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INDIAN PEDIATRICS VOLUME 35-APRIL 1998

Personal Practice

Subacute Sclerosing order. Children infected with measles


Panencephalitis under age of 1 year carry a risk of 16 times
greater than those infected at age 5 years or
later(4,5). A higher incidence (male/female
R.K. Garg ratio 3:1) has been noted in boys. The inci-
B. Karak dence is higher among rural children than
A.M. Sharma city children, children with two or more
siblings, children of lower socio-economic
status, and mentally retarded children.
Subacute scelorsing panencephalitis Neither the age of exposure to measles, nor
(SSPE) is a common and serious disease of severity of infection seem to affect the age
the central nervous system (CNS), and is of onset of SSPE or course of illness. Wide-
caused by a mutant measles virus. Measles spread immunization has produced greater
virus is an RNA virus which belongs to than 90% reduction in the incidence of
the morbillivirus subgroup of paramyxo- SSPE in developed nations (6). In vaccinat-
viruses. SSPE is an example of CNS disease ed children a prolongation of age of onset
caused by aberrant viral gene expression and latency of infection had been observed.
and persistent viral infection of neural There is no evidence to suggest that attenu-
cells. ated vaccine virus is responsible for spo-
radic cases of SSPE(l).
Epidemiology
Pathogenesis
In western part of world it is considered
a rare disease, with less than 10 cases SSPE virus is distinguished from the
per year reported in the United States(l). wild type of measles virus in that there
The incidence has declined substantially appears to be a defect in assembly of the
since introduction of an effective measles virus within the nervous system, and
vaccine. The annual incidence of SSPE is which is related to an abnormality of
quite high but variable among developing matrix of 'M' protein of the virus. These
countries. Saha et al.(2) reported an annual conclusions are based on the studies that
incidence rate of 21 per million population show that the matrix protein is the only
in India, in comparison to 2.4 per million structural protein which is undetected in
population in Middle East(3). Most patient brain cells from patients with SSPE, and on
give history of primary measles infection at observation of a selective decrease in anti-
an early age (< 2 years), which is followed bodies to the matrix protein in these
after a latent period of 6 to 8 years by the patients. Studies on SSPE cell lines further
onset of a progressive neurological dis- suggest that the M protein may be synthe-
sized but fails to accumulate and there may
From the Division of Neurology, Institute of Medical be defective translation of matrix messen-
Sciences, Banaras Hindu University, 221 005. ger RNA. Thus, an immune response can
Reprint requests: Dr. R.K. Garg, Division of be made against the viral hemagglutination
Neurology, Institute of Medical Sciences, resulting in very high levels of neutralizing
Banaras Hindu University, Varanasi 221 005. antibody, and yet the antibody is ineffec-

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PERSONAL PRACTICE

tive in eradicating the virus. So, M-protein the meninges and in the brain parenchyma.
is necessary for correct assembly of pro- Inclusion bodies are seen within both
geny virus at the surface of infected cells, nucleus and cytoplasm of neurons and glial
mutations in this protein lead to an anti- cells. Cowdry type-A inclusion bodies con-
genically distinct form, that can no longer sisting of homogenous eosinophilic materi-
bind to viral nucleocapsid that initiate al, are diffusely seen in neurons and oligo-
virus maturation. The absence of function- dendroglia in patients with rapidly pro-
ally intact, budding virus particle, results gressive fatal disease. Another, Cowdry
in intracellular accumulation of incomplete type-B inclusion bodies are small and mul-
measles virus in brain cells(7-12). tiple, and are almost always present in
brainstem. These later type of inclusions
In addition, modulation of measles anti-
are less often seen. Late in the course of the
gen on the surface of infected cells by
disease it may be difficult to find typical
antimeasles antibody has been described,
and this modulation might make the cell areas of inflammation, and the main
vulnerable to attack by the immune system histopathological changes are marked with
parenchymal necrosis and gliosis(1,14,15).
and could alter expression of virus within
the cell. It is also possible that antigenic Measles viral antigens can be demon-
challenge of a second infection could alter strated by labeled antibody technique with-
the dormant state of SSPE virus and result in the inclusions as well in cells without in-
in disease expression. Sero-epidemiological clusions. Data from several studies suggest
data suggest that an exposure to another that the endothelial cells in the brain are
virus, such as Epstein-Barr virus or influen- frequently infected during acute fatal mea-
za type I virus may transform the measles sles. This site of infection may provide a
virus into a defective virus(13,14). portal of entry for virus in persons who
subsequently develop SSPE or measles in-
Pathology clusion body encephalitis(16,17).
Brain biopsy performed in the early Clinical Features and Classification
stages of SSPE shows mild inflammation of
the meninges and brain parenchyma in- The clinical features and time course of
volving cortical and subcortical grey matter SSPE are highly variable. The initial symp-
as well as white matter, with cuffs of plas- toms are subtle and include intellectual de-
ma cells and lymphocytes around blood terioration and behavioral changes without
vessels. In the subsequent stage, gross neurological signs or findings. As disease
examination of brain may reveal mild progresses non-specific manifestations give
to moderate atrophy of cerebral cortex. way to marked disturbance in motor func-
Microscopic examination shows wide- tion and the development of periodic
spread degeneration of neurons and dis- myoclonic jerks. Myoclonic jerks initially
organization in the cortex. Parieto-occipital involve the head and subsequently trunk
region of cerebral hemisphere is most and limbs. Muscular contraction is fol-
severely affected; subsequently, it spreads lowed by 1 to 2 seconds of relaxation
to the anterior portions of cerebral hemi- associated with a decrease in muscle action
sphere, the subcortical structrures, brain- potential or complete electrical silence. The
stem and spinal cord. Focal or diffuse myoclonic jerks do not interfere with con-
perivascular infiltrates of lymphocytes, sciousness. They are exaggerated by excite-
plasma cells and phagocytes are present in ment, and may disappear during sleep.

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INDIAN PEDIATRICS VOLUME 35-APRIL 1998

Initially they are infrequent and might be logical signs, partial seizures, or papill-
regarded as stumbling or clumsiness. At edema, these findings can lead to an erro-
this stage seizures may occur. Macular neous diagnosis of an intracranial space-
chorioretinitis is seen in up to 50% of cases. occupying,lesion.
Retinopathy and optic atrophy may devel-
op in addition to cerebellar ataxia and Cerebrospinal Fluid (CSF)
dystonia. Few patients may present with The CSF pattern may be diagnostic.
cortical blindness. The late stage of the dis- The fluid is usually cellular with a normal
ease is marked by stupor and coma, auto- or mildly elevated protein level and a
nomic failure with loss of thermoregulation markedly elevated gamma-globulin level
leading to temperature fluctuations and (comprising at least 20% of total CSF
disturbed sweating. In late stages, protein)(21,22).
myoclonic jerks diminish in intensity and
eventually disappear. In majority of cases Electroencephalography (EEG)
death occurs between 1 and 3 years after
onset of symptoms. Ten per cent of the pa- Early in the course of disease, the EEG
tients have a fulminant course, dying with- may be normal or show only moderate,
in months, and 10 per cent survive for 4-10 non-specific slowing. The typical EEG pat-
years with extended periods of stabiliza- tern is usually seen in myoclonic phase and
tion. Spontaneous improvement may also is diagnostic. EEG picture is characterized
occur during any of the stage of the disease by periodic complexes consisting of bi-
and may last for a variable period of time laterally symmetrical, synchronous, high-
before eventual relapse occurs(5,18,19). voltage (200-500mv) bursts of polyphasic
stereotyped delta waves. They remain
Staging of SSPE is done according to identical in any given lead. These periodic
modified Jabbour classification(20), as fol- complexes repeat at fairly regular 4 to 10
lows: Stage-I: mental and behavioral second intervals and have a 1 :1 relation-
changes, forgetfulness, irritability and leth- ship with myocolonic jerks (Fig. 1). Earlier
argy; Stage-II: mycolonic jerks, dyskinesia, each complex lasts between 0.5 and 2 sec-
choreoathetosis, ataxia; Stage-Ill: decer- onds, may recur as infrequently as every 5
brate rigidity and decorticate rigidity; and minutes. These complexes may be present
Stage-IV: severe loss of all cortical function, only during sleep, and may be elicited
flexion posturing of limbs and mutism. by afferent stimuli. Later in the course
of illness, the EEG becomes increasingly
Diagnosis disorganized and shows high-amplitude,
Despite characteristic signs and symp- random dysrhytmic slowing, in terminal
toms early diagnosis of SSPE is not always stages the amplitude may fall(23-25).
easy, early detection of myoclonus is im- In addition to type-I EEG abnormalities
portant to make reasonable diagnosis. Sub- just described, few other types of EEG ab-
tle behavioral changes are easily missed normalities have also been recognized
by the relatives and these patients are often which have some effect on prognosis of the
treated by a psychiatrist at this stage. In disease. Type-II abnormalities are charac-
some cases myoclonus is not present in the terized by periodic giant delta waves inter-
early stages, only atonia may be present mixed with rapid spikes as fast activity.
and can be overlooked. Occasionally, the EEG background is usually slow. Type-Ill
patient can demonstrate lateralizing neuro- EEG pattern in patients of SSPE is charac-

