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Brief report: Autism and herpes simplex encephalitis



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Journal of Autism and Developmental Disorders, Vol. 22, No. 1, 1992
Brief Reports
Brief Report: Autism and Herpes
Simplex Encephalitis
Mohammad Ghaziuddin, 1 Luke Y. Tsai,
Laura Eilers, and N. Ghaziuddin
Department of Child and Adolescent Psychiatry, University of
Michigan Hospital, Ann Arbor
It is now generally accepted that autism is a behavioral syndrome with
an underlying organic pathology. It can be associated with a variety of dis-
orders affecting the central nervous system, such as encephalitis. DeLong,
Bean, and Brown (1981) described three children, ages between 5 and 11
years, who developed acute encephalitic illness accompanied by autistic fea-
tures that resolved after clinical recovery. One of the patients had high
serum herpes simplex titers, and a computerized tomography (CT) scan of
the head revealed an extensive lesion of the temporal lobes, mainly on the
left side. The other two patients had normal CT scans, and no etiological
agent was defined. Gillberg (1986) described the case of a 14-year-old girl
who developed "typical" autistic syndrome following an attack of herpes
simplex encephalitis. The CT of the head showed widespread bilateral
destruction of brain parenchyma and the temporal lobes, with some medial
involvement of the lower parts of the parietal lobes. The autistic symptoms
persisted long after the acute symptoms of herpes encephalitis, such as
fever and alteration of consciousness, subsided.
All the above cases met the criteria for autism except the typical age
of onset. For example, DeLong et al.'s cases ranged in age from 5 to 11
1Address all correspondence to Mohammad Ghaziuddin, Division of Child Psychiatry,
Taubman Center-Box 0390, University of Michigan Hospitals, 1500 East Medical Center
Drive, Ann Arbor, Michigan 48109-0390.
0162-3257/92/0300-0107506.50/0 9 1992 Plenum Publishing Corporation
108 Ghaziuddin, Tsai, Eilers, and Ghaziuddin
years when they developed the symptoms, and Gillberg's patient was 14
years old; whereas the onset of autism is usually defined before the age of
3 years. We describe below two children who developed herpes virus in-
fection in the intrauterine or early postnatal period, and presented with
features of autism around 2 years of age.
B, a 4-year-old white boy, was referred by his mother for a diagnostic
evaluation to rule out autism.
Developmental history revealed that he was born after a full-term normal
pregnancy and weighed 10 lb at birth. Problems arose during delivery when
meconium staining of the amniotic fluid was noted. The delivery was assisted
by forceps. Immediately after birth, B was noted to be tachypneic and was
diagnosed as having a "wet lung." He was discharged at 4 days of age with a
probable diagnosis of aspiration pneumonitis. His IgM level was 15.7 (normal
6.3 to 25); a herpes titer was not done. He was readmitted 10 days later with
signs of an upper respiratory infection, vomiting, and a failure to gain weight.
He was treated by oxygen and intravenous antibiotics following which he made
a slow recovery. ~ A final diagnosis of sepsis neonatorum and chlamydial laryn-
gotracheobronchitis was made. At this time, the titer for TORCH organisms
(toxoplasmosis, syphilis, rubella, cytomegalovirus, and herpes virus) was
described as negative in the discharge summary. However, according to the
pathology report, the herpes titer was read as outside the reference range; it
was 1:4 whereas the reference range of the laboratory where it was done was
less than 1:2. Skull X-ray and CT scan of the head were done and were within
normal limits.
B's early motor development was normal. He was able to sit at 6
months of age and could walk without support at 989 months. His language
development was, however, delayed. He showed no attention span and also
indulged in frequent temper tantrums. At 19 months he was evaluated and
was found to be functioning at the 8- to 10-month level. Apart from some
basic consonant-vowel combinations, his speech was minimal. In addition,
his social development was also substantially delayed and inappropriate.
