|Ahead of print
SSPE in children younger than 3 years: A case report and systematic review of clinical manifestation and outcome
Neeraj Kumar, Shweta Pandey, Ravi Uniyal, Imran Rizvi, Hardeep Singh Malhotra, Ravindra Kumar Garg
Department of Neurology, King George’s Medical University, Lucknow, Uttar Pradesh, India
|Date of Submission||05-Oct-2020|
|Date of Decision||10-Jan-2021|
|Date of Acceptance||11-Feb-2021|
|Date of Web Publication||11-Oct-2021|
Department of Neurology, King George’s Medical University, Lucknow, Uttar Pradesh.
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Subacute sclerosing panencephalitis (SSPE) is typically observed in school-going children, adolescents, and young adults. Herein, we report a 3-year-old boy of SSPE and systematically review all such reported cases (age ≤3 years). We searched PubMed database on June 16, 2020 with “English language & Human only” restrictions. Eligible publications were screened and retrieved by three authors (NK, SP, and RU). Variables like author, year of publication, country, age of onset, sex, duration of illness, immunization, history of measles, clinical presentation, neuroimaging, treatment, and outcome were extracted. Neurological outcome was assessed in terms of improvement, static course or death. The defined search criteria resulted in 791 manuscripts (1951 to June 16, 2020). Only 47 manuscripts were eligible for data extraction. Seventy cases were retrieved. The mean age of onset was 26.34 months. The M:F ratio was 3.2:1. Turkey (19 cases), India (10 cases), and Japan (10 cases) collectively comprised more than half cases of SSPE. Only six children were immunized, 17 have no measles immunization, and the rest 47 had insufficient immunization records. Preceding history of measles was present in 27 cases. Most patients presented in stage II/III with altered sensorium, myoclonic jerks, and seizures. The most common reported outcome was death (18/70) followed by vegetative state (10/70). The absence of measles vaccination is frequently associated with childhood SSPE. Early measles vaccination may prevent SSPE in toddlers. Perinatal measles infection results in short onset latency and fulminant course. Outcome was not good in reviewed age group of ≤3 years.
Keywords: Measles, myoclonus, subacute sclerosing panencephalitis
|How to cite this URL:|
Kumar N, Pandey S, Uniyal R, Rizvi I, Malhotra HS, Garg RK. SSPE in children younger than 3 years: A case report and systematic review of clinical manifestation and outcome. J Pediatr Neurosci [Epub ahead of print] [cited 2021 Dec 9]. Available from: https://www.pediatricneurosciences.com/preprintarticle.asp?id=327902
| Introduction|| |
Subacute sclerosing panencephalitis (SSPE) is a chronic inflammatory disorder of the brain that is caused by a persistent infection with mutated measles virus. SSPE is clinically characterized by progressive mental decline, periodic myoclonic jerks, and deteriorating motor functions that ultimately culminate into a vegetative state. Death is inevitable in almost all the cases.
SSPE is a commonly encountered disease in poor and resource-constrained countries. The WHO has estimated its incidence to be approximately 4–11 cases per 100 000 cases of measles. Measles infection acquired very early in life is associated with a much higher risk (18 per 100 000 cases) of SSPE, and a risk as high as 27.9 SSPE cases per 100 000 cases of measles has been reported. In western countries, including those with complete measles vaccination coverage, SSPE cases are generally observed after an outbreak of measles. In Georgia, USA, there were 8377 and 11,495 measles cases during the 2004–2005 and 2013–2015 outbreaks, respectively. Sixteen SSPE cases in USA were observed between 2008 and 2017. Eleven (92%) of 12 SSPE cases with a known history of measles had infection at or less than 2 years of age. The overall estimate of SSPE risk (based on 8377 reported cases of measles) was 1 per 1396 cases of measles.
Generally, SSPE is reported in school-going children, adolescents, and young adults. We, hereby, present an atypical case of SSPE in a 3-year-old child and further analyze the course and outcome of SSPE in children up to 3 years of age.
