14698749, 2019, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/dmcn.14166 by Nat Prov Indonesia, Wiley Online Library on [03/02/2023].

See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY INVITED REVIEW

Subacute sclerosing panencephalitis: clinical phenotype,

epidemiology, and preventive interventions
MOHAMMED MEKKI 1 | BRIAN ELEY 2 | DIANA HARDIE 3,4 | JO M WILMSHURST 1
1 Paediatric Neurology Division, Department of Paediatrics and Child Health, Neuroscience Institute, Red Cross War Memorial Children’s Hospital, University of Cape
Town, Cape Town; 2 Paediatric Infectious Diseases Unit, Department of Paediatrics and Child Health, Faculty of Health Sciences, Red Cross War Memorial Children’s
Hospital, University of Cape Town, Cape Town; 3 Division of Medical Virology, Department of Clinical Laboratory Sciences, Faculty of Health Sciences, University of
Cape Town, Cape Town; 4 National Health Laboratory Service, Cape Town, South Africa.
Correspondence to Jo M Wilmshurst at Paediatric Neurology Division, Department of Paediatrics and Child Health, Neuroscience Institute, Red Cross War Memorial Children’s Hospital,
University of Cape Town, Cape Town 7700, South Africa. E-mail: jo.wilmshurst@uct.ac.za

Subacute sclerosing panencephalitis (SSPE) is a preventable condition reported in 6.5 to 11

PUBLICATION DATA per 100 000 cases of measles, and highest in children who contracted measles infection when
Accepted for publication 7th December they were less than 5 years of age. Children residing in areas with poor vaccination coverage
2018. and high prevalence of human immunodeficiency virus are at increased risk of developing
Published online 25th January 2019. SSPE. SSPE is life-threatening in most affected children. This report documents current data
relating to the clinical phenotype, epidemiology, and understanding of SSPE, inclusive of pre-
ABBREVIATIONS ventive interventions. While improvements in disease progression with immunomodulation
CSF Cerebrospinal fluid may occur, overall there is no cure. Most therapies focus on supportive needs. Seizures and
HIV Human immunodeficiency virus abnormal movements may respond to carbamazepine. Many countries advocate policies to
IFN Interferon enhance vaccination coverage. Effective preventive health care programmes, assurance of
SSPE Subacute sclerosing parental perceptions, and crisis support for unprecedented events obstructing effective pri-
panencephalitis mary health care are needed. Until measles is eradicated worldwide, children in all regions
remain at risk.

Despite the availability of widespread and effective vaccina-
tion programmes, measles remains a major cause of child-
hood mortality worldwide. The Global Vaccine Action Plan
aims to achieve elimination in at least five World Health
Organization regions by 2020.1 However, the highly infec-
tious nature of the measles virus, suboptimal vaccination
coverage, and international travel challenge this intention.
Until the disease is eradicated globally, children in all
regions of the world remain at risk. The legacy of measles
virus goes beyond the immediate complications. Subacute
sclerosing panencephalitis (SSPE) is a progressive and fatal
neurodegenerative encephalitis caused by the persistence of
the measles virus in the central nervous system (CNS). This
review describes the current understanding of SSPE, includ-
ing diagnosis, treatment, clinical course, and outcome.
HISTORY
Worldwide epidemiological studies established the associa-
tion between the incidence of clinical measles and the subse-
quent occurrence of SSPE.1,2 The significant morbidity and
mortality from measles infection led to a worldwide measles
immunization programme that started in 1963 and resulted
in a dramatic reduction in the occurrence of measles.2
EPIDEMIOLOGY
The incidence of SSPE is inversely related to measles
vaccination coverage.2 This is illustrated in high-income
countries, where the prevalence of SSPE has steadily
declined since the introduction of the vaccine in the
1960s. In regions where measles epidemics occur, cases
of SSPE are more prevalent in the following 4 to
10 years (latency period).2 The global incidence of SSPE
is not known, but a study from the USA extrapolated
data and concluded a risk of 6.5 to 11 cases of SSPE for
each 100 000 cases of measles.3 A regional population
study documented for children from Germany who were
younger than 5 years of age when they contracted
measles to have a 1 in 1700 to 1 in 3300 risk of subse-
quently developing SSPE; for those who contracted
measles younger than 3 years of age, the risk was 1.7-
fold higher.4 A study from California found that the inci-
dence of SSPE was 1 in 1367 for children younger than
5 years of age and 1 in 607 for those younger than
1 year of age when they had contracted measles.5 Table I
shows the incidence data of SSPE in various countries.
The high incidence of SSPE in Papua New Guinea is
related to low rates of protective immunity (seroconver-
sion) to measles in children, despite them receiving one
or both doses of the measles vaccine before 1 year of
age, in addition to measles outbreaks occurring every 3
to 4 years, and cold-chain problems.6 Similarly high inci-
dence rates are reported in India, which are assumed to
be related to crowded living environments and poor vac-
cination coverage.2,7