For example, he showed no interaction with others and frequently treated
people as inanimate objects. He also engaged in self-abuse in the form of
head-banging and face-scratching. He never showed any inclination to in-
teract with children of his age. His speech production was limited to making
minimal sounds and prolonged screaming. His nonverbal communication,
as well as his ability to imitate, were impaired. During psychological testing,
Autism and Herpes Simplex Encephalitis 109
Fig. 1. Head CT Scan of Case 1 showing hypodense areas in the left temporal region.
he showed no representational play or curiosity of object use. It was not
possible to give a score to his IQ level because of his problems with at-
tention and concentration. However, on the basis of clinical observation,
his IQ was placed below 50.
At 2 years of age, B received a neurological evaluation to assess the
possibility of a seizure disorder and was, in fact, placed on carbamazepine.
Ghaziuddin, Tsai, Eilers, and Ghaziuddin
He had a history of 2- to 3-second periods of rolling back his eyes with
fluttering of eyelids. An EEG showed no evidence of seizures. ACT scan
of the head showed definite hypodense areas in the temporal regions on
both sides, more on the left. According to the radiologist, the area of at-
tenuation on the left and involvement of the contralateral temporal lobe
in nearly identical topography was unusual for a vascular, metabolic, or
ischemic reason. The most likely cause was felt to be inflammatory, espe-
cially herpes simplex encephalitis. Other features consistent with this diag-
nosis were the overall slight decrease in the brain volume for age and the
presence of some calcification along the pulvinar of the thalamus. This is
shown in the CT scan picture (Figure 1).
At the same time, a repeat of the TORCH titers revealed persisting
antibodies to herpes virus but none to cytomegalovirus and toxoplasmosis.
On the basis of the positive antibody titer to herpes virus and the evidence
of cortical damage on CT scan of the head, it was concluded that B had
been infected with herpes simplex either in the intrauterine period or in
the postnatal period. The lack of clinical evidence of herpes infection in
either parent left the possibility that the infection had probably occurred
in the neonatal period although the exact time of infection could not be
identified in retrospect.
So far as the behavioral symptoms were concerned, based on the his-
tory and the collateral evaluations, B met the criteria for autistic disorder
as defined in the DSM-III-R (American Psychiatric Association [APA],
1987). Also, his aunt and his mother rated him on at least 8 of the 16
criteria required for the diagnosis of autistic disorder based on the DSM-
III-R. These included his qualitative impairment in reciprocal social inter-
action and impairments in language and play even when his mental age
was taken into consideration. Some of his behaviors included marked lack
of awareness of the existence of others, impaired imitation, lack of social
play, gross impairment in the ability to initiate peer interaction, minimal
mode of communication, abnormal nonverbal communication, absence of
imaginative activity, stereotyped movements, and so forth. On the modified
Autism Behavior Checklist (Krug, Arick, & Almond, 1980), his scores were
84 and 96 given by his aunt and mother, respectively, which further
strengthened the diagnosis of autistic disorder. In addition, he suffered
from mental retardation.
S, an 11-year-old boy with severe mental retardation, was referred
for a diagnostic evaluation and management of his behavioral symptoms.
Autism and Herpes Simplex Encephalitis 111
These consisted of frequent temper tantrums, self-injurious behavior, and
long periods of spinning and rocking. His eye contact was minimal and
inappropriate. He had little verbal speech which consisted of grunting
sounds with a tendency to persistent repetition.
He was the product of a full-term normal delivery. The perinatal
period was uncomplicated; however, on the 11th day, mother noted that
he did not wake with normal frequency during the night; also, his oral
intake had markedly decreased. On examination, he was lethargic but
arousable. A spinal tap showed elevated white cells and protein. Skull
X-ray was normal but a CT scan was not done. TORCH screen was
negative. On the 17th day, a small vesicle on the right eyelid was noted,
which was sent for viral culture. Three days later, he was noted to have
tonic-clonic movements of his left arm and leg with deviation of the
eyes to the left. Results of the vesical culture showed herpes simplex.
An EEG showed paroxysmal discharges, maximal on the left side. In
addition, an ophthalmologic consultation revealed bilateral corneal
staining with bilateral uveitis. He later developed seizures and was
treated with anticonvulsants. On the basis of these findings, a diagnosis
of herpes simplex encephalitis was made for which he was started on a
course of arabinoside. Throughout the hospital course, he showed
general improvement in feeding and activity. A repeat spinal tap showed
a decrease in white blood cells and protein, and he was discharged home
on arabinoside eye ointment and phenobarbitone. The discharge diag-
nosis was herpes encephalitis and keratouveitis.
