Optical Coherence Tomography Angiographic Follow-Up in a Case of Subacute Sclerosing Panencephalitis and Unilateral Necrotising Retinitis

ABSTRACT

We present a 20-year-old woman who was diagnosed with subacute sclerosing panencephalitis (SSPE) 20 months after presenting with unilateral retinitis. At presentation, the patient had two inferotemporal macular lesions in her left eye. Corresponding to these areas, optical coherence tomography (OCT) showed hyporeflective spaces with loss of nearly all of the retinal layers. OCT-angiography (OCTA) demonstrated some flow deficit areas with a reduction in the vessel density. Her serum measles antibody titre was high (IgG >5000.0 mIU/ml). Twenty months later the macular lesions had diminished in size, and there was some focal retinal thinning with interruption of the ellipsoid zone. OCTA showed that the flow deficit areas were diminished in size together with the relatively improved perfusion density. Neurological examination disclosed myoclonic jerks. Neuropsychological assessment demonstrated impaired executive function, attention, and narrowed lexical fluency. Measles IgG antibody was high in the cerebrospinal fluid (>230.0 U/ml). Brain magnetic resonance imaging demonstrated bilateral, non-specific, small foci of T2 hyperintensity in the frontoparietal subcortical white matter and centrum semiovale. The present case is the first where OCTA findings of SSPE-related retinal lesions have been described.

Introduction

Subacute sclerosing panencephalitis (SSPE) is a rare progressive central nervous system disorder affecting both the grey and white matter in the brain and caused by measles virus that can be prevented by immunisation.¹ However, post-immunisation SSPE can also occur,² and this is presumed to be related to wild measles infection prior to immunisation.³ The latent period between the measles infection and SSPE may vary between 3 months to 18 years and the disease occurs two to three times more frequently in males.⁴ Although the disease has an insidious onset, lethargy, myoclonus, seizures, dysautonomia, behavioural changes, and progressive encephalopathy with dementia can ensue.⁵

The diagnosis of SSPE is based on clinical findings, electroencephalography (EEG), and the titre of measles antibodies in the cerebrospinal fluid (CSF). Dyken’s criteria can be used to establish the diagnosis of SSPE. It consists of: (1) typical clinical presentation with progressive intellectual deterioration with signs of myoclonus; (2) characteristic EEG changes; (3) elevated CSF globulin levels; (4) elevated measles antibody titres in the serum (≥1:256) and/or CSF (≥1:4); and (5) brain biopsy suggestive of measles.^6–9

Visual involvement may occur in 10–50% of the SSPE cases.¹⁰ These manifestations include papilloedema, optic neuritis, necrotising retinitis, retinal vasculitis, chorioretinitis, multifocal subretinal lesions, acute multifocal placoid pigment epitheliopathy-like lesions, outer retinitis, optic atrophy, temporal pallor, homonymous visual field deficits, and cortical blindness.^11–13 A transient relative afferent pupillary defect and anterior uveitis can also be noted.¹⁴ Nystagmus, supranuclear gaze paresis, ocular motor nerve paresis, Bell’s palsy, and other involuntary eye movements, usually become manifest relatively late in the disease course.^15,16

We herein report a case of slowly progressing SSPE that presented first with unilateral macular necrotising retinitis and describe fundus findings on multimodal imaging including optical coherence tomography (OCT) angiography (OCTA) at presentation and after 20 months of follow-up.

