropriate for some autish-
spectrum children, my research has shown (a) Prednisone therapy is likely to be
injurious to some autism-spectrum children, (b) extensive medical testing is the
only way to determine which kids are likely to be injured by Prednisone, and (c)
for some children, the physician's and parents' choice to use steroid therapy
may preclude therapies that would be more helpful and less injurious.Subgroups in autism
Whether determined by traits, by identifiable factors that are etiologicallly
significant, and/or by responses to various treatments (eg, acyclovir) -- the
existence of autism subgroups makes clear that no single treatment works for all
autism-spectrum kids. Corollaries of this principle include:
(a) a therapy that works for one child is not likely to work for all
autism-spectrum children, and
(b) a therapy that does not work for one child may work well for a
number of other autism-spectrum children.
(c) Many studies find only weak associations between autism and
various etiological factors, be they genetic, immune, or infectious;
in many published studies, these soft assocations and necessarily
weak conclusions derive from the researchers' omission of subgroups
within the trait-based category "autism".Subgroups of Prednisone responses
If a person listens to a large number of parents of autism spectrum children,
he or she learns, by these anecdotal testimonies, that Prednisone has worked in
some autism-spectrum kids; however, some parents report that the improvement was
only temporary, and some parents report that their child deteriorated during or
soon after the steroid treatment.
In other words, to the best of my belief and knowledge, steroid treatment
does not have beneficial effects for *all* autism-spectrum children; and, given
glucocorticoids well documented immunosuppressive effects, the documentation of
immune impairments in a large subgroup of autism-spectrum children (eg, 1-2),
and anecdotal evidence of child deterioration while on steroid therapy,
Prednisone therapy appears to be injurious to some autism-spectrum children.
Immune panels and other medical data
In recent years my research has included perusing immune panels and other
medical data provided me by autism-spectrum children's parents, many of whom had
pursued this data (a) in cooperation with Hugh Fudenberg, MD, or (b) in respect
for his methodology -- wherein a large amount of medical data was used to
identify etiologically significant factors and also to design a treatment
protocol for each particular child (3-a,b).
The various immune panels and other medical data sent me reveal that a
significant subgroup of autism-spectrum children have atypical immune profiles;
and the medical data of many such children point towards atypical chronic-active
infections, often including hematopoietic effects consistent with the identified
pathogen's known effects (eg, HHV6; CMV, EBV; 4-a,b,c,d).
Importantly, many of these children do not look "sick"; outward appearances
are not a sufficient guideline. If the parents had not purchased extensive lab
tests, the child's underlying immune-shifts and chronic-active infections would
not have been identified. In several cases, had the data not been obtained, (a)
appropriate treatments that have been helpful would not have been initiated, and
(b) treatments likely to be injurious for these specific children -- eg,
Prednisone --might have been attempted.
A discussion of lab-tests is presented on a webpage:
Merely autoimmune, an outmoded model
A lingering paradigm, or perhaps we ought say "model", seems to remain strong
among pediatricians and neurologists involved with autism-spectrum children ).
This model appears to derive from brain imagings that show localized
demyelination; and, at least preliminarily, this model gains support because
research findings (5) and purchased lab-assays data indicate antibodies levels
against myelin basic protein (MBP). For some children, this finding is
accompanied by an elevated titer of anti-GFAP antibodies.
** When these findings are observed and treatment is contemplated, the
lingering paradigm in widespread clinical practice appears to include
the precept that the underlying process is autoimmune and thus
Prednisone is warranted. I believe that this model (a presumption of
autoimmunity) is inaccurate and, for some specific children, leads to
Prednisone therapy injurious because of the child's underlying
infections and immune atypicalities.Towards a more accurate model
I grant a priori that autoimmune-presumption model may be valid for *some* kids
having localized demyelination plus anti-MBP antibodies with or without anti-
GFAP titers. However, another possibility for children with these med-data signs
is that an underlying, chronic-active, subclinical infection is continually
infiltrating across the blood-brain barrier ("barrier") and is causing astrocyte
activation and demyelination -- as has been documented for measles (eg, 6).