As S grew up, he was noted to be "socially different." He tended to
ignore his surroundings, including the members of his family, and did not
reach out to be picked up. Occasionally, he showed no startle response to
loud noises. He walked at about 12 months of age and initially insisted on
walking only on toes. He began saying single words, such as mom, dad,
and so forth, around 2 years of age, but word usage gradually diminished
to undifferentiated sounds which was his level of communication at the
time of referral. At about the age of 3-4 years, he was place in a program
for mentally retarded children but his behavioral symptoms continued to
increase. Thus, at 7-8 years of age additional services were recommended
prior to the referral to our clinic.
Based on the above findings, a DSM-III-R diagnosis of autistic dis-
order (APA, 1987) with mental retardation, was made. The criteria in favor
of this diagnosis were a marked tack of awareness of the existence of others,
sometimes treating people as inanimate objects; absence of imitation and
lack of eye contact; absence of social play and interaction, even when his
mental retardation was taken into account; presence of stereotyped move-
ments such as spinning and flapping etc; marked abnormalities in the form
112 Ghaziuddln, Tsai, Eilers, and Ghaziuddin
and content of speech; and absence of any social or imaginative play; and
strong reactions to changes in the environment.
These case reports document the occurrence of autistic disorder in
two children with a past history of herpes encephalitis. The exact time of
occurrence of the infection was not clear; it was probably in the in-
trauterine or the early postnatal period. The infection was demonstrated
by the presence of antibody titers and the involvement of the temporal
lobes on the CT scan of the head in the first patient. In the second patient,
involvement of the central nervous system was suggested by altered con-
sciousness, tonic--clonic movements of the left side of the body, electroen-
cephalographic changes, and abnormalities on the spinal tap. This was
strongly suspected to be herpetic in origin because of the positive vesical
culture and the characteristic involvement of the eyes.
Greer, Lyons-Crews, Mauldin, and Brown (1989) recently commented
on the cognitive and behavioral deficits of temporal lobe damage in herpes
encephalitis. They described a 14-year-old boy, who was apparently normal
till the second grade when he was admitted to hospital with herpes simplex
encephalitis. He later developed significant and persistent language, social,
and memory deficits. Herpes virus appears to have a predilection for the
temporal lobes (Greer et al., 1989). Several studies have implicated the
temporal lobes in the pathogenesis of autism (e.g., Heltzer & Griffin, 1981).
Jones and Kerwin (1990), for instance, described a patient with Asperger
syndrome, widely regarded as a mild variant of autism, who showed left
temporal lobe damage on computerized tomography. This does not imply,
however, that temporal lobe pathology is commonly associated with autism.
In fact, a variety of lesions in the brain have been documented as associated
with autism, in particular the cerebellum (see Courchesne, 1991).
Despite the evidence pointing to the involvement of temporal lobes
in herpes encephalitis, no causative role for the virus in the etiology of the
disorder has been established. The report by DeLong et al. (1981) sug-
gested that herpes encephalitis may cause reversible autistic-like symptoms,
whereas Gillberg's (1986) report suggested that herpes simplex virus-in-
duced autism may result even at the age of 14 years. To our knowledge,
no one has yet reported any case of autism with such a late age of onset.
Both cases described in this report had an early history of herpes simplex
encephalitis as well as of autism. This is important because symptoms aris-
ing from the failure of development of temporal lobes in early life may be
different from those arising from late destruction of previously normal
Autism and Herpes Simplex Encephalitis 113
lobes. This report adds further support to the hypothesis that herpes
simplex encephalitis, possibly through the involvement of temporal lobes,
is associated with autism but does not propose a direct cause-and-effect
relationship between the two. A systematic investigation of the cognitive
and behavioral deficits of children with an early history of herpes virus
encephalitis, using a large number of patients, is needed to further explore
the nature of this association.
American Psychiatric Association. (1987). Diagnostic and statistical manual of mental disorders
(3rd ed., rev.). Washington, DC: Author.
Courchesne, E. (1991). Neuroanatomic imaging in autism. Pediatrics, 87 (Suppl. part 2), 781-
DeLong, G. R., Bean, S. C., & Brown, F. R., III. (1981). Acquired reversible autistic syndrome
in acute encephalopathic illness in children. Archives of Neurology, 38, 191, 194.