Case report

A 20-year-old otherwise healthy woman was referred to us in December 2020 due to subtle visual symptoms in her left eye without overt systemic complaints. On examination, her best-corrected visual acuity (BCVA) was 1.0 in both eyes. Slit-lamp examination was unremarkable in the right eye but there was mild vitritis in the left eye. While the right fundus was normal, there were two reddish patch-like inferotemporal macular lesions with relatively distinct borders and a few retinal haemorrhages in the left eye (Figure 1a). The patchy lesions looked hyperautofluorescent on fundus autofluorescence imaging (Figure 1b), while the right fundus autofluorescence image was unremarkable (Heidelberg Spectralis, Heidelberg Engineering, Heidelberg, Germany). Fluorescein angiography (Heidelberg Spectralis, Heidelberg Engineering, Heidelberg, Germany) showed no abnormality in the right eye whereas there was staining of the two lesions in the left eye (Figure 1c,d). OCT (Heidelberg Spectralis, Heidelberg Engineering, Heidelberg, Germany) depicted normal foveal contours in both eyes but the tomographic sections corresponding to the patchy lesions of the left macula revealed hyporeflective spaces with loss of nearly all retinal layers, described as a ‘moth-eaten’ appearance of the retina with sparing of the retinal pigment epithelium (RPE) and inner limiting membrane (Figure 1e,f). OCTA (Triton, Topcon Inc., Oakland, New Jersey, USA) depicted the flow deficit areas with a reduction in the vessel density on the superficial capillary plexus (SCP) and deep capillary plexus (DCP) slabs (3 × 3 and 6 × 6 mm) corresponding to the lesions at the left fundus and there were well‐demarcated areas on en-face OCT, most prominent at the level of the DCP (Figure 2a–d). The vessel density maps at the admission (3 × 3 OCTA) are shown in Figure 3a,b.

Figure 1.

Left eye at the first presentation (December 2020). (a) Colour fundus photograph depicting two reddish patch-like inferotemporal macular lesions with relatively distinct borders (arrows) and a few retinal haemorrhages. (b) Fundus autofluorescence image demonstrating that the patchy lesions look hyperautofluorescent (arrows). (c) Early and (d) late phases of fluorescein angiography exhibiting staining of the two lesions (arrows). (e and f) Optical coherence tomography images corresponding to the patchy lesions revealing hyporeflective spaces with loss of nearly all retinal layers but with sparing of the retinal pigment epithelium and inner limiting membrane.

Figure 2.

Left eye at the first presentation (December 2020). Optical coherence tomography angiography - (a) 3 × 3 and (b) 6 × 6 scans showing the flow deficit areas with a reduction in the vessel density at the superficial and deep capillary plexus slabs (arrowhead). En-face optical coherence tomography - (c) 3 × 3 and (d) 6 × 6 sections delineating the well‐demarcated areas, most significant at the level of deep capillary plexus (arrowhead).

Figure 3.

3 × 3 optical coherence tomography angiography vessel density maps of the left eye. At the first presentation (December 2020) – superficial (a) and (b) deep capillary plexus slabs. At the last examination (August 2022) – superficial (c) and deep (d) capillary plexus slabs showing the relatively improved perfusion density.

A routine laboratory work up was carried out. The white blood cell count, haemoglobin level, erythrocyte sedimentation rate, blood glucose, electrolytes, liver and kidney function tests, thyroid-stimulating hormone, anti-double-stranded deoxyribonucleic acid antibody, anti-nuclear antibody, chest radiograph, echocardiography, and abdominal ultrasound were normal. Serology tests for human immunodeficiency virus, hepatitis B/C viruses, Varicella zoster virus, toxoplasma, syphilis, and Borrelia were negative. The quantiferon test was also negative. Strikingly, the blood measles antibody titre was very high (IgG >5000.0 mIU/ml; negative < 200).

A diagnosis of SSPE was suspected though she had received measles immunisation in early infancy as it is mandatory in Turkey. A lumbar puncture and detailed neurological evaluation were planned but the patient refused further investigations at that time.

In August 2022, 20 months after the first visit, she was re-examined as she accepted our invitation for a follow-up eye visit despite having no further ocular symptoms. Her BCVA was 1.0 and her anterior segment was normal in both eyes. On ophthalmoscopy, the previously noted two lesions could be faintly seen as slightly hypopigmented areas (Figure 4a). These areas were hypoautofluorescent (Figure 4b). On OCT, the lesions had diminished in size and there was focal retinal thinning with significant disorganisation and interruption of the ellipsoid zone (Figure 4c,d). The 3x3 OCTA   scans showed that the low deficit areas had diminished in size with relatively improved perfusion density at the level of the SCP and DCP corresponding to the previous lesion locations (Figure 4e). En-face 3 x 3 OCT scans demonstrated an almost homogeneous hyperreflective area at the level of the SCP and DCP (Figure 4f). The vessel density maps at the last visit (3 × 3 OCTA) are shown in Figure 3c,d demonstrating the relative improvement.