The mechanism by which chronic infection-induced demyelination occurs is as
follows:
Monocytes slowly but continually infiltrate the brain, which has its
own immune processes (7-10;11-12). A number of pathogens
preferentially inhabit monocytes and impair their function (eg,
Yersinia enterocolitica, HHV6, CMV), and the intra-monocyte pathogen
can be dormant even while inducing altered monocyte function, and
localized viral reactivation can occur (13-16). As infected monocytes
cross the bbb, astrocyte activation, demyelination, and excessive
GFAP production can ensue (eg, 6; see also 25).Three autism-spectrum subgroups
Let us consider three subgroups of autism-spectrum children:
-- children for whom Prednisone therapy is warranted and helpful.
-- children whose medical signs indicate that predisone therapy may
be warranted, but it has no apparent beneficial effect and does not
appear to injure the child.
-- children with an underlying immune atypicality and/or with a
chronic-active infection, ie, children likely to be injured by
steroid therapy.
Since, in autism-spectrum children, significant infections and immune
atypicalities are often subclinical and chronic and are revealed only by
extensive testing, to procede to steroid therapy without first obtaining
thorough immune testing and related medical data is:
(a) to act upon a model wherein "autoimmune processes" are a
presumption and, correspondingly,
(b) to act while ignoring a growing amount of medical data indicating
(i) that astrocyte activation and demyelination
can result from continual infiltration of
infected cells into and through the bbb, and
(ii) that a number of pathogens can establish residency
within monocytes and bone marrow.
Furthermore, given that a large subgroup of autism-spectrum children have
immune-atypicalities and/or chronic-active infections, to prescribe Prednisone
without first obtaining extensive immune-related and other medical data is to
subject a goodly number of autism-spectrum children to a risk of further
deterioration induced by steroid-induced exacerbation of underlying infections
and immune atypicalities.
Consider a recent summary from Nathan and Oski's Hematology of Infancy and
Childhood, 5th edition, 1998:
"Corticosteroids impair neutrophil chemotaxis; and at high dosages,
polymorphonuclear leukocyte phagocytosis, microbicidal activity, and
antibody-dependent cytotoxicity also may be altered... In addition,
corticosteroids may cause monocytopenia as well as defects in
monocyte chemotaxis, phagocytosis, and killing of bacteria and fungi.
Corticosteroids also may... increase skin fragility, and depress
lymphocyte function and the production of cytokines and humoral
immune response, making the host susceptible for a variety of
infections [or, in my opinion, serving to exacerbate chronic active
infections]. Importantly, the signs and symptoms of even severe
infections may be 'masked' or greatly reduced in patients receiving
corticosteroids." p1744, v2Medical science versus habits in clinical practice
The American College of Physicians has online an important essay about the
distance between medical science and clinical practice (17). This distance
between science and clinical practice is reflected in the common aphorism heard
by young physicians in training: If you hear hoofbeats, don't think zebras.
In general practice and for most patients, this counsel is quite useful,
but autism-spectrum children stand in stark contrast. Many such kids have the
subtle immune impairments and/or seemingly subclinical but significant chronic-
active infections (a) that, while the bedevilment of profitable clinical
practice, are increasingly described in medical-science literature, and (b) that
can only be indentified via extensive medical testing.
Progress in autism
Gradually, old models (eg, demyelination must be an autoimmune pathology) are
giving way to a growing realization that a goodly number of autism-spectrum kids
have significant immune atypicalities and/or chronic-active infections --
medical conditions in which steroids such as Prednisone are contraindicated.
However, the ordering of sufficient lab tests for autism-spectrum children
has not yet reached beyond a growing number of determined parents. Medical
testing is expensive, and interpreting the data may require extensive, time-
consuming research. For these reasons, it is far more cost effective for a
physician to offer arguments against the tests and to use treatments (eg,
Prednisone) rooted in traditional clinical practice -- and to do so despite a
growing amount of medical-science studies indicating that such treatments are
likely to be injurious to a goodly percentage of autism-spectrum children.
Triggers and Models
Subgroups: When considering possible etiologies, the autism-spectrum contains
a number of subgroups. For many specific kids, the underlying etiology is not
known. For other specific kids, certain treatments have helped significantly.
-- Acyclovir brings improvement to many but certainly not all autism-
spectrum children.
-- Child-specific amino-acid and/or fatty-acid supplementation
programs have helped some children, occasionally when combined with
an appropriate anti-pathogen pharmaceutical.
-- GF and/or CF and/or corn-free etc have helped a goodly number of
kids.
Triggers: The phrase "hit and run" is often used to describe pathogens whose
sequelae can include autoimmune processes within the CNS. However, a growing
body of medical science literature documents that some pathogens establish
residence within bone marrow and also within monocytes, thereby impairing
immunity and hematopoiesis, even as a few infected monocytes continually
infiltrate the blood brain barrier, thereby having the potential to activate
astrocytes, induce demyelination, and increase GFAP production.
These relatively recent insights regarding chronic active infections
suggest a concept of "trigger" quite different from that of "hit and run"
pathogens. Instead, in some children, there may be chronic active infections
that provide a continual, bbb-crossing trigger for demyelination and that would
be exacerbated by Prednisone therapy.Conclusion: the example of Herpes simplex
A number of parents report that acyclovir has been extremely helpful for their
child (18), and these reports are given credence by testimony from physicians
such as Michael Goldberg and Sid Baker, each of whom treats a large number of
autism-spectrum children.
The fact that acyclovir generates positive responses in a significant autism-
subgroup (a) strongly suggests the presence of an acyclovir-responding
subclinical infection, and (b) indicates that the following statement needs be
clarified and expanded:
"Steroid therapy should be avoided in children with a history of
herpes virus encephalitis (CMV, herpes simplex) in the past." (19).
Importantly, a number of 1990s articles about HSV have documented (i) that HSV
can be within the CNS of persons having no peripheral signs or symptoms, (ii)
that HSV can enter the CNS via intraneuronal migration without causing a
noticable encephalitis (20); and CMV can be present within monocytes of
individuals having no peripheral anti-CMV antibodies (21-22).
Furthermore, HSV has long been associated with language deficits and
increasingly is realized to be associated with epilepsy and with
seizure foci in epilepsy patients (23-24).
These findings, especially in the context of a large number of anecdotal reports
about acyclovir helping an autism-spectrum subgroup, suggest that in some
children with seizures and/or language deficits, the underlying cause may be HSV
even though the child has no medical history of HSV encephalitis. In such
children and because, once infected, herpes class viruses are never fully
cleared from the human body, Dr. Riikonen's counsel is worth restating:
"Steroid therapy should be avoided in children with a
[possibility of significant herpes virus infection or with
a] history of herpes virus encephalitis (CMV, herpes
simplex) in the past." Prednisone therapy ought not be
initiated without thorough lab data revealing that
underlying infections, immune atypicalities, or
hematopoietic processes will not be exacerbated.
Teresa Binstock
Researcher in Developmental and Behavioral Neuroanatomy
aspergerian@yahoo.com
1-a. J Autism Dev Disord 1997 Apr;27(2):187-92
Brief report: immunoglobulin A deficiency in a subset of autistic subjects.
Warren RP, Odell JD, Warren WL, Burger RA, Maciulis A, Daniels WW, Torres AR
Utah State University, Logan 84322, USA.
1-b. Mol Chem Neuropathol 1996 May-Aug;28(1-3):77-81
Immunogenetic studies in autism and related disorders.
Warren RP, Singh VK, Averett RE, Odell JD, Maciulis A, Burger RA, Daniels WW,
Warren WL
1-c. Neuropsychobiology 1996;34(2):72-5
Elevated serotonin levels in autism: association with the major
histocompatibility complex.
