Susac’s syndrome as HIV-associated immune reconstitution inflammatory syndrome
© Ferretti et al.; licensee BioMed Central Ltd. 2013
Received: 17 June 2013
Accepted: 24 August 2013
Published: 3 September 2013
Susac’s Syndrome (SS) is an autoimmune endotheliopathy of cerebral, retinal and cochlear arterioles. We report of an HIV-infected woman who developed a first SS episode following a spontaneous reduction of plasma viral load and several relapses six years later, following initiation of combined antiretroviral therapy (cART). Corticosteroids and intravenous immunoglobulins alone did not control the disease, which improved after combined treatment with acyclovir and ganciclovir. SS onset in HIV infection and relapses during cART-induced immune reconstitution are consistent with the dysimmune nature of the disease. The response to anti-herpes drugs suggests a viral contribute in this case of SS.
Susac’s syndrome (SS) is a rare autoimmune microangiopathic disorder, affecting precapillary arterioles of the brain, retina and cochlea . Until now, approximately 200 cases have been reported , mainly in women. Headache, focal neurological signs, deafness and ocular symptoms are the most common clinical manifestations, but do not necessary occur simultaneously. SS is almost never fatal , however it is characterized by spontaneous remissions and relapses that can only partially be controlled or delayed by immunosuppressive drugs and often lead to irreversible neurological sequelae and poor quality of life.
We here describe a case of SS in an HIV-infected woman, who developed a first episode following a spontaneous decrease of plasma viral load, and several relapses 6 years later, following introduction of combined antiretroviral therapy (cART), as likely expression of an immune reconstitution inflammatory syndrome (IRIS). Notably, the neurological picture was not controlled by corticosteroids and intravenous immunoglobulins alone, but only when acyclovir and ganciclovir were administered concomitantly, suggesting a possible role of herpes viruses in SS pathogenesis in this case.
Clinical, laboratory, neuroradiological findings and therapies for each Susac Syndrome episode
New neurological symptoms
Ongoing therapy (duration)
New therapy (duration)
First episode September 2002
Headache, facial paresthesias, hemianopsia, amaurosis, tinnitus, vertigo
T2-hyperintense Gd-enhancing lesions (brain)
FO and RFA: retinal branch occlusion. Auditory examination: initial left neurosensorial hypoacusia. VEP, AEP: normal
IV MEP 20 mg bid (3 days). IV GCV 5 mg/Kg bid (14 days)
VL: 2000 c/mL
VDRL and TPHA neg
Proteins: 89 gr/dL
Microbiology * neg
Viral genomes ** neg
First relapse March 2008
Headache, facial, lingual, oral and hand paresthesias
Increased T2 hyperintensity of old lesions; new T2 hyperintense non Gd-enhancing lesion (brain) (Figure 1a)
EEG: focal slow abnormal activity in the left temporal region
cART: TDF, FTC, ATV (6 weeks)
Oral PDN 50 mg qd (5 days), then 25 mg qd (3 days). Stop cART
VDRL and TPHA neg
First relapse, follow-up (SS diagnosis) April 2008
Left hemiparesis, acute left hypoacusia
Further increased T2 hyperintensity of old lesions; new T2 hyperintense non Gd-enhancing lesions (cerebellum) (Figure 1b)
Visual field: central scotoma of right eye, arcuate scotoma in the superior and inferior field of left eye. FO: right retinal vasculopathy. RFA: acute bilateral retinal vasculitis with reduced perfusion. VEP: absent response of right eye, reduced response of left eye; AEP: mixed bilateral hypoacusia.
IV MEP 1 g qd (5 days), then oral PDN 50 mg qd (10 days). cART: TDF, FTC, ATV
Proteins: 23 g/dL
Viral genomes*: neg
Oligoclonal bands: neg
IgG: 64 mg/dL
Albumin ratio: 4.52
Intrathecal HSV-1/2, VZV and CMV-specific IgG synthesis: neg
Second relapse April 2008
Blurred vision, hallucinations, gait and balance deficit
Blood c-ANCA, