Ilka Kleffner

Characteristics of Susac syndrome: a review of all reported cases

In Susac syndrome, occlusions of microvessels—presumed to be mediated by an autoimmune response to an as yet unknown antigen—lead to a characteristic clinical triad of CNS dysfunction, branch retinal artery occlusions, and sensorineural hearing impairment. Susac syndrome is considered a rare but important differential diagnosis in numerous neurological, psychiatric, ophthalmological, and ear, nose and throat disorders. Improved understanding of this disorder is crucial, therefore, to ensure that patients receive appropriate treatment and care. Current knowledge on Susac syndrome is largely based on reports of single patients, small case series, and nonsystematic reviews. The aim of this Review is to extend these previous, primarily anecdotal findings by compiling data from all 304 cases of Susac syndrome that have been published worldwide, which were identified following a literature search with predefined search, inclusion and exclusion criteria. From this data, we present an overview of demographic, clinical and diagnostic data on Susac syndrome, providing a reliable basis for our current understanding of this rare disease. Where possible, we make recommendations for clinical diagnosis, differential diagnosis, and management of patients with suspected Susac syndrome.

Lesion morphology at 7 Tesla MRI differentiates Susac syndrome from multiple sclerosis

Background: Although an orphan disease with still obscure aetiopathogenesis, Susac syndrome has to be considered as differential diagnosis in multiple sclerosis (MS), since its clinical presentation and paraclinical features including routine magnetic resonance imaging (MRI) findings partially overlap. Objective: We aimed to study a potential benefit of 7T MRI for (i) the differentiation between Susac syndrome and MS and (ii) the clarification of pathogenesis of Susac syndrome. Methods: Five patients suffering from Susac syndrome, 10 sex- and age-matched patients with relapsing–remitting MS (median Expanded Disability Status Scale (EDSS) score 1.5) and 15 matching healthy controls were investigated at 7 Tesla MRI. The protocol included T1-weighted MPRAGE, T2*-weighted FLASH, and TIRM sequences. Results: Almost all T2* FLASH lesions in patients with MS were centred by a small central vein (325 lesions; 92%) and often showed a small hypointense rim (145 lesions; 41%). In contrast, white matter lesions in Susac syndrome exhibited a perivascular setting significantly less frequently (148 lesions; 54%, p=0.002), and very rarely exhibited a hypointense rim (12 lesions; 4%, p=0.004). Furthermore, in addition to callosal atrophy, Susac patients showed cerebrospinal fluid-isointense lesions within the central part of corpus callosum that are not commonly seen in MS. Conclusion: At 7T MRI, plaques in MS patients and patients with Susac syndrome differed substantially with respect to morphology and pattern. Thus, lesion morphology at 7T (i) may serve as a marker to distinguish Susac syndrome from MS and (ii) reflects a different pathophysiological mechanism underlying Susac syndrome, for example microinfarction rather than demyelination.

A brief review of Susac syndrome.

Susac syndrome was named after J.O. Susac who first described the syndrome in 1979. It is characterized by the clinical triad of encephalopathy, branch retinal artery occlusion, and sensorineural hearing loss. It mainly occurs in young women. This underdiagnosed disease needs to be considered in the differential diagnosis of a broad variety of disorders. In Susac syndrome, autoimmune processes leading to damage and inflammation-related occlusion of the microvessels in brain, retina, and inner ear are thought to play a causal role. The diagnosis is based primarily on the clinical presentation, the documentation of branch retinal artery occlusion by fluorescence angiography, and characteristic findings on cerebral MRI, that help in distinguishing Susac syndrome from other inflammatory entities, like multiple sclerosis. Antiendothelial cell antibodies could be detected in some patients. Patients are successfully treated with immunosuppression, however, the best regimen still needs to be defined. As a result of the rarity of the disease, controlled therapeutic trials are missing so far. In this review, we want to demonstrate the clinical features, natural history, treatment, and clinical course of Susac syndrome, illustrated by a typical case history.

The Role of Aquaporin-4 Polymorphisms in the Development of Brain Edema After Middle Cerebral Artery Occlusion

Background and Purpose— Some patients develop severe brain edema after complete middle cerebral artery occlusion, whereas others do not. Aquaporin-4 (AQP4) is the main water channel in the brain and has been shown to be critical for the development of brain edema after ischemia. We asked whether genetic variation in the AQP4 gene is related to the severity of brain edema after middle cerebral artery occlusion. Methods— We genotyped 10 single nucleotide polymorphisms distributed across the AQP4 gene in 41 patients with middle cerebral artery occlusion with and without severe brain edema and assessed single marker association as well as the linkage dysequilibrium structure across AQP4. Results— One single nucleotide polymorphism (rs9951307) at the 3′ end of AQP4 was associated with severe brain edema (dominant model, P=0.01; OR, 0.10; 95% CI, 0.02 to 0.49 for the protective G-allele). Linkage dysequilibrium across AQP4 was low; no clear haplotype blocks could be identified for the assessment of haplotype association. Conclusions— This explorative study shows that genetic variation in AQP4 might contribute to brain edema formation after middle cerebral artery occlusion and warrants further investigation.