Warren RP, Singh VK
1-d. Neuropsychobiology 1995;31(2):53-7
DR-positive T cells in autism: association with decreased plasma levels of the
complement C4B protein.
Warren RP, Yonk J, Burger RW, Odell D, Warren WL
1-e. Clin Exp Immunol 1991 Mar;83(3):438-40
Increased frequency of the null allele at the complement C4b locus in autism.
Warren RP, Singh VK, Cole P, Odell JD, Pingree CB, Warren WL, White E
2-a. J Neuroimmunol 1998 May 1;85(1):106-9
Th1- and Th2-like cytokines in CD4+ and CD8+ T cells in autism.
Gupta S, Aggarwal S, Rashanravan B, Lee T
Department of Medicine, University of California, Irvine 92697-4075, USA.
2-b. Neuropsychobiology 1994;29(1):12-6
Lymphocyte function in autism and Rett syndrome.
Plioplys AV, Greaves A, Kazemi K, Silverman E
Division of Neurology, Mercy Hospital and Medical Center, Chicago, IL 60616.
2-c. Clin Immunol Immunopathol 1998 Oct;89(1):105-8
Serological association of measles virus and human herpesvirus-6 with brain
autoantibodies in autism.
Singh VK, Lin SX, Yang VC
College of Pharmacy, University of Michigan, Ann Arbor, Michigan, 48109-1065,
USA.
3-a. Biotherapy 1996;9(1-3):143-7
Dialysable lymphocyte extract (DLyE) in infantile onset autism: a pilot study.
Fudenberg HH
3-b. Ann N Y Acad Sci 1988;540:602-4
Immunodiagnosis and immunotherapy in autistic children.
Singh VK, Fudenberg HH, Emerson D, Coleman M
Medical University of South Carolina, Charleston 29425.
4-a. J Virol 1999 Jan;73(1):754-9
Human herpesvirus 6 latently infects early bone marrow progenitors in vivo.
Luppi M, Barozzi P, Morris C, Maiorana A, Garber R, Bonacorsi G, Donelli A,
Marasca R, Tabilio A, Torelli G
Section of Hematology, Department of Medical Sciences, University of Modena,
Modena, Italy.
We have studied the in vivo tropism of human herpesvirus 6 (HHV-6) for
hemopoietic cells in patients with latent HHV-6 infection. Having used a
variety of cell purification, molecular, cytogenetic, and immunocytochemical
procedures, we report the first evidence that HHV-6 latently infects early bone
marrow progenitor cells and that HHV-6 may be transmitted longitudinally to
cells which differentiate along the committed pathways.
PMID: 9847383, UI: 99102636
4-b. J Med Virol 1997 Aug;52(4):406-12
Suppressive effects of human herpesvirus 6 on in vitro colony formation of
hematopoietic progenitor cells.
Isomura H, Yamada M, Yoshida M, Tanaka H, Kitamura T, Oda M, Nii S, Seino Y
Department of Pediatrics, Okayama University Medical School, Shikatacho, Japan.
4-c. In Vivo 1994 Jul-Aug;8(4):533-42
Demonstration of active and latent Epstein-Barr virus and human herpevirus-6
infections in bone marrow cells of patients with myelodysplasia and chronic
myeloproliferative diseases.
Krueger GR, Kudlimay D, Ramon A, Klueppelberg U, Schumacher K
Laboratory of Immunopathology, University of Cologne, Germany.
