Susac Syndrome with Cerebral Venous Sinus Thrombosis – A Rare Association

Sir, A 27-year-old gentleman, with no comorbid illnesses presented with acute-onset, severe and holocranial headache in July 2015. From the next day onwards, he had altered sensorium, apathy, and reduced word output. There were no seizures. He was admitted in a nearby hospital and treated with intravenous steroids, followed by a short course of oral steroids, with that he improved completely. On tapering steroids, he had a relapse of altered sensorium, along with urinary retention, and was referred to our center. On examination, he was drowsy, with exaggerated deep tendon reflexes. There were no signs of meningeal irritation. Magnetic resonance imaging (MRI) of the brain showed T2 and FLAIR hyperintensities involving the rostrum, body, and splenium of corpus callosum, bilateral frontal and parietal deep white matter, posterior limb of the right internal capsule and bilateral middle cerebellar peduncles without any diffusion restriction or contrast enhancement. MRI of the whole spine was normal. Cerebrospinal Fluid (CSF) study showed normal cell count with mildly elevated protein (58 mg/dl). CSF IGG index was slightly elevated (0,73), while CSF oligoclonal bands were negative. Antinuclear antibody (ANA) profile, RF (rheumatoid factor) and vasculitis workup was negative. CSF gram stain, AFB stain, bacterial and TB culture were negative. Serological tests for Human Immunodeficiency virus (HIV), hepatitis B, hepatitis C and TPHA (treponema pallidum hemagglutination) were negative. He was treated with intravenous methyl prednisolone followed by oral prednisolone with that he had good improvement. At the time of discharge, he was conscious and oriented with a normal cognitive examination. One month later, while on prednisolone 40 mg/day, he presented with a recurrence of headache, along with behavioral changes and difficulty in walking, with dragging of the right lower limb. A repeat MRI of brain [Figure 1a–d] showed new lesions with diffusion restriction in the corpus callosum and periventricular region. Digital subtraction angiography did not show any abnormalities.Figure 1: (a) T2 weighted MRI showing central corpus callosal lesions with snowball appearance. (b) Multiple FLAIR hyperintensities in bilateral cerebral hemispheres. (c) Axial FLAIR image showing hyperintensity in right middle cerebellar peduncle. (d) DWI showing multiple areas of diffusion restriction in corpus callosum, bilateral cerebral hemispheres. (e) MR venogram showing partial filling defects in right transverse and sigmoid sinusesOphthalmological evaluation showed a visual acuity of 6/6 on the left and 6/9 on the right. Fundus examination revealed hemorrhages around the supertemporal veins, suggestive of bilateral peripheral retinal vasculitis. Fundus fluorescein angiography (FFA) revealed peripheral capillary occlusion. On reviewing the history, he reported tinnitus and hearing impairment in the right ear. Pure tone audiogram showed profound hearing loss on the right with mild sensorineural hearing loss on the left. Recurrent episodes of encephalopathy with a typical MRI picture of snowball lesions in corpus callosum, peripheral capillary occlusion on FFA and sensorineural hearing loss on audiometry, were consistent with the diagnostic triad of Susac syndrome. He was given monthly intravenous cyclophosphamide pulse therapy for 4 months, which had to be stopped in view of recurrent infections and was thereafter continued oral prednisolone and azathioprine. Four years into the illness, while on prednisolone 5 mg daily dose and azathioprine 150 mg/day, he again presented with severe holocranial headache with nocturnal worsening. There was no history of drug or alcohol abuse, and he had no other comorbid illnesses. MRI Brain with MR venogram (MRV) [Figure 1e] showed chronic thrombosis of the right transverse and sigmoid sinuses and torcula with partial recanalization. He was started on oral anticoagulation with warfarin. Prothrombotic workup including antiphospholipid antibody and lupus anticoagulant was negative. Follow-up MRV after 6 months showed complete recanalization. Six years into the illness, he presented with slurring of speech and hoarseness of the voice. ENT evaluation revealed left vocal cord abduction paresis. Repeat MRI brain did not show any new lesions. CT thorax ruled out an extrinsic lesion compressing the larynx. The dose of prednisolone was increased and he was continued on azathioprine, following that his symptoms improved. Repeat laryngoscopy after 6 months showed improved vocal cord mobility. He has remained asymptomatic thereafter on azathioprine with low-dose prednisolone. Discussion SS is a rare autoimmune micro vasculopathy, marked by a clinical trial of encephalopathy, sensorineural hearing loss, and branch retinal artery occlusion (BRAO). However, the full triad is observed in only 13%–30% of patients at the onset of the disease.