Figure 4.

Left eye at the last examination (August 2022). (a) Colour fundus photograph showing that the two previously noted lesions can be faintly recognised and look slightly hypopigmented (arrows). (b) Autofluorescence image outlining the areas as hypoautofluorescent spots (arrows). (c and d) Optical coherence tomography images depicting the diminished sized lesions with a focally thinned and disorganised macula. (e) 3 × 3 optical coherence tomography angiography exhibiting that the flow deficit areas are diminished in size with relatively improved perfusion density at the level of superficial and deep capillary plexuses (arrowhead) corresponding to the previous lesion locations. (f) 3 × 3 en-face optical coherence tomography sections revealing an almost homogeneous hyperreflective area at the level of superficial and deep capillary plexuses (arrowhead).

On neurological assessment, she looked markedly irritated and had inappropriate social behaviour that could be interpreted as impulsive. She was uncooperative, impersistent, and unattentive during the examination. Her mother reported that she had a hard time maintaining attention at work and had therefore quit her job due to low job performance. Neurological examination showed subtle myoclonic jerks over her whole body that did not affect her walking or maintaining the daily tasks. There were no pyramidal, cerebellar, or extrapyramidal signs.

CSF analysis showed no cells on cytology with a normal protein level (28.5 mg/dl) but the CSF measles IgG antibody titre was significantly high (>230.0 U/ml; normal <25 U/ml). Sleep-activated EEG showed alpha rhythm without any abnormality. Neuropsychological assessment demonstrated impaired executive function and attention, as well as narrowed lexical fluency. Brain magnetic resonance imaging (MRI) showed bilateral, non-specific, small foci of T2 hyperintensity in the frontoparietal subcortical white matter and centrum semiovale (Figure 5). Diffusion-weighted imaging was normal. We concluded that the disease was possible SSPE stage 2.

Figure 5.

Brain magnetic resonance imaging. (a) Coronal fluid attenuated inversion recovery (FLAIR) image showing foci of hyperintensity in the subcortical white matter (arrows). (b) Axial T2-weighted image showing foci of hyperintensity in the centrum semiovale (arrows).

Discussion

SSPE can be diagnosed based on whether the patient fulfils any three of the five Dyken’s criteria.⁷ Raised anti-measles antibody titres of 1:256 or greater in serum, and 1:4 or greater in CSF are also considered diagnostic of SSPE.⁶ The present case fulfils the typical clinical presentation due to her progressive intellectual deterioration with signs of myoclonus, and the elevated measles antibody titres in serum and CSF. Thus, the present case was possible SSPE. Unfortunately, CSF globulin levels could not be measured at the hospital due to the lack of a testing kit. There were no typical EEG findings probably due to the early stage of the disease.

The classic clinical course of SSPE has been divided into four stages. In stage 1, behavioural changes and cognitive decline occurs; stage 2 is manifested by myoclonus and motor deterioration; stage 3 consists of pyramidal and extrapyramidal manifestations, disappearance of myoclonus, and alteration in the sensorium; and a vegetative state occurs in stage 4.⁶ Fulminant SSPE may not follow the usual course of the disease.¹⁷ The first sign of SSPE is generally subtle intellectual impairment, often leading to a decline in school performance. Cognitive decline is also considered as one of the dominant findings of adult SSPE.¹⁸ Myoclonic jerks are usually the most prominent physical manifestation of the disease.¹⁹ Early in the course of disease, the EEG may show only moderate, non-specific slowing and can stay normal, as in the present case.^1,20,21

The characteristic histopathological finding of SSPE is the presence of type A acidophilic intranuclear inclusion bodies in the brain and neuronal cells of the retina.²² Optic nerve changes are thought to be secondary to elevated intracranial pressure or direct infection and inflammation caused by the virus.²³ Intranuclear inclusions may be found in the optic nerve, thus explaining the optic neuritis.²⁴ Neuronal loss, demyelination, perivascular lymphocytic infiltrates, and neurofibrillary tangle formation are among the other neuropathological findings.²⁵

