Prednisone: OK for some, not for others

Many physicians prescribe Prednisone for autism spectrum children; however,
*thorough* immune-panels that some autism-spectrum kids' parents have purchased
indicate that significant, chronic-active infections are occurring -- as judged,
for example, by highly elevated antibodies levels against CMV, HSV, measles,
HHV6, enteroviruses, Yersinia species, etc. Other immune-atypicalities are also
identified amidst the lab data of many such kids -- eg, extremely low or
virtually non-existent titres against antigens for which the child has been
vaccinated. 
     The chance of worsening an autism-spectrum child's underlying infection
(or several!) is important and, if possible, ought be avoided, this this
researcher's concern for the prescribing of Prednisone. This webpage presents
brief summaries of a number of glucocorticoid-related citations, followed by the
citations and abstracts.
     My intention is that these summaries and citations convey the impression
that physicians treating autism-spectrum children ought order *thorough*
immune-panel and other lab tests before prescribing steroid pharmaceuticals.

                              Teresa Binstock
          Researcher in Developmental and Behavioral Neuroanatomy

Summaries and Quotations

[a]  "A 55-year-old woman developed aphasia and delirium during ophthalmic
herpes zoster infection treated with oral prednisone and ophthalmic steroids,
which was followed by progressive cognitive decline without acute neurologic
events for 5 years. At age 60, the patient presented with new onset of
seizures, hemiparesis, and hemianopsia." (1)
[b]  "Atypical [herpes simplex virus encephalitis] HSVE was associated with
HSV-2 infection (two of the four patients), immunosuppression by steroid
therapy or coexisting HIV infection (three of the four patients), or disease
predominantly involving the nondominant temporal lobe (two of the four
patients)." (2)
[c]  Intestinal HHV6 and/or EBV, and interferon alpha therapy after
prednisone and other common therapies had ceased to produce benefits.
[d] An example of endogenous elevated-cortisol plus multiple infections (4).

[e] Here is an example of a Coxsackie virus infection treated successfully
with a combination of pharmaceuticals, noting also that her case was
especially severe and included alterations of consciousness, "After the
combined administration of ara-A, dexamethasone and anti-convulsant, the
consciousness level was recovered within a month." This case illustrates that
in certain emergency situations, diminishing inflammatory processes with
Prednisone and similar pharmaceuticals is important -- but these cases are
different from those of children with symptoms onset and who have not yet had
thorough immune tests.  Also, note that despite a Coxsackie infection
apparently generating neurologic signs, "There were no neurological findings
that suspected cerebral focal lesions." (5).
[f]  Another study documenting HSV in the jejunem, albeit not found until
after a transplantation had occurred (6); RM Gesser and colleagues have shown
that gastointestinal HSV can migrate into the CNS, even into the temporal
lobe.
[g] This study was a surprise to me. Even a stress like prolonged long noise
can impair the offspring's ability to generate antibody responses (7). 
[h]  In Bell's Palsy, treating the virus (HSV; acyclovir) is a better therapy
than treating the inflammation alone (via prednisone) (8); this reminds me of
the smoldering herpes/seizures study wherein treatment improved significantly
after treating-the-virus was initiated (8). [Too bad that recognition had not
occurred years earlier.]

[i] We recall also that a citation and abstract presented earlier in this
Orlando-8 series of posts documented atypical demyelination in response to
intraneuronal HSV. We note that HSV can migrate from the eye into the
brainstem and, while so doing, can generate no noticable symptoms; :
"Following corneal inoculation with HSV-1, the virus invaded the nervous
system and replicated in the brainstem without clinical signs of disease.
During this asymptomatic brainstem infection with HSV-1, significant changes
were found in the function of the HPA axis... We therefore suggest that
asymptomatic acute infection of the brainstem with HSV-1 may affect brain
regions involved in the regulation of the HPA axis..." (9)
[j]  Another example of when life-threatening inflammation is occurring
prednisone plus anti-viral therapy is effective (10).
[k]  In this study, dexamethasone was used to *induce* viral reactivation.
(11)
[l]  Group A strep, with latent HSV reactivated by glucocorticoid therapy for
adolescent female (12).