© 2019 Mac Keith Press DOI: 10.1111/dmcn.14166 1139


Table I: Incidence of subacute sclerosing panencephalitis in different
countries
When data
Region were collected
North America
Canada50 1997–2000
West Asia
Turkey27 2002–2004
East Asia
Japan51 2012
India7 2001
Oceania
Papua New Guinea6 2007–2009
RISK FACTORS
As illustrated above, the earlier the age of measles infec-
tion, the greater the risk of developing SSPE.4,5 Risk fac-
tors that make young children more vulnerable to
contracting measles and putting them at risk of developing
SSPE include poor socio-economic status, low level of par-
ental education, failure to receive the measles vaccination,
a higher number of siblings, and a higher birth order (i.e.
a higher chance of being exposed to somebody with
measles before the age of 5y).8
Class 3 studies (observational case series) suggest that
individuals with human immunodeficiency virus (HIV)
infection, or those who are born to mothers with HIV
infection, might be at higher risk of developing SSPE after
measles infection.9,10 These children seem to have a more
aggressive course, with an earlier onset of SSPE.10 Chil-
dren born to HIV-infected mothers have lower antibody
levels, leading to earlier susceptibility to measles virus
infection.11 An autopsy study from Abidjan, Ivory Coast,
examined the distribution of measles virus in the CNS of
18 measles-infected children (13 HIV seropositive and five
HIV seronegative) aged 5 months to 8 years who predomi-
nantly died from respiratory complications. Of the HIV-
seropositive children, measles virus antigen and genome
were isolated in the CNS from three. None of the five
HIV-seronegative children were affected.12 At our centre
in South Africa, of seven children who have presented with
SSPE since 2015, three were HIV-infected and two were
HIV-exposed but uninfected.9 All the children had con-
tracted measles in infancy (median age of onset 4y 5mo).
As such, the disease manifested predominantly in children
who were infected with or exposed to HIV. Although pop-
ulation-based South African estimates of SSPE are lacking,
these cases support an additional risk from HIV infection
or exposure to the subsequent evolution of SSPE in chil-
dren infected with measles early in life.9
REASONS FOR POOR VACCINATION
Global measles immunization programmes have focused on
increasing routine vaccine coverage in young children
through the World Health Organization’s Expanded Pro-
gramme on Immunization.1 However, measles remains a
1140 Developmental Medicine & Child Neurology 2019, 61: 1139–1144
14698749, 2019, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/dmcn.14166 by Nat Prov Indonesia, Wiley Online Library on [03/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
What this paper adds
• Measles contracted under 5 years of age has highest risk of developing
subacute sclerosing panencephalitis (SSPE).
Incidence • Children with, or exposed to, human immunodeficiency virus infection, who
per million contract measles may be at increased risk of SSPE.
0.06 leading cause of vaccine-preventable death in children
younger than 5 years of age in many regions of the world,
2.2 particularly sub-Saharan Africa and South East Asia.13
0.3 In southern African countries, the principal cause of
21 these outbreaks is failure to vaccinate eligible persons,
despite routine immunization services and supplemental
29
immunization activities. In this region the situation is com-
pounded by complacency in measles vaccination efforts, as
well as nomadic lifestyles, and some apostolic religious
communities that are reluctant to vaccinate.14,15 Parental
knowledge and attitudes also affect the vaccination of chil-
dren.14,15 Socio-economic crises, such as the conflict in
Syria, and other diseases (e.g. the Ebola virus outbreak in
West Africa) which then dominate health care are addi-
tional causes.16
Although the number of measles deaths has declined
progressively since 2000, during 2016 to 2017, the number
of reported acute measles cases increased by 31% globally,
as documented by the World Health Organization.17 Five
of the six World Health Organization regions have
reported increased cases, with The Americas, Eastern
Mediterranean Region, and Europe experiencing the big-
gest increases in cases in 2017.17
Layperson and professional perceptions that vaccinations
contain dangerous chemicals, or cause autism spectrum
disorder, have negatively affected parental attitudes toward
paediatric immunizations, particularly the vaccination
against measles, mumps, and rubella.18 There is no scien-
tific evidence to support an association between autism
spectrum disorder and the measles, mumps, and rubella
vaccine.18 Many countries advocate policies to enhance
vaccination coverage, including a mandatory vaccine record
for public school entry (North America, Slovenia, France,
Italy),19 signatures from caregivers who decline vaccination
(Latvia),20 mass school vaccination (Malaysia),20 and link-
ing vaccination to social grants and benefits (Australia).21
Despite these initiatives in Italy, the law compelling chil-
dren to have 10 vaccinations in order to enrol at state
schools, which came into effect in March 2018, was abol-
ished in August 2018 when the Five Star Movement
pushed legislation through the Italian Senate.22
Virology
Although measles is a monotypic virus, 22 genotypes of
wild-type virus are recognized; many genotypes are associ-
ated with endemic circulation of measles virus in certain
geographical regions or are documented regarding an out-
break, or epidemic, in an area.23 In the seven southern
African countries’ epidemic of 2009 to 2010, the measles
virus genotype detected was predominantly B3.14 The sub-
sequent case series of children who developed SSPE
 14698749, 2019, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/dmcn.14166 by Nat Prov Indonesia, Wiley Online Library on [03/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
showed, for the first time, that genotype B3 is linked to Table II: The clinical manifestations of stage 1–4 subacute sclerosing
this disease.9 Analyses of measles virus sequences in brain panencephalitis52 and electroencephalography correlate32
tissue samples obtained from children with SSPE have
identified only wild-type measles virus, and the virus geno- Clinical features EEG correlate
types identified are consistent with the genotype of measles Stage 1 Overall: personality changes, Background (normal),
virus that circulated in the area where the patients lived failure in school, strange periodic complexes
behaviour and anterior delta ++
and to which the affected children were exposed before the
1A Mild mental and/or
onset of SSPE.23 Genetic studies support epidemiological behavioural changes
evidence that the measles vaccine virus does not cause 1B Marked mental changes
Stage 2 Overall: massive, repetitive, Background (normal),
SSPE.2 In cases of SSPE that developed in children or
and frequent myoclonic periodic complexes
adults with no history of prior measles infection, but who jerks, seizures, and in most cases and
did have a history of vaccination against measles virus, dementia anterior delta in
2A Myoclonus and/or other most cases +++
analysis of measles virus sequences confirmed the presence
involuntary movements and Focal slowing in
of the wild-type genome, indicating that the individuals epileptic seizures about 50% cases
had suffered an undiagnosed measles virus infection.3 2B Focal deficits (speech From stages 2A to 2C
disorders, loss of vision, increasing
Recent evidence suggests that mutations that alter viral
and limb weakness) epileptogenic
envelope glycoproteins, in particular the F protein, are 2C Marked involuntary activity, less
responsible for neurovirulence.24,25 Measles virus is movements, severe evident by
myoclonus, or focal deficits stage 2D
believed to enter the brain during the primary infection.
enough to impair full daily
By remaining in cells, the virus evades the host’s immune activities
response.24,25 Strong antiviral immune responses in the 2D Akinetic mutism, vegetative
state, decerebrated,
host are evidenced by high levels of specific antibody in
decorticated rigidity, or
blood and cerebrospinal fluid (CSF) and are a characteris- coma
tic feature of this condition.23 Stage 3 Rigidity, extrapyramidal Background (abnormal),
symptoms, and progressive periodic complexes
unresponsiveness and anterior delta +
Clinical course of SSPE Stage 4 Coma, vegetative state, Background (abnormal),
SSPE typically begins with behavioural and intellectual dis- autonomic failure, and periodic complexes and
akinetic mutism anterior delta
ability followed by paroxysmal movements, myoclonic jerks,
and/or negative myoclonia (head drops).23,26–28 Periodic +, less common; ++, more common; +++, much more common; ,
myoclonus often leads to difficulty in walking and repeated absent.
falls. Typically, the myoclonic jerks are generalized and
involve the head, trunk, and limbs, they do not interfere
with consciousness, and are exacerbated by the state of CSF analysis and serology
excitement.26 Clinical manifestations occur, on average, Enzyme-linked immunosorbent assay of CSF for measles
6 years after measles virus infection and progressive neuro- virus IgG has a sensitivity of 100%, a specificity of 93.3%,
logical deterioration with death generally occuring within and a positive predictive value of 100% in individuals with
4 years (range 45d–12y; Table II).27 Other complications, SSPE.33 Polymerase chain reaction for measles is typically
reported in case reports and series, include ophthalmologi- negative in CSF. This is due to the absence of a typical pro-
cal abnormalities (optic atrophy) and pyramidal signs.26 ductive infection in the brain with extracellular release of
virus. If this screen is the only CSF investigation, the results
DIAGNOSIS can be misleading and result in delays in diagnostic confir-
Diagnosis is principally suspected based on clinical presen- mation.9 CSF oligoclonal bands are usually positive, but this
tation, and confirmed by immunological evidence of raised finding is not specific to SSPE.34 Although not specific, the
CSF measles virus antibodies in a clinically compatible set- CSF IgG index is very high in SSPE, higher than in multi-
ting.29,30 Tissue analysis from brain biopsy is seldom now ple sclerosis which is often cited as a prototype of intrathe-
used. Ancillary investigations include electroencephalogra- cal IgG synthesis.29 The antibody index that measures the
phy (EEG) and magnetic resonance imaging (MRI).31,32 measles-specific IgG fraction in CSF provides additional
Neither of these tests is specific or sensitive to the diagno- specificity but is mainly a research tool.29
sis of SSPE and may correlate poorly with the clinical
stage of the disease. Dyken’s modified criteria, often the EEG
diagnostic tool used in medical reports, includes clinical Periodic complexes found in 65% to 83% of individuals
history, elevated CSF measles antibody titres as major with SSPE are stereotyped, bilaterally synchronous, and
markers, typical EEG, increased CSF immunoglobulin G symmetrical (Fig. 1).35,36 Once the disease progresses, the
(IgG), brain biopsy, and special molecular diagnostic tests electrical complexes become periodic and are less likely to
to identify measles virus mutated genome as minor mark- be elicited by external sensory stimuli, unless these stimuli
ers.28 Typically, diagnosis of SSPE requires two major and are given in a way that triggers a volitional response from
one minor criteria.28 the individual.28 The background activity becomes

