Preliminary evidence of cardiac dysfunction in subacute sclerosing panencephalitis: a systematic review and meta-analysis

Abstract

Purpose

Subacute sclerosing panencephalitis (SSPE) is a catastrophic neurological disorder that typically presents in infancy and early adolescence. Cardiac arrhythmia in SSPE is a significant but often under-recognized complication of the disease. The persistent measles virus infection that characterizes SSPE can have widespread effects on the central nervous system, including areas that regulate autonomic function, which in turn can impact cardiac rhythm. In this article, we aim to comprehensively review articles describing cardiac dysfunction associated with SSPE.

Methods

We conducted a literature search in PubMed, Scopus, ProQuest, Emerald, and Google Scholar databases of articles published till October, 2025, identified items for review, and conducted a meta-analysis.

Results

A total of 947 results were identified across five databases, with 378 studies initially screened, and 569 articles were excluded (10 duplicates and 559 unrelated to the study). Only 4 articles met the eligibility criteria. Our meta-analysis of the three studies showed a pooled mean difference of 11.20 beats per minute (95% confidence interval, 5.52–16.88), with case groups having significantly higher heart rates than controls.

Conclusion

The few available studies provide preliminary evidence suggesting that cardiac autonomic disturbances, including elevated heart rates and reduced HRV, occur in a subset of patients with SSPE. More rigorously designed investigations are needed to clarify the prevalence, mechanisms, and clinical impact of cardiac dysfunction in SSPE.

Introduction

Subacute sclerosing panencephalitis (SSPE) is a severe neurodegenerative disorder caused by chronic and persistent encephalitis following aberrant measles virus infection. It affects both gray and white matter in the brain, leading to demyelination, neuron loss, atrophy, inflammation, and overall central nervous system degeneration [1]. The disorder progresses through intellectual deterioration, cognitive decline, behavioral changes, scholastic performance decline, myoclonus, mutism, akinesia, seizures, ataxia, visual disturbances, spasticity, and eventually a vegetative state [2]. The average survival duration post-diagnosis is approximately 18 months, with children and young individuals typically having a life expectancy of 1 to 3 years from the onset of symptoms [3]. Although the manifestation of SSPE from an acute measles infection has a variable latency period of one month to 27 years, it generally spans 4 to 10 years. Risk factors include early measles infection, large family size, older maternal age, higher birth order, lower parental education, fewer cultural activities, and rural birthplace [4]. Tauopathies in SSPE are crucial due to their role in the disease's pathology. Brain inflammation, induced by the measles virus, leads to tauopathy, where phosphorylated tau is distributed independently of the virus [5]. Although SSPE is a rare neurological disease with a low survival rate that can occur as a complication of measles infection, it often leads to severe and fatal outcomes. Limited observations suggest that autonomic dysfunction contributes to the pathophysiology of the terminal event in SSPE. Heart rate variability (HRV) serves as a valuable indicator of cardiac autonomic function, providing insight into the balance between sympathetic and parasympathetic control and potential autonomic dysregulation in neurological disorders [6]. Understanding and managing autonomic dysfunction is crucial for optimizing patient care and improving outcomes.

In this systematic review, we synthesize evidence to identify patterns, mechanisms, and clinical implications of cardiac disturbances in SSPE, thereby contributing to a deeper understanding of its systemic impact. We conducted a systematic review to identify associations between cardiac dysfunction and SSPE by analyzing findings from existing studies.

Methods

Literature search

We followed the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) 2020 for this systematic review and meta-analysis. This study does not require ethics approval as it is based on published literature. We searched PubMed, Scopus, Emerald, ProQuest, and Google Scholar databases from inception to October 17, 2025. The MeSH terms used and the search strategy are described in Table 1.

Table 1.