After previous serological screening for Epstein-Barr virus (EBV), human
herpesvirus-6 (HHV-6) and human cytomegalovirus (HCMV) showed elevated antibody
titers against EBV and HHV-6 in more than 50% of patients with myelodysplasia
and chronic myeloproliferative diseases, the present study was carried out in
order to investigate viral antigen expression and distribution in bone marrow
cells of these patients. Trephine biopsies were studied from 60 patients with
myelodysplasia (MDS), 36 patients with chronic myelogenous leukemia (CML) and
18 patients with osteomyelofibrosis (PMF). Elevated anti-EBV EA titers were
found in 62% of the MDS cases, in 33% of the CMLs and in 62% of the OMF
patients. HHV-6 titers were elevated in 18% of the MDS cases, but in only one
case each of CML and OMF. Antigen expression in bone marrow cells was even more
frequent: EBV-EA was 76% in MDS cases, 77% in CML and 40% in OMF. HHV-6 p41 was
observed in 47% of the MDS cases, in 54% of the CML cases and in 20% of the
OMFs. In comparing these data with those from the literature and with our own
studies in Hodgkin's disease, it is hypothesized that the reactivated
herpesviruses may contribute to the pathogenesis of these hematopoietic
disorders by interfering with the cytokine regulation of cell proliferation and
differentiation.
PMID: 7893980, UI: 95201205
4-d. Leuk Lymphoma 1999 Mar;33(1-2):1-13
Human cytomegalovirus infection of human hematopoietic progenitor cells.
Maciejewski JP, St Jeor SC
Department of Microbiology, University of Nevada, Medical School, Reno 89503,
USA.
5. Brain Behav Immun 1993 Mar;7(1):97-103
Antibodies to myelin basic protein in children with autistic behavior.
Singh VK, Warren RP, Odell JD, Warren WL, Cole P
6. Mesquita et al. Measles virus antigen in macrophage/microglial cells and
astrocytes of subacute sclerosing panencephalitis. APMIS 106.553-61 1998.
7. Hickey WF. Leucocyte traffic in the central nervous system: the participants
and their roles. Seminars in Immunology 11.125-137 1999.
8. Hickey WF, Kimura H. Perivascular microglia are bone marrow derived and
present antigen in vivo. Science 239.290-2 1988.
9. Hickey WF et al. Bone marrow derived elements in the central nervous
system... J Neuropathol Exp Neurol 51.246-56 1992.
10. Unger ER et al. Male donor-derived cells in the brains of female sex-
mismatched bone marrow transplant recipients: a Y-chromosome specific in situ
hybridization study. J Neuropathol Exp Neurol 52.460-9 1993.
11. Streit WJ, Kincaid-Colton CA. The brain's immune system. Scientific American
273.54-5,58-61 1995.
12. Keane, RW, Hickey WF; editors. Immunology of the Nervous System. Oxford U
Press, 1997.
[an excellent overview!, many fine, clearly
written reviews, still current!]
13. Reiner NE. Altered cell signaling and mononuclear phagocyte deactivation
during intracellular infection. Immunology Today 15.8.374-381 1994.
14. Virus Res 1993 Jul;29(1):79-90
Human herpesvirus 6 (HHV-6)-associated dysfunction of blood monocytes.
Burd EM, Carrigan DR
Department of Pathology, Medical College of Wisconsin, Milwaukee 53226.
15. APMIS 1997 Feb;105(2):89-98
The effect of human cytomegalovirus on selected functions of peripheral blood
monocytes.
Holberg-Petersen M, Rollag H, Beck S, Degre M Kaptein W.
Wilhelmsen og Frues Institute of Microbiology, Rikshospitalet, Oslo, Norway.
16. Circ Res 1997 Jul;81(1):8-16
Monocytes harboring cytomegalovirus: interactions with endothelial cells,
smooth muscle cells, and oxidized low-density lipoprotein. Possible mechanisms
for activating virus delivered by monocytes to sites of vascular injury.
Guetta E, Guetta V, Shibutani T, Epstein SE
17. http://www.acponline.org/public/sugar/chapter4.htm
This American College of Physicians webpage presents an essay about
the distance between medical science and clinical practice. What I, many
parents, and a very few researchers and physicians are doing is turning to
medical literature, finding useful science therein, and then are turning in
frustration to clinical physicians who manifest exactly the distance from
medical science (eg, use of thorough immune panels) that the ACP essay
delineates.