Review 1141
 14698749, 2019, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/dmcn.14166 by Nat Prov Indonesia, Wiley Online Library on [03/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
SENS 10:25:56[0000:01:17] [SENS 10 HF 15 TC 0.3 CAL 50] Date: 2014/04/29
100 uV Patt. Common Ave ACFilt. ON. Refer. OFF Reset OFF
x1

1 Fp2-F4

2 F4-C4

3 C4-P4

4 P4-O2

5 Fp1-F3

6 F3-C3

7 C3-P3

8 P3-O1

9 Fp2-F8

10 F8-T4

11 T4-T6

12 T6-O2

13 Fp1-F7

Fp1 Fp2
14 F7-T3
13 5 1 9

14 6 2 10
15 T3-T5
15 7 3 11

16 8 4 12
16 T5-O1

M Common Ave
Scale 83% 0 5 10 s

Figure 1: The typical electroencephalography (EEG) appearance of the periodic paroxysmal bursts of activity on a suppressed background in a child
with subacute sclerosing panencephalitis from our centre. At the time of the study this female patient was 7 years of age, infected with human immun-
odeficiency virus, on antiretroviral therapy, and clinically correlated with stage 2 at the time of the EEG epoch.

abnormal and has low amplitude as the disease stages
increase.32 Injection of diazepam during the EEG study
increases the sensitivity of detecting the periodic com-
plexes.37 The study by Demir et al.36 comprehensively
reports on the EEG evolution in SSPE, the diversity of
potential EEG findings, and the overlap in features with
epilepsy syndromes such as Lennox–Gastaut syndrome,
electrical status epilepticus during slow-wave sleep, and
epileptic spasms. The paper highlights that SSPE should
remain as a diagnostic differential in these cases.36
Neuroimaging
Although imaging is not diagnostic in SSPE, the radiolo-
gist has a unique opportunity to highlight SSPE as a dif-
ferential diagnosis based on supportive MRI findings.31,38
SSPE should remain in the differential list of childhood
demyelinating diseases, even when the presentation is unu-
sual.31 However, a normal initial brain MRI does not
exclude the condition.31 Abnormal MRI findings are signif-
icantly more frequent in the later disease stages, with the
thalamus, corpus callosum, and basal ganglia usually
affected after the cortex has already shown signs of
disease.38 MRI changes may progress despite clinical stabi-
lization and the severity of MRI changes may not correlate
well with the clinical findings.26
Brain biopsy
Brain histopathology, while considered a definitive investi-
gation is invasive, and so may be better restricted to excep-
tional cases where the diagnosis is suspected and the CSF
studies are inconclusive.30
TREATMENT AND OUTCOMES
SSPE is usually a life-threatening disease with no cure,
despite the development of antiviral and immunomodula-
tor drugs.39 Generally, death occurs within 4 years of
onset, although with targeted therapy survival can extend
beyond this.27 In a survey of 500 patients with SSPE
from seven countries, physicians reported that isopri-
nosine monotherapy and isoprinosine plus ribavirin were
the standard treatments, but also intravenous
immunoglobulin therapy, intrathecal a-interferon (a-IFN),
and amantadine therapy.30 A multicenter non-randomized
study of 98 patients with SSPE treated with isoprinosine