| Case Report|| |
A 3-year-old boy presented with walking difficulty, recurrent falls, and generalized tonic-clonic seizures persisting for the last 1 month. The patient was fully vaccinated and never had measles in early childhood. The patient was born out of a normal uneventful full-term delivery. He had attained normal milestones so far, and his general examination was normal. Neurological examination revealed severe cognitive decline. The patient suffered from recurrent generalized myoclonus occurring at regular intervals [Video 1], failed to maintain posture, and had recurrent falls. Fundus examination was normal, and the motor and sensory examinations did not reveal any abnormality. All blood hematological and biochemical parameters were normal. Cerebrospinal fluid examination was normal with cell count 5 cells per mm3 (all lymphocytes), protein level 48 mg/dL, and glucose 50 mg/dL. Anti-measles antibody titer (41.054 NTU vs. control <9 NTU) was markedly elevated. Iron profile and serum ceruloplasmin levels were normal. Electroencephalography revealed generalized periodic spike wave discharges [Figure 1]. Magnetic resonance imaging demonstrated periventricular T2/fluid attenuation inversion recovery (FLAIR) hyperintensity [Figure 2]. Patient was treated with valproate, clonazepam, and weekly intrathecal interferon alpha. After 2 months, reduced intensity and frequency of myoclonic jerks was observed. At 2-years follow-up, he was still non-communicating and was unable to stand or walk unsupported. Now, the patient is on monthly interferon alpha with marked improvement in seizure control, myoclonic jerks, and sitting posture.
|Figure 1: Electroencephalogram showing bilateral asymmetrical, high voltage, periodic discharges|
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|Figure 2: Magnetic resonance imaging showing periventricular and supratentorial white matter changes in T2 axial, sagittal, and coronal sequence (A, C, and D) and T2 FLAIR sequence (B)|
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Video demonstrates recurrent generalized myoclonus occurring at regular intervals
We systematically compiled and analyzed 47 eligible publications, reporting 70 cases of SSPE, in whom symptoms appeared at the age of 3 years or less. The focus of this review was to analyze clinical presentation, course, and outcome in early age group SSPE patients. Moreover, was this group different from commonly encountered age group of SSPE patients?
| Materials and Methods|| |
We searched PubMed database on June 16, 2020 with “English language & Human only” restrictions. The following search strategy on PubMed advanced search option was done: ((((((((sspe[MeSH Terms]) OR (subacute sclerosing panencephalit*[MeSH Terms])) OR (Bosin’s disease[MeSH Terms])) OR (Dawson’s encephalitis[MeSH Terms])) OR (sclerosing leukoencephalit*, subacute[MeSH Terms])) OR (von bogaert encephalitis[MeSH Terms])) OR (inclusion body encephalitis, measles[MeSH Terms])) OR (subacute sclerosing leukoencephalit*[MeSH Terms])) AND ((child[MeSH Terms] OR Kid[MeSH Terms] OR Infant[MeSH Terms] OR Newborn[MeSH Terms])). Three authors (NK, SP, and RU) screened and retrieved articles. Two authors (NK and HSM) searched information in all articles and compiled all eligible cases. Titles, abstracts, and full texts were searched. All tables and flowchart were also searched in the selected manuscript. References were also searched for any additional eligible cases for inclusion [Figure 3].
|Figure 3: PRISMA flow diagram depicting the flow of information through the different phases of systemic review|
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We included all studies based on mentioned search criteria. This included meta-analysis, original studies, case series, and case reports of SSPE patient with onset at ≤3 years of age.
Data were manually extracted by NK from all included articles. Variables like author, year of publication, country, age of onset (months), sex, duration of illness, immunization status, past history of measles, presenting clinical manifestation, unusual manifestation, neuroimaging, treatment, and outcome were extracted in an excel sheet and also presented in compiled form in [Table 1].,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,
|Table 1: Summary of all published articles in PubMed (last searched on 16 June 2020) on subacute sclerosing panencephalitis (SSPE) in children of up to 3 years of age|
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We focused on neurological manifestation and outcome in terms of improvement, static course, or death.
| Results|| |
The defined search criteria resulted in 791 manuscripts (1951 to June 16, 2020). Only 47 manuscripts were eligible for data extraction as per our inclusion criteria [Figure 3]. A total of 70 cases were retrieved and relevant required data were compiled [Table 1].,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,
The mean age of onset was 26.34 months (range 2–36 months). Only six cases were ≤1 years of age. The male-to-female ratio was 3.2:1 (n = 51). In our review, Turkey (19 cases), India (10 cases), and Japan (10 cases) collectively comprised more than half cases of SSPE. Only six children were immunized, 17 have no measles immunization, and rest 47 cases had insufficient record regarding immunization. Preceding history of measles was present in 27 cases. Three mothers had measles during perinatal period. Most patients presented in stage II or III with altered sensorium, myoclonic jerks, and seizures. The median duration of illness before presentation was 8 weeks (mean 11.85 ± 13.4 weeks; range 1–52 weeks).
Measles IgG antibody was used as a diagnostic marker. EEG and brain imaging (CT/MRI) were also used for supporting the diagnosis of SSPE. The findings have been compiled in [Table 1].
