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Journal of Pediatric Neurology, Vol. 2, No. 3, July-Sept, 2004, pp. 121-124
EDITORIAL
Some aspects about the clinical and pathogenetic characteristics
of the presumed persistent
measles infections: SSPE and MINE
Paul Richard Dyken
Institute for Research in Childhood
Neurodegenerative
Diseases, Mobile, Alabama, U.S.A.
Correspondence: Paul
Richard Dyken, M.D., MLA, BS. Director of the USA/World
SSPE
Registry since 1980 Offices
located in Institute for Research in Childhood Neurodegenerative Diseases 283
Wingfield Drive Mobile, Alabama,
36607, U.S.A. Tel: 1 251-478-6424, fax:
1 251-476-8277. E-mail:
pdyken@aol.com
Received: June 4, 2004. Accepted: June
5, 2004.
Code Number: pn04025
It is well known that Subacute Sclerosing PanEncephalitis (SSPE) is due
to an aborted form of the wild measles virus which results from a faulty immune
reaction of the human body (1). The pathogenesis of this particular slow virus
disease begins when an immunologically incompetent individual is attacked by
the virus and is thereby unable to launch a full immune response, allowing
parts of the aborted virus to harbor in the central nervous system. As is typical
of all slow virus diseases, the aborted virus remains quiescent for a number
of months to years only to break out to produce the neurological and ophthalmic
symptoms of SSPE. The major components of the disease results from the progressive
deterioration of
the hosts nervous system, first starting with sometimes subtle and nonspecific
higher cortical symptoms such as abnormal behavior, learning disabilities, single
epileptic seizures and visual disturbances which formulate in months into a characteristic
clinical period called stage I. Then the near diagnostic period of repetitive
massive myoclonic jerks, beginning mental failure, motor disability in its early
stages and immobility are seen which constitutes what has been called stage II.
This stage is also progressive and in a few months the involuntary movements
disappear and the dementia worsens. Stage III is a nonambulatory state of clinical
affairs with ultimately complete motor failure, loss of the previously seen involuntarymovements
and severe dementia. Stage IV represents a severe vegetative stage which plateaus
to severe neurological disability of at least 90% or death. This typical clinical
progression is closely
correlated with a rostral-caudal neural destruction. Most of what is thought
to be clinically typical about this disease, is a manifestation of the neuropathological
and clinical happenings which occur in stage II. This stage represents the
classical subacute progressive clinical picture of what I call the subacute
progressive form (SPF) of SSPE. There are other more atypical forms of the
disease. The classical or SPF form and presentation represents only about 75%
of the cases of SSPE which has been reported to the USA/World SSPE Registry
since 1989.
In the 1960s, in the heyday of SSPE and natural measles
in the USA, about 60 cases of SSPE were reported per year whereas there were
over 500,000 cases of natural measles infections reported, giving a ratio of
1 case of SSPE to 10,000 cases of measles exanthema. After the first national
immunization program against measles was initiated in this country in the early
1960s, measles began to drop in frequency. There is usually a 7 to 10 year latent
or interval period in the development of SSPE after the first contact with the
wild measles virus. After correcting for the interval period, SSPE was also shown
to drop in frequency (2). Because of these phenomena, other countries began to
develop national immunization programs, and they soon found, in most instances,
that mass
immunization produced similar dramatic results.
In the USA, it is generally believed that SSPE is a figment disease of
antiquity. It is true that only 80 cases of SSPE has been reported to the Registry
by USA physicians in the last 15 years. Yet, because of the diseases well
worked out mechanisms of etiology, pathogenesis and near elimination, understanding
is of
great importance, to USA pediatric neurologists and other health care workers.
This understanding is even of greater importance to the health care workers in
developing and developed nations outside of the USA where the incidence of this
disease is at present
greater than in the USA. It is particularly important because, in spite of a
declining incidence due to effective national measles immunization programs,
these mechanisms of disease may be an explanation for entirely new or unrecognized
disorders with similar pathogenesis and etiology. In other words, other diseases
of similar nature, such as the progressive childhood neurodegenerative diseases,
specifically and generally, may also be caused by similar mechanisms. It goes
without saying that the childhood neurodegenerative diseases of unknown or uncertain
cause represent a large portion of any practice of pediatric neurology in both
the developed and the developing nations of the world.