DIFFUSION TENSOR IMAGING DEMONSTRATES FIBER IMPAIRMENT IN SUSAC SYNDROME

Susac syndrome is a rare disease, characterized by the triad of hearing loss, branch retinal artery occlusions, and encephalopathy with predominantly cognitive and psychiatric symptoms.1,2 Focal ischemic lesions in the corpus callosum detectable by conventional MRI are a typical feature of Susac syndrome.3,4 The lesions detectable by conventional MRI do not, however, explain the type and severity of the neuropsychological deficits.5,6 In this study, we tested the hypothesis of whether widespread tissue damage of the otherwise normal-appearing white matter (NAWM) could be detected in patients with Susac syndrome using diffusion tensor imaging (DTI).7 DTI is a noninvasive technique for detection of macro- and microstructural impairment of fiber integrity on the basis of normal values for the fractional anisotropy (FA).8 We hypothesized that the neuropsychological symptoms in patients with Susac syndrome correlated well with the FA aberrations detected with DTI. ### Methods. We investigated four patients with clinically diagnosed Susac syndrome. Their encephalopathic symptoms varied from mild cognitive impairment to severe acute psychosis. The symptoms were dyscalculia, impaired memory, hallucinations, paranoia, disorientation, emotional indifference, and strongly reduced alertness, motivation, concentration and cognitive flexibility. Diagnosis of Susac syndrome was established by the documentation of branch retinal artery occlusions, sensorineural hearing loss, encephalopathy, and the characteristic multifocal snowball-like hyperintense lesions on T2-weighted images (figure 1). In all patients, the diagnosis was based on the typical clinical triad, supported by the detection of the typical white matter (WM) lesions on T2-weighted MRI. Figure 1 T2-weighted images illustrating “snowball” lesions in the corpus callosum of Patients 1 through 4 (A) Patient 1 showed a lesion in the genu of the corpus callosum. (B) “Snowball” lesion in the splenium of the corpus callosum of Patient 2

Patterns of retinal damage facilitate differential diagnosis between Susac syndrome and MS.

Susac syndrome, a rare but probably underdiagnosed combination of encephalopathy, hearing loss, and visual deficits due to branch retinal artery occlusion of unknown aetiology has to be considered as differential diagnosis in various conditions. Particularly, differentiation from multiple sclerosis is often challenging since both clinical presentation and diagnostic findings may overlap. Optical coherence tomography is a powerful and easy to perform diagnostic tool to analyse the morphological integrity of retinal structures and is increasingly established to depict characteristic patterns of retinal pathology in multiple sclerosis. Against this background we hypothesised that differential patterns of retinal pathology facilitate a reliable differentiation between Susac syndrome and multiple sclerosis. In this multicenter cross-sectional observational study optical coherence tomography was performed in nine patients with a definite diagnosis of Susac syndrome. Data were compared with age-, sex-, and disease duration-matched relapsing remitting multiple sclerosis patients with and without a history of optic neuritis, and with healthy controls. Using generalised estimating equation models, Susac patients showed a significant reduction in either or both retinal nerve fibre layer thickness and total macular volume in comparison to both healthy controls and relapsing remitting multiple sclerosis patients. However, in contrast to the multiple sclerosis patients this reduction was not distributed over the entire scanning area but showed a distinct sectorial loss especially in the macular measurements. We therefore conclude that patients with Susac syndrome show distinct abnormalities in optical coherence tomography in comparison to multiple sclerosis patients. These findings recommend optical coherence tomography as a promising tool for differentiating Susac syndrome from MS.

Inhibition of N‐cadherin and β‐catenin function reduces axon‐induced Schwann cell proliferation

N‐cadherin and β‐catenin are involved in cell adhesion and cell cycle in tumor cells and neural crest. Both are expressed at key stages of Schwann cell (SC) development, but little is known about their function in the SC lineage. We studied the role of these molecules in adult rat derived SC‐embryonic dorsal root ganglion cocultures by using low‐Ca2+ conditions and specific blocking antibodies to interfere with N‐cadherin function and by using small interfering RNA (siRNA) to decrease β‐catenin expression in both SC‐neuron cocultures and adult rat‐derived SC monocultures. N‐cadherin blocking conditions decreased SC‐axon association and reduced axon‐induced SC proliferation. In SC monocultures, β‐catenin reduction diminished the proliferative response of SCs to the mitogen β1‐heregulin, and, in SC‐DRG cocultures, β‐catenin reduction inhibited axon‐contact‐dependent SC proliferation. Stimulation of SC cultures with β1‐heregulin increased total β‐catenin protein amount, phosphorylation of GSK‐3β and β‐catenin presence in nuclear extracts. In conclusion, our findings suggest a previously unrecognized contribution of β‐catenin and N‐cadherin to axon‐induced SC proliferation.