18. Anecdotes shared on NIDs list (NeuroImmune Dysfunction, NIDS@onelist.com)
and on autism-list of St Johns University (autism@maelstrom.stjohns.edu).
19. Riikonen R. Infantile spasms: infectious disorders. Neuropediatrics 1993
Oct;24(5):274-80.
Department of Child Neurology and Pediatrics, Children's
Hospital, University of Helsinki, Finland.
ab: Infections were considered to be etiological factors in 29 patients (10%)
with infantile spasms; congenital CMV (n = 5), congenital or acquired CMV (n =
1), acquired CMV (n = 5), congenital rubella (n = 2), herpes simplex virus (n
= 5), enterovirus (n = 1), adenovirus (n = 1), viral encephalitis of unknown
agent (n = 3), meningococcus (n = 4), pneumococcus (n = 1) and pertussis (n =
1). The children with congenital infections had long-lasting tremor and
convulsions from birth. Early EEG pattern was characteristic for children with
herpes encephalitis but not for other patients. Infantile spasms appeared only
some weeks after viral encephalitis. One patient with enterovirus and another
with probable adenovirus infection had necrotic changes in their brain CT
resembling those of herpes encephalitis. The response to ACTH was poor (38%)
compared to the whole series (60%). The long-term outcome was also poor compared
to the whole series; mental retardation in 90%, convulsions in 62%, abnormal EEG
in 89%. Four children died during the follow-up of 7 years. Autopsy showed
disseminated CMV infection in one patient and chronic CMV infection in another.
The outcome of children with infectious etiology appears to be particularly
poor. Thus, the prevention and specific diagnosis and treatment are important.
Steroid therapy should be avoided in children with a history of herpes virus
encephalitis (CMV, herpes simplex) in the past.
20. A discussion and citations regarding HSV, epilepsies, and language
atypicalities can be found at:
http://www.jorsm.com/~binstock/lks-hsv.htm
21. Cornford ME, McCormick GF. Adult-onset temporal lobe epilepsy associated
with smoldering herpes simplex 2 infection. Neurology 1997 Feb;48(2):425-30.
Department of Pathology, Harbor UCLA Medical Center,
Torrance 90509, USA.
ab: A 40-year-old man with chronic genital herpes simplex infection developed
partial complex temporal lobe seizures of insidious onset, with EEG and MRI
evidence of a unilateral temporal lobe destructive, atrophic process. Extensive
workup did not reveal an infectious etiology. Three years of escalating number
and severity of daily seizures with memory loss led to temporal lobectomy.
Histologic study revealed active, low-level viral infection in the resected
hippocampus and temporal lobe cortex, with immunohistochemical evidence for
infection by herpes simplex 2, principally in neurons. In situ hybridization
confirmed the presence of herpes simplex virus in neurons.
Anticonvulsant-resistant seizure episodes began to recur several times daily
soon after surgery, but the addition of acyclovir to the treatment regimen
resulted in a substantial reduction in seizure occurrence, maintained for the
subsequent 2.5 years.
22. Sanders VJ et al. Presence of herpes simplex DNA in surgical tissue
from human epileptic seizure foci detected by polymerase chain reaction:
preliminary study. Archives of Neurology 54.8.954-60 1997.
23. Taylor-Wiedeman J. Hayhurst GP. Sissons JG. Sinclair JH.
Polymorphonuclear cells are not sites of persistence of human cytomegalovirus
in healthy individuals. Journal of General Virology. 74 ( Pt 2):265-8, 1993
24. Przegl Lek 1995;52(7):354-7
[Congenital and acquired cytomegalovirus infection in infants confirmed by
virologic studies]. [Article in Polish]
Zawilinska B, Kruszewska M, Stopyrowa J, Zgorniak-Nowosielska I
25. Binstock TC. Intra-monocyte pathogens define autism-spectrum subgroup.
October 1999. http://www.jorsm.com/~binstock/monocyte.htm