[m]  Tonic pupils, autonomic dysfunction, demyelination stemming from HSV in
a person with Guillain-Barre Syndrome (13).
[n]  Steroid-related HSV2-croup: "Prolonged infections may involve other
pathogens. To date and to our knowledge, there has been but a single case
report of herpes simplex virus type 1 (HSV-1) infection prolonging croup
attributed to prolonged use of corticosteroids." (14)
[o] Intestinal pathogy induced by the steroid therapy in conjunction with HSV
(15).
[p] An herb root with anti-HSV and anti-Measles properties. Warning! I do not
know if this herb is safe for human consumption. In the very least, the
citations suggests that an antiviral for measles may exist or could be
developed. (16)

[q] A number of the immune-panels I've perused indicate extreme elevations of
EBV. EBV infection is exacerbated by glucocorticoids (17-18).
[r]  A clear test-tube/petri-dish example of steroid effects (19)

References:

1. Sharfstein SR et al. Adult-onset MELAS presenting as herpes encephalitis.
Arch Neurol 1999 Feb;56(2):241-3 
          Department of Neurology, Long Island Jewish Medical
          Center, Long Island Campus for the Albert Einstein
          College of Medicine, New Hyde Park, NY 11042, USA.
OBJECTIVE: To report an unusual presentation of mitochondrial
encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)
manifested in late life with a clinical picture of herpes simplex
encephalitis. DESIGN: Case report. SETTING: Clinical neurology department in
a tertiary care hospital. CASE DESCRIPTION: A 55-year-old woman developed
aphasia and delirium during ophthalmic herpes zoster infection treated with
oral prednisone and ophthalmic steroids, which was followed by progressive
cognitive decline without acute neurologic events for 5 years. At age 60, the
patient presented with new onset of seizures, hemiparesis, and hemianopsia.
Subsequently she developed cortical blindness, multiple traumatic soft tissue
injuries from falls, acute psychosis, and severe dementia with periods of
agitation. She died in a nursing home in March 1997, 6 years after initial
presentation. RESULTS: Magnetic resonance imaging scan of the brain showed
hyperintensity on T2-weighted images involving temporal, parietal, and
occipital lobes bilaterally as well as mild atrophy of brainstem and
cerebellum. Single photon emission computed tomographic imaging showed
hypoperfusion of temporal, parietal, and occipital lobes. Results of video
electroencephalographic monitoring showed periodic lateralizing epileptiform
discharges in temporal and occipital areas. The serum lactate level was
normal in May 1996 and elevated in October 1996. The creatine kinase level
was elevated with a 100% MM fraction in August 1991 and normal in March 1996.
Results of repeated cerebrospinal fluid analyses indicated elevated protein
levels. Analysis of DNA was diagnostic of MELAS by mitochondrial DNA point
mutation at position 3243. The results of autopsy showed moderate cerebral,
cerebellar, and brainstem atrophy with signs of infarction in temporal and
parietal lobes bilaterally. CONCLUSIONS: The clinical presentation as well as
age at onset of MELAS are highly variable. Onset of mitochondrial disorders
can be provoked by febrile illness when there is mismatch between energy
requirements and availability. In the differential diagnosis of herpes
encephalitides, MELAS syndrome should be considered.