Sodium-dependent vitamin C transporter 2 deficiency causes hypomyelination and extracellular matrix defects in the peripheral nervous system.

Ascorbic acid (vitamin C) is necessary for myelination of Schwann cell/neuron cocultures and has shown beneficial effects in the treatment of a Charcot-Marie-Tooth neuropathy 1A (CMT1A) mouse model. Although clinical studies revealed that ascorbic acid treatment had no impact on CMT1A, it is assumed to have an important function in peripheral nerve myelination and possibly in remyelination. However, the transport pathway of ascorbic acid into peripheral nerves and the mechanism of ascorbic acid function in peripheral nerves in vivo remained unclear. In this study, we used sodium-dependent vitamin C transporter 2-heterozygous (SVCT2+/−) mice to elucidate the functions of SVCT2 and ascorbic acid in the murine peripheral nervous system. SVCT2 and ascorbic acid levels were reduced in SVCT2+/− peripheral nerves. Morphometry of sciatic nerve fibers revealed a decrease in myelin thickness and an increase in G-ratios in SVCT2+/− mice. Nerve conduction velocities and sensorimotor performance in functional tests were reduced in SVCT2+/− mice. To investigate the mechanism of ascorbic acid function, we studied the expression of collagens in the extracellular matrix of peripheral nerves. Here, we show that expression of various collagen types was reduced in sciatic nerves of SVCT2+/− mice. We found that collagen gene transcription was reduced in SVCT2+/− mice but hydroxyproline levels were not, indicating that collagen formation was regulated on the transcriptional and not the posttranslational level. These results help to clarify the transport pathway and mechanism of action of ascorbic acid in the peripheral nervous system and may lead to novel therapeutic approaches to peripheral neuropathies by manipulation of SVCT2 function.

Retinal pathology in Susac syndrome detected by spectral-domain optical coherence tomography

Objective: The aim of this non-interventional study was to characterize retinal layer pathology in Susac syndrome (SuS), a disease with presumably autoimmune-mediated microvessel occlusions in the retina, brain, and inner ear, in comparison to the most important differential diagnosis multiple sclerosis (MS). Methods: Seventeen patients with SuS and 17 age- and sex-matched patients with relapsing-remitting MS (RRMS) and healthy controls (HC) were prospectively investigated by spectral-domain optical coherence tomography (OCT) including intraretinal layer segmentation in a multicenter study. Patients with SuS additionally received retinal fluorescein angiography (FA) and automated perimetry. Results: Patchy thinning of the retinal nerve fiber layer, ganglion cell layer, inner plexiform layer, inner nuclear layer, and outer plexiform layer compared to corresponding sectors in RRMS and HC eyes (p < 0.003 for SuS vs RRMS and HC) was observed in 23/34 (68%) SuS eyes, particularly in temporal quadrants. The outer nuclear layer (ONL) and photoreceptor layers (PRL) were not affected. FA performed in 15/17 patients with SuS was negative for disease-specific branch retinal artery occlusions in all but 1 eye at the time of OCT examination and revealed no additional vascular abnormalities, even in severely damaged OCT areas. In a subset of patients with SuS, associations of visual field data with distinct retinal layers were observed. Conclusion: Distinct OCT patterns of scattered, scar-like intraretinal pathology in SuS eyes, sparing the ONL and PRL, suggest a retinal, but not choroidal, vascular pathomechanism and clearly differentiate SuS from RRMS. Depending on the disease stage, OCT and FA provide specific complementary diagnostic information in SuS.

Diagnostic criteria for Susac syndrome.

Background Susac syndrome is characterised by the triad of encephalopathy with or without focal neurological signs, branch retinal artery occlusions and hearing loss. Establishment of the diagnosis is often delayed because the triad is complete only in a minority of patients at disease onset. This leads to a critical delay in the initiation of appropriate treatment. Our objective was to establish criteria for diagnosis of either definite or probable Susac syndrome. Method The establishment of diagnostic criteria was based on the following three steps: (1) Definition of a reference group of 32 patients with an unambiguous diagnosis of Susac syndrome as assessed by all interdisciplinary experts of the European Susac Consortium (EuSaC) team (EuSaC cohort); (2) selection of diagnostic criteria, based on common clinical and paraclinical findings in the EuSaC cohort and on a review of the literature; and (3) validation of the proposed criteria in the previously published cohort of all Susac cases reported until 2012. Results Integrating the clinical presentation and paraclinical findings, we propose formal criteria and recommend a diagnostic workup to facilitate the diagnosis of Susac syndrome. More than 90% of the cases in the literature fulfilled the proposed criteria for probable or definite Susac syndrome. We surmise that more patients could have been diagnosed with the recommended diagnostic workup. Conclusions We propose diagnostic criteria for Susac syndrome that may help both experts and physicians not familiar with Susac syndrome to make a correct diagnosis and to prevent delayed treatment initiation.