Vision Loss in Subacute Sclerosing Panencephalitis: A Systematic Review of Case Reports and Case Series

ABSTRACT.

Vision loss is a presenting complaint in many patients with subacute sclerosing panencephalitis (SSPE). Data related to vision loss in SSPE is available only in the form of case reports. In this systematic review, we evaluated characteristics of vision loss, affected anatomic site, and patient course and outcome. We extracted data from four databases: PubMed, Embase, Scopus, and Google Scholar. The last search was done on October 26, 2022. We adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The protocol was registered with PROSPERO (CRD42022362652). Dyken’s criteria were used for the diagnosis of SSPE. The data were recorded in an Excel sheet. The Joanna Briggs Institute Critical Appraisal tool was used to assess the quality of data. The mean age of patients with SSPE was 17.9 years. Males outnumbered females (60:34). In 73 patients (76%), duration of illness/onset of vision loss was less than 6 months. In 76% patients (n = 73), visual manifestations appeared before encephalopathy. Involvement of the retina (58 of 96, 60.4%), optic nerve (9 of 96, 9.3%), or cerebral cortex (29 of 96, 30.2%) was responsible for vision loss. T2/fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) parieto-occipital hyperintensities were the most frequent (71.4%) neuroimaging abnormality. Retinal biopsy revealed similar findings revealed by brain histopathology. All patients died and became akinetic mute during the follow-up period, which ranged from a few weeks to a few years. In conclusion, retinal involvement was the most common cause of vision loss. Vision loss often precedes encephalopathy. Cortical vision loss was associated invariably with T2/FLAIR MRI hyperintensities in the parieto-occipital region.

INTRODUCTION

Subacute sclerosing panencephalitis (SSPE) is a relentlessly progressing brain disorder caused by a persistent measles virus infection of the brain. SSPE generally affects children and young adults. Clinically, SSPE is characterized by diffuse encephalopathy. SSPE manifests with declining scholastic performance, periodic myoclonus, and gait abnormalities. Disease progresses universally to an akinetic mute state, culminating in death. In the usual course, death occurs 1 to 3 years after diagnosis. In acute fulminant form, death occurs within 6 months. Electroencephalography characteristically reveals periodic changes. Neuroimaging shows periventricular T2/fluid-attenuated inversion recovery (FLAIR) white matter signal changes. In advanced stages, there is marked cerebral atrophy. A definitive diagnosis requires the demonstration of elevated measles antibody titters in cerebrospinal fluid. Currently, there is no effective treatment available for SSPE.¹

Vision loss is a presenting complaint in many patients. Virtually every component of the visual pathway, from the retina to the cortex, is likely to be affected.¹ The bulk of data related to vision loss in SSPE are available in the form of isolated case reports or case series. In our systematic review, we reviewed all published case reports or case series with the purpose of evaluating the clinical characteristics of vision loss and possible affected anatomic locations in the visual pathway. We also assessed the course and outcome of SSPE in patients presenting with vision loss.

MATERIALS AND METHODS

Study design.

We performed a systematic review of published case reports and case series of patients with SSPE who either presented with vision loss or developed visual abnormality during the course of the disease. For our systematic review, we adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The protocol was registered with PROSPERO (CRD42022362652).²

Search strategy.

We searched four databases: PubMed, Scopus, Embase, and Google Scholar. The last literature search was performed on October 26, 2022. No language restrictions were applied. The search strategy used is provided in Supplemental Table S1.

Inclusion criteria.

We included all case reports and case series of patients with SSPE (published up to October 26, 2022) in which vision loss/blindness was described as a clinical manifestation. Dyken’s³ criteria were used to confirm the diagnosis of SSPE (Table 1).

Table 1.

Diagnostic criteria of subacute sclerosing panencephalitis

Criterion	Description
Clinical	Progressive decline in mental function with periodic myoclonus
Electroencephalographic	Periodic, stereotyped, high-voltage discharges
CSF	Globulin levels > 20% of the total CSF protein
	Elevated titer of measles antibodies
Brain biopsy	Suggestive of panencephalitis, inclusion bodies in neurons, demonstration of measles virus or its components in brain/retinal tissues

CSF = cerebrospinal fluid.