The treatment regime varied in different publications. Interferon only (1 case), Isoprinosine only (12 cases), or both (9 cases) were used in most cases [Table 1]. Interferon alpha or interferon beta were used via intramuscular, subcutaneous, and intrathecal routes. The dosing varied from 1 to 10 million units in weekly/twice weekly/thrice weekly schedule. After intensive phase of 4–6 weeks, monthly schedule was followed. Additional use of IVIG and lamivudine have been reported too. In a study by Aydin et al., the use of subcutaneous Interferon alpha (10 mU/m2/three times a week), oral Isoprinosine (100 mg/kg/day), and lamivudine (10 mg/kg/day) resulted in better remission rate but in age group up to 3 years, the prognosis was dismal (out of 3; 2 died and 1 progressed to stage IV). Supportive use of antiepileptics was also reported.
The most common reported outcome was death (18/70) followed by vegetative state (10/70). Though static course was reported in four cases, improvement was reported in only one case. No outcome was reported in 37/70 cases.
| Discussion|| |
Globally, the average age of onset for SSPE ranges between 6 and 13 years, except in Papua New Guinea where the average age of onset is 4.9 years (range 0–56 years). SSPE usually manifests more than 6 years after childhood measles infection. In SSPE cases from Georgia, the age at presentation was between 4 and 16 years (median, 9 years). Wendorf et al. reported that the median age at presentation of SSPE, in USA, was 12 years (range, 3–35 years), and among 17 confirmed SSPE cases, only one was of 3 years of age. The latency period between measles infection and SSPE diagnosis ranged from 2.5 to 34 years (median 9.5 years). In an older study (1990–2002), Miller et al., in England and Wales, reported the age at onset of SSPE ranged from 4 to 26 years (median 12.5). Lack of measles vaccination is considered responsible for SSPE in toddlers.
Our systematic review of early onset SSPE shows that approximately 40% of early SSPE patients had measles infection in infancy. Mothers of six patients acquired measles infection during peripartum period with three patients developing measles like illness during neonatal period.
A history of prior immunization for measles was forthcoming only in six (9%) children. Most other cases were either unimmunized (17/70) or with no available data of immunization. SSPE in children with measles vaccination raises question about vaccine induced SSPE. The scientific evidence of such correlation is lacking. Other possibilities may be inadequate/inappropriate vaccination, poor immune response, and genetic susceptibility.
Yilmaz et al., in a series of nine patients, noted that SSPE patients under the age of 4 years have a poor prognosis as a result of progressive or rapidly progressive course, despite medical treatment. Our analysis revealed that the majority of these cases belonged to three countries, India, Turkey, and Japan. Failure to achieve universal immunization against measles may be a reason for early presentation. In our analysis, the duration of illness at first presentation ranged from 1week to 1year, and the majority presented within 8 weeks. Our review further indicated that the majority of patients with early onset SSPE had a rapidly progressive course. Majority of patients either died or became vegetative within 6 months, indicating an acute fulminant course [Table 1].,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,
The human immune system, at birth, is relatively immature. At 6 months, infants have blood anti-measles antibody levels that are below the crucial protective threshold. In addition, measles virus cause a long-lasting immunosuppression and both innate and adaptive immune mechanisms are severely affected. Measles virus evolves many mechanisms to circumvent host’s immune system. Experiments with wild-type measles virus have demonstrated that measles infection leads to depletion of memory immune cells and subsequently immune amnesia. A premature immunity in infancy against infections along with measles virus-associated immunosuppression possibly leads to a rapid viral multiplication viral persistence in the brain resulting in fulminant SSPE.
We also reported a child with SSPE who presented at 3 years of age and had rapid progression. In this patient, treatment with weekly intrathecal interferon alpha halted the progression and increased the survival. In our review, we noted that, interferon alpha and/or oral Isoprinosine were the most commonly used treatments. Results were variable, in some cases, stabilization of disease course was noted, but in the majority, relentless progression continued [Table 1].,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,
In conclusion, the absence of measles vaccination is frequently associated with SSPE in young children. Early measles vaccination, before 9 months of age, may help in preventing SSPE in toddlers. Strict monitoring of cold chain, vaccine quality, and administration technique should be done to prevent post-vaccination measles or SSPE. Measurement of serological titer for immune response can be explored. Perinatal measles infection may result in SSPE with a short onset latency and fulminant course. Interferon alpha with/without oral Isoprinosine may be used in the treatment of SSPE. Stabilization of disease may be achieved in some cases.
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Conflicts of interest
The authors report no conflict of interest
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