2. Fodor PA, Levin MJ, Weinberg A et al. Atypical herpes simplex virus
encephalitis diagnosed by PCR amplification of viral DNA from CSF. Neurology
1998 Aug;51(2):554-9.
          Department of Neurology, University of Colorado Health
          Sciences Center, Denver Veterans Affairs Medical Center,
          80220, USA.
OBJECTIVE: To determine the frequency of mild/atypical herpes simplex virus
encephalitis (HSVE) among patients with CSF specimens submitted to a
university diagnostic virology laboratory for HSV PCR. BACKGROUND: HSVE is
the most commonly recognized cause of acute sporadic encephalitis in the
United States. Recognized clinical features are based on autopsy- or brain
biopsy-confirmed cases. This is likely to produce ascertainment bias for
features associated with severe disease and under-recognition of mild or
atypical cases. Amplification of HSV DNA by PCR from CSF provides a sensitive
and specific method for diagnosis of HSVE. METHODS: Results of all HSV CSF
PCR tests sent to a university diagnostic virology laboratory (January 1,
1993, to December 31, 1996) were reviewed. Clinical information was
prospectively collected and retrospectively reviewed. Patients with positive
HSV CSF PCR tests were classified as having meningitis, encephalitis, or
neonatal infection. Encephalitis was considered typical or atypical based on
published criteria. RESULTS: A total of 7.6% of 1,224 CSF specimens were
positive for HSV DNA. CSF HSV DNA-positive patients had meningitis (52%),
encephalitis (26%), neonatal infection (17%), or nonclassifiable disease
(5%). A total of 17% of HSVE patients had mild or atypical disease
characterized by the absence of focal findings and slow progression in the
absence of antiviral therapy. Atypical HSVE was associated with HSV-2
infection (two of the four patients), immunosuppression by steroid therapy or
coexisting HIV infection (three of the four patients), or disease
predominantly involving the nondominant temporal lobe (two of the four
patients). CONCLUSIONS: Approximately one-fifth of HSVE patients have mild or
atypical disease. CSF PCR for HSV DNA should be performed in patients with
febrile encephalopathy even in the absence of focal features, initial CSF
pleocytosis, or abnormal CT. Mild or atypical HSVE may be associated with
infection with either HSV-1 or HSV-2. Mild or atypical HSVE was frequently
associated with immunocompromise or asymmetric HSV infection affecting
predominantly the nondominant temporal lobe.

3. Ruther U et al. Interferon alpha (IFN alpha 2a) therapy for herpes
virus-associated inflammatory bowel disease (ulcerative colitis and Crohn's
disease). Hepatogastroenterology 1998 May-Jun;45(21):691-9.
          Center for Internal Medicine, Department of General
          Internal Medicin, Stuttgart, Germany.
BACKGROUND/AIMS: The etiology and pathogenesis of ulcerative colitis and
Crohn's disease remain unclear, so that exact causal therapy is not yet
possible. In our UC and CD patients, viral infections, particularly of the
upper respiratory tract, aggravated the underlying disease. This had led us
to use in-situ hybridization to investigate intestinal mucosa for viral
agents such as HSV I + II- and Epstein-Barr virus DNA. We found these DNA in
the cell nuclei in the surface and glandular epithelia of the affected mucosa
of the small intestine and the colon. These findings indicated that viruses
may exacerbate these inflammatory bowel diseases. METHODOLOGY: Over a period
of 1-4.7 years, we treated 16 patients aged 25-65 with Crohn's disease (12
patients) or ulcerative colitis (four patients). In 14 patients, inflammatory
bowel disease had been diagnosed years before (mean, 15.3 years). When we
started therapy, 75% of the patients with Crohn's disease had
extra-intestinal manifestations; and the CDAI after Best averaged
considerably above 150. All patients had been taking either prednisone or
prednisolone and/or 5-ASA or SASP and/or azathioprine or metronidazole for
many years. Using PCR, mucosal specimens of the small intestine and/or the
colon were tested for EBV-, HSV I + II, HHV6- and CMV DNA. In 12 of the 16
patients. EBV- and/or HHV6 DNA were found in the affected mucosa. Since
interferon alpha administration has proven effective in chronic hepatitis-B
therapy, we decided to administer interferon alpha 2a (13,46,47,55). After
stopping the above-mentioned basic therapies, we commenced treatment with 6
million units of interferon alpha 2a subcutaneously 3 times per week for at
least six months. Four of the patients showed no signs of improvement, and
their therapy was stopped after three months. For the others, therapy was
continued until patients were clinically symptom-free and viral DNA could no
longer be traced in their mucosal biopsies. RESULTS: With interferon therapy,
12 of the 16 patients showed slow but continual improvement. Particularly
impressive was the remission of the extra-intestinal manifestations, which
did not recur in any patient during interferon therapy. Four patients did not
show any improvement, and the clinical symptom of diarrhea continued. Two
patients with ulcerative colitis suffered relapses three and four years
later, after severe bouts of para-influenza of the upper respiratory tract.
In these two patients, EBV- and HHV6 DNA was found in the inflamed mucosa of
the colon. Renewed therapy with interferon alpha 2a successfully cleared up
the inflammation. The patient group needed an average of eight weeks to
become clinically symptom-free, and an average of six months to achieve
complete virus elimination in the pathologically altered mucosa. CONCLUSIONS:
For herpesvirus-associated ulcerative colitis and Crohn's disease, interferon
alpha 2a treatment should be started as early as possible to prevent disease
becoming chronic. Whether this kind of antiviral treatment will be as
effective in the long term, and whether malignant transformation (herpes
viruses are potential tumor inducers) will be delayed or prevented, are
questions that can be answered only by future long-term studies.