Search strategy

Search set	Search terms
#1	"Randomized clinical trial" OR "randomized controlled trial" OR "controlled clinical trial" OR "clinical trial" OR "clinical trials" OR “case-control study” OR “case report” OR “case series” OR "random allocation" OR "double-blind method" OR "single-blind method" OR “double-blind studies”
#2	“Subacute Sclerosing Panencephalitis” OR “SSPE”
#3	“Heart Rate Variability” OR “Bradycardia” OR “Tachycardia” OR “Cardiac Rhythm Aberrations” OR “Arrhythmia” OR “Autonomic Dysfunction” OR “Cardiovascular functions” OR “Echocardiographic evaluation” OR “ECG” OR “Holter Study” OR “Pulse Doppler”
#4	#1 AND #2 AND #3

Inclusion and exclusion criteria

Inclusion criteria

Eligible studies included randomized controlled trials, case reports, case-control studies, and single or double-blind studies that investigated cardiac rhythm variability or aberrations in SSPE patients. The studies utilized diagnostic tools including Holter recordings, echocardiography, M-mode, pulse Doppler, tissue Doppler imaging, myocardial performance index, and electrocardiogram recordings to assess cardiac rhythm variability or aberrations in SSPE patients.

Exclusion criteria

Studies that did not investigate the relationships between SSPE and cardiac abnormalities in patients were excluded. Specifically, studies focusing solely on the measles virus, myoclonus, dystonia, or case series without cardiac implications in SSPE patients or using animal models were not considered.

Study selection and data extraction

Two investigators (NP and NRD) defined inclusion and exclusion criteria and independently analyzed titles, abstracts, and full texts. The selection process was mutually accepted by both reviewers without conflict. NP extracted, gathered, and compiled the data into one final report, whereas NRD edited, designed, and outlined the study plan. All data from studies that observed direct links between autonomic dysfunction and SSPE were included. For further analysis, data were extracted into a table (Table 2) containing each author’s name, study duration, type of diagnostic tool used, study design, sample sizes of cases and controls, conclusion, and results of the study. Any disagreements were resolved through discussions with the third reviewer (DJ) on the basis of predefined eligibility criteria.

Table 2.

Descriptions of studies

Study (year)	Type of study	Group		SPSS clinical stage	Investigation	Conclusion
		Study group	Control group
Aydin et al. [9] (2005)	Observational study	29 SSPE patients (24 males, 5 females)	20 (13 males, 7 females)	Stage 1B: n = 7 patients	Holter study (computerized Holter scanner)	Reduced HRV parameters in affected individuals, indicating imbalances in the ANS, which could predict arrhythmias or sudden death. However, no direct correlations were found between HRV parameters, disease severity, or survival outcomes.
				Stage 2B: n = 3
				Stage 2A: n = 3
				Stage 3B: n = 14
				Stage 4: n = 1 (Gascon et al. [8])
Çimen et al. [10] (2014)	Prospective observational study	49 (32 males, 17 females)	26 (17 males, 9 females)	Stage 2: n = 29	Echocardiography, M-mode, pulse doppler, tissue doppler imaging, and myocardial performance index	There was no detection of considerable cardiac dysfunction in patients with SSPE except for sinus tachycardia.
				Stage 3: n = 20
Viswanathan et al. [11] (2025)	Prospective single-center study	30 (23 males, 7 females)	30	Stage 1: n = 1 (3.3%)	Electrocardiogram recordings	HRV was reduced in SSPE patients but did not differ significantly between SSPE stages or according to clinical variables.
				Stage 2: n = 21 (70%)
				Stage 3: n = 8 (26.7%)
				Stage 4: n = 0 (Jabbour staging)
Parida et al. [12] (2024)	Case report	22-year-old male patient			Electrocardiography, two-dimensional echocardiography, and 48-hour Holter monitoring	There was no detection of considerable cardiac dysfunction except for sinus bradycardia.

ANS, autonomic nervous system; SSPE, subacute sclerosing panencephalitis.

Meta-analysis

All three case-control studies had the same exposure and outcome variables, which allowed for meta-analyses to be carried out. A forest plot and funnel plot were prepared using STATA SE 18 (StataCorp LLC.) to describe individual studies and the pooled mean. Heterogeneity between studies was indicated by the I² value. I² statistics of less than 50% were considered low and indicated greater similarity between studies. Statistical significance was fixed at a p-value less than 5% because meta-analysis is a type of observational study. Errors can occur in study inclusion and analysis, resulting in incorrect results.