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PERSONAL PRACTICE

terized by long spike-wave discharges be seen after a prolonged course, but CT


interrupted by giant delta waves(24,26). scans are normal sometimes as late as 5
Yaqub(24) recently demonstrated that vid- years after onset of the disease(27,28). Low
eo-split electroencephalographic monitor- attenuation areas in the basal ganglion
ing is a more sensitive technique for early have also been observed(19). MR is better
diagnosis and detection of atonia or in visualizing white matter lesions. White
myoclonus time-related to EEG periodic matter involvement is usually multifocal
complexes. He further observed that type- and more prominent in parieto-occipital
Ill EEG discharges were related to worst region and is better seen in T2-weighted
outcome while patients with type-II had images. This finding is non-specific and
the best outcome. In this study outcome of relatively poor diagnostic value in
was determined by the progression of the SSPE(29). Single photon emission comput-
disease. ed tomography (SPECT) may reveal hypo-
perfusion of cerebral blood flow in the oc-
Neuroimaging
cipital areas and other affected parts of the
Computed tomography (CT) and mag- brain as early as stage-I of SSPE.
netic resonance (MR) imaging have limited
Brain Biopsy
role in the early diagnosis of SSPE. CT scan
of brain is normal in early stages of disease, Brain biopsy or autopsy reveals
in later stages it shows small ventricles and perivascular inflammation, neuronal loss,
obliteration of hemispheric sulci and inter- astrocytosis and gliosis and intranuclear
hemispheric fissure due to diffuse cerebral inclusions in neurons or glial cells. Brain
edema. Generalized or focal cerebral atro- biopsy is rarely required for establishing a
phy and ex-vacuo ventricular dilation can proper diagnosis(16).

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INDIAN PEDIATRICS VOLUME 35-APRIL 1998