4. Bakker RC et al. Cushing's syndrome complicated by multiple opportunistic
infections. J Endocrinol Invest 1998 May;21(5):329-33.
          Department of Endocrinology and Metabolism, Academic
          Medical Centre, Amsterdam, The Netherlands.
The case history of a 56-year-old man is described who suffered from severe
adrenocorticotrophic hormone (ACTH)-dependent Cushing's syndrome. The
clinical course was complicated by simultaneous infections with Pneumocystis
carinii, Staphylococcus aureus, Candida albicans, Aspergillus fumigatus and
Herpes simplex, which proved to be fatal. A study of the literature shows
that opportunistic infections in endogenous Cushing's syndrome are associated
with severe cortisol excess and carry a high mortality. Opportunistic
infections are most prevalent in the ectopic ACTH syndrome explained by the
very high plasma cortisol concentrations in this condition. Infections with
Aspergillus species, Cryptoccus neoformans, Pneumocystis carinii and Nocardia
asteroides predominated. Cushing's syndrome with a very high plasma cortisol
concentration causes a severe immunocompromized state. Prompt evaluation of
the cause of the hypercortisolism, initiation of cortisol lowering therapy,
primary prophylaxis for Pneumocystis carinii infection when plasma cortisol
exceeds 2500 nmol L-1 and a search for concomitant infectious disease is
recommended.

5. Hirayama M et al. [Coxsackie virus B4 encephalitis in a young female who
developed mental symptoms, and consciousness disturbance, and completely
recovered]. Rinsho Shinkeigaku 1998 Jan;38(1):60-2. 
[Article in Japanese]
     ab: An 18-year-old female had common cold and insomnia in early March
1987. Later, abnormal speech and behavior, emotional incontinence, anorexia
and consciousness disturbance appeared. On March 19, she was admitted to our
hospital in semi-comatose state. Myoclonus-like movement on hands was
observed, and epileptic attacks with tonic and clonic convulsions
occasionally occurred. There were no neurological findings that suspected
cerebral focal lesions. The respiration was assisted through tracheal
intubation. Laboratory examinations showed inflammatory reactions (CRP+2, WBC
10,600) and transient high levels serum CK (6,215 IU). As she had bradycardia
(30-40/min) with complete AV block on ECG, the pacemaker was implanted. The
complication of myocarditis was suspected. EEG showed bilateral slow waves
(3-6Hz), dominantly in frontal areas. Brain CT and CSF examinations were
normal. After the combined administration of ara-A, dexamethasone and
anti-convulsant, the consciousness level was recovered within a month. The
serum antibody against coxsackie virus B4 alone was significantly increased.
We concluded that coxsackie virus B4 caused acute encephalitis with mental
symptoms and myocarditis with AV block. Recently, cytomegalovirus was
reported to be the causative virus in a young female with non-HSV
encephalitis who showed mental symptoms with good prognosis, but coxsackie
virus B4 should also be considered as one of the causative viruses.

6. Kingreen D et al. Herpes simplex infection of the jejunum occurring in the
early post-transplantation period. Bone Marrow Transplant 1997
Dec;20(11):989-91.
     ab: Reactivation of infections with herpes viruses is a frequent and
major cause of morbidity after bone marrow transplantation. In this case
report we stress that HSV infections of the colon and small intestine should
be considered in the differential diagnosis of diarrhea and intestinal
bleeding in the early post-transplantation period. Severe acute GVHD and
subsequent intensive immunosuppressive treatment may increase the risk for
reactivation of HSV infection particularly in situations in which acyclovir
prophylaxis has been omitted.

7. Sobrian SK et al.   Gestational exposure to loud noise alters the
development and postnatal responsiveness of humoral and cellular components
of the immune system in offspring. Environ Res 1997;73(1-2):227-41.
          Department of Pharmacology, Howard University College of
          Medicine, Washington, DC 20059, USA. 
ab: Gestational exposure of the female to environmental toxins can alter
immune function in the offspring. We have recently shown that prenatal
maternal stress, that is, stress applied to or induced in the female during
pregnancy, can also alter the development of humoral immunocompetence in the
offspring and their hormonal and immunologic responses to postnatal stress.
This report presents data from two experiments on the effects of prenatal
exposure to loud noise-prenatal sound stress (PSS)-on the development and
responsiveness of in vitro and in vivo humoral and cellular immune function
in the offspring. Pregnant rats were exposed daily from Day 15 to Day 21 of
gestation to an inescapable loud noise (an 85- to 90-decibel fire alarm bell)
delivered randomly for 1 hr. In developing offspring, PSS produced
age-dependent and mitogen-specific alterations in lymphoproliferative
activity and reduced immunoglobulin G levels at Postnatal Day 21. Antibody
titers to herpes simplex virus type 1 were also reduced. Exposure to loud
noise before or after infection produced an additional reduction in titers in
these offspring. Arthus skin reaction (AR) to old tuberculin was reduced by
PSS. Combined prenatal/postnatal sound stress further reduced this response
and the AR to bovine serum albumin (BSA). Delayed hypersensitivity reaction
to BSA was reduced in PSS offspring; postnatal sound stress enhanced the
reaction to both antigens, but only in males. Antibody titers to BSA were
increased by PSS; adjuvant-induced inflammation was attenuated by postnatal
sound stress. These data suggest that in utero exposure to loud noise, which
can occur in the workplace, is toxic to the developing immune system.
Copyright 1997 Academic Press.

8. Adour KK et al. Bell's palsy treatment with acyclovir and prednisone
compared with prednisone alone: a double-blind, randomized, controlled trial.
Ann Otol Rhinol Laryngol 1996 May;105(5):371-8.
          Department of Head and Neck Surgery, Kaiser Permanente
          Medical Center, Oakland, CA 94611-5693, USA.
In a double-blind study, we compared the final outcome of 99 Bell's palsy
patients treated with either acyclovir-prednisone (53 patients) or
placebo-prednisone (46 patients). For patients receiving acyclovir, the
dosage was 2,000 mg (400 mg 5 times daily) for 10 days. Electrical tests
included electroneurography and the maximal stimulation test. Univariate
comparisons of outcome and electrical tests between the two groups were made
with chi 2 analysis, Fisher's exact test, and t-tests. The outcome in
acyclovir-prednisone-treated patients was superior to that in
placebo-prednisone-treated patients. Treatment with acyclovir-prednisone was
statistically more effective in returning volitional muscle motion (recovery
profile of 10; p = .02) and in preventing partial nerve degeneration (p =
.05) than placebo-prednisone treatment. The t-tests indicated that the
recovery profile and index means were significantly better for the
acyclovir-treated group (recovery profile t = 1.99, p = .051; recovery index
t = 2.10, p = .040). We conclude that acyclovir-prednisone is superior to
prednisone alone in treating Bell's palsy patients and suggest that herpes
simplex is the probable cause of Bell's palsy.

