Subacute sclerosing panencephalitis.
ABSTRACT Subacute sclerosing panencephalitis (SSPE) is a progressive neurological disorder of childhood and early adolescence. It is caused by persistent defective measles virus. Brain biopsies or postmortem histopathological examination show evidence of astrogliosis, neuronal loss, degeneration of dendrites, demyelination, neurofibrillary tangles, and infiltration of inflammatory cells. Patients usually have behavioral changes, myoclonus, dementia, visual disturbances, and pyramidal and extrapyramidal signs. The disease has a gradual progressive course leading to death within 1-3 years. The diagnosis is based upon characteristic clinical manifestations, the presence of characteristic periodic EEG discharges, and demonstration of raised antibody titre against measles in the plasma and cerebrospinal fluid. Treatment for SSPE is still undetermined. A combination of oral isoprinosine (Inosiplex) and intraventricular interferon alfa appears to be the best effective treatment. Patients responding to treatment need to receive it life long. Effective immunisation against measles is the only solution presently available to the problem of this dreaded disease.
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ABSTRACT: Viral infections of the central nervous system(CNS) mostly represent clinically important, often life-threatening complications of systemic viral infections. After acute measles, CNS complications may occur early (acute postinfectious measles encephalitis, APME) or after years of viral persistence (subacute sclerosing panencephalitis, SSPE). In spite of a presumably functional cell-mediated immunity and high antiviral antibody titers, an immunological control of the CNS infection is not achieved in patients suffering from SSPE. There is still no specific therapy for acute complications and persistent MV infections of the CNS. Hamsters, rats, and (genetically unmodified and modified) mice have been used as model systems to study mechanisms of MV-induced CNS infections. Functional CD4+ and CD8+ T cells together with IFN-gamma are required to overcome the infection. With the help of recombinant measles viruses and mice expressing endogenous or transgenic receptors, interesting aspects such as receptor-dependent viral spread and viral determinants of virulence have been investigated. However, many questions concerning the lack of efficient immune control in the CNS are still open. Recent research opened new perspectives using specific antivirals such as short interfering RNA (siRNA) or small molecule inhibitors. Inspite of obvious hurdles, these treatments are the most promising approaches to future therapies.Medical Microbiology and Immunology 04/2010; 199(3):261-71. · 3.55 Impact Factor
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ABSTRACT: Mutations of SQSTM1 occur in about10% of patients with Paget's disease of bone (PDB), but it is unclear whether they play a causal role or regulate susceptibility to an environmental trigger. Here we show that mice with a proline to leucine mutation at codon 394 of mouse sqstm1 (P394L), equivalent to the P392L SQSTM1 mutation in humans, develop a bone disorder with remarkable similarity to PDB. The P394L mutant mice developed focal bone lesions with increasing age and by 12 months, 14/18 (77%) heterozygotes and 20/21 (95%) homozygotes had lesions, compared with 0/18 (0%) wild-type littermates (P< 0.001). Lesions predominantly affected the lower limbs in an asymmetric manner and were characterized by focal increases in bone turnover, with increased bone resorption and formation, disruption of the normal bone architecture and accumulation of woven bone. Osteoclasts within lesions were larger and more nucleated than normal and some contained nuclear inclusions similar to those observed in human PDB. Osteoclast precursors from P394L mutant mice had increased sensitivity to RANKL in vitro resulting in the generation of osteoclasts that were larger and more nucleated than those generated from wild-type littermates. There was increased expression of sqstm1, autophagy-related gene 5 (atg5) and light chain 3 gene (lc3) in osteoclast precursors and increased LC3-II protein levels in Bafilomycin-treated osteoclasts from P394L mutant mice compared with wild-type suggesting dysregulation of autophagy and enhanced autophagosome formation. These studies demonstrate that SQSTM1 mutations can cause a PDB-like skeletal disorder in the absence of an additional trigger and provide a new disease model for PDB.Human Molecular Genetics 07/2011; 20(14):2734-44. · 7.69 Impact Factor
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ABSTRACT: Juvenile parkinsonism, with onset prior to age 21 years, is a relatively rare syndrome. It is caused by a group of heterogeneous entities that can present with a clinical picture similar to idiopathic Parkinson's disease or manifest parkinsonism as part of a spectrum of other signs. Diagnostic testing is guided by the presenting symptoms and aimed at uncovering potentially reversible and/or treatable causes. If an underlying condition is found, treatment is tailored accordingly. Otherwise, treatment is symptomatic and relies on medications commonly employed to treat idiopathic Parkinson's disease. Juvenile parkinsonism patients tend to be plagued by treatment-induced complications, so caution must be employed.CNS Drugs 06/2010; 24(6):467-77. · 4.38 Impact Factor
Subacute sclerosing panencephalitis
R K Garg
Postgrad Med J 2002;78:63–70
Subacute sclerosing panencephalitis (SSPE) is a
progressive neurological disorder of childhood and
early adolescence. It is caused by persistent defective
measles virus. Brain biopsies or postmortem
histopathological examination show evidence of