1142 Developmental Medicine & Child Neurology 2019, 61: 1139–1144


reported increased survival for over 2 years in the inter-
vention group.40 Another international multicenter ran-
domized unblinded trial placed 121 patients with SSPE
into two groups, those on isoprinosine and those on
intraventricular a-IFN.41 The estimated satisfactory out-
comes, defined as stabilization and improvement with the
two agents, were 34% and 35% respectively. The benefit,
although relatively modest, is above the 5% to 10%
spontaneous remission rate reported in the literature.
There were no statistically significant differences in mor-
tality between the group treated with isoprinosine alone
versus the combined isoprinosine and intraventricular
a-IFN in the same study. The remission and/or improve-
ment rate in 18 children with SSPE treated with oral
isoprinosine (100mg/kg/d) and intraventricular a-IFN 2b
was found to be 44%.
Another case–control study compared the outcome of 19
children who were treated with a combination of oral isopri-
nosine (100mg/kg/d), subcutaneous a-IFN 2a (10mU/m2/
three times weekly), and oral lamivudine (10mg/kg/d) at least
for 6 months and a control group who did not receive antivi-
ral therapy (n=13 children), the remission rate was 36.8%
versus 0% in the control group.42 b-IFN has also been used
to treat SSPE, with reports suggesting similar benefits, espe-
cially when delivered subcutaneously three times weekly com-
bined with isoprinosine.43 The antiviral agent, ribavirin, is
associated with partial clinical improvement. A recent study
supports clinical benefit through the maintenance of CSF
levels with a subcutaneous continuous infusion mode of
delivery.44 Overall there is a marginal improvement in clinical
course with the interventions listed above but no definitive
cure. Further class 1 studies (randomized controlled trials)
are needed to establish optimal regimens.39
ALTERNATIVE INTERVENTIONS FOR SSPE
Intervention with amantadine, cimetidine, intravenous
immunoglobulin, plasmapheresis, and corticosteroids have
variable results.28 Fusion inhibitor peptides that bind to
the viral fusion proteins are in development as potential
therapeutic agents.24 These forms of treatment need more
evaluation before they can be considered in the routine
management of SSPE.
Symptomatic treatment
Collaboration with a palliative care team, parent support
group, and psychiatrists is important. Parents are at risk of
additional emotional stress from the realization that their
child contracted an avoidable disease. Most of these par-
ents have initial reactions of guilt or denial.
There should be early monitoring of, and intervention
for, feeding and sleeping challenges. Antispasticity medica-
tions such as baclofen should be commenced as needed.28
The antiepileptic drugs sodium valproate and clonazepam
can help control the myoclonus. Benzodiazepines such as
intravenous diazepam and midazolam are also used. Leve-
tiracetam is reported to have mild improvement in myoclo-
nus.45 Improvement in myoclonus with carbamazepine is
14698749, 2019, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/dmcn.14166 by Nat Prov Indonesia, Wiley Online Library on [03/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
also reported.9,46 This agent is considered a first-line inter-
vention for the symptomatic treatment of seizures in
patients with SSPE in countries such as Turkey and South
Africa.9,46 Although carbamazepine is known to exacerbate
a variety of seizures, including myoclonic seizures, the
exact mechanism of action of carbamazepine in SSPE is
not known. The aetiology for the myoclonus is thought to
be due to basal ganglia involvement of the virus, whose
pathways are not governed by alterations in sodium chan-
nels.47 Children coinfected with HIV and SSPE are chal-
lenging to manage, as the cross-drug interactions between
carbamazepine and antiretroviral agents such as protease
inhibitors or non-nucleoside reverse transcriptase inhibitors
may result in virological failure, thus requiring careful
monitoring of HIV viral titres and carbamazepine levels.48
This situation is largely relevant to sub-Saharan Africa
where 83% of children with HIV infection reside and data
to support development of recommendations to optimize
care in this setting are limited.49
CONCLUSIONS
SSPE is an avoidable disorder. The medical professional
should be the child’s advocate, ensuring that parents are
fully informed and comfortable with the factual evidence
surrounding the safety of vaccinations. Health professionals
should strongly endorse compliance with vaccination pro-
grammes to eradicate diseases from polio to measles, which
no child should be infected with in the current age. Health
authorities must be proactive when interruptions or gaps
in childhood immunization programmes become apparent.
SSPE can be challenging to recognize, but with the
recent global increase in acute cases of incident measles
clinicians should have a heightened awareness of the
potential manifestations in affected children.17 Early diag-
nosis is promoted by this adequate awareness and vigilance
leading to investigations that are both specific and sensitive
for the condition.
Therapies specific to the condition are limited to
immunomodulation and antiviral agents with marginal effec-
tiveness. Collaborative multicentre trials are needed to eval-
uate the efficacy of new and existing treatment modalities.
Limitation of resources is a significant challenge in the
care of these children, as management usually requires
expertise of a multidisciplinary team as well as costly medi-
cations and procedures. Optimal antiepileptic drugs with
which to control myoclonus needs further exploration,
especially in the setting where drug-to-drug cross-interac-
tions are a risk, such as in immunocompromised children
who are also receiving antiretroviral therapy.
Countries that advocate policies to enhance vaccination
coverage should be emulated. Until measles is eradicated
worldwide, children in all regions of the world remain at
risk of developing SSPE.
A CK N O W L E D G E M E N T S
The authors have stated that they had no interests that might be
perceived as posing a conflict or bias.
Review 1143