In most SSPE patients, visual symptoms develop concurrently with the neurological symptoms or ocular symptoms develop shortly after the onset of the neurological symptoms.^26,27 Measles virus-acquired virulent neurotropism may occur in the retina before involvement of the central nervous system.^6,28 Neurological symptoms may even occur years after ocular involvement, but only in a small number of patients, such as the present case. Table 1 shows the previously published cases of SSPE where neurological findings developed long after the appearance of fundus findings.^{1,10,19,24,26,27,29–34} Measles virus spreads among neurons by axonal connections; nevertheless, it has been postulated that the measles virus attaches to a cell receptor, that is concentrated at the synapses, to enter the neurons.³⁵ The inner nuclear and ganglion cell layers appear to be more severely affected than the other retinal layers.²⁴

Table 1.

Previously published cases of subacute sclerosing panencephalitis where neurological findings appeared long after the fundus findings.

Author reference number	Number of cases	Age/Sex	Laterality	Type of fundus presentation	Interval between the onset of visual complaints and the neurological symptoms	Interval between the initial visual symptoms and worsening of the general condition
Hwang et al.1	1	14/F	BE (LE 27 months after RE)	Macular retinitis	At the same time	84 months
Babu et al.10	1 of 2	25/M	BE	Macular retinitis	36 months	N/A
Zagami et al.19	1	14/M	RE	Chorioretinal scar	20 months	28 months
De Laey et al.24	1 of 2	15/M	RE	Serous macular detachment with retinal infiltrates	36 months	39 months
Jeevagan et al.26	1	36/M	LE	Chorioretinitis	24 months	24 months
Oray et al.27	1	15/F	BE (LE 2 days after the LE)	Optic neuritis and necrotising retinitis	48 months	N/A
Serdaroğlu et al.29	1 of 2	14/M	BE	Macular retinitis	18 months	N/A
Holmes et al.30	1	37/Transgender F	LE	Neuroretinitis	39 months	42 months
Salmon et al.31	1	16/F	BE (LE 9 months after the RE)	Vein occlusion due to vasculitis	24 months	28 months
Baillif et al.32	1	39/M	BE (LE 36 months before the RE)	Macular vasculitis	37 months	39 months
Chawla et al.33	1	20/F	BE (LE 3 months after the RE)	Macular chorioretinitis	54 months	72 months
Tomoda et al.34	1	8/M	BE (LE 20 months after RE)	Chorioretinitis	24 months	24 months
Present case	1	20/F	LE	Extramacular necrotising retinitis	20 months	N/A

BE = both eyes; F = female; LE = left eye; M = male; N/A = not available RE = right eye.

The most characteristic ophthalmological lesion is macular necrotising retinitis.²⁸ Retinal oedema, retinal folds, retinal haemorrhages, sensory retinal detachment, retinal venous dilatation, retinal vasculitis, retinal vascular occlusions, and RPE detachments are among the findings that may accompany retinitis.²³ Focal retinitis may be seen with or without macular involvement, unilaterally or bilaterally and usually not associated with any apparent vitreous reaction in SSPE patients.³⁶ Retinal lesions are usually bilateral and macular involvement is common but there can be unilateral presentation, such as in our case.

Structural OCT is a very valuable tool to evaluate inner retinal necrosis in patients with SSPE. In a recent case report, Cam et al. defined necrotising retinitis as a severe loss of retinal structure, characterised by a moth-eaten-like retinal appearance.²⁸ At the earliest disease stage, they observed oedema in the internal and external plexiform layers, increased reflectivity of the inner retinal layers, and interruption of the ellipsoid zone in OCT sections. They also pointed out that when necrotising retinitis progresses, inner retinal layers show increased reflectivity, there is necrosis of the retinal nerve fibre layer, ganglion cell layer, and inner nuclear layer; and hyporeflective cystoid cavities can be seen on OCT in association with the internal limiting membrane detachment. The lesions progress over time with necrosis in the outer retinal layers, hyperreflective retinal and choroidal cavities, and some retinal atrophy tomographically.²⁸