astrogliosis, neuronal loss, degeneration of dendrites,
demyelination, neurofibrillary tangles, and infiltration of
inflammatory cells. Patients usually have behavioral
changes, myoclonus, dementia, visual disturbances, and
pyramidal and extrapyramidal signs. The disease has a
gradual progressive course leading to death within 1-3
years. The diagnosis is based upon characteristic
clinical manifestations, the presence of characteristic
periodic EEG discharges, and demonstration of raised
antibody titre against measles in the plasma and
cerebrospinal fluid. Treatment for SSPE is still
undetermined. A combination of oral isoprinosine
(Inosiplex) and intraventricular interferon alfa appears to
be the best effective treatment. Patients responding to
treatment need to receive it life long. Effective
immunisation against measles is the only solution
presently available to the problem of this dreaded
defective measles virus (table 1). The term
subacute sclerosing panencephalitis has been
used since Greenfield suggested it in 1960 to des-
ignate a condition due to a persistent infection by
a virus involving both grey matter and white
In fact, SSPE had originally been
described as three different neuropathological
entities. In 1933 Dawson, for the first time,
described a child with progressive mental deterio-
ration and involuntary movements who, at
necropsy, was found to have a dominant involve-
ment of grey matter in which neuronal inclusion
bodies were abundant.2He suggested the term
“subacute inclusion body encephalitis”. Later
Pette and Doring (1939) reported a single case of
what they called “nodular panencephalitis”a dis-
ease with equally severe lesions in both grey and
white matter.3Six years later, Van Bogaert drew
attention to the presence of dominant demyelina-
tion and glial proliferation in the white matter
and suggested the term “subacute sclerosing
leukoencephalitis”.4A viral aetiology was sug-
gested by Dawson, but it was Bouteille et al, in
1965, who on electron microscopy demonstrated
ubacute sclerosing panencephalitis (SSPE)
is a serious disorder of the central nervous
system. It is a slow virus infection caused by
the presence of viral structures resembling
measles virus in the brain.5In 1969 measles virus
was actually recovered from the brain of a patient
with SSPE.6Since then a lot of progress has been
made towards understanding of this potentially
lethal disorder.Various treatment modalities have
been tried with little success. In this article all
recent information will be reviewed.
SSPE has been reported from all parts of the
world, but in the West it is considered a rare dis-
ease with fewer than 10 cases per year reported in
the United States.7The reported frequency of
SSPE in the United States was approximately one
per million childhood population from 1960 to
1970.8The incidence declined substantially after
introduction of an effective measles vaccine. The
annual incidence of SSPE is still quite high but
variable among developing countries. Saha et al
reported an annual incidence of 21 per million
population in India,9in comparison with 2.4 per
million population in the Middle East.10 11
Most patients with SSPE have a history of pri-
which is followed, after a latent period of 6–8
years, by the onset of progressive neurological
disorder. Children infected with measles under
the age of 1 year carry a risk of 16 times greater
than those infected at age 5 years or later. Since
the incubation period is typically less than a dec-
ade, SSPE is commonly a disease of childhood. A
higher incidence (male/female ratio 3:1) has been
noted in boys, although primary measles infec-
tion shows no such sex disparity. The incidence is
higher among rural children,children with two or
more siblings, and children with mental retarda-
tion. It is also more common in children with a
lower birth order and in children living in
overcrowded environments.12–15Aaby et al have
suggested that these features (age of exposure,
sex, and geography) are indicative of intensive
measles exposure as a risk factor.16Other factors,
also identified as risk factors for SSPE, may
modify the course of acute measles infection—for
example, a close temporal relationship of measles
with another viral infection such as Epstein-Barr
virus or parainfluenza type-1 virus.
greater than 90% reduction in the incidence of
SSPE in developed nations.17When the disease
occurs in vaccinated children, it is thought to
Abbreviations: EEG, electroencephalogram; ELISA,
enzyme linked immunosorbent assay; MRI, magnetic
resonance imaging; SSPE, subacute sclerosing
. . . . . . . . . . . . . . . . . . . . . . .
Dr Ravindra Kumar Garg,
Department of Neurology,
King George’s Medical
College, Lucknow 226
Submitted 22 May 2001
Accepted 4 September
result from a subclinical measles infection that occurred
before the age of 1 year,when immunisation is usually begun.
There is no evidence to suggest that attenuated vaccine virus
is responsible for sporadic cases of SSPE.1
Measles is caused by an RNA virus,which belongs to the mar-
billivirus subgroup of paramyxoviruses. Despite the long
interval between the acute infection and symptoms of SSPE,
there is evidence that measles virus infection of brain occurs
soon after the acute infection with subsequent spread
throughout the brain.18Measles virus is thought to reach the
brain through infection of cerebral endothelial cells, perhaps
during the acute exanthema of measles when other endothe-
lial cells are also infected.19Access into the brain by circulating
inflammatory cells is also possible.20The measles virus
particles are pleomorphic,spherical structures having a diam-
eter of 100 to 250 nm and consisting of six proteins. The inner
capsid is composed of a coiled helix of RNA and three proteins.
The outer envelope consists of a matrix protein bearing two
types of short surface glycoprotein projections of peplomers.
One peplomer is a conical haemagglutinin (H) and the other
dumbbell shaped fusion (F) protein. The envelope carries pro-
jections of the H and F proteins. The M (matrix) protein sits
within the envelope membrane and can interact with
cytoplasmic domains of H and F proteins. In contrast to mea-
sles virus infection of non-neuronal cells, which is cytopathic
and spreads both by extracellular virus and by cell fusion
resulting in multinucleated syncytia formation,little extracel-
lular infectious virus can be recovered from brains of SSPE
fibroblasts.21High levels of neutralising antibody are present
in the serum and cerebrospinal fluid of SSPE patients; it fur-
ther suggests that extracellular virus might not be responsible
for measles virus spread in the central nervous system.22
Recently, a trans-synaptic transmission of virus has been
Measles virus isolated from specimens of the brains of such
patients may interfere with the replication of the wild type of
measles virus and may have a clonal origin.18 24Numerous
alterations in M protein have been described in SSPE because
of extensive point mutations in viral genome, possibly result-
ing in persistent viral infection.25–30The type II transmembrane
protein H mediates virus cell attachment by binding to the cell
surface protein CD46 (it is a measles virus receptor protein,
which is, in fact, a complement regulating protein with
isoforms present on neurons),31and is an essential cofactor for
fusion.32Changes in the H and F proteins can also be
associated with persistent infection, with M protein remain-
ing relatively unaffected.33 34Since all three proteins are asso-
ciated with viral budding from infected cells and the putative
fusion with uninfected cells, the persistent nature of the
infection is thought to be due to defects in these two
processes.35The exact factors and influences that allow the
measles infection to persist are unclear, but may include sev-
eral immunological factors. For example, in tissue culture, the
addition of antibodies against measles virus may alter the
pattern of viral gene expression.36This observation may
explain why measles infection at a very early age, when
maternal antibodies are still present in the blood of the
patient, carries an increased risk of SSPE.35There is evidence
that persistent measles virus infection can be found through-
out the body in patients with SSPE.37
Recently studies have suggested that apoptosis of various
cell types may contribute to the neuropathogenesis of measles
virus infection in the human central nervous system,either as
a direct effect of viral infection or of cytokine mediated
responses, resulting in oligodendroglial and neuronal cell
death in SSPE.38 39
Brain biopsy performed in the early stages of SSPE shows mild
inflammation of the meninges and brain parenchyma involv-
ing cortical and subcortical grey matter as well as white mat-
ter. There is often evidence of neuronal degeneration, gliosis,
proliferation of astrocytes, perivascular cuffing, lymphocytic
and plasma cell infiltration,and demyelination.Viral infection
of oligodendrocytes may be responsible for extensive demyeli-
nation, which is often present in patients with SSPE.40In later
stages, gross examination of brain may reveal mild to moder-
ate atrophy of the cerebral cortex. Microscopic examination
shows widespread degeneration of neurons and disorganisa-
tion of cortical structures. The parieto-occipital region of the
brain is most severely affected, subsequently; pathological
involvement spreads to the anterior portions of cerebral hemi-
spheres, subcortical structures, brainstem, and spinal cord.
Focal or diffuse perivascular infiltrates of lymphocytes,plasma
cells, and phagocytes are present in the meninges and in the
brain parenchyma. Inclusion bodies are seen within both
nucleus and cytoplasm of neurons and glial cells. Cowdry
type-A inclusion bodies, consisting of homogeneous eosi-
nophilic material, are diffusely seen in neurons and oligoden-
droglia in patients with rapidly progressive fatal disease.
Another Cowdry type-B inclusion bodies, small and multiple,
are almost always present in the brainstem. Subsequent stud-
ies have shown that these nuclear inclusions correspond to
viral particles and contain viral antigens.22Neurofibrillary
tanglesmayalso be seen
oligodendrocytes.41In situ hybridisation methods have shown
that cells containing tangles often contain the viral genome,
suggesting that viral infection causes the formation of
tangles.42Late in the course of disease it may be difficult find
typical areas of inflammation and even inclusion bodies. The
histopathological changes are marked with parenchymal
necrosis and gliosis.43Studies of inflammatory cell infiltrate in
brain tissue from patients with SSPE have shown that the
perivascular cells are predominantly CD4+ T cells,with B cells
seen more frequently in the parenchymal inflammatory
infiltrate.44Little infectious virus can be recovered from the
brain tissue but viral antigen can be identified immunocyto-
chemically and viral genome can be detected by in situ
hybridisation method or by polymerase chain reaction ampli-
fication method.22 45 46
The initial symptoms are usually subtle and include mild
intellectual deterioration and behavioural changes without
any apparent neurological signs or findings. Parents and
Table 1 Various neurological complications of measles
• Post-measles encephalitis
• Measles inclusion body encephalitis
Develops soon after infection, reflect an autoimmune reaction
Develops weeks or months after infection, in patients with defective cell
mediated immunities like HIV infection
Persistent defective measles virus infection
Acute immune reaction
Rare, acute immune reaction
• Subacute sclerosing panencephalitis
• Transverse myelitis
teachers may notice progressive deterioration in scholastic
performance.As disease advances non-specific manifestations
evolve into disturbances in motor function and development
of periodic stereotyped myoclonic jerks. Myoclonic jerks
initially involve the head and subsequently trunk and limbs.