Virological Studies polymerase-chain reaction (PCR) amplfica-


tion method(1).
Antibodies against measles virus can be
demonstrated in both serum and CSF by a Diagnostic Criteria
variety of techniques. Usually, the ratio of SSPE can be diagnosed if the patient
antibody content in ,CSF compared to se- fulfills three of the following five criteria:
rum is disproportionately high. When the (a) typical clinical presentation; (b) typical
CSF is examined by electrophoresis or iso- electroencephalographic changes with ste-
electric focusing oligoclonal band of immu- reotyped periodic complexes; (c) typical
noglobulins are often observed. IgG and histo-pathological finding in brain biopsy
IgM antibodies to measles virus are not or autopsy; (d) elevated CSF globulin
normally found in unconcentrated CSF. In levels, greater than 20% of total CSF pro-
patients of SSPE these antibodies make up tein; and (e) elevated CSF measles antibody
most of the immunoglobulins of CSF, and titers of 1/4 or more by hemagglutination
can be detected in dilutions of 1: 4 or more. inhibition method, or 1/20 or more by
Various serological methods used are ELISA(25).
complement fixation, hemagglutination Treatment
inhibition (HAI), enzyme linked immuno-
sorbent assay (ELISA)(30-32) and virus No adequate therapy is currently avail-
neutralization(14). Quantitation of measles able for the patients of SSPE. Observations
virus-specific antibodies reveals that the of some non-randomized studies suggest
majority of IgG antibodies in CSF are that certain immuno-modulator anti-viral
measles specific, with the specific antibody agents can prolong life if long-term treat-
index for measles virus usually greater ment is given. Issue of treatment is further
than ten(22). In rare instances measles anti- complicated by extremely variable natural
bodies may be undetectable, but become course as few patients may have spontane-
positive on subsequent study(33). Anti- ous prolonged remission(34).
body titers may fluctuate during natural Isoprinosine (Inosiplex)
course of illness, and during therapy. In a
study by Saha et al.(2), antibody titer (HAI Isoprinosine is an anti-viral drug which
method) ranged from 2 to 32 in CSF and in acts by activating body's immunological
sera from 8 to 2048. The normal ratio of system against measles virus. This drug
titer in serum to titer in CSF is reduced increase the number of CD4+lymphocytes,
(below 200) for measles antibodies, where- augment natural killer (NK) cell functions,
as serum-CSF ratios are normal for other potentiate interferons and increase the pro-
viral antibodies and for albumin, indicating duction of interleukin-1 and interleukin-2.
that increased amounts of measles antibod- Treatment with isoprinosine (Inosiplex) re-
ies in CSF of children with SSPE result mains controversial but has been reported
from synthesis within the nervous system to prolong survival and produce clinical
and the blood brain barrier is normal. improvement in some patients. This drug is
recommended in daily dose of 100 mg/kg/
Measles virus can also be cultivated day and without major side effects(l,14).
from brain tissue using special cultivation Nunes et al. (35) observed good results com-
technique. Viral antigen can be identified bining trihexyphenidyl and isoprinosine in
immunocytochemically and viral genome controlling myoclonus refractory to sodium
can be detected by in situ hybridization or valproate.

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PERSONAL PRACTICE

-interferons observe any worsening in cimetidine-treat-


ed group during the study period, where-
The pathophysiology of natural remiss-
as placebo group deteriorated significantly.
ions and relapses in SSPE in unknown.
The stable state may depend on a balance Symptomatic Treatment
between viral replication and body's im-
The good general nursing care is the
mune response, as state of immune system
most important aspect in the management
possibly has a role in remissions. The CSF
of SSPE. Anticonvulsants, sodium valpro-
interferon levels are low in these patients.
ate and clonazepam, are helpful in control-
Exogenous interferons suppress replication
ling the myoclonus. If spasticity is marked,
of virus and also influence immune system.
beclofen and other antispastic drugs may
Intravenous administration of a-interferon
be tried.
has not proved useful because of poor
penetration of blood brain barrier. The Conclusion
modest improvement with intraventricular
and intrathecal routes (6 million unit/ One of the most important limitation in
dose/week) of administration have been treatment of SSPE is the inability to detect
observed in small number of patients(36). early manifestations of the disease, when
There are early relapses after discontinuing the inflammatory changes are possibly still
interferon therapy. A prolonged therapy is reversible. There is a need for more aware-
needed for sustained response(37). Several ness of the disease amongst primary care
authors have reported combined use of a- physicians and pediatricians. Home care
interferon plus isoprinosine. In a recent system for these handicapped children is
study, Anlar et al.(38) observed a higher very important and meaningful to increase
survival rate in the 22 patients after long- "quality of life" in them and their families.
term (56-108 months) treatment with intra- Their families have to have a lot of physi-
ventricular alpha-interferon and inosiplex cal, psychological and economical stress to
as compared to those who did not receive endure. A great deal of external support is
a-interferon regimen. However, this com- needed for these suffering families to cope
bination did not affect oligoclonal bands up these stresses.
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