Gillberg, C. (1986). Brief report: Onset at age 14 of a typical autistic syndrome. A case report
of a girl with herpes simplex encephalitis. Journal of Autism and Developmental Disorders,
16, 369-375.
Greer, M. K., Lyons-Crews, M., Mauldin, L. B., & Brown, F. R., III. (1989). A case study of
the cognitive and behavioral deficits of temporal lobe damage in herpes simplex en-
cephalitis. Journal of Autism and Developmental Disorders, 19, 317-326.
Hetzler, B., & Griffin, J. (1981). Infantile autism and the temporal lobe of the brain. Journal
of Autism and Developmental Disorders, 11, 31%330.
Jones, P. B., & Kerwin, R. W. (1990). Left temporal lobe damage in Asperger's syndrome.
BHtish Journal of Psychiatry, 156, 570-572.
Krug, D. A., Arick, J. R., & Almond, P. J. (1980). Behavior checklist for identifying severely
handicapped individuals with high levels of autistic behavior. Journal of Child Psychology
and Psychiatry, 2L 221-229.
... Since the early '70s, it was discovered that viral infections during pregnancy (Chess, 1971;Deykin and MacMahon, 1979;Ghaziuddin et al., 1992;Yamashita et al., 2003;Zerbo et al., 2015) can create an inflammatory immune environment and trigger the production of maternal cytokines and chemokines, which can exert aberrant effects on fetus development by crossing the placenta and entering in the fetal compartment (Dipasquale et al., 2017;Meltzer and Van de Water, 2017). ...
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with a multifactorial etiology. Latest researches are raising the hypothesis of a link between the onset of the main behavioral symptoms of ASD and the chronic neuroinflammatory condition of the autistic brain; increasing evidence of this connection is shedding light on new possible players in the pathogenesis of ASD. The endocannabinoid system (ECS) has a key role in neurodevelopment as well as in normal inflammatory responses and it is not surprising that many preclinical and clinical studies account for alterations of the endocannabinoid signaling in ASD. These findings lay the foundation for a better understanding of the neurochemical mechanisms underlying ASD and for new therapeutic attempts aimed at exploiting the renowned anti-inflammatory properties of cannabinoids to treat pathologies encompassed in the autistic spectrum. This review discusses the current preclinical and clinical evidence supporting a key role of the ECS in the neuroinflammatory state that characterizes ASD, providing hints to identify new biomarkers in ASD and promising therapies for the future.
... It is also reported that patients that are diagnosed with autism spectrum disorders (ASD) are observed to have HSV-1 infection (Ghaziuddin, Tsai, Eilers, & Ghaziuddin, 1992;Gillberg, 1986). A few reports also confirmed the occurrence of antibodies to HSV in children diagnosed with ASD, but the conflict is observed in final outcomes (Jörgensen, Vejlsgaard Goldschmidt, & Vestergaard, 1982;Mora et al., 2009). ...
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Aim: Several authors have hypothesized an association between congenital viral infections and the onset of autism spectrum disorders (ASD). We aimed to assess the prevalence of congenital varicella zoster virus (VZV) infection in patients with ASD. Patients & methods: Congenital infection by VZV was evaluated in a cohort of 38 children with ASD and in 44 healthy controls. PCR for VZV-DNA performed on dried blood spots collected at birth. Results & conclusion: No VZV infection was detected in both groups. With the limitation of the small sample size of this study, the results are not in favor of a role of VZV in the etiology of ASD.
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Studies are reviewed that support the hypothesis that infantile autism results from a neuropathology of the temporal lobes of the brain. First, there are parallels between symptoms noted in autism and those found in the Kluver-Bucy and amnesic syndromes. Second, there is a similarity between developmental dysphasia and autism. Third, the formation of cross-modal associations may be deficient in autistic children, a symptom resembling aspects of Geschwind's disconnection syndromes. Finally, a large number of organic factors have been associated with the development of autism, some of these having specific implications for temporal lobe involvement. It is concluded that the main autistic symptoms are most consistent with a neurological model involving bilateral dysfunction of the temporal lobes. Individual differences in the extent of bilateral involvement and/or other coexistent neuropathologies could contribute to the heterogeneity of the autistic population.
