Paracentral acute middle maculopathy in Susac syndrome after dual exposure to SARS-CoV-2 antigen

Background

Retinal findings following SARS-CoV-2 infection have been reported and are mostly related to the hypercoagulable state and consequent thrombotic microangiopathy.1 Paracentral acute middle maculopathy (PAMM) is considered a tomographic finding of the acute phase of retinal intermediate and deep capillary plexuses ischaemia and has been previously associated with SARS-CoV-2 infection.2 PAMM has also been described as a complication in association with Susac syndrome, a rare autoimmune microangiopathy of the brain, retina and inner ear that typically occurs in young women.3 We herein report a case of Susac syndrome that presented with the atypical PAMM manifestation of retinal compromise, leptomeningitis and inner ear impairment, following dual exposure to SARS-CoV-2 antigen, the first being acute infection, with subsequent vaccination with an inactivated coronavirus vaccine. The highlight of this case is the presentation of this rare autoimmune complication related to a hypercoagulable state after exposure to the SARS-CoV-2 antigen.

Case presentation

A woman in her 50s, a physician specialising in pathology, presented to the emergency department with fever, myalgia, headache and scotoma in the left eye (LE). Two months prior to admission, she had a mild case of SARS-CoV-2 infection which did not require hospitalisation. After a 1-month interval, following the Brazilian National Board of Health recommendation, she received the first dose of an inactivated virus COVID-19 vaccine (Sinovac Biotech, China) 1 month prior to admission. On emergency department admission, she underwent clinical, laboratorial and imaging investigation. Of note, she had a raised D-dimer level (1877 μg/mL, normal values <500), erythrocyte sedimentation rate (ESR) of 51 mm, raised factor VIII activity (169%, normal value <150%) and lymphocytopenia (600 cells).

Admission’s orbit MRI showed a discrete gadolinium (Gd) enhancement of the perineural region in the orbitary segment of both optic nerves that was relatively symmetric, suggestive of perineuritis. Additionally, the brain MRI demonstrated a tenuous increase in signal intensity of posterior supratentorial cortical sulcus in the post-Gd fluid-attenuated inversion recovery (FLAIR) sequence and Gd enhancement of the internal acoustic canal, compatible with leptomeningitis. A subsequent MR angiography of intracranial vessels was unremarkable, except for the identification of increased signal intensity of the left cochlea in post-Gd FLAIR acquisition (figure 1).

Investigations

Laboratory investigation included serological tests and a nasal swab to rule out infections; the extensive infectious work-up was negative, including a negative test for SARS-CoV-2. Extensive rheumatological investigation was also negative.

Cerebrospinal fluid (CSF) analysis revealed a lymphocytic meningitis (70 cells/mm³, 80% lymphocytes) with a high protein level (116 mg/dL) and normal glucose concentration. A molecular panel for meningitis/encephalitis (FilmArray) was carried out and resulted negative for bacteria, viruses, fungi, Mycobacterium tuberculosis and toxoplasma. Cultures for bacteria, mycobacteria and fungi were negative as well; SARS-CoV-2 was not detected in the CSF.

The intrathecal albumin index was 28.21 (normal value below 9.0); immunoglobulin G level was normal and the Felgenhauer and Reiber diagram suggested compromised blood–brain barrier without IgG production in the central nervous system. The CSF IgG level was high (9.60 mg/dL, normal values 0.30–3.40).

After 3 days of hospital admission, she complained of scotoma also in the right eye (RE), and visual acuity testing revealed 20/25 in RE and 20/100 in the LE. Anterior segment examination was unremarkable. Dilated fundus evaluation showed subtle white lesions at the macula in RE and marked lesions in LE. Optical coherence tomography (OCT) showed focal hyper-reflective change in the inner nuclear layer and inner plexiform layers consistent with PAMM. Fluorescein angiography and OCT angiography showed enlargement of the foveal avascular zone (FAZ) bilaterally (figure 2).

Full-field eletroretinogram (ERG) showed a mild reduction of the ganglion cell function with normal photoreceptor responses in both eyes; multifocal ERG showed reduced foveal and parafoveal responses in both eyes, the LE being more affected (figure 3).

The patient also complained of hearing impairment, and audiometry showed bilateral neurosensory loss in frequencies between 3000 and 8000 Hz (right ear) and 2000 and 8000 Hz (left ear). Speech recognition threshold was obtained at 20 dB, bilaterally. Speech recognition percentage index was 88% at 50 dB (right) and 84% at 50 dB (left) for monosyllables and 96% at 5 dB (right and left) for disyllables. Auditory brainstem response was normal.

Differential diagnosis

Laboratory investigation for etiologic agents ruled out SARS-CoV-2 and other respiratory pathogens (enterovirus, rhinovirus, influenza, metapneumovirus, respiratory syncytial virus, Bordetella pertussis, Chlamydophila pneumoniae and Mycoplasma pneumoniae), dengue, HIV, syphilis, hepatitis C, Epstein-Barr virus, CMV, Bartonella, toxoplasma, tuberculosis (interferon-gamma release assay) and coxsackievirus. Rheumatological investigation resulted in the following negative results: antinuclear antibodies (ANA), rheumatoid factor, antineutrophil cytoplasmic antibodies (ANCA), anti-Ro, anti-La, anticardiolipin, anti-beta2 glycoprotein and serum anti- myelin oligodendrocyte glycoprotein (MOG).

Besides having ruled out infectious causes for meningitis/encephalitis with the molecular panel, metagenomic CSF analysis did not detect RNA associated with pathogenic micro-organisms either.

Due to the severity of clinical presentation, empirical antibiotic and antiviral treatment was introduced before test results became available. The patient received empirical intravenous antibiotic therapy with ceftriaxone (100 mg/kg/day) and ampicillin (200 mg/kg/day), sulfamethoxazole–trimethoprim (800–160 mg two times per day) and the antiviral acyclovir (10 mg/kg three times a day).

Treatment

Three days after empirical therapy was started, investigation came back negative for infectious causes; having ruled out infection, empirical therapy was stopped.

Due to the clinical presentation of central nervous system, retinal and cochlear involvement, the exclusion diagnosis of Susac syndrome was made, and the patient was started on intravenous pulse therapy, which consisted of methylprednisolone (1 g/day) for 5 days and prophylactic enoxaparin 40 mg/day. After 5 days of intravenous pulse therapy with methylprednisolone, she noted an improved vision: 20/20 RE and 20/30 LE; she also showed reduction in the ESR and normalisation of CSF parameters (3 cells/mm³ and 22 mg/dL of protein). After completing intravenous steroid treatment, she received oral steroids, starting with 60 mg/day and gradual tapering down (10 mg/week).

Outcome and follow-up

The patient presented 1 month later with improvement of visual acuity (20/25 RE and 20/30 LE); the affected areas on the retina evolved with resolution of the white lesions and very subtle retinal thinning, which is consistent with the natural history of PAMM and better evidenced at the follow-up OCT scan. Due to the favourable clinical response to steroid therapy, it was considered there was no need to introduce further immunosuppressive therapy. OCT angiography showed persistence of FAZ enlargement (figure 4).

After 6 months of the initial complaints, there was improved visual acuity (20/15 OU); ERG showed diffusely decreased responses in both eyes compatible with sequelae of the original autoinflammatory insult (figure 3).4 5 During steroid tapering, the patient presented with a headache, and 10 mg/day was found to be the cut-off dose. There were no other neurological symptoms or neuroimaging signs of disease activity. Despite not receiving chronic immunosuppressive therapies, the patient did not experience any relapses after 6 months of follow-up.