Challenges in the differential diagnosis of multiple sclerosis and Susac syndrome

Introduction

The MRI pattern of multifocal brain involvement may be caused by a large number of diseases with different etiologies and pathogenetic mechanisms. One of the most common causes of such changes is multiple sclerosis (MS). Despite the presence of highly specific MRI features, there is a group of disorders with which the differential diagnosis of MS is challenging. One of them is retinocochleocerebral angiopathy (RCCA), first described by John Susac in 1979 in young women.

Although the term “Susac syndrome” is currently generally accepted in the international literature, the same syndrome has been described by different groups of authors under other names, such as SICRET (small infarcts of cochlear, retinal, and encephalic tissue), RED-M (retinopathy, encephalopathy, deafness-associated microangiopathy), and retinocochleocerebral microvasculopathy.

In this article, we present clinical observations of two patients with RCCA who were initially misdiagnosed with MS, and provide a brief literature review on the role of MRI in the differential diagnosis between demyelinating diseases and Susac syndrome.

Pathogenesis and immunological features

Although the cause of RCCA remains unclear, it is known that the underlying process is a microangiopathy affecting small vessels of the retina, inner ear, and central nervous system (CNS). Pathomorphological studies of brain biopsy material performed by different research groups have demonstrated similar changes in the form of perivascular inflammation of the walls of small arterioles without necrosis of the vessel wall itself, which would be typical for true vasculitis.

In addition, changes of the arteriolar endothelium have been described, indicating the presence of autoantibodies against endothelial cells, which supports an autoimmune etiology of RCCA. Some authors consider Susac syndrome a variant of antiphospholipid syndrome (APS); indeed, a low titer of antiphospholipid and antinuclear antibodies is sometimes found.

Intrathecal production of oligoclonal immunoglobulins (oligoclonal bands, OCB) is extremely rare, which further complicates the differential diagnosis with MS.

Clinical manifestations

In accordance with the target organs, patients with RCCA develop a characteristic symptom triad: encephalopathy, sensorineural hearing loss, and visual disturbances. CNS involvement may manifest as focal neurological deficits and/or psychiatric symptoms. Typically, the disease has an insidious onset, and the complete triad of symptoms is rarely present at the very beginning.

Based on their own observations and published clinical cases, V. Vishnevskia-Dai et al. proposed the following diagnostic criteria for Susac syndrome:

1) probable — absence of cardiovascular risk factors, one feature from the classical triad, and at least one of the following: woman aged 20–40 years, woman in the first year postpartum, or the presence on MRI of a characteristic lesion pattern in the corpus callosum or periventricular white matter;
2) incomplete — two features from the triad;
3) complete — all three features of the triad.

Hearing loss is usually bilateral, more often asymmetric, and predominantly affects low and mid-range frequencies. Visual disturbances are caused by retinal microinfarcts and clinically present with photopsias and scotomas. In severe cases, complete loss of hearing and/or vision is possible.

To diagnose retinal vessel involvement, the method of choice is fluorescein angiography of the retina (FAG), which reveals branch retinal artery occlusions (BRAO), hyperfluorescence of arteriolar walls, and dye “leakage”.

MRI features in Susac syndrome

Encephalopathy is one component of the classical triad, but its neurological manifestations require objectification with MRI, including for the purpose of differential diagnosis with other causes of neurological deficit. Thus, detecting MRI abnormalities is an obligatory component of establishing the diagnosis of RCCA.

Angiopathy of cerebral arterioles leads to multiple microinfarcts located both in the gray and white matter, subcortically and periventricularly. The most vulnerable brain regions are those with a poor collateral network, such as subcortical structures, the corpus callosum, and the brainstem. Infarcts are typically round and small, with a diameter of up to about 1 cm. At different stages of their evolution, ischemic lesions may show diffusion restriction in the acute phase and contrast enhancement in the subacute phase.

Multiple ischemic foci often occur in the internal capsules, forming chains of round lesions that have been described as a “string of pearls” pattern.

A characteristic feature of corpus callosum involvement is selective damage to its central fibers, while the superior and inferior margins usually remain intact. The lesions themselves may be round (“snowball” pattern) or linear (“spoke” pattern). In the chronic phase of infarcts, cyst-like changes form in the corpus callosum, producing a typical “black hole” pattern on T1-weighted images.

On post-contrast series, in addition to enhancement of subacute ischemic foci, leptomeningeal enhancement is very often seen, predominantly in the posterior cranial fossa along the surface of the cerebellum.

Clinical case No. 1

A 23-year-old woman fell ill in 2014, when she suddenly lost consciousness against the background of full health, followed by the development of right-sided hemiparesis and hemihypesthesia. She was hospitalized with suspected acute cerebrovascular accident (stroke), which was not confirmed. Brain MRI revealed multifocal lesions, and a preliminary diagnosis of multiple sclerosis was made. Cerebrospinal fluid analysis demonstrated no oligoclonal bands. A cerebral vasculitis was considered in the differential diagnosis.

Two years later, progressive hearing loss and visual impairment developed. Initially, visual disturbances were interpreted as retinal detachment; however, subsequent FAG revealed multiple retinal vessel thromboses.

On follow-up MRI, a pattern characteristic of RCCA with corpus callosum involvement was observed (Fig. 1). Based on the combination of clinical and radiological findings, a diagnosis of Susac syndrome was established. Under treatment with repeated courses of cyclophosphamide and methotrexate, the patient’s condition partially stabilized, with some regression of the paresis in the right arm; paresis and hypesthesia in the leg persisted. Hearing and visual deficits did not show clear progression.