In the last decade, neuroimaging research has established that neuroanatomical abnormalities often occur in autistic individuals, but no single type of reported abnormality is ubiquitous in autism. Abnormalities in cerebral cortex, thalamus, basal ganglia, and brainstem have been inconsistently found or infrequently reported, but definitive studies remain to be done. Enlargement of cerebrospinal fluid spaces is present in some autistic people.1-10 One of the most frequently found abnormalities in autism with and without mental retardation is a reduction of cerebellar tissue.1,2,4,5,11-22 The reduction in cerebellar tissue appears to be greatest in neocerebellar regions within the vermis and hemispheres.4,11,12,15,16,18-22 The reduction appears to be the result of developmental hypoplasia rather than damage following full development, and so it may serve as a temporal marker to identify the events that damage the developing brain in autism, including other neural structures that may be concomitantly damaged.11 CEREBRAL HEMISPHERES, THALMUS, BASAL GANGLIA, AND LATERAL AND THIRD VENTRICLES Quantitative Imaging Studies Early quantitative computed tomography (CT) studies reported unusual parietooccipital and frontal asymmetries in autistic patients.23 Fourteen recent CT and magnetic resonance (MR) studies involving 283 autistic subjects have quantitated the size, volume, night-left asymmetry, and radio density on signal intensity of either the cerebral hemispheres, thalamus, basal ganglia, limbic structures, lateral ventricles, or third ventricle (Tables 1 and 2). In addition, these structures have been microscopically examined at autopsy in several cases of autism (Table 1). As seen in Tables 1 and 2, in quantitative neuroimaging studies there is no substantial evidence of abnormality in the cerebral hemispheres, corpus callosum, thalamus, basal ganglia, brain volume, lateral ventricles, and third ventricles.
In the search for neurobiological factors in the aetiology of autism, interest has focused on the temporal lobes. We present a case of Asperger's syndrome in an otherwise healthy adult with direct evidence of left temporal lobe damage on computerised tomography.
Herpes simplex viral encephalitis is a fairly common nonepidemic encephalitis which produces severe neurological sequelae in survivors. Most viral infections of the central nervous system produce diffuse damage, but the herpes simplex virus demonstrates a predilection for localization in the temporal and orbitofrontal regions of the brain. This case study illustrates the highly significant language difficulties, marked memory deficits, and propensity for physical aggression following temporal lobe damage brought about by herpes encephalitis, and presents the usefulness of a new diagnostic measure in delineating such a variable cognitive pattern.
In seeking the neurologic substrate of the autistic syndrome of childhood, previous studies have implicated the medial temporal lobe or the ring of mesolimbic cortex located in the mesial frontal and temporal lobes. During an acute encephalopathic illness, a clinical picture developed in three children that was consistent with infantile autism. This development was reversible. It was differentiated from acquired epileptic aphasia, and the language disorder was differentiated aphasia. One child has rises in serum herpes simplex titers, and a computerized tomographic (CT) scan revealed an extensive lesion of the temporal lobes, predominantly on the left. The other two, with similar clinical syndromes, had normal CT scans, and no etiologic agent was defined. These cases are examples of an acquired and reversible autistic syndrome in childhood, emphasizing the clinical similarities to bilateral medial temporal lobe disease as described in man, including the Klüver-Bucy syndrome seen in postencephalitic as well as postsurgical states.
An autism checklist was developed with behaviors selected from a variety of checklists and instruments used to identify autism. Content validity of the behaviors was established, and 3000 of the checklists were sent throughout the United States and Canada to professionals acquainted with handicapped children. 1049 checklists completed on individuals 18 months to 35 years old were returned. A chi-square analysis indicated that 55 of the 57 behaviors listed were significant predictors of autism (P<0.001) when compared to severe mental retardation. A weighted score, determined by statistics (4 indicating the highest predictor of autism, 1 the lowest), was assigned to each other.
Diagnostic and statistical manual of mental disorders
American Psychiatric Association. (1987). Diagnostic and statistical manual of mental disorders (3rd ed., rev.). Washington, DC: Author.