Muscular contraction is followed by 1–2 seconds of relaxation
associated with a decrease in muscle action potential or com-
plete electrical silence. The myoclonic jerks do not interfere
with consciousness. They are exaggerated by excitement and
may disappear during sleep. Myoclonus can present as a diffi-
culty in gait, periodic dropping of the head, and falling. The
myoclonus may not be obvious early in the disease but can be
elicited by the patient standing with feet together and arms
held forward and then watching for periodic dropping of the
head, neck, trunk, or arm; these are often concomitant with
contraction of facial musculature and slow eye blinks.Patients
may, frequently, develop pyramidal and extrapyramidal signs.
Few patients may develop ataxia, dystonia, and dyskinesia.
Generalised tonic-clonic seizures and partial seizures may also
occur.7 9 47Ocular and visual manifestations (box 1) are
reported in 10%–50% of patients, which include cortical
blindness, chorioretinitis, and optic atrophy. Visual symptoms
usually concurrent with neurological manifestations but they
may precede neurological manifestation by several years.48 49
Park et al, in a patient presenting with chorioretinitis, have
demonstrated numerous filamentous, microtubular, and
intranuclear viral inclusions in the nuclear layers of retina
consistent with the measles virus.50
In advanced stages of the disease, patients become quadri-
paretic, spasticity increases, and myoclonus may decrease or
disappear.There is autonomic failure with loss of thermoregu-
lation leading to marked temperature fluctuations. There is
progressive deterioration of sensorium to a comatose state and
ultimately the patient becomes vegetative. Decerebrate and
decorticate rigidity appear, breathing becomes noisy and
irregular. At this stage, patients frequently die due to
Once myoclonus is evident the clinical diagnosis is seldom a
problem. However, subtle behavioural changes at an early
stage of disease are frequently missed by relatives. Many such
patients are often treated by a psychiatrist at this stage. In
some cases myoclonus is not present; atonia may be present
but can be overlooked.11At times SSPE may need to be
distinguished from various neurodegenerative conditions in
which myoclonus and some other progressive neurological
disorder are dominant clinical manifestations (box 2).
Occasionally, patients with SSPE can present with lateralising
neurological signs, partial seizures, or papillo-oedema; these
findings can lead to an erroneous diagnosis of an intracranial
space occupying lesion.52The diagnosis is based upon typical
cerebrospinal fluid changes and a characteristic electroen-
cephalography pattern. The diagnosis of SSPE can be reliably
established if patient fulfils three of the five criteria given by
(A) Cerebrospinal fluid
Cerebrospinal fluid examination is usually normal. Fre-
quently, it is acellular with normal or a mildly raised protein
concentration. The most remarkable feature of the cerebro-
spinal fluid examination is a markedly raised gammaglobulin
level, which is usually greater than 20% of total cerebrospinal
fluid protein. Because of the large increase of intrathecal syn-
thesis of IgG, cerebrospinal fluid IgG concentration ranges
from 10–54 µg/dl compared with 5–10 µg/dl in normal
children.53 54In most cases raised levels of locally synthesised
gammaglobulins indicate either an infection or other type of
inflammatory process within the central nervous system.
When the cerebrospinal fluid is examined by agarose gel elec-
trophoresis or isoelectric focussing, an oligoclonal band of
immunoglobulins are often observed. The oligoclonal band
signifies the production of gammaglobulin of a restricted class
and also implies that there are clones of B cells that have dif-
ferentiated into plasma cells within the central nervous
In patients with SSPE most of IgG in the cerebrospinal fluid
has been shown to be directed against measles virus, and the
oligoclonal bands can be adsorbed by measles virus.56So raised
titres of antimeasles antibodies in the cerebrospinal fluid are
diagnostic of SSPE.Antimeasles antibody titres are also raised
in serum as well. Raised antimeasles antibody titres of 1:256
or greater in serum,and 1:4 or greater in cerebrospinal fluid is
considered diagnostic of SSPE. The characteristic ratio of
Box 1: Ophthalmological abnormalities with SSPE
• Optic atrophy.
• Macular or perimacular chorioretinitis.
• Cortical blindness.
• Anton’s syndrome (cortical blindness with denial of
Table 2 Diagnostic criteria of SSPE47
1. ClinicalProgressive, subacute metal
deterioration with typical signs like
Periodic, stereotyped, high voltage
Raised gammaglobulin or oligoclonal
Raised titre in serum (>1:256)
and/or cerebrospinal fluid (>1:4)
Suggestive of panencephalitis
3. Cerebrospinal fluid
4. Measles antibodies
5. Brain biopsy
Definitive: criteria 5 with three more criteria; probable: three of the
Box 2: Other neurodegenerative myoclonic conditions
A. Progressive myoclonic epilepsies (early
myoclonus and generalised tonic-clonic seizures)
• Unverricht-Lundborg syndrome.
• Myoclonic epilepsy ragged red fibre (MERRF).
• Lafora body disease.
• Neuronal ceroid lipofuscinoses.
• Hereditary dentatorubral- pallidoluysian atrophy.
B. Progressive myoclonic encephalopathies (where
myoclonus is generally over shadowed by other
• GM2 gangliosidosis.
• Non-ketotic hyperglycinaemia.
• Niemann-Pick disease.
• Juvenile Huntington’s disease.
• Alzheimer’s disease.
• Creutzfeldt-Jakob disease.
C. Progressive myoclonic ataxias (seizures are either
absent or late)
• Spinocerebellar degeneration.
• Wilson’s disease.
• Coeliac disease.
• Whipple’s disease.
Subacute sclerosing panencephalitis65
cerebrospinal fluid titre to serum titre ranges from 1:4 to 1:128
(below 200), this ratio is low compared with the normal ratio
(1:200–1:500).Serum cerebrospinal fluid ratios are normal for
other viral antibodies and for albumin, indicating that the
increased amounts of measles antibodies result from synthe-
sis within the central nervous system and that the blood brain
barrier is also normal.57 58Various serological methods used are
complement fixation, haemagglutination inhibition, virus
neutralisation, and enzyme linked immunosorbent assay
(ELISA). ELISA is highly sensitive in detecting measles virus
specific IgG as well as IgM.59
It is possible to make an accurate diagnosis of SSPE by
detecting the measles virus genome in the cerebrospinal fluid.
Measles virus RNA can be detected by reverse transcription
polymerase chain reaction.
Early in the course of the disease, the electroencephalogram
(EEG) may be normal or show only moderate, non-specific
generalised slowing.The typical EEG pattern is usually seen in
myoclonic phase and is virtually diagnostic.The EEG picture is
characterised by periodic complexes consisting of bilaterally
symmetrical, synchronous, high voltage (200–500 mv) bursts
of polyphasic, stereotyped delta waves. Waveforms remain
identical in any given lead.These periodic complexes repeat at
fairly regular 4–10 second intervals and have 1:1 relationship
with myoclonic jerks (fig 1). Frequently there is shortening of
interval between periodic complexes with progression of the
disease.60The periodic complexes of SSPE first appear during
sleep, when they are not accompanied by myoclonic spasms.
Often these periodic complexes can be brought out when the
patient is awake, if diazepam is administered intravenously
during the routine electroencephalographic recording. Late in
the course of disease,the EEG may become increasingly disor-
ganised and show high amplitudes and random dysrhythmic
slowing. In terminal stages the amplitude of waveforms may
In addition to type I periodic electroencephalographic com-
plexes just described, few other forms of periodic complexes
have also been recognised.11These various types of periodic
complexes have been shown to have some association with the
prognosis of the disease. Type II abnormalities are character-
ised by periodic giant delta waves intermixed with rapid
spikes as fast activity. In this pattern of periodic complexes,
EEG background is usually slow. The type III periodic
complexes pattern is characterised by long spike-wave
discharges interrupted by giant delta waves. Yakub demon-
strated that video-split EEG monitoring is a more sensitive
technique for early diagnosis and detection of atonia or
myoclonus,11which are time related to EEG periodic com-
plexes. He further observed that type III periodic complexes
were associated with the worst outcome, while patients with
type II periodic complexes had the best outcome.In this study
outcome was determined by the rate of progression of disease.
Neuroimaging has a limited role in the early diagnosis of
SSPE. Computed tomography of brain is normal in early
stages of disease, in later stages it shows small ventricles and
obliteration of hemispheric sulci and interhemispheric fissure
due to diffuse cerebral oedema. Generalised or focal cerebral
atrophy and ex vacuo ventricular dilatation can be seen after a
very prolonged course, but sometimes, computed tomograms
are normal as late as five years after the onset of the disease.
Low attenuation areas in the cortex and basal ganglion have
also been observed.61
Magnetic resonance imaging (MRI) is more sensitive in
detecting white matter abnormalities. Early changes are ill
defined high signal intensity areas on T2-weighted images (fig
2), more commonly seen in the occipital subcortical white
matter than in the frontal region.In most of the cases the grey
matter is spared even in advanced clinical and MRI stages.
However, Tuncay et al observed early involvement of grey
matter.62In this study,early lesions were dominantly involving
grey matter and subcortical white matter. These lesions were
asymmetrical and had a predilection for the posterior parts of
cerebral hemispheres (fig 3). Later, high signal changes in
deep white matter and severe cerebral atrophy were observed.
Parenchymal lesions were significantly correlated with the
duration of disease. Though mass effect and contrast
enhancement of lesions are not usual feature of SSPE, some
authors have reported mild mass effect and contrast enhance-
ment in few patients, especially in the early stages of the
Brismar et al have developed a staging system based on
neuroimaging findings for SSPE that reflects the degree of
white matter changes and atrophy.64Though, the radiological
staging of this SSPE is not always exactly correlated with its
clinical manifestations, even then, sequential MRI may be
useful for following the course of the disease.64
(D) Brain biopsy
Brain biopsy is seldom required to establish the diagnosis of
SSPE. When performed, it will often show the typical
histopathological findings described earlier. Examination of
frozen sections by immunofluorescence technique may
demonstrate the presence of measles virus antigens. Reverse
transcription polymerase chain reaction can detect various
regions of the measles virus RNA in frozen and even paraffin
embedded brain tissue specimens of patients with SSPE.
Nucleic acid hybridisation techniques have also been used to
demonstrate the measles virus genome.
SSPE IN ADULTS
SSPE, being a disorder of childhood and adolescence, may not
be readily recognised when a patient presents later in the life.
Approximately 50 cases of SSPE have been reported in those
over 18 years of age.Patients with adult onset SSPE present at
a mean age of 25.4 years (range 20–35 years). A higher
proportion of adult patients have either negative or an
undocumented history of prior measles infection in child-
hood. Visual manifestations, especially cortical blindness, are
the commonest mode of clinical presentation. The disease
apparently has a more aggressive course in adults and disease
is rapidly fatal in majority of the patients.65In a preliminary
study, Gokcil et al observed that treatment with oral isoprino-
sine plus interferon alfa is effective for adult onset SSPE.66
SSPE AND PREGNANCY
SSPE can rapidly progress during pregnancy. It has been sug-
gested that the relative older age of presentation, and unusu-
ally rapid neurological deterioration, are partially due to
immunological and hormonal alterations of pregnancy. In
several reported cases, the disease was associated with the
death of the child in utero, or in the immediate peripartum
a healthy infant by caesarean section in the 28th gestational
week.68Serum analysis of the infant revealed slowly diminish-
ing IgG measles virus antibody titres. After six months, the
maternal measles antibodies were no longer detectable in the
child’s serum. Cortical blindness has been reported as the
most common presenting manifestation of SSPE even in
pregnancy.Characteristic myoclonus may not be apparent;the
clinical picture resembles that of eclampsia (see case report).
ACUTE FULMINANT SSPE
Most of the patients with SSPE survive for 1–3 years after
diagnosis, with a mean survival of about 18 months. In acute
fulminant SSPE the disease rapidly evolves leading to death
within three months of the diagnosis.In the series of Risk and
Haddad, approximately 10% of patients had such a fulminant
course.51In rapidly evolving SSPE various stages of disease
cannot be recognised. The exact mechanism producing an
acute fulminant course is not known. Several factors such as
exposure to measles at an early age, viral virulence, impaired
host defence mechanisms, and concurrent infections with
other viruses, have been suggested as responsible for produc-
ing a rapid course of the disease.69–71
No adequate therapy is currently available for the treatment of
SSPE. Observations of some non-randomised trials suggest
that certain antiviral drugs and immunomodulator agents can
prolong life if long term treatment is given (box 3). The issue
of the success of treatment is frequently complicated by an
extremely variable natural course as a few patients may have
very prolonged spontaneous remissions.51 72 73
(A) Isoprinosine (Inosiplex)
Isoprinosine is an antiviral drug, which acts by activating the
body’s immunological system against measles virus.This drug
increases the number of CD4+ lymphocytes,augment natural
killer cells function, potentiates the function of interferons,
interleukin-2.Treatment with isoprinosine remains controver-
sial because of conflicting results.74Few uncontrolled studies
have reported that isoprinosine prolongs the survival and pro-
duces clinical improvement in some patients.75 76Nunes et al
increasesthe productionof interleukin-1and
pattern with slow wave complexes
recurring at intervals of 4–6 seconds.
EEG showing a periodic
demyelination in an 8 year old boy with SSPE.
T2-weighted MRI scan showing diffuse white matter
occipital regions (see case report).
T2-weighted MRI scan showing hyperintensity in the both
Box 3: Drugs used in the treatment of SSPE
• Interferon alfa.
• Interferon beta.
• Isoprinosine (Inosiplex).
• Intravenous immunoglobulin.
Combination of intraventricular interferon alfa plus oral
isoprinosine is the best effective treatment available.
Subacute sclerosing panencephalitis67
observed good results combining trihexyphenidyl and isopri-
nosine in controlling myoclonus refractory to sodium
valproate.77This drug is administered in daily doses of 100
mg/kg/day and without major side effects. Recurrence of
symptoms has been reported frequently; treatment needs to
the continued even after apparent remission, possibly for life.