9. Ben-Hur T et al. Effects of HSV-1, a neurotropic virus, on the
hypothalamic-pituitary-adrenocortical axis in rats. Brain Res 1995 Dec
8;702(1-2):17-22.
          Department of Neurology, Hebrew University--Hadassah
          Medical School, Jerusalem, Israel.
ab: It is well established that the hypothalamic-pituitary-adrenocortical
(HPA) axis is activated during systemic viral diseases. In this study we
examined the effects of a neurotropic virus, herpes simplex virus type 1
(HSV-1), on the HPA axis in male rats. Following corneal inoculation with
HSV-1, the virus invaded the nervous system and replicated in the brainstem
without clinical signs of disease. During this asymptomatic brainstem
infection with HSV-1, significant changes were found in the function of the
HPA axis: On days 3, 7 and 14 post-infection (p.i.) basal ACTH and
corticosterone (CS) levels were markedly elevated, and photic stressful
stimulation failed to further increase the levels of these hormones. In
addition, the elevated basal serum levels of ACTH and CS could not be
suppressed by pretreatment with dexamethasone. The content of CRF-41 in the
paraventricular nucleus of the hypothalamus and in the median eminence
measured at 6 days p.i. was similar to that of vehicle inoculated rats. By 4
weeks p.i. the basal levels of ACTH and CS returned to normal and these
animals responded to photic stimulation and dexamethasone similar to vehicle
inoculated rats. Systemic (intraperitoneal) inoculation of HSV-1 did not
induce any changes in the HPA axis responses. We therefore suggest that
asymptomatic acute infection of the brainstem with HSV-1 may affect brain
regions involved in the regulation of the HPA axis, and that those effects
are mediated centrally and not by a systemic mechanism.

10. Choy AC et al. Virus induced erythema multiforme and Stevens-Johnson
syndrome. Allergy Proc 1995 Jul-Aug;16(4):157-61.
          Department of Medicine, Northwestern University Medical
          School, Chicago, IL 60611, USA.
ab: Erythema Multiforme is an acute, self-limited inflammatory cutaneous
disorder characterized by distinctive target lesions. Stevens-Johnson
syndrome (SJS) is defined as severe erythema multiforme with mucosal
involvement, visceral involvement, or both. Both diseases are part of a
continuum of immunologically mediated mucocutaneous diseases at various
grades of severity. Viral infections are known triggers of these skin
disorders. We report the success of a management strategy of acyclovir and
prednisone for herpes simplex virus-associated erythema multiforme. In
addition we describe the apparent first case of primary varicella infection
as a direct cause of SJS. The two cases are presented and a single-case
statistical analysis has been employed to evaluate the significance of the
management protocol. The method of analysis is presented in the appendix.
When a patient with primary varicella infection develops bullous lesions, SJS
should be considered in the differential diagnosis, as early and intense
corticosteroid therapy may be lifesaving. A regimen of prophylactic acyclovir
and therapy for an exacerbation of herpetic lesions with acyclovir and
prednisone was effective in inducing significant control of recurrent
erythema multiforme secondary to herpes simplex in our patient.

11. Tanaka S et al. Analysis by RNA-PCR of latency and reactivation of herpes
simplex virus in multiple neuronal tissues. J Gen Virol 1994 Oct;75 ( Pt
10):2691-8.
     ab: Following intracameral inoculation with herpes simplex virus type 1
(HSV-1), BALB/c mice develop acute necrotizing chorioretinitis and infectious
virus is detected in the eyes, trigeminal ganglia, brain, spinal cord and
adrenal glands during acute infection. In this study, we analysed the latent
phase of this experimental animal system. In mice which survived the acute
infection, latent HSV-1 was recovered from the trigeminal ganglia, brain and
adrenal glands by co-cultivation with Vero cells. In these tissues, both the
unspliced latency-associated transcript (LAT) and the spliced LAT were
detected by RNA-PCR. Following in vivo administration of cyclophosphamide and
dexamethasone to induce viral reactivation, ICP0 mRNA became detectable in
the multiple neural tissues, and the spliced LAT disappeared whereas the
unspliced LAT remained detectable by RNA-PCR. Sequence analysis of the
RNA-PCR products revealed that the GC-AG splicing signal previously reported
for LATs from trigeminal ganglia was also detected in LATs from the brain and
adrenal glands, suggesting that the splicing of LATs might be associated with
the maintenance of and/or reactivation from latency. The generalized latent
infection of HSV-1 described in this study might serve as an experimental
model of possible viral reactivation from organs that do not innervate the
primary port of entry.

