Susac syndrome

Key Points at a Glance

Susac syndrome (SuS) is a rare autoimmune microangiopathy affecting precapillary arterioles of the brain, retina, and inner ear.
The clinical triad consists of encephalopathy, branch retinal artery occlusion (BRAO), and sensorineural hearing loss, but only about 13% present with all three at initial diagnosis.
It is more common in women (female:male ≈ 3–3.5:1), with a peak age of onset between 20 and 40 years. ¹⁾
Brain MRI shows characteristic snowball-like lesions in the central corpus callosum, an important finding for differentiating from multiple sclerosis.
No established RCTs exist; treatment is mainly empirical, combining high-dose steroids, IVIG, and immunosuppressants. ²⁾
Delayed diagnosis can lead to severe sequelae, so SuS should be considered in young patients presenting with concurrent unexplained headache, visual field defects, and hearing loss.

1. What is Susac Syndrome?

Susac syndrome (SuS) is a rare autoimmune endotheliopathy first described in 1979 by American neurologist John Susac. It is a microangiopathy affecting precapillary arterioles of the brain, retina, and inner ear, also known as SICRET (Small Infarcts of Cochlear, Retinal, and Encephalic Tissue).

Epidemiology

Sex difference: More common in women (female:male ≈ 3–3.5:1). ¹⁾
Peak age of onset: 20–40 years (reported range 7–72 years).
Incidence: 0.024–0.13 per 100,000 people per year in Central Europe. ²⁾ Konitsioti et al. reported 0.24 per 1,000,000 people. ¹⁾
Cumulative reported cases: Approximately 500 cases as of 2021. ³⁾
Pediatric cases: About 1% of all reports. The youngest case was 2.5 years old. ³⁾
Distribution: More common in white populations in North America and Europe. Cases during pregnancy and postpartum have also been reported.

Classification of Clinical Course

Monocyclic: Spontaneous remission within 2 years.
Polycyclic: Recurrence beyond 2 years.
Chronic continuous: Persists without remission.

In a review of 151 cases, the recurrence rate was 24% (36 cases), and the median time from diagnosis to recurrence was 4 months. ¹⁾

Q How rare is Susac syndrome?

The annual incidence in Central Europe is 0.024–0.13 per 100,000 people, and as of 2021, the cumulative number of reported cases worldwide is approximately 500. ²⁾³⁾ Because it is a very rare disease, diagnosis may take an average of 5 months.

2. Main Symptoms and Clinical Findings

The triad is rarely present at onset; in a review of 304 cases, only 13% had the triad at the initial visit. The average time from initial symptoms to completion of the triad is about 5 months. CNS symptoms are the most common initial presentation, followed by visual symptoms, and then vestibular/cochlear symptoms.

Subjective Symptoms

Headache: Migraine-like headache occurs in 80% of patients and may precede other symptoms by several months.
CNS symptoms: cognitive dysfunction, confusion, emotional disturbance, behavioral changes, apathy, psychotic state, decreased level of consciousness.
Other CNS symptoms: ataxia, dizziness, gait abnormality, sensory disturbance, upper motor neuron signs, paralysis, dysarthria, diplopia, urinary disturbance.
Visual symptoms: blurred vision, photopsia, visual field defects (scotoma, severe defects).
Vestibular and cochlear symptoms: bilateral (sometimes unilateral) sensorineural hearing loss. Often affects low to mid frequencies. May be accompanied by tinnitus and dizziness.

Clinical Findings (Findings Confirmed by Physician Examination)

Fundus and Imaging Findings

BRAO: Occlusion at the retinal arteriole level. Often bilateral and asymmetric. ³⁾

Gass plaques: Small yellow dots appearing at bifurcations of retinal arteriolar walls. Reflect sites of endothelial damage. ⁴⁾

AWH: Arteriolar wall hyperfluorescence. Confirmed by FA and SD-OCT.

OCTA findings: Areas of decreased blood flow in superficial and deep vascular plexuses, enlargement of FAZ. ⁴⁾

MRI and Hearing Findings

Corpus callosum snowball lesions: T2/FLAIR hyperintense lesions, commonly in the central corpus callosum, 3–7 mm. ³⁾

Corpus callosum holes: In advanced stages, T1 hypointense “holes”, icicle-shaped, or spoke-like patterns.

Leptomeningeal enhancement: Detected in 100% on post-contrast FLAIR. ³⁾

Sensorineural hearing loss: Typically bilateral elevation of thresholds in low to mid frequencies.