REFERENCES
1. World Health Organization. Measles vaccines: WHO
position paper, April 2017 – recommendations. Vaccine.
pii: S0264-410X(17)30974-X. https://doi.org/10.1016/
j.vaccine.2017.07.066. [Epub ahead of print].
2. Campbell H, Andrews N, Brown KE, Miller E. Review
of the effect of measles vaccination on the epidemiology
of SSPE. Int J Epidemiol 2007; 36: 1334–48.
3. Bellini WJ, Rota JS, Lowe LE, et al. Subacute scleros-
ing panencephalitis: more cases of this fatal disease are
prevented by measles immunization than was previously
recognized. J Infect Dis 2005; 192: 1686–93.
4. Sch€
onberger K, Ludwig MS, Wildner M, Weissbrich B.
Epidemiology of subacute sclerosing panencephalitis
(SSPE) in Germany from 2003 to 2009: a risk estima-
tion. PLoS One 2013; 8: e68909.
5. Wendorf KA, Winter K, Zipprich J, et al. Subacute
sclerosing panencephalitis: the devastating measles com-
plication that might be more common than previously
estimated. Clin Infect Dis 2017; 65: 226–32.
6. Manning L, Laman M, Edoni H, et al. Subacute scle-
rosing panencephalitis in papua new guinean children:
the cost of continuing inadequate measles vaccine cover-
age. PLoS Negl Trop Dis 2011; 5: e932.
7. Mishra B, Kakkar N, Ratho RK, Singhi P, Prabhakar S.
Changing trend of SSPE over a period of ten years.
Indian J Public Health 2005; 49: 235–7.
8. Onal AE, Gurses C, Direskeneli GS, et al. Subacute
sclerosing panencephalitis surveillance study in Istanbul.
Brain Dev 2006; 28: 183–9.
9. Kija E, Ndondo A, Spittal G, Hardie DR, Eley B, Wilm-
shurst JM. Subacute sclerosing panencephalitis in South
African children following the measles outbreak between
2009 and 2011. S Afr Med J 2015; 105: 713–18.
10. Manesh A, Moorthy M, Bandopadhyay R, Rupali P.
HIV-associated sub-acute sclerosing panencephalitis –
an emerging threat? Int J STD AIDS 2017; 28: 937–9.
11. de Moraes-Pinto MI, Almeida AC, Kenj G, et al. Pla-
cental transfer and maternally acquired neonatal IgG
immunity in human immunodeficiency virus infection. J
Infect Dis 1996; 173: 1077–84.
12. McQuaid S, Cosby SL, Koffi K, Honde M, Kirk J,
Lucas SB. Distribution of measles virus in the central
nervous system of HIV-seropositive children. Acta Neu-
ropathol 1998; 96: 637–42.
13. Strebel P, Cochi S, Grabowsky M, et al. The unfinished
measles immunization agenda. J Infect Dis 2003; 187
(Suppl. 1): S1–7.
14. Shibeshi ME, Masresha BG, Smit SB, et al. Measles
resurgence in southern Africa: challenges to measles
elimination. Vaccine 2014; 32: 1798–807.
15. Ferrari MJ, Grais RF, Bharti N, et al. The dynamics of
measles in sub-Saharan Africa. Nature 2008; 451: 679–84.
16. Takahashi S, Metcalf CJ, Ferrari MJ, et al. Reduced vac-
cination and the risk of measles and other childhood
infections post-Ebola. Science 2015; 347: 1240–2.
17. Dabbagh A, Laws RL, Steulet C, et al. Progress towards
regional measles elimination – worldwide, 2000–2017.
Wkly Epidemiol Rec 2018; 93: 649–60.
18. Bester JC. Measles and measles vaccination: a review.
JAMA Pediatr 2016; 170: 1209–15.
1144 Developmental Medicine & Child Neurology 2019, 61: 1139–1144
19. Vanderslott S, Roser M. Vaccination. https://ourworldin
data.org/vaccination (accessed 12 December 2018).
20. Walkinshaw E. Mandatory vaccinations: the interna-
tional landscape. CMAJ 2011; 183: E1167–8.
21. Immunisation. Current Issues. Australian Government.
Department of Health. http://www.health.gov.au/interne
t/main/publishing.nsf/Content/MC14-004203-Immunisa
tion (accessed 17 December 2018).
22. Mezzofiore G. Why Italy’s U-turn on mandatory vacci-
nation shocks the scientific community. https://edition.
cnn.com/2018/08/07/health/italy-anti-vaccine-law-measles-
intl/index.html (accessed 12 December 2018).
23. Griffin DE. Measles virus and the nervous system.
Handb Clin Neurol 2014; 123: 577–90.
24. Sato Y, Watanabe S, Fukuda Y, Hashiguchi T, Yanagi Y,
Ohno S. Cell-to-cell measles virus spread between human
neurons is dependent on hemagglutinin and hyperfuso-
genic fusion protein. J Virol 2018; 92: e02166–17.
25. Watanabe S, Ohno S, Shirogane Y, Suzuki SO, Koga R,
Yanagi Y. Measles virus mutants possessing the fusion
protein with enhanced fusion activity spread effectively
in neuronal cells, but not in other cells, without causing
strong cytopathology. J Virol 2015; 89: 2710–17.
26. Erturk O, Karslıgil B, Cokar O, et al. Challenges in
diagnosing SSPE. Childs Nerv Syst 2011; 27: 2041–4.
27. Guler S, Kucukkoc M, Iscan A. Prognosis and demo-
graphic characteristics of SSPE patients in Istanbul,
Turkey. Brain Dev 2015; 37: 612–17.
28. Gutierrez J, Issacson RS, Koppel BS. Subacute scleros-
ing panencephalitis: an update. Dev Med Child Neurol
2010; 52: 901–7.
29. Jacobi C, Lange P, Reiber H. Quantitation of intrathe-
cal antibodies in cerebrospinal fluid of subacute scleros-
