Table 1 summarizes the demographic data, signs and symptoms upon presentation. Seven patients (4 females, 3 males) were diagnosed with SuS. There is no available data on the incidence of SuS in Israel. Two patients were diagnosed with SuS in Tel-Aviv Medical Center from 2013-2016 (Supplementary figure 1). We calculated the expected number of patients per year in Israel, based on annual incidence evaluation in Austria of 0.024/100000 (age over 19), to be 1.3. Therefore, our case series represent at least a 5.4-fold increase in the annual incidence of SuS compared to a published registry and a 7-fold increase in the annual incidence expected in our medical center.
Five patients fulfilled the criteria for definite SuS and two patients for probable SuS. Their mean age at presentation was 30 years (range 20-38 years). All cases were diagnosed during the summer-autumn seasons (July-October). One women was pregnant in her 7th gestational week. The mean duration from the onset of the symptoms to diagnosis was three weeks (2-9 weeks). Mean duration of follow-up was 24 months and one patient was lost to follow after 2 months. No patient had previous neurological disease. Based on the detailed personal history, no common demographic characteristics were found among patients. Toxic environmental exposure was not reported.
At clinical onset, the most common manifestations were CNS symptoms. Disease severity was determined according to the extent of CNS involvement; one patient was defined as extremely severe SuS, two patients as severe SuS, three patients as moderate SuS and one as mild SuS. All patients suffered from different severity of encephalopathy characterized by cognitive impairment (mainly deficits in executive function, language and memory) or confusion. Three patients had a psychiatric manifestation of depression and anxiety. Three patients presented with focal neurological signs; sensory disturbance (two patients) and severe hemiparesis (one patient). Five patients had severe migrainous or oppressive headache. Visual disturbances were described as flashing lights in one patient, and visual field defects in three patients. Vestibulocochlear involvement was the least common presentation; three patients suffered from acute sensorineural hearing loss, one of these patients also suffered from vertigo. Gastrointestinal (GI) symptoms, i.e. abdominal pain and diarrhea were reported in three patients.
Characteristic brain MRI findings included: 1. All patients presented with Flair/T2 hyperintense lesions located in the supratentorial white and gray matter areas. Three patients had additional infratentorial lesions. 2. Typical corpus callosum "snow ball" lesions that are considered a characteristic sign of SuS (Figure 1A1) [21-23] were detected in all of our patients although was not evident on the initial imaging upon presentation in one patient. 3. Punctuate DWI hyperintense lesions with corresponding ADC hypointensity (restricted diffusion) were associated with disease activity in all of our patients (Figure 1A) . 4. Leptomeningeal enhancement was demonstrated in four patients (Figure 1A6), three of these patients suffered from severe headache. 5. Corpus callosum hypointense T1 lesions were found in all our patients and corpus callosum atrophy was evident in five patients . One of our patients (patient number 6) had a cervical spinal cord MRI done at disease onset. No evidence of cervical spine involvement was detected.
FA was pathological in all our patients, even though three patients had no ocular symptoms. Abnormalities included BRAOs and arterial wall hyperfluorescence (AWH) (Figure 1B) [21, 22, 25]. One case had both arterial and venous occlusions. Audiometry showed low-frequency sensorineural hearing loss in five cases (Figure 1C) [1, 6, 9, 18, 26], three were bilateral and two were unilateral. Of note, two patients had SNHL on audiometry with no auditory symptoms. All our patients performed OCT. Three patients showed signs of acute retinal hypoxia indicating an acute macular BRAO. Additionally, five patients showed signs of macular retinal thinning, compatible with previous events of macular ischemia. Two patients had normal OCT.
Serology for cytomegalovirus (CMV) was available in four patients. Three patients had IgM antibodies for CMV. CMV serology was retested in two patients; in one patient (Patient number one) there was sero-conversion from IgM to IgG and in the second patient (Patient number four) both IgG and IgM levels remained high during follow-up, this patient showed clinical and laboratory evidence of CMV reactivation. CMV PCR in the serum was done in two patients; patient number one had 543 IU/ml and patient number four had 70,635 IU/ml. CMV IgM antibody in the CSF were not measured. CMV immune-stain was done on tissue obtained from brain biopsy. One patient had high titer of anti-streptolysin antibodies. anti-streptolysin titer in the CSF was not measured.
CSF analysis was performed in six patients (Table 1). Elevated protein levels were observed in all these patients (mean levels 107 mg/dl; 61- 140 mg/dl) and mean CSF cell count was 6 cells/µl (1-14 cells/µl). The presence of oligoclonal bands (OCB) in the CSF was examined in four patients and were all negative providing no evidence of intrathecal synthesis of OCB. Brain angiography was performed in two patients and was unremarkable. One of our patients (patient number 6) who presented with severe encephalopathy underwent stereotactic brain biopsy from an active lesion on his right parietal lobe. The samples include fragments of cortex, white matter and some vessels from subarachnoid space. There was no evidence of vasculitis or inflammatory reaction. CMV immune-stain was negative.
Figure 1 demonstrates typical diagnostic findings.
Treatment regimen and clinical outcomes
Table 2 summarizes treatment regimens, major side effects and patient outcomes. Patients were treated according to disease course and the severity of CNS involvement based on the recently published treatment guidelines (Supplementary Table 2) . IV Methyprednisolone (IVMP), intravenous immune globulin (IVIG) and mycophenolate mofetil were used for mild cases. An addition of Cyclophosphamide (CPM) and Rituximab (RTX) is optional for the treatment of moderate cases and is recommended to use in severe CNS involvement. All seven patients were treated with IV Methyprednisolone (IVMP) within the first month following the onset of symptoms and during relapses, followed by very slow tapering of prednisone. In addition, all patients received mycophenolate mofetil (MMF) or azathioprine. Six patients were treated with intravenous immune globulin (IVIG) 2 gr/kg every 3-4 weeks or 1 gr/mg every 2 weeks until clinical stability achieved. Cyclophosphamide (CPM; after fertility preservation) was administered in one patient with moderate SuS and in four patients with severe or extremely severe SuS. Three patients were treated with rituximab. Anti- aggregation is not included in the treatment guidelines and evidence for its efficiency in SuS in lacking [14, 15, 27], nevertheless, all seven patients were treated with an anti- aggregation agent.
Patients were clinically monitored with frequent clinical assessments in addition to routine brain MRI, FA and audiometry to evaluate treatment response and outcome. Treatment led to clinical and radiological stability in all patients. One patient who presented with severe encephalopathy and hemiparesis was stable under this regimen but suffered from a residual mild hemiparesis, ataxia, memory impairment, attention deficit and behavioral disinhibition. Another patient experienced a relapse after discontinuation of medication due to adherence problem. This patient has a residual mild cognitive decline. Three patients had no residual neurological deficits. Brain MRI lesions remained unchanged in five patients however, in one patient some lesions disappeared on follow-up MRI. Follow up MRI revealed global brain atrophy and corpus callosum atrophy in four patients.
Two patients had residual visual field defects. . Three patients who presented with SNHL did not improve on follow up auditory testing. Major side effects of the treatment included pathological fracture in one patient and reactivation of CMV infection in two patients that caused GI symptoms and was diagnosed by testing CMV PCR in serum. Patient number 4 suffered from severe diarrhea and serum CMV PCR reached a maximum level of 70,635 IU/ml and return to negative after treatment with valcyclovir.
The maintenance treatment included aspirin, mycophenolate mofetil (MMF) 1000 mg BID, prednisone with very slowly tapering down, decreasing doses of IVIG and Rituximab every 6 months.