Uric acid levels should be monitored,because isoprinosine can
cause hyperuricaemia and renal stones.35
(B) Interferon alfa
The pathophysiology of natural remissions and relapses in
SSPE is unknown. The stable state may depend on a balance
between viral replication and the body’s immune response, as
the state of the immune system has a role in producing remis-
sion. The cerebrospinal fluid interferon levels are found to be
low in patients with SSPE. Exogenous administration of
interferons possibly suppresses viral replication and augments
the immune system of the body. Interferon alfa was initially
given by the intravenous and intrathecal routes with
questionable effect. Panitch et al were the first to use the drug
by the intraventricular route with the help of an Ommaya res-
ervoir planted subcutaneously and a catheter placed in the
frontal horn of the right lateral ventricle under general
anaesthesia.78In this series, the authors found improvement
in all the three patients; two of them, however, relapsed after
completion of treatment.
The treatment regimen consists of six week courses of
natural interferon alfa, started as 100 000 units/m2of body
surface area and subsequently increased to 1 million units/m2
body surface area per day given for five days a week. Courses
are repeated up to six times, at 2–6 months intervals.
At present, combined treatment of oral isoprinosine and
intraventricular interferon alfa appears to be a more effective
treatment for SSPE.79–81Gokcil et al, in their recent article,
reviewed 53 patients who had been treated by intraventricular
interferon alfa with or without oral isoprinosine; 30 (59%) of
improvement.66They also reported better efficacy with a com-
bination of oral isoprinosine and intraventricular interferon
alfa even in adult patients with SSPE. Cerebrospinal fluid
measles antibody, and renal and hepatic functions, need to be
followed up during treatment. The laboratory end point of
treatment is the eradication of detectable measles antibody
from the cerebrospinal fluid. Systemic (subcutaneous) inter-
feron alfa, in daily doses of up 5 million units, has been used
with intrathecal interferon alfa simultaneously to treat
peripheral reservoirs of measles virus and lymphoid and glan-
Side effects of interferon alfa include fever, lethargy,
anorexia, and chemical meningitis. At times, treatment needs
to be temporarily discontinued because of an increase in liver
enzyme levels. Although, most of the patients treated with
intraventricular interferon and oral isoprinosine have not
shown side effects of a serious nature, prolonged repeated
treatments do carry risks of developing meningitis, interferon
alfa induced encephalopathy, and upper and lower motor
The antiviral drug ribavirin has been tested in animal models
of SSPE and was found effective. Recently, this drug has been
used in patients with SSPE. Tomoda et al used a combined
treatment of high dose intraventricular interferon alfa along
with intravenous ribavirin in two non-responding cases of
SSPE.83In both the patients no further progression was noted.
In one patient the hypertonicity, bladder incontinence, and
dysphagia improved three months after starting the combina-
tion treatment. Similar, efficacy of high doses of ribavirin and
intraventricular interferon alfa has been noted by Hosoya et al
in two patients.84
(D) Other drugs used for the treatment of SSPE
Amantadine is an anti-RNA agent that retards the maturation
of viruses by not allowing them to replicate. This drug is very
well absorbed from the gastrointestinal tract, and crosses the
blood brain barrier,but the response to treatment in few cases
of SSPE is disappointing.85Cimetidine, an H2-receptor antago-
nist, was used in the treatment of SSPE. Anlar et al did not
observe any worsening in seven cimetidine treated patients
during a study period of two months, whereas seven patients
in the placebo group deteriorated significantly.86In isolated
reports interferon beta plus Inosiplex,87intravenous immuno-
globulin,88plasmapharesis,and corticosteroids have been tried
with variable results. These forms of treatment need more
evaluation before they can be considered for regular manage-
ment of SSPE.
(E) Symptomatic treatment
Good general nursing care is the most important aspect in the
management of SSPE. Anticonvulsants, like sodium valproate
and clonazepam, are helpful in controlling the myoclonus. If
spasticity is marked and affecting nursing care, baclofen and
other antispasticity drugs may be used.
SSPE is a progressive disorder and death usually occurs in 1–3
years. Apart from this classical course, a chronic very slowly
progressive form, a very fulminant form leading to death in
weeks, and a “stuttering” form of disease with remission and
relapses, have been observed. Approximately 5% of the
patients can have substantial spontaneous long term improve-
ment. Santoshkumar and Radhakrishnan reported a women
with SSPE with almost 17 months of progressive neurological
deterioration to the extent that she was completely bedridden
and incapable of self care.73She experienced a substantial
spontaneous improvement; during the next seven years the
patient became ambulatory and was independent for her daily
activities. Grunewald et al recently reported a 35 year old
patient who remained in remission for almost 25 years.72
Spontaneous remission may occur during any stage of the
disease and last for a variable period of time before eventual
relapse occurs.Santoshkumar and Radhakrishnan have noted
the factors that may predict spontaneous remission and
prolonged survival in SSPE.73The age of onset of SSPE less
than 12 years, disappearance of periodic complexes, the
tendency for normalisation of the background of follow up
EEGs, and a progressive increase in measles antibody titres in
cerebrospinal fluid are the factors that appear to be associated
with favourable outcome in SSPE. However, these observa-
tions need further evaluation. The exact mechanisms respon-
sible for spontaneous improvement are not known.