ing panencephalitis, herpes simplex encephalitis and
multiple sclerosis: discrimination between microorgan-
ism-driven and polyspecific immune response. J Neu-
roimmunol 2007; 187: 139–46.
30. H€ausler M, Aksoy A, Alber M, et al. A multinational
survey on actual diagnostics and treatment of subacute
sclerosing panencephalitis. Neuropediatrics 2015; 46:
377–84.
31. Cece H, Tokay L, Yildiz S, Karakas O, Karakas E, Iscan
A. Epidemiological findings and clinical and magnetic
resonance presentations in subacute sclerosing panen-
cephalitis. J Int Med Res 2011; 39: 594–602.
32. G€
urses C, Ozt€
urk A, Baykan B, et al. Correlation
between clinical stages and EEG findings of subacute
sclerosing panencephalitis. Clin Electroencephalogr 2000;
31: 201–6.
33. Lakshmi V, Malathy Y, Rao RR. Serodiagnosis of suba-
cute sclerosing panencephalitis by enzyme linked
immunosorbent assay. Indian J Pediatr 1993; 60: 37–41.
34. Owens GP, Gilden D, Burgoon MP, Yu X, Bennett JL.
Viruses and multiple sclerosis. Neuroscientist 2011; 17:
659–76.
35. Dyken PR. Subacute sclerosing panencephalitis. Current
status. Neurol Clin 1985; 3: 179–96.
36. Demir N, Cokar O, Bolukbasi F, et al. A close look at
EEG in subacute sclerosing panencephalitis. J Clin Neu-
rophysiol 2013; 30: 348–56.
14698749, 2019, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/dmcn.14166 by Nat Prov Indonesia, Wiley Online Library on [03/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
37. Anlar B, Yalaz K, Ustacelebi S. Symptoms and clinical
signs, laboratory data in 80 cases of subacute sclerosing
panencephalitis. Rev Neurol (Paris) 1988; 144: 829–32.
38. Yilmaz K, Yilmaz M, Mete A, Celen Z. A correlative
study of FDG PET, MRI/CT, electroencephalography,
and clinical features in subacute sclerosing panencephali-
tis. Clin Nuclear Med 2010; 35: 675–81.
39. Kannan L, Garg SK, Arya R, Sankar MJ, Anand V.
Treatments for subacute sclerosing panencephalitis.
Cochrane Database Syst Rev 2013; 12: CD010867.
40. Jones CE, Dyken PR, Huttenlocher PR, Jabbour JT,
Maxwell KW. Inosiplex therapy in subacute sclerosing
panencephalitis. A multicentre, non-randomised study in
98 patients. Lancet 1982; 1: 1034–7.
41. Gascon GG, International Consortium on Subacute Scleros-
ing Panencephalitis. Randomized treatment study of inosiplex
versus combined inosiplex and intraventricular interferon-
alpha in subacute sclerosing panencephalitis (SSPE): interna-
tional multicenter study. J Child Neurol 2003; 18: 819–27.
42. Aydin OF, Senbil N, Kuyucu N, G€
urer YK. Combined
treatment with subcutaneous interferon-alpha, oral iso-
prinosine, and lamivudine for subacute sclerosing panen-
cephalitis. J Child Neurol 2003; 18: 104–8.
43. Anlar B, Aydin OF, Guven A, Sonmez FM, Kose G,
Herguner O. Retrospective evaluation of interferon-beta
treatment in subacute sclerosing panencephalitis. Clin
Ther 2004; 26: 1890–4.
44. Miyazaki K, Hashimoto K, Suyama K, et al. Maintain-
ing concentration of ribavirin in cerebrospinal fluid by a
new dosage method; three cases of subacute sclerosing
panencephalitis treated using a subcutaneous continuous
infusion pump. Pediatr Infect Dis J 2018. https://doi.org/
10.1097/inf.0000000000002181 [E-pub ahead of print].
45. Jovic NJ. Epilepsy in children with subacute sclerosing
panencephalitis. Srp Arh Celok Lek 2013; 141: 434–40.
46. Yi
git A, Sarikaya S. Myoclonus relieved by carba-
mazepine in subacute sclerosing panencephalitis. Epileptic
Disord 2006; 8: 77–80.
47. Ravikumar S, Crawford JR. Role of carbamazepine in
the symptomatic treatment of subacute sclerosing panen-
cephalitis: a case report and review of the literature. Case
Rep Neurol Med 2013; 2013: 327647.
48. Okulicz JF, Grandits GA, French JA, et al. The impact of
enzyme-inducing antiepileptic drugs on antiretroviral drug
levels: a case-control study. Epilepsy Res 2013; 103: 245–53.
49. Sutcliffe CG, van Dijk JH, Bolton C, Persaud D, Moss
WJ. Effectiveness of antiretroviral therapy among HIV-
infected children in sub-Saharan Africa. Lancet Infect Dis
2008; 8: 477–89.
50. Campbell C, Levin S, Humphreys P, Walop W, Bran-
nan R. Subacute sclerosing panencephalitis: results of
the Canadian Paediatric Surveillance Program and
review of the literature. BMC Pediatr 2005; 5: 47.
51. Abe Y, Hashimoto K, Iinuma K, et al. Survey of suba-
cute sclerosing panencephalitis in Japan. J Child Neurol
2012; 27: 1529–33.
52. Ozt€
urk A, G€
urses C, Baykan B, G€
okyigit A, Eraksoy M.
Subacute sclerosing panencephalitis: clinical and mag-
netic resonance imaging evaluation of 36 patients. J
Child Neurol 2002; 17: 25–9.
 14698749, 2019, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/dmcn.14166 by Nat Prov Indonesia, Wiley Online Library on [03/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY INVITED REVIEW