SD-OCT findings: In the acute phase, thickening and hyperreflectivity of the inner retinal layers. In the chronic phase, patchy thinning of the RNFL to OPL (especially temporally). The outer nuclear layer and photoreceptor layer are preserved.
CSF findings: Mild lymphocytic pleocytosis and elevated protein. Oligoclonal bands are usually negative (differentiating from MS).
Skin findings (rare): Livedo reticularis and livedo racemosa. Five cases have been reported in the literature. ⁶⁾

Q Can all three symptoms be present from the onset?

In a review of 304 cases, only 13% had the triad of encephalopathy, BRAO, and sensorineural hearing loss at initial presentation. It takes an average of 5 months from the first symptom to the complete triad. Therefore, early diagnosis at the stage of 1–2 symptoms is important.

3. Causes and Risk Factors

The etiology of SuS is presumed to be autoimmune endothelial cell damage. No clear preventive measures have been established.

CD8-positive T cell (CTL)-mediated endothelial damage: Oligoclonal expansion of terminally differentiated activated CD8+ T cells is considered the main mechanism. ³⁾ CTLs adhere to microvascular endothelium, causing endothelial injury, increased vascular permeability, and microinfarctions. ⁶⁾
Anti-endothelial cell antibodies (AECAs): Detected in about 30% of SuS patients. They may mediate intravascular thrombus deposition but are not specific to SuS. ⁶⁾
Mechanism of autoreactive CTL generation: Chronic TCR signaling, changes in genomic methylation profiles, and increased TOX gene expression are thought to be involved. ⁶⁾
Association with infection: Case reports of onset after SARS-CoV-2 infection exist. ⁵⁾
Onset after vaccination: A case report of onset 5 days after COVID-19 vaccination (BNT162b2) has been reported. ⁷⁾
Hormonal factors: Suggested by the predominance in women and reports of onset during pregnancy and postpartum.
The reason why arterioles in the brain, retina, and inner ear are selectively affected is unknown.

4. Diagnosis and Examination Methods

EuSaC Diagnostic Criteria (2016)

The European Susac Consortium (EuSaC) diagnostic criteria proposed by Kleffner et al. in 2016 are widely used. ³⁾¹⁾

Definite SuS: Findings in all three organs: brain, eye, and ear.
Probable SuS: Findings in two organs.
Possible SuS: Findings in one organ.

Organ-Specific Confirmation Methods

Brain: MRI (FLAIR/T2 hyperintense lesions, characteristic snowball-like lesions in the central corpus callosum).
Eye: FA (BRAO, AWH, Gass plaques), SD-OCT (inner retinal layer changes), OCTA (microvascular hypoperfusion). ⁴⁾
Ear: Pure-tone audiometry (low-to-mid frequency sensorineural hearing loss).

Auxiliary Tests

CSF examination: Elevated protein, mild lymphocytosis. Negative oligoclonal bands are useful for excluding MS.
EEG: May be performed to confirm encephalopathy (e.g., diffuse slowing). ³⁾
Cerebral angiography: Usually normal (affected vessel caliber <100 μm). ³⁾
Biomarkers (research stage): Neurofilament light chain (NfL) and GFAP are promising for monitoring relapses and severity. ²⁾

Differential Diagnosis

The main diseases that need to be differentiated from SuS are listed below.

Disease	Key differentiating features
Multiple sclerosis (MS)	Corpus callosum lesions in MS are typically on the lower surface, while in SuS they are central. Positive OCB suggests MS.
ADEM	Large, asymmetric demyelinating lesions
SLE / Sarcoidosis	Differentiated by systemic findings and serological tests of each disease

In young patients with recurrent BRAO, SuS should be considered in the differential diagnosis. The triad of low-frequency hearing loss, CNS lesions centered on the corpus callosum, and BRAO provides clues.

Q What is the difference from multiple sclerosis?

The most important differentiating point is the location of corpus callosum lesions. In MS, lesions are typically on the lower surface (callosal-septal interface), while in SuS they are central. Also, MS is often positive for oligoclonal bands, whereas SuS is usually negative. ³⁾

5. Standard Treatment

There are no RCTs for SuS; all treatments are based on case series and expert opinion. ³⁾²⁾

Acute Phase Treatment

High-dose steroids: Methylprednisolone (MP) 1000 mg/day intravenously for 3–7 days, followed by oral prednisone 1 mg/kg/day, tapered over several weeks. ²⁾
IVIG (intravenous immunoglobulin): 2 mg/kg for 2 days, every 2 weeks. Recommended for prevention of acute relapses during steroid tapering. Continue for at least 12 months. ²⁾
Acetylsalicylic acid (aspirin): Recommended for early use due to antiplatelet and anti-inflammatory effects. ²⁾
Rapid-acting immunosuppressants for severe cases:
- Cyclophosphamide: First-line for severe CNS lesions. 10–15 mg/kg (max 1200 mg) intravenously for 2 cycles over 2 weeks. ²⁾
- Rituximab: 1000 mg intravenously, repeated after 14 days, then every 6 months. Recommended for severe SuS or recurrent cases. ²⁾
Plasmapheresis: Adjunctive therapy for refractory cases.