The relationship of SSPE to persistent measles infection is well established,
but the second syndrome discussed in this paper is not. The syndrome (3) that
I call MINE (Measles Induced Neuroautistic Encephalopathy) is properly categorized
as a childhood neurodegenerative disease but with uncertain etiology. In the
last few years, this syndrome has been shown to be related to the live measles
vaccination, if not proven to be caused by it. The syndrome was first recognized
in the late 1990s by Wakefield
et al. (4), a gastroenterologist in Britain. What was initially described was
a syndrome consisting of chronic recurrent enterocolitic symptoms starting in
young children. These patients also seemed to have chronic neurological symptoms
which were considered to be autistic in nature. Wakefield et al. (4) considered
the syndrome to be related to the immunization of infants with live-attenuated
measles vaccine. Over the following years, approximately 2000 children with variants
of this autistic-colitic syndrome were reported. Because of my interests in SSPE,
I was
able to carefully evaluate 12 of these patients, sharing the patients clinical
information and full laboratory data with the Solicitor firm (5) which handled
the rather large class action suit resulting from these reports.
Altogether, the key features of this syndrome were not always associated
with both enterocolitis and pervasive developmental disorder. In the review
of 12 patients, two major varieties of the syndrome were identified, one with
pure neuroautistic features (n=4) and the second with additional chronic recurrent
enterocolitis (n=8). In addition to at least two of the four classic symptoms
of autism (i.e. defects of intellect, behavior, social adjustment and language
development), the children who were evaluated had other neurological symptoms
such as epileptic seizures, micrencephaly, dysgenetic features and rarely progressive
mental retardation which would more
rightly be considered to be frank dementia. Both of these variations, that is,
the pure neuroautistic and the neuroautistic/enterocolitic patients seemed to
be induced by the live-attenuated measles virus vaccination, after a latency
period of several months. In each patient, regardless of type, measles virus
genes were found in the tissues studied, such as blood, gut and spinal fluid.
In those with enough antigen identified, the genes were found to arise from the
vaccine-related live-attenuated measles virus and not from the usual wild measles
virus which is associated with measles exanthema. The two viruses have the same
antigenic make-up. The proteins are the same but one of them is wildly alive
and the other is alive but attenuated.
These
are the constellation of features
which make up the MINE syndrome
-
All the patients have had a live-attenuated measles vaccination between
12 and 21 months of age; at this time none of the children showed any neuroautistic
features or preliminary signs of enterocolitis;
-
All of the patients developed neurological-behavioral symptoms many months
after the initial measles immunization (i.e. an interval period is characteristic
of all slow viral diseases) which for the most part
were autistic in nature;
-
Prior to vaccination there was a history of severe, recurrent infection
or frank allergy, suggesting that each patient had some sort of pre-existing
immunological problem, prior to the immunization and the
neurological symptoms;
-
There was a history in all
patients of some sort of familial suspected dysgenetic or inherited problem
such as schizophrenia, 21 trisomy or birth
defects; one patient, a girl, had the clinical characteristics of Rett
syndrome (6) and gene analysis showed a defect in the location of the MECP2
gene (7)
which has been associated with this syndrome; this was the only female
in the series and the only one who had micrencephaly, all others had larger
than the
mean for-age-and-gender head sizes on routine measurement of the occipito-frontal
circumference; the gene analysis features in the female suggested a defective
gene mechanism which might predispose a susceptible patient to the effects
of the live-attenuated measles virus in spite of the fact that the clinical
effects of both Rett and MINE are quite similar; none of the males showed
any evidence for a known gene-related disorder;
-
Only 67% (n=8) of the population studied had a history of chronic, recurrent
enterocolitis in addition to their neuroautistic symptoms;
-
92% (n=11) of the 12 patients were male, an interesting fact since male
predominance also features the cousin disease, SSPE; all of the males showed
normal male chromosome karyotypes and all had head measurements which were
larger but less than 2 standard deviation above the mean for occipito-frontal
circumferences for their age and gender;
-
Recurrent, severe epileptic seizures and a developmental dysphasia occurred
in one of the patients and he was considered to have the Landau-Kleffner syndrome
(7), and in others both epileptic seizures and language and speech problems
were frequently present;
-
Although all the patients
had at least two of the four characteristics of the autistic spectral syndrome,
some had only mild forms such as in two
brothers who were considered to have Aspergers syndrome (9); some had
the full extent of the autistic syndromes including progressive loss
of cognitive
skills emblematic of Heller infantile dementia (10); most had all the
characteristics of the children Kanner (11) described in 1943;
-
All of the patients studied had measles genes identified by molecular genetic
studies from the enterocolon, blood, and spinal fluid, although none of them
had had clinical symptoms suggesting that they ever had contact with the measles
virus except through the live-attenuated measles immunization which each of
them received; furthermore in situations where there was enough measles antigen
present more sophisticated molecular genetics were performed which identified
the vaccine-related form of the measles virus gene distinguished from the more
virulent wild measles virus gene;
-
None of the children had brain postmortem studies or had received brain
biopsies.