RESUMEN
PANENCEFALITIS ESCLEROSANTE SUBAGUDA: FENOTIPO CL
INICO, EPIDEMIOLOG
IA E INTERVENCIONES PREVENTIVAS
La panencefalitis esclerosante subaguda (SSPE, por sus siglas en ingle
s) es una afeccio
n prevenible notificada en 6,5 a 11 por
cada 100 000 casos de sarampio
n, y es ma
s alta en los nin
~ os que contrajeron una infeccio
n de sarampio
n cuando ten
ıan menos
de 5 an~ os de edad. Los nin
~ os que residen en a
reas con una cobertura de vacunacio
n deficiente y una alta prevalencia del virus de
inmunodeficiencia humana tienen un mayor riesgo de desarrollar SSPE. La SSPE es potencialmente mortal en la mayor
ıa de los
~ os afectados. Este informe documenta los datos actuales relacionados con el fenotipo cl
ınico, la epidemiolog
ıa y la
nin
comprensio
n del SSPE, incluidas las intervenciones preventivas. Si bien pueden producirse mejoras en la progresio
n de la
enfermedad con la inmunomodulacio
n, en general no hay cura. La mayor
ıa de las terapias se centran en las necesidades de
apoyo. Las convulsiones y los movimientos anormales pueden responder a la carbamazepina. Muchos pa
ıses abogan por pol
ıticas
para mejorar la cobertura de vacunacio
n. Se necesitan programas de atencio
n me
dica preventiva eficaces, seguridad de las
percepciones de los padres y apoyo a la crisis para eventos sin precedentes que obstruyan la atencio
n primaria de salud efectiva.
Hasta que se erradique el sarampio
n en todo el mundo, los nin ~ os en todas las regiones siguen en riesgo.