To assess the presence of small-study effects (a potential indicator of publication bias), we conducted Egger’s/Begg’s regression test using a random-effects model with the restricted maximum likelihood (REML) estimation method. The test regresses the standardized effect sizes on their standard errors.

Quality assessment

The National Heart, Lung, and Blood Institute critical appraisal tools were used for case-control studies in this systematic review [7]. These criteria included a total of 12 questions, with each question answered as “yes,” “no,” or “unclear.” To assess risk of bias in single case reports, we used a critical appraisal checklist developed by Moola et al. [8].

Results

All studies fulfilled the criteria for good quality studies (Table 3) including the case report, as it satisfied seven appraisal items out of 8 (Table 4). The aim of this assessment is to decrease bias due to study design, eligibility criteria, methods, and outcomes of analysis. The quality assessment improves data synthesis and interpretation of the included research articles.

Table 3.

The National Heart, Lung, and Blood Institute critical appraisal tool used to assess the included case-control studies

Criteria	Aydin et al. [9]	Viswanathan et al. [11]	Çimen et al. [10]	Others (CD, NR, NA)
1. Was the research question or objective in this paper clearly stated and appropriate?	Yes	Yes	Yes
2. Was the study population clearly specified and defined?	Yes	Yes	Yes
3. Did the authors include a sample size justification?	Yes	Yes	No
4. Were controls selected or recruited from the same or similar population that gave rise to the cases (including the same timeframe)?	Yes	Yes	Yes
5. Were the definitions, inclusion and exclusion criteria, algorithms, or processes used to identify or select cases and controls valid, reliable, and implemented consistently across all study participants?	No	Yes	Yes
6. Were the cases clearly defined and differentiated from controls?	Yes	Yes	Yes
7. If less than 100 percent of eligible cases and/or controls were selected for the study, were the cases and/or controls randomly selected from those eligible?	No	No	No
8. Was there use of concurrent controls?	Yes	Yes	Yes
9. Were the investigators able to confirm that the exposure/risk occurred prior to the development of the condition or event that defined a participant as a case?	Yes	Yes	Yes
10. Were the measures of exposure/risk clearly defined, valid, reliable, and implemented consistently (including the same time period) across all study participants?	Yes	Yes	Yes
11. Were the assessors of exposure/risk blinded to the case or control status of participants?	No	No	No
12. Were key potential confounding variables measured and adjusted statistically in the analyses? If matching was used, did the investigators account for matching during study analysis?	Yes	Yes	Yes

CD, cannot determine; NR, not reported; NA, not applicable.

Table 4.

Critical appraisal of case reports included in this review following Moola et al. [8]

Item	Parida et al. [12] (2024)
Were the patient’s demographic characteristics clearly described?	Yes
Was the patient’s history clearly described and presented as a timeline?	Yes
Was the current clinical condition of the patient on presentation clearly described?	Yes
Were diagnostic tests or assessment methods and the results clearly described?	Yes
Was the intervention(s) or treatment procedure(s) clearly described?	Yes
Was the post-intervention clinical condition clearly described?	Yes
Were adverse events (harms) or unanticipated events identified and described?	Yes
Does the case report provide takeaway lessons?	No
Overall appraisal: Include □ Exclude □ Seek further info □	Include

Studies published till October 2025 were considered for this review. A total of 947 results were found: PubMed (n = 731), Scopus (n = 8), Emerald (n = 1), ProQuest (n = 135), and Google Scholar (n = 72). Duplicate records (n = 10) were removed, leaving a total of 937 studies, of which 559 articles were excluded, the studies as they did not match the inclusion criteria. Then, 374 articles were excluded because they were not relevant to the topic. These irrelevant studies included EEG studies (n = 52) and studies focused only on measles and myoclonus (n = 322). Ultimately, four articles were included in the final analysis. All passed the inclusion criteria for good quality studies. This systematic review has been registered in PROSPERO with registration ID of CRD42025631116. A detailed summary of the screening process is presented in Figure 1.

Figure 1. PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) flowchart of the study.