SSPE is a slow virus infection caused by aberrant measles
virus.This disease is still common in developing and underde-
veloped countries. One of the most important limitations in
treatment of SSPE is difficulty in recognising early manifesta-
tions of disease,when the inflammatory changes are,possibly,
still reversible. Diagnosis is especially problematic in adult
patients with SSPE; differential diagnoses are also different.
Treatments available are very costly and are available only at a
few centres in the world. Moreover, these treatments are not
curative and only help in buying time for these patients. The
families of patients with SSPE have a lot of physical, psycho-
logical, and economical stresses to endure. A great deal of
external support is required for these suffering families to
cope with these stresses. At present effective measles vaccina-
tion seems to be the only solution to problem of this dreaded
neurological disorder (box 4).
AN ADULT PATIENT WITH SSPE: CASE REPORT
A 33 year old previously healthy woman was admitted to the
obstetrics ward complaining of blurring of vision during the
24th week of her first pregnancy. In the next three days
behavioural changes and disorientation were observed,
progressing to a drowsy state. She was transferred to the neu-
rology ward. The patient’s history was not suggestive of mea-
sles infection during early childhood.
General physical examination revealed pedal oedema and
hypertension (160/94 mm Hg); a gynaecological examination
disclosed a viable fetus consistent with gestational age. Her
neurological evaluation revealed that the patient was drowsy,
disoriented to time, place, and person, unable to answer sim-
ple questions properly, or count to 10. The patient was unable
to perceive even hand movements or a beam of light.
were of normal size and direct and consensual light reflexes
were normal. Other cranial nerves were normal. Her gait was
mildly ataxic,she had generalised hypertonia,all deep tendon
reflexes were exaggerated, and both plantars were extensor.
There was no sign of meningeal irritation.
Laboratory workup did not reveal any abnormality in blood
and urine. Cranial computed tomography was normal. A
possibility of eclamptic encephalopathy was considered and
she was treated accordingly. She did not improve and became
deeply comatose and developed left sided hemiparesis in the
next few days.On careful observation the patient had periodic
stereotyped left sided hemimyoclonic jerks involving her left
shoulder, arm, and leg; she also had subtle hemifacial jerks
with simultaneous closure of both the eyes.Brainstem reflexes
were normal. She had frequent bouts of hyperpyrexia, tachy-
cardia,hypertension,and irregular breathing.Electroencepha-
lography was performed and revealed diffuse symmetrical
slow wave activity. MRI revealed bilateral a symmetrical
hyperintensity in T2-weighted images involving both occipital
lobes (fig 3). Cerebrospinal fluid examination showed protein
0.6 g/l, glucose 3.2 mmol/l, and 3–4 cells, all mononuclear.
Both serum and cerebrospinal fluid were strongly positive for
antimeasles IgG antibodies.An assay of antimeasles IgM anti-
body assay by ELISA was also positive (value 1.857; positive
>0.404, Novum kit).
In the next eight weeks the patient’s condition remained
unchanged.In the 32nd gestational week,spontaneous labour
began and a dead fetus was delivered per vagina. Intrauterine
death of the fetus was noted just before delivery. The patient’s
condition remained unchanged on symptomatic treatment.
Eventually, decerebrate rigidity appeared, her autonomic
instability worsened, she developed severe pulmonary infec-
tion, and died.
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Box 4: Summary points
• SSPE is a slow virus disease caused by persistent mutant
measles virus infection.
• It affects children, it is uncommon after 18 years of age,
and the disease has a more aggressive course in adults.
• The disease is very rare in developed countries, but is still
common in developing and poor countries.
• Measles vaccine is not associated with an increased risk of
• A defective expression of either the matrix, the fusion, or the
haemagglutinin proteins of measles virus is responsible for
viral persistence in brain cells and its escape by immune
• Pathological changes involve both white and grey matter.
Neurons and oligodendrocytes contain eosinophilic inclu-
sion bodies. Marked gliosis occurs in brain along with
perivascular lymphocytes and plasma cell cuffing.
• The disease starts with subtle mental deterioration followed
by seizures, dementia, ataxia, stereotyped myoclonus, and
visual disturbances, usually leading to a decorticated state,
and death after 1–3 years.
• The EEG is characteristic and reveals periodic, stereotyped
high voltage discharges occurring every few seconds.
• Cerebrospinal fluid shows raised gammaglobulin with IgG
• Raised measles antibody titre in cerebrospinal fluid and
serum is diagnostic.
• No curative treatment is available. Combination of
intraventricular interferon plus oral isoprinosine is effective
in halting the progression of the disease.
• Relapse is usually a problem even after good initial results.
• An effective measles vaccination is the only solution
available to this fatal disease.
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