Any three of the five criteria are required for a diagnosis of subacute sclerosing panencephalitis.

Exclusion criteria.

Review articles, conference abstracts, editorials, comments on published cases, and guidelines were excluded. We excluded all reports in which vision loss was not described as a clinical manifestation.

Data extraction.

The study was performed in two stages. In the first stage, titles and abstracts were evaluated by two independent reviewers (R. K. and I. R.). Subsequently, the full text of selected articles was reviewed by two reviewers according to the inclusion criteria (R. K. and I. R.). In the case of disagreements between the two authors/reviewers, the issue was resolved with the help of a third author (A. A. A.). Two independent reviewers (N. K. and P. A.) assessed the quality of the included cases, and all disagreements were resolved by mutual agreement. Incomplete records were removed.

The EndNote 20 Web tool (Clarivate, Philadelphia, PA) was used to manage duplicate records. Sorting of duplicate records was also done, again by two reviewers (A. A. A. and P. A.). Any issue that arose was resolved with the help of another reviewer. The number of retrieved and assessed records at each stage are provided in form of a PRISMA flow chart (Figure 1). EndNote 20 was used to make a PRISMA flow chart (Supplemental Table S2)

Figure 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram of the study depicts the process of article selection for systematic review. SSPE = subacute sclerosing panencephalitis.

Quality assessment.

Two independent reviewers (V. P. and R. K.) assessed the quality of the included cases. Disagreements were resolved amicably after discussion with other authors.

The Joanna Briggs Institute checklist was used to appraise the quality of included cases critically. The Joanna Briggs Institute Critical Appraisal tool for case reports consists of an eight-item scale that includes patient’s demographic characteristics, clinical details, details of laboratory workups, treatment provided, follow-up clinical condition, adverse events, and the key message from the case reports⁴ (Supplemental Table S3).

Data analysis.

Individual patient demographic characteristics, the status of measles vaccination in childhood, measles infection in childhood, duration of illness, duration and type of vision loss, clinical presentation, details of workup done, neuroimaging, anatomic localization for vision loss, and the course and outcome were recorded. We also recorded histopathological findings of the brain and/or retinal biopsies as well. Data are presented in tables with numbers and percentages. We used Microsoft Excel (Microsoft Corp., Redmond, WA) software for data collection and analysis.

RESULTS

Our systematic search revealed 88 reports describing the details of 96 patients. (Supplemental Table S4). We present our data in accordance with PRISMA guidelines. The PRISMA flowchart of our systematic review is provided as Figure 1. The critical appraisal report of all included cases as per the Joanna Briggs Institute checklist has been provided as Supplemental material 4). Demographic, clinical, neuroimaging, and brain/retina biopsy data of patients with SSPE with vision loss are summarized in Table 2.

Table 2.

Summary of epidemiological, clinical features, neuroimaging findings, histopathological features, and outcome of patients of SSPE with vision loss (N = 96)

Characteristic	Value
Age
Mean, years	17.86
Median, years	15
Mode, years	14
Range, years	2–62
NA, n	2
Gender
Female, n (%)	34 (34.4)
Male, n (%)	60 (62.5)
NA, n	2
Measles vaccination, n (%)
Yes	14 (14.6)
No	14 (14.6)
NA	68 (70.8)
Childhood measles, n (%)
Yes	46 (47.9)
No or NA	14 (14.6)
Geographic areas of reported cases (N = 88), n (%)
Indian subcontinent	24 (27.2)
Europe, except Turkey	23 (26.1)
Turkey	15 (17.0)
United States and Canada	14 (15.9)
Japan and Taiwan	6 (6.8)
Australia	4 (4.5)
Africa	1 (1.1)
West Indies	1 (1.1)
Duration of illness, n (%)
Sudden/acute	14 (14.6)
≤ 15 days	28 (29.1)
16 days–2 months	12 (12.5)
> 2–6 months	19 (19.8)
> 6 months–2 years	10 (10.4)
> 2 years	7 (7.3)
NA	6 (6.3)
Preceding vision loss, n (%)	73 (76)
Neuroimaging, n
NA	26
CT only	8
Normal	4
Cerebral atrophy	2
White-matter hypodensity	2
MRI
Normal	9
T2/FLAIR hypodensity	50
Cerebral atrophy	1
Spinal lesions only	1
Basal ganglion/thalamus involvement	3
Cortical ribboning	1
Splenium of the corpus callosum and hippocampus	2
Disappearing lesions	1
Site of lesion, n (%)
Retina and choroid	58 (60.4)
Optic nerve	9 (7.3)
Cerebral cortex	29 (30.2)
Brain biopsy, n	29
Retinal biopsy, n	7

CT = computed tomography; FLAIR = fluid-attenuated inversion recovery; MRI = magnetic resonance imaging; NA = not available; SSPE = subacute sclerosing panencephalitis.

The mean age of patients with SSPE was 17.9 years (median, 15 years; range, 2–62 years). Males outnumbered females (60:34). For two patients, demographic characteristics were not available. Childhood measles infection was confirmed in 46 (48%) patients. In the majority of patients (71%), information about measles vaccination was not available. Only in 14 patients (15%) was confirmed information about childhood measles vaccination available.

The duration of total illness/onset of vision loss ranged from sudden onset to more than 2 years. In 73 patients (76%), duration of illness/onset of vision loss was less than 6 months. In 73 patients (76%), visual manifestations appeared before the onset of encephalopathy. In SSPE, involvement of the retina (58 of 96, 60.4%) optic nerve (9 of 96, 9.3%), or cerebral cortex (29 of 96, 30.2%) was responsible for vision loss. Unilateral or bilateral viral chorioretinitis with macular involvement, or necrotizing retinitis with or without pigmentary retinal changes was demonstrated in the majority of patients with retinal lesions. The optic nerve was also involved concomitantly in several cases. Dominant optic nerve involvement was either in the form of optic atrophy or papillitis. In 29 patients (30%), cortical vision loss was reported.

In 70 patients, neuroimaging findings were recorded. T2/FLAIR magnetic resonance imaging (MRI) hyperintensity, present predominantly in the parieto-occipital region, was the most frequent (50 of 70, 71.4%) neuroimaging abnormality.

Brain and/or retinal biopsy data were available for 30 patients. In seven patients, histopathological findings of the retinal biopsy were described. Brain biopsy revealed features of diffuse encephalitis. Retinal biopsies revealed similar histopathological findings as were seen in SSPE-affected brain tissue. In seven brain/retinal biopsy tissues, either the measles virus or its component was detected.

In 60 patients, outcome details were available. All patients died, became akinetic mute, or the course of illness remained static during the follow-up period, which ranged from a few weeks to a few years. Only in one patient was there some improvement in neuroimaging.

DISCUSSION

Our systematic review of patients with SSPE with vision loss revealed that vision loss frequently precedes encephalopathy. The majority of patients had an acute fulminant course. The involvement of the retina was responsible for vision loss in the majority of patients. One third of patients had cortical blindness. Viral chorioretinitis with macular involvement or necrotizing retinitis with or without pigmentary retinal changes were typical retinal lesions demonstrated in SSPE. Retinal biopsy revealed similar histopathological changes, as demonstrated in brain tissues.

A WHO expert committee estimated the global incidence of SSPE as 4 to 11 patients with SSPE per 100,000 measles cases. In poor and developing countries with unsatisfactory measles immunization coverage, the incidence of SSPE is much greater.⁵ Currently, the majority of patients with SSPE are being reported from the Indian subcontinent, Turkey, and Papua New Guinea.¹ Even in our review, 41% of patients with SSPE with vision loss were either from the Indian subcontinent or from Turkey. Approximately 26% of patients (23 of 96) were from European countries. In developed countries, patients with SSPE are encountered infrequently, generally as a result of sporadic measles outbreaks. Another important observation from our review is that 76% of patients had an acute fulminant course; vision loss in many such patients was sudden or acute.