Table 5 summarizes three studies comparing heart rate (beats per minute [bpm]) between case and control groups. Aydin et al. [9] observed a higher mean heart rate in the case group (74.7 bpm) compared to controls (66.4 bpm), with a mean difference (MD) of 8.3 bpm (SE, 4.03). Çimen et al. [10] reported a larger difference, with cases showing a mean heart rate of 101.63 bpm versus 85.0 bpm in controls (MD, 16.6; SE, 3.60). Viswanathan et al. [11] found an MD of 8.1 bpm (SE, 3.87), again indicating higher heart rates among cases.

Table 5.

Summary of studies comparing heart rate (beats/min)

Study (year)	Study group		Control group		Mean difference	Standard error
	No. of cases	Heart rate (beats/min)	No. of cases	Heart rate (beats/min)
Aydin et al. [9] (2005)	29	74.7 ± 18.8	20	66.4 ± 9	8.3	4.03
Çimen et al. [10] (2014)	49	101.63 ± 17.76	26	85 ± 13	16.6	3.60
Viswanathan et al. [11] (2025)	30	94.6 ± 16.1	30	86.5 ± 13.8	8.1	3.87

Values are presented as number only, or mean ± standard deviation. SD

A meta-analysis of three studies assessing heart rate differences between case and control groups showed a significant overall effect. The pooled MD (Figure 2) was 11.20 bpm (95% confidence interval [CI], 5.52–16.88, p < 0.001), indicating higher heart rates in cases. Individual study estimates ranged from 8.10 to 16.60 bpm. Heterogeneity was moderate (τ² = 10.54, I² = 41.83%), and the test for heterogeneity was not significant (Q(2) = 3.40, p = 0.18). The analysis used a random-effects model (REML), reflecting variability across studies. These findings support a consistent trend of elevated heart rate in the case groups.

Figure 2. Forest plot of random effects meta-analysis for mean difference of heart rate.

CI, confidence interval.

The funnel plot (Figure 3) assesses potential publication bias among the three included studies. The plot appears symmetric, with studies distributed around the pooled effect estimate, suggesting no strong evidence of small-study effects. However, with only three studies, the funnel plot has limited power to detect asymmetry or bias reliably. This visual impression aligns with statistical tests: Egger’s test (β = –21.08, SE = 12.30, z = –1.71, p = 0.087) and Begg’s test (Kendall’s score = –1.00, SE = 1.92, z = –1.04, p > 0.999), both of which indicated no significant publication bias.

Figure 3. Funnel plot with pseudo 95% CI for mean difference of heart rate.

CI, confidence interval.

Discussion

SSPE is a progressive, inflammatory viral disease of the central nervous system caused by persistent infection with the measles virus. It is typically a fatal neurodegenerative condition with a variable rate of progression, often leading to death within 1 to 3 years. As the disease advances, dysfunction occurs across multiple organ systems [1]. Autonomic nervous system involvement is particularly prominent in advanced stages of the disease, leading to difficulties with urination and defecation, hyperhidrosis, thermoregulatory abnormalities, and visual/Balint syndrome [12]. However, HRV is rarely discussed in evaluations of sympathetic autonomic dysfunction. In the present systematic review, we identified only three case-control studies and a single case report describing HRV in SSPE. Although this review is the most comprehensive and unique analysis on the topic to date, the limited number of available studies remains an important constraint.

Our meta-analysis of three studies showed a pooled MD of 11.20 bpm (95% CI, 5.52–16.88), with case groups having significantly higher heart rates than controls. Although the individual studies showed a consistent direction of effect, the meta-analysis was constrained by the inclusion of only three studies and moderate heterogeneity (I² = 41.8%), making the pooled estimate exploratory rather than conclusive. Similarly, with only four studies and relatively large SEs, the funnel plot had limited power to detect publication bias, despite no obvious asymmetry. Larger, well-designed studies are needed to strengthen the evidence base and allow more reliable conclusions.

In one prospective observational study [9] involving 29 SSPE patients, 24-hour Holter monitoring showed lower HRV including lower standard deviation of all normal sinus intervals and a reduced triangular index, both indicators of impaired autonomic regulation, in 12 of the 15 patients who died over the course of illness compared to normal individuals. However, those who survived also had reduced HRV, as well as brain cortical lesions. Although a substantial number of patients with reduced HRV died during follow-up, no statistically significant difference in HRV parameters was observed between survivors and non-survivors. Additionally, no correlations were found between brain MRI findings and HRV indices. These results support the presence of autonomic dysfunction in SSPE, likely attributable to central nervous system involvement, although its direct prognostic value remains uncertain.