12.  Shane SA et al. Herpes simplex dissemination following glucocorticoids
for upper airway obstruction in an adolescent girl. Pediatr Emerg Care 1994
Jun;10(3):160-2.
          Department of Pediatrics, Eastern Virginia Medical
          School, Norfolk.
ab: A previously healthy adolescent female suddenly developed a severe
febrile pharyngitis and impending upper airway obstruction. Her Monospot test
was positive, and her throat culture grew group A beta-hemolytic
streptococcus. After treatment with antibiotics and glucocorticoids, she
developed a fulminant course dominated by disseminated intravascular
coagulation and hepatic necrosis. At autopsy, herpes simplex virus type-1 was
cultured from lung, liver, and spleen tissue. We believe this is the first
report of disseminated herpes simplex infection after steroid use for upper
airway obstruction.

13.  Anzai T et al. Guillain-Barre syndrome with bilateral tonic pupils.
Intern Med 1994 Apr;33(4):248-51.
     ab: A 53-year-old patient with Guillain-Barre syndrome preceded by
herpes simplex virus infection developed bilateral tonic pupils with
light-near dissociation. Pharmacological tests for pupils suggested
postganglionic involvement of the parasympathetic and sympathetic nerves. A
demyelinating process of peripheral autonomic nerves was suspected to be the
cause of the tonic pupils and autonomic dysfunction.

14. Inglis AF Jr. Herpes simplex virus infection. A rare cause of prolonged
croup. Arch Otolaryngol Head Neck Surg 1993 May;119(5):551-2.
          Department of Otolaryngology-Head and Neck Surgery,
          University of Washington, Seattle.
ab: Pediatric acute subglottic croup is generally of limited duration
(usually 2 to 7 days) and caused by influenza or parainfluenza viruses.
Prolonged infections may involve other pathogens. To date and to our
knowledge, there has been but a single case report of herpes simplex virus
type 1 (HSV-1) infection prolonging croup attributed to prolonged use of
corticosteroids. Other authors have reported a wide range of HSV-1 infections
of the upper and lower respiratory tracts in all age groups that are usually
associated with immunocompromise. Two immunocompetent toddlers with prolonged
croup associated with HSV-1-positive subglottic lesions are described herein.
In one case the culture was obtained 11 days after just three doses of
dexamethasone treatment. In the second case the culture was obtained after 10
days of prednisone therapy; the infection cleared quickly following treatment
with acyclovir and rapid taper of the prednisone dose. These cases suggest
that prolonged croup-like symptoms warrant thorough airway evaluation. Herpes
simplex virus type 1 should be a suspected pathogen in cases of prolonged or
atypical croup. Herpes simplex virus type 1 croup is not necessarily
associated with immunocompromise or prolonged corticosteroid therapy.
Acyclovir seems to be effective in treating other airway HSV infections, and
by analogy it is the treatment of choice in recalcitrant herpetic croup. It
is unknown whether HSV-1 represents a primary or secondary pathogen in
prolonged croup.

15. Wasselle JA et al. Intestinal herpes simplex infection presenting with
intestinal perforation. Am J Gastroenterol 1992 Oct;87(10):1475-7.
     Department of Surgery, University of South Florida, Tampa.
ab: A 77-yr-old man who had received systemic steroids for more than 6 yr
presented with an acute abdomen. Laparotomy revealed an ulcerative jejunitis
with purulent peritonitis. The patient underwent resection of involved bowel
followed by a 10-day course of aciclovir, with excellent results. Pathologic
examination showed a necrotizing enteritis with intranuclear inclusions
typical of Herpesvirus that reacted immunocytochemically with antibodies to
herpes simplex virus types I and II. A rising herpes simplex virus serum
antibody titer confirmed the diagnosis. Intestinal herpes infection with
perforation should be added to the list of complications from herpes simplex
in the immunocompromised patient.