[1] Typically, central nervous system (CNS) symptoms appear first, followed by visual symptoms and finally hearing disturbances. Headache is often, an early manifestation.[2] Brainstem dysfunction, such as dysarthria, dysphagia, or diplopia, is rarely reported.[3] The most important differential diagnosis is multiple sclerosis (MS). Apart from the additional ophthalmological findings and hearing loss, rounded lesions in the center of corpus callosum are seen in SS, while lesions on the under-surface of corpus callosum (callososeptal margin) are seen in MS.[4] Hearing loss and tinnitus in SS is believed to be due to loss of apical cochlear cells.[5] Ophthalmological evaluation usually reveals peripheral artery or capillary blockage.[6] While our patient had the classical triad of SS, the laryngeal palsy that was noted late in the illness is unusual. Jarius et al.,[3] in their multicenter study, reported brainstem features including dysarthria, dysphagia and internuclear ophthalmoplegia in 3 of 25 patients. A systematic review noted that dysarthria or aphasia is seen in 17% of cases.[7] While dysarthria could be due to the subcortical or brainstem lesions, the laryngeal palsy in our patient is likely due to a small brainstem lesion that could not be picked up on MRI. Cerebral venous thrombosis (CVT) was observed during this illness, a finding not previously reported in Susac’s syndrome. Association with CVT has been described in ANCA-associated vasculitis (AAV), Neuro-Behcet disease, Sjogren syndrome and systemic lupus erythematosus.[8] The mechanisms postulated for the same in AAV include antiplasminogen antibodies, endothelial damage due to ANCA antibodies and the procoagulant effect of hypoalbuminemia.[9] As anti-endothelial cell antibodies have been detected in Susac syndrome, endothelial damage is the likely mechanism for CVT.[10] Brain biopsy specimens in Susac syndrome have shown microangiopathic changes, with lymphocytic inflammation of the arteriolar walls and infarcts secondary to microvascular occlusion.[11] A similar process extending to the cerebral veins and dural venous sinuses could be the cause of CVT in Susac syndrome. As headache is a common and presenting clinical feature, a high index of suspicion is needed to detect CVT in SS. A new onset persistent headache, change in the character or severity of pre-existing headache, features of raised intracranial tension including papilledema or double vision in a patient with diagnosed SS, should alert the clinician to rule out CVT as a cause. Standard guidelines for treatment of SS are lacking. First-line treatment includes high-dose intravenous corticosteroids followed by high-dose oral corticosteroids with a gradual taper. Additional agents include mycophenolate mofetil, rituximab, cyclophosphamide, and azathioprine.[12] Although encephalopathy and visual disturbances often respond to treatment, hearing loss tends to be irreversible.[13] The duration of treatment required is not well-established and the risks of highly efficacious treatment (as seen in our case with cyclophosphamide) must be balanced with the benefits. An initial induction phase with highly active immunotherapy followed by oral maintenance therapy, as used in other systemic vasculitic syndromes could be tried, though high-quality evidence specific to SS is lacking. Many SS cases remain underdiagnosed and underreported, leading to gaps in understanding its diverse presentations and in establishing treatment guidelines. This case is notable for its rare clinical features, including laryngeal weakness and cerebral venous thrombosis. Further research is essential to clarify the underlying mechanisms of SS, which could improve early diagnosis and treatment of this rare syndrome. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.