The results of this study are in line with the results of another study by Çimen et al. [10], who evaluated cardiac function in children with SSPE using tissue Doppler echocardiography and compared them with age-matched controls. Despite the presence of sinus tachycardia in approximately 39% of patients, no statistically significant differences were found in key systolic or diastolic function parameters including ejection fraction, shortening fraction, and myocardial performance index, between SSPE patients (Stages 2 and 3) and controls. These findings suggest that cardiac function is largely preserved even in the advanced stages of SSPE and may not significantly contribute to mortality risk in this patient group.

Another prospective study [11] from Southern India investigated cardiac autonomic function in 30 patients with SSPE using only echocardiographic examination, unlike the other two studies. Although frequency-domain parameters showed no significant differences, a negative correlation was observed between HRV measures and disease severity. This is a preliminary indication that autonomic dysfunction may progress alongside neurological deterioration in SSPE, possibly reflecting involvement of central autonomic regulatory networks. Likewise, in the single case report [12] of Balint’s syndrome accompanied by sinus bradycardia, suggestive of underlying autonomic dysfunction, the patient experienced rapid clinical deterioration and ultimately succumbed to the illness despite receiving treatment.

In SSPE, autonomic dysfunction can also arise due to seizures, epileptic discharges, and elevated intracranial pressure, all of which disrupt central autonomic networks (Figure 4) [13]. EEG findings, including long-interval periodic discharges and myoclonus [14], suggest that cortical excitation interferes with autonomic control, potentially triggering cardiac arrhythmias [15]. Reduced HRV, particularly in low-frequency power, has been observed in SSPE patients, aligning with patterns seen in sudden unexpected death in epilepsy [16]. Elevated intracranial pressure, linked to reduced HRV and increased mortality in brain injuries, further highlights the importance of monitoring HRV in SSPE.

Figure 4. Involvement of neurological systems in SSPE and their possible influence on the heart.

SSPE, subacute sclerosing panencephalitis.

It is important to recognize that elevated heart rates and reduced HRV in SSPE may not solely reflect central autonomic network damage. Secondary factors common in advanced SSPE such as antiepileptic drug use, prolonged deconditioning from a bedridden state, malnutrition, and recurrent infections can also influence sympathetic tone and contribute to tachycardia. While central autonomic dysfunction is not amenable to direct therapeutic interventions, certain peripheral autonomic abnormalities, particularly HRV changes, may still be modifiable. Although anti-seizure medications like carbamazepine can affect autonomic function, no consistent association with arrhythmic mortality has been established [17]. Overall, these considerations indicate that autonomic dysfunction in SSPE, whether primary or secondary, may play a role in clinical deterioration, potentially contributing to disease progression in a manner similar to other neurodegenerative disorders such as prion diseases [18].

Because the statistical power to detect funnel-plot asymmetry is extremely limited with only three studies and standard publication-bias tests are unreliable under such conditions, the small-study effect remains a major limitation of this review. In addition, the absence of follow-up data in most studies further restricts our ability to identify subtle variations in autonomic function across patient groups and to determine the long-term clinical significance of autonomic dysfunction. Future studies with larger, more homogenous samples, standardized methods, and longer follow-up are needed to better understand the role of cardiac dysfunction in SSPE.

Collectively, these studies suggest preliminary indications that although cardiac contractile function may remain largely preserved in SSPE, subtle disturbances in autonomic regulation that are particularly reflected in time-domain HRV parameters could be present in some patients. These autonomic alterations may be related to central nervous system involvement, potentially affecting brainstem or cortical autonomic centers, but current evidence remains insufficient to establish a definitive mechanism. While reduced HRV appears to show a trend toward association with disease severity, its utility as a predictor of mortality is still unclear due to inconsistent findings across the limited available studies. Even so, these early observations highlight the potential relevance of routine HRV monitoring in SSPE as a supportive clinical tool, warranting further investigation through larger, methodologically robust studies.