16. Ushio Y, Abe H. Inactivation of measles virus and herpes simplex virus by
saikosaponin d. Planta Med 1992 Apr;58(2):171-3.
          Research Institute of Oriental Medicine, Kinki
          University, Osaka, Japan.
ab: Saikosaponin d, isolated from the roots of Bulpleurum falcatum L. was
investigated for both its inactivating effects on some viruses and its
antiviral effects against the viruses in vitro. Saikosaponin d at a
concentration of more than 5 microM had direct inactivating effects on both
measles virus and herpes simplex virus after incubation of the viruses with
the agent for more than 10 min at room temperature. In contrast, exposure of
poliovirus to even 500 microM of saikosaponin d resulted in no loss of
infectivity, while the same concentration of saikosaponin d induced complete
loss of infectivity in both measles virus and herpes virus. In addition,
saikosaponin d was ineffective against the replication of measles virus,
herpes virus, and polio virus at a concentration of 0.1 microM, whereas
saikosaponin d did not induce an inhibitory effect on the growth of Vero
cells, when Vero cells were treated with saikosaponin d 24 h before the
inoculation (pretreatment) and immediately or 24 h after the infection of the
viruses (post-treatment).

17. Schuster C et al. Evidence for a functional glucocorticoid responsive
element in the Epstein-Barr virus genome. Mol Endocrinol 1991
Feb;5(2):267-72.
     ab: Glucocorticoids induce the expression of Epstein-Barr virus early
antigens in latently infected Daudi cells. By sequence analysis, we found
that fragment C of the BamHI digested Epstein-Barr virus B95-8 genome
contains a region with a large degree of homology to the glucocorticoid
responsive element of known glucocorticoid-regulated genes. By transfection
experiments in Daudi and HeLa cells, different lengths of this region, cloned
in front of the bacterial chloramphenicol acetyl transferase linked to the
Herpes Simplex virus thymidine kinase promoter (pBLCAT.2), were assayed for
their responsiveness to dexamethasone; our results led us to the conclusion
that the hormonal effect observed was mediated by a minimal sequence of 15
base pairs presenting 85% homology with the consensus glucocorticoid
responsive element sequence.

18. Kupfer SR, Summers WC. Identification of a glucocorticoid-responsive
element in Epstein-Barr virus. J Virol 1990 May;64(5):1984-90.
          Radiobiology Laboratories, Yale University School of
          Medicine, New Haven, Connecticut 06510-8039.
ab: Immortalization of B lymphocytes by Epstein-Barr virus (EBV) is complex
and poorly understood. However, some evidence suggests that glucocorticoids
influence this process. We identified a glucocorticoid-responsive element in
the BamHI C fragment of EBV which we call ES-1. In glucocorticoid-treated
cells, ES-1 enhanced chloramphenicol acetyltransferase gene expression from
the herpes simplex virus thymidine kinase promoter, as well as the EBV Bam-C
promoter, from which several latent viral gene products are transcribed. By
Northern blot analysis, glucocorticoid treatment enhanced transcription from
the Bam-C promoter in Jijoye cells, a Burkitt's lymphoma cell line. In
addition, the DNA-binding domain of the glucocorticoid receptor bound
specifically to the ES-1 region. These glucocorticoid effects on the Bam-C
promoter region may provide some insight into the process of EBV
immortalization.

19. West PG et al. Increased detection of herpes simplex virus in MRC-5 cells
treated with dimethyl sulfoxide and dexamethasone. J Clin Microbiol 1989
Apr;27(4):770-2.
     SmithKline Bio-Science Laboratories, Norristown, Pennsylvania
     19403.
ab: Treatment of MRC-5 cells with dexamethasone, dimethyl sulfoxide, or a
combination of the two enhanced the detection of herpes simplex virus by
three- to fourfold in these cells. Fluorescent plaques were noticeably larger
on cover slips treated with the enhancing agents. Low-positive clinical
specimens were stored and tested in parallel in treated and untreated shell
vials, and 6 to 40% of these stained positive in the treated cultures but not
in the untreated controls. In standard tube cultures, cytopathic effect began
earlier and was more extensive in treated tubes.