An opinion can be given that MINE develops in the same fashion as does
SSPE. Although the syndromes are different the etiology and the pathogenesis
are similar. For both syndromes, two factors are required: an immature or
defective immune system which is unable to inactivate the attacking measles
virus whether
it is the wild or the live-attenuated form. In the situation of SSPE the
full antigenic wild virus is only partially inactivated, allowing the remaining,
aborted form to escape and harbor within the large neurons of the cerebral
cortex where they are sheltered and persist, to grow. Then, in years, the
persistent
virus breaks out, devastatingly inflames and destroys in a rostral-caudal
fashion other neurons, endothelial cells, glial elements and cellular processes.
It
is presumed that in SSPE, susceptible patients have had contact with the
wild measles virus before immunization if they are ever immunized. Yet, this
is
the reason the incidence of both measles exanthema and SSPE are dropping
with the institution of effective national immunization programs. All data
that
has been accumulated suggests that measles immunization does not cause SSPE,
but the opposite occurs. In the situation of MINE, the child has not been
exposed to the wild measles virus yet but instead is immunized with a much
less virulent
but antigenically comparable live-attenuated measles virus. Most individuals
become immune to the wild measles virus when the live-attenuated one is given
them, but a relatively small portion of them react in a different fashion.
This small portion is
judged to be 1 in 10,000; based on the fact that in Britain about 20,000,000
children have been immunized in the last 20 years and about 2,000 have developed
the MINE syndrome. Those who develop MINE do not completely neutralize the live-attenuated
virus and an aborted form of the virus ensues. The aborted form escapes and harbors
in the nervous system in particularly susceptible areas such as the hippocampus,
limbic system and older portions of the cerebral cortex where the blood-brain
barrier is less protective, especially in the temporal-limbic areas where dysfunction
may be important in the formation of the clinical features of the various autistic
syndromes. Opposed to the lengthy
period of quiescence seen in SSPE when the escape of the aborted, partially
damaged wild measles virus acts upon the larger neurons residing in neocortical
areas, the interval period in MINE is only a matter of months. It would appear
that break-out is not as devastating as in SSPE and the clinical symptoms after
the short interval may be more due to chronic sapping of the selected host
cells metabolic activity. Although this pathogenesis explains the neuroautistic
symptoms of MINE, it does not explain the often associated enterocolonic symptomatology.
Since vaccine-related measles genes are found in the enterocolon literally years
after the immunization of an affected individual, it is probable, as opposed
to the situation in SSPE, that some of the aborted live-attenuated virus harbors
in gut as well, which periodically breaks out rather than harbor for long periods
of time as occurs in SSPE.
There are many questions which are still unanswered about SSPE and MINE.
Yet, there is still enough known to identify the syndromes as real ones.
Certainly the recognition of the MINE syndrome represent at least one explanation
for
the increased incidence of the infantile pervasive disorders in the so-called
developed nations of the world, but also the increase in learning disabilities,
behavioral problems, seizure disorders and neurodegenerative diseases seen
in the practices of most pediatric neurologists
of the world.
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neurologic syndrome. J Child Neurol 2004; 19: 296 (Abstract).
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Copyright 2004 - the Society of Pediatric Science, Yüzüncü Yil
University, Faculty of Medicine, Department of Pediatric Neurology, Van, Turkey
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