RESUMO


PANENCEFALITE ESCLEROSANTE SUB-AGUDA: FENOTIPO CL
INICO, EPIDEMIOLOGIA, E INTERVENC ~ PREVENTIVAS
ß OES
A panencefalite esclerosante sub-aguda (PEES) e
uma condicßa~o preven
ıvel reportada em 6,5 to 11 por 100.000 casos de sarampo,
ee
mais alta em criancßas que contra
ıram infeccßa ~o por sarampo com menos de 5 anos de idade. Criancßas que residem em a
reas
com pobre cobertura vacinal e alta prevale ^ ncia de v
ırus da imunodeficie ^ncia humana apresentam maior risco de desenvolver
PEES. A PEES representa risco de vida para as criancßas mais afetadas. Este relato documenta dados atuais relacionados a

tipo cl
ınico, epidemiologia, e compreensa
feno ~ o da PEES, incluindo intervencßo ~ es preventivas. Enquanto melhoras na progressa ~o
da doencßa com a imunomodulacßa ~o podem ocorrer, em geral na ~ o ha

cura. A maior parte das terapias foca em necessidades de
suporte. Convulso ~ es e movimentos anormais podem responder a carbamazepina. Muitos pa
ıses defendem pol
ıticas para melhorar
a cobertura vacinal. Programas efetivos de cuidado preventivo em sau ~ es parentais, e suporte de crise

de, reforcßo das percepcßo
para eventos sem precedentes obstruindo o cuidado prima
rio efetivo sa
~o necessa
rios. Ate

que o sarampo esteja erradicado em
todo o mundo, criancßas de todas as regio ~ es permanecem em risco.