A 30-year-old previously well man presented with a four-week history of progressive right-sided hearing loss, wide-based gait, and cognitive disturbance characterized by short-term memory loss, impaired attention span, and verbal fluency. The patient had neither a personal nor family history of pertinent medical problems, and he did not smoke, drink excessive alcohol, or take illicit drugs.
On examination, he had cerebellar signs characterized by dysdiadochokinesis and ataxia of gait.
MRI of the brain at presentation demonstrated multiple hyperintense lesions in the corpus callosum, periventricular white matter, cerebellar hemispheres, and leptomeninges (Figure 1).
MRI of the spine was normal. The CSF showed a small pleocytosis with normal cytology and an elevated protein 3.06 g/L. There was an absence of oligoclonal bands in both CSF and serum. CSF microbiologic investigations revealed a Gram-negative stain, syphilis serology, and cryptococcal antigen. PCR analysis of the CSF did not detect EBV, CMV, HSV, VZV, enterovirus, M. tuberculosis, or fungal pathogens. Widespread triphasic waves consistent with encephalopathy but with no focal or generalised epileptic activity were demonstrable on an electroencephalogram (EEG). CT of the chest, abdomen, and pelvis did not reveal any lesions.
The full blood count, electrolytes, creatinine, and liver function tests were normal. The ANA, ANCA, anticardiolipin antibodies, and lupus anticoagulant were negative. Evaluation for autoimmune and paraneoplastic encephalitis with serum and CSF antibodies to NMDAR (N-methyl-D-aspartate receptor), AMPAR (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor), LGI1 (leucine-rich glioma-inactivated 1), Caspr 2 (contactin-associated protein-like 2), GABA (gamma-aminobutyric acid) B receptor, and IgLON5 were negative, and ANNA-(antineuronal nuclear antibody-)1, ANNA-2, PCA (Purkinje cell antibody), PCA 2, Ma 1, Ma 2, CV2/CRMP5 (collapsin response mediator protein 5), Tr, and SOX antibodies were also not detected. Antiaquaporin-4 antibodies and anti-heat shock 70 antibodies were negative.
The differential diagnosis included acute disseminated encephalomyelitis, aquaporin-4 negative neuromyelitis optica, neurosarcoidosis, and primary angiitis of the CNS.
Despite treatment with intravenous methylprednisolone 1 g daily for 3 days followed by a tapering course commenced at 1 mg/kg daily, he suffered progressive bilateral hearing loss over the following four weeks and impaired vision from the right eye. Audiometry demonstrated low-frequency sensorineural hearing loss bilaterally. Neuropsychometric assessment revealed severe global cognitive impairment including difficulties with verbal fluency, as well as deficits in short-term memory and executive function.
A biopsy of the cerebellum and meninges was performed due to disease progression and lack of response to the high-dose corticosteroid therapy. The histopathology showed mild, nonspecific perivascular inflammation and a diffuse pial infiltrate dominated by CD8 T lymphocytes and macrophages with microinfarctions in the territory of the small pial arteries. There was no evidence of vasculitis or malignancy. Culture and PCR analysis of the specimen excluded mycobacterial or fungal infection.
The patient developed painless scotomata, and a branch retinal artery occlusion (BRAO) of the right temporal retina was identified on fundal photography and retinal fluorescein angiography (Figure 2). Subsequently, Susac's syndrome was diagnosed based on the triad of encephalopathy, right BRAO, and bilateral sensorineural hearing loss.
Methylprednisolone 1 g daily for 3 days was subsequently readministered followed by oral prednisolone 1 mg/kg daily concurrently with intravenous cyclophosphamide 1 g (15 mg/kg) monthly for 6 months and intravenous immunoglobulin (IVIg) 2 g/kg loading and 0.4 g/kg per month for 6 months. Adjunctive treatments included cotrimoxazole prophylaxis against Pneumocystis jiroveci, risedronate for osteoprotection, and aspirin to aid vessel patency.
Clinical remission was achieved by 6 weeks, but there was no improvement in the sensorineural deafness on the right side. Maintenance of remission was attempted with methotrexate 20 mg (0.3 mg/kg) weekly following cyclophosphamide.
Another clinical relapse, however, occurred 3 months after the maintenance therapy with methotrexate was started, characterized by recurrent bilateral hearing loss, bilateral BRAOs, and new T2 hyperintensities shown by MRI of the brain. Further remission was achieved with methylprednisolone 1 g daily for 3 days, and plasma exchange was administered daily for four consecutive days. In addition, rituximab 375 mg/m2 weekly for four weeks was used as an induction agent, and methotrexate was replaced with mycophenolate mofetil (MMF) 1.5 g BD. Prior to rituximab, enumeration of lymphocyte subsets on peripheral blood revealed 302 x 106 CD19+ cells/L with CD19 suppression (<25 x 106 cells/L) maintained for 18 months following therapy. Oral prednisolone was slowly tapered to a maintenance dose of 12.5 mg (0.18 mg/kg) daily.
Despite this treatment, the patient relapsed again two months later, i.e., 11 months following initial treatment, suffering a generalised tonic-clonic convulsion, encephalopathy, recurrent bilateral hearing loss, fresh BRAOs, and new MRI lesions. His neurological status improved after methylprednisolone 1 g daily was administered for 3 days. His dose of oral prednisolone was increased to 1 mg/kg daily, IVIg 2 g/kg monthly was recommenced, and MMF continued at a dose of 1.5 g BD. MRI brain with MR venogram demonstrated right transverse venous sinus thrombosis. A procoagulant screen was positive for the lupus anticoagulant. Review of a previous MR venogram 3 months prior showed that the thrombus had been present for some time and was not changing in morphology or size. For these reasons, aspirin rather than warfarin was continued as an anticoagulant.
A further clinical relapse occurred 3 months later, i.e., 14 months (Figure 3) after initial treatment was commenced, characterized by sudden painless partial visual loss in the right eye with new BRAO encroaching on the central retina, persisting hearing loss, and MRI changes demonstrating diffuse cerebellar, leptomeningeal, and parenchymal enhancement. Infliximab 5 mg/kg was started using a loading regimen at 0, 2, and 6 weeks for induction and then 8 weekly treatments for maintenance. Over the following 4 weeks, there was both clinical and radiological remission of disease. His dose of prednisone was tapered completely from 12.5 mg daily over 4 months. The thrombus resolved, and the patient returned to work. Two years after remaining on the maintenance infliximab therapy, the patient has been free of relapses, the visual acuity is normal, and there are no cognitive deficits on follow-up neuropsychological testing. He continues to be troubled by partial bilateral deafness, for which cochlear implantation has proven helpful. Consideration is being given to stepping down immunosuppression to MMF.