Maintenance Therapy (approximately 2 years)

Mycophenolate mofetil (MMF): Current first-line immunomodulator. Used alone or in combination with tacrolimus. ²⁾
Azathioprine: Alternative to MMF. ²⁾
Methotrexate: Used alone or in combination with AZA/MMF. Caution for teratogenicity (as peak age overlaps with reproductive age). ²⁾
Taper steroids every 2–4 weeks, transitioning to immunosuppressants with lower long-term side effect risk.

Management in Remission

Before discontinuing treatment, periodically monitor for recurrence using MRI and FA.
BRAO recurrence often resolves spontaneously; only close monitoring is recommended.
For residual hearing loss, hearing aids or cochlear implants are options.

Q How long should treatment be continued?

Maintenance therapy is generally recommended for about 2 years. Before discontinuing treatment, it is important to check for recurrence using brain MRI and FA. Some cases may relapse upon steroid tapering, so careful gradual reduction is necessary. ²⁾

6. Pathophysiology and detailed pathogenesis

Endothelial injury mediated by CD8+ T cells

Oligoclonal expansion of terminally differentiated activated CD8+ T cells (CTLs) is considered the core pathology of SuS. ³⁾

CTLs adhere to microvascular endothelium, causing endothelial injury → increased vascular permeability → microinfarction. ³⁾¹⁾
Lesions commonly occurring in the corpus callosum, inner ear, retina, and cerebellum reflect this mechanism. ³⁾
Generation of autoreactive CTLs involves chronic TCR signaling, genomic methylation changes, and increased TOX gene expression. ⁶⁾

Anti-endothelial cell antibodies (AECAs)

Detected in approximately 30% of patients with definite SuS. ⁶⁾²⁾ They are hypothesized to mediate thrombotic deposition within blood vessels, but are not specific to SuS.

Microvascular-level pathology

Microcortical lesions undetectable by MRI exist, explaining the discrepancy between imaging findings and clinical symptoms (diffuse encephalopathy). ³⁾ Contrast enhancement and its reversibility in the acute phase are thought to result from capillary leakage. ³⁾

Association with COVID-19

SARS-CoV-2 may contribute to endothelial dysfunction and microvascular occlusion via ACE-2 receptors, and has been suggested as one mechanism for SuS onset after infection. ⁵⁾

7. Latest research and future perspectives (investigational reports)

Natalizumab

An anti-α4 integrin antibody that inhibits the VLA-4 pathway of CD8+ T cell-mediated endothelial damage.

Konitsioti et al. (2025) reported off-label use in two female patients, achieving clinical and imaging stability for 16 and 22 months. ¹⁾ Disease improvement has also been reported in mouse models. However, 2 of 4 patients relapsed after discontinuation, and stabilization was achieved by shortening the dosing interval from 8 weeks to 6 weeks. One case of incomplete SuS worsened after natalizumab administration. Use requires negative JC virus antibody status. ¹⁾

Biomarker research

Grygiel-Górniak et al. (2025) reported that NfL (neurofilament light chain) significantly increases during relapse and is promising for monitoring disease activity. GFAP (glial fibrillary acidic protein) increases in severe SuS, but its dynamic changes during relapse are less pronounced than NfL. ²⁾

OCTA (Optical Coherence Tomography Angiography)

Non-invasive perfusion assessment of superficial and deep vascular plexuses is possible, and it is expected as an alternative or complementary method to FA. ⁴⁾

8. References

Konitsioti AM, Grajewski R, Schlamann M, et al. Successful Natalizumab Treatment of Two Female Individuals With Susac Syndrome. Eur J Neurol. 2025.
Grygiel-Górniak B, Joks MM, Mazurkiewicz L, et al. Susac syndrome – different treatment approaches for one disease (analysis of case series). Neurol Sci. 2025.
Benbrahim FZ, Belkouchi L, Allali N, et al. Susac syndrome: A rare pediatric case. Radiol Case Rep. 2024.
Bagaglia SA, Passani F, Oliverio GW, et al. Multimodal Imaging in Susac Syndrome: A Case Report and Literature Review. Int J Environ Res Public Health. 2021.
Raymaekers V, D’hulst S, Herijgers D, et al. Susac syndrome complicating a SARS-CoV-2 infection. J NeuroVirol. 2021.
Srichawla BS. Susac Syndrome With Livedo Reticularis: Pathogenesis and Literature Review. Cureus. 2022.
Fisher L, David P, Sobeh T, et al. Susac syndrome following COVID-19 vaccination: a case-based review. Clin Rheumatol. 2023.

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