The pathogenesis of retinal and brain involvement is not precisely clear. The measles virus acquired during early childhood, possibly via a hematogenous route, spreads to the retina and brain. The measles virus uses lymphocytes and other inflammatory cells to enter the brain and retina, crossing the blood–brain barrier via a Trojan horse mechanism. Once inside the neuronal tissues, the measles virus undergoes several genetic conformational changes that help the virus to persist in neural tissues. Genetic mutations in the M protein are considered responsible for viral persistence. Genetic mutations in the F protein (an envelope protein) confer hyperfusogenic properties to the measles virus, facilitating trans-synaptic spread across the neurons^6,7 (Figure 2).

Figure 2.

Diagram explains possible pathogenetic mechanisms responsible for brain and retinal damage.

Retinal histopathological changes in SSPE are similar to what has been described in the SSPE-affected brain. These changes include perivascular cuffing and inflammatory cell infiltration, astrocytic gliosis, neuronal loss, and eosinophilic intranuclear inclusion bodies. Infrequently, genomic measles virus components were identified in brain and retinal tissues.⁸ In the retina, the inner plexiform and outer plexiform layers are affected predominantly. The synapses, crucial for the transneuronal spread of the measles virus, are generally concentrated in these layers.^9–11 The outer pigmentary retinal epithelium is generally spared.

Subacute sclerosing panencephalitis first affects the retina; the choroid layer is affected much later. Focal or multifocal choroiditis occurs after spillover of inflammatory changes to the choroid. Similarly, the virus spreads to the prelaminar optic nerve and leads to papillitis and optic neuritis.¹² Retinal changes in SSPE generally commence from the posterior pole, and the macular region is affected predominantly. Initially, there is an intense inflammatory change in the retina, leading to focal necrotizing macular retinitis. The adjacent choroid layer is also affected, giving a moth-eaten appearance. Macular pigmentary changes in SSPE are the result of the spillover of inflammatory changes to the retinal pigment epithelium. Later, there is macular scar formation, leading to retinal detachment and/or dragging of the surrounding retinal vessels.^10,13,14 Baillif et al.,¹⁵ with the help of high-resolution spectral domain optical coherence tomography, demonstrated that the nuclear layers were affected predominantly with retinitis and inflammation that spread from the inner layers to the outer layers, resulting in a characteristic moth-eaten appearance (Figure 3).

Figure 3.

Sketch diagram depicts that visual changes start primarily from the retina. Subsequently, other structures such as the optic nerve head and choroid layer are involved.

In one third of patients, vision loss was of cortical origin. In cortical vision loss, there are no ophthalmological causes and normal pupillary response. Brain biopsy studies have demonstrated that pathological abnormalities affect parieto-occipital brain areas predominantly.¹⁶ Subacute sclerosing panencephalitis first affects the occipital areas pathologically, then spreads to the anterior portion of the cerebral hemispheres. Subcortical structures, the brainstem, and the spinal cord are affected subsequently.¹⁷ Neuroimaging abnormalities are also present predominantly in the parieto-occipital periventricular regions. In our review, we recorded T2/FLAIR MRI hyperintensity in more than 70% of patients. These hyperintensities were demonstrated uniformly in almost all patients with SSPE who presented with cortical vision loss.

In conclusion, familiarity with abnormalities of visual pathways, such as characteristic retinal lesions, will help to make an early diagnosis of SSPE, as vision loss often precedes its other clinical manifestations. There was a disruption of measles vaccination during the lockdown and COVID-19 pandemic. In such a scenario, a greater incidence of SSPE is likely globally.

Note: Supplemental material appears at www.ajtmh.org.