OCTA technology is a relatively new imaging tool to evaluate the posterior segment diseases, but its place has not been defined as certain as dye angiographies yet in uveitis. OCTA utilises speckle, phase variance, or amplitude decorrelation techniques to detect the motion contrast and thereby visualise blood flow in various layers of the retina and choroid.³⁷ In a previously reported SSPE case, wide-field fluorescein angiography revealed leakage from the retinal vessels with perivascular staining, capillary nonperfusion, retinal vessel drop-out, and arteriovenous loop formation.³⁸ In accordance with those fluorescein angiographic findings, we demonstrated areas of flow deficit and diminished perfusion density corresponding to the retinal lesions on OCTA examination in the present case.

In a recent review, we suggested that OCTA might help to detect the inflammatory choroidal neovascularisation and evaluate the lesion nature in some white dot entities.³⁹ Although active toxoplasmic chorioretinitis lesions can be quantified with OCTA technology and concurrent image analysis techniques,⁴⁰ it is hard to say whether OCTA and en-face OCT images gave us additional diagnostic clues in the present case over structural OCT. However, two retinal necrotic sites could easily be visualised, especially in the SCP and DCP slabs.

As seen during the follow-up of our patient, macular lesions exhibit areas of patchy pigmentation with a depigmented rim and can be markedly different from other inflammatory retinal disorders, such as the toxoplasmic chorioretinitis.^10,19 On the other hand, an SSPE scar is often poorly demarcated, exhibits less retinal and choroidal destruction, and has scarce peripheral pigmentation.³⁶ Still, some of the SSPE cases were misdiagnosed as chorioretinal toxoplasmosis and treated accordingly.^33,41

Some reports suggest that the disease course is mild and spontaneous remission rate is high in cases presenting with ophthalmological symptoms.^42,43 Yuksel et al. evaluated 59 patients with SSPE and found that 25 patients (42.4%) had ocular findings including: exotropia (one patient); temporal or diffuse atrophy of the optic nerve head (seven eyes/four patients); optic nerve head oedema (15 eyes/eight patients); absence of the foveal reflex (three eyes/two patients); retinal pigment epithelial changes/defects most prominent in the fovea (eight eyes/five patients); active foci of chorioretinitis (six eyes/four patients); chorioretinitis scar (one eye); increased tortuosity of the retinal vessels (four eyes/two patients); and retinal oedema (five eyes/three patients). Ocular involvement was bilateral in 22 (88%) patients.²⁵

Brain imaging studies may be very helpful in the differential diagnosis. Anlar et al. evaluated 34 MRI studies of 26 patients with SSPE and showed that brain lesions frequently involved the periventricular or subcortical white matter and exhibited high signal intensity in T2-weighted images most commonly. They also underlined that lesions tended to start in the cortex-subcortical white matter and showed progression with periventricular white matter involvement and diffuse cerebral atrophy.⁴⁴ In the present case, MRI showed bilateral non-specific small foci of T2 hyperintensity in the frontoparietal subcortical white matter and centrum semiovale with no diffusion restriction. SSPE tends to show bilateral confluent lesions in the subcortical area and deep white matter along the frontoparietal region, which may have diffusion restriction.^45,46 Our patient’s MRI findings are not specific for SSPE encephalitis and there is no relationship between the patient’s symptoms and the extent of brain MRI lesions.

Measles still occurs as epidemics in developing countries and, as mentioned above, visual complaints may occasionally be the presenting symptom of SSPE. Fundus changes may precede the neurological symptoms and signs and may give a clue to the clinician to reach the diagnosis earlier. SSPE should be in the differential diagnosis, especially in young patients, for necrotising retinitis and mild vitreous inflammation, irrespective of the presence of neurological symptoms and signs. In cases with established neurological involvement the diagnosis of SSPE retinitis is relatively less challenging. To our best knowledge, evolution of the OCTA features was described first in the present case.

Funding Statement

The authors reported there is no funding associated with the work featured in this article.

Disclosure statement

No potential conflict of interest was reported by the authors.