Clinical case No. 2

A 17-year-old young woman fell ill in 2019 when she developed dark spots in the visual field of the right eye, gait unsteadiness, speech impairment described as “having a mouthful of porridge”, intermittent numbness of different areas of the face and limbs, urinary difficulties, and headaches.

Brain MRI revealed multifocal white matter lesions with contrast enhancement in some of the foci. Blood tests for systemic connective tissue diseases were negative. A diagnosis of multiple sclerosis was established. Pulse therapy with methylprednisolone was administered, resulting in almost complete regression of symptoms.

However, two months later, a dark spot reappeared in the visual field of the left eye; ophthalmologic examination showed occlusion of a branch of the retinal artery in the left eye. One month later, bilateral hearing loss developed. Audiometry confirmed bilateral sensorineural hearing loss.

FAG revealed signs of peripheral focal phlebitis. The patient repeatedly received glucocorticoid therapy, with a good clinical effect. A review of her MRI archive showed progressive multifocal white matter involvement with a pattern typical of RCCA in the corpus callosum and contrast enhancement (Fig. 2). Based on the combined clinical and radiological findings, a diagnosis of Susac syndrome was made.

Results and discussion

Susac syndrome is a rare disorder, but because it predominantly affects young individuals and may lead to severe disability, it is clinically very important.

In the first patients described in the literature, the complete triad of symptoms was present, including hearing loss, visual impairment, and encephalopathy. However, according to current concepts, the diagnosis can be made at earlier stages of the disease, without waiting for the full triad to manifest. In this context, differential diagnosis of RCCA with other CNS diseases, primarily demyelinating disorders, becomes especially important.

Both MS and RCCA show multifocal white matter lesions with involvement of the corpus callosum and infratentorial structures, contrast enhancement of some lesions, and the appearance of new lesions over time. Thus, dissemination in time and space, which is a key criterion for the diagnosis of MS, may also be observed in RCCA. The neurological manifestations of these two conditions may likewise be very similar.

At the same time, in MS, unlike RCCA, periventricular lesions are usually not round but elongated, with their long axis oriented perpendicular to the corpus callosum (Dawson’s fingers). Lesions of the corpus callosum in MS typically involve its margins, with the lesion border reaching the surface of the structure, whereas in RCCA selective involvement of the central fibers is characteristic. Leptomeningeal contrast enhancement can be detected in MS but usually appears as single small foci.

Thus, there is a combination of sufficiently striking distinguishing features that make it possible to differentiate RCCA from MS (see Table). Clinical signs indicating involvement of the visual and auditory systems may also help guide the diagnostic work-up in the right direction.

In all presented clinical cases, the onset of Susac syndrome represented an incomplete triad of symptoms: in case No. 1, acute CNS involvement; in case No. 2, a combination of encephalopathy and visual disturbances. Brain MRI performed shortly after clinical onset revealed multifocal white matter lesions. Thus, at disease onset, according to the classification proposed by Vicktoria Vishnevskia-Dai and colleagues, the diagnosis of Susac syndrome should have been regarded as “probable”.

However, the relapsing course, the presence of “active” contrast-enhancing lesions on MRI, and the favorable response to glucocorticoid therapy complicated the diagnosis until the complete triad of symptoms became apparent.

In case No. 2, a review of the MRI archive showed that during one of the disease exacerbations not only contrast enhancement of some white matter lesions was present, but also fairly intense enhancement along the penetrating vessels in the centrum semiovale. Perivascular contrast enhancement has not previously been described in RCCA; on the contrary, J.C.J. Bot et al. reported that such a type of enhancement does not occur in Susac syndrome. At the same time, given the data on perivascular inflammatory infiltrates in RCCA, this type of enhancement appears entirely plausible.

Another radiological feature of the presented cases was the presence of cyst-like lesions on FLAIR images in the corpus callosum and periventricular white matter, characterized by a hypointense center and a hyperintense rim. This feature has been noted in only two clinical cases of Susac syndrome described in the literature and therefore is probably not typical.

It should be noted that in case No. 1 three years elapsed from disease onset to the appearance of the complete triad of symptoms, whereas in the second patient the interval was only one year. Analysis of the MRI archive in case No. 1 made it possible to follow the evolution of focal lesions in RCCA over a relatively long period. Over time, we observed confluence of lesions and atrophy of the corpus callosum, which made the radiological picture less specific and more “similar” to MS.

Conclusion

Susac syndrome remains a relatively rare disease, and to date there are no unified clinical guidelines on the management of such patients. It is believed that early initiation of immunosuppressive therapy significantly improves prognosis and helps maintain quality of life for a prolonged period. Therefore, it is essential to establish the correct diagnosis as early as possible and to initiate pathogenetic treatment.

At the same time, despite the presence of rather characteristic features, establishing the correct diagnosis may be difficult until the full triad of symptoms becomes manifest. Detection of the characteristic MRI features of RCCA may be a key diagnostic criterion in patients at early stages of the disease.

When a pattern of multifocal brain involvement is detected on MRI, especially in young women, Susac syndrome should be included in the differential diagnosis. It is important to remember that at early stages the lesions have a more typical appearance, whereas with long-standing disease MRI-based differential diagnosis becomes more challenging because lesions change their characteristics, tend to merge, and may be interpreted as lesions seen in secondary progressive MS. The presence of the other two components of the triad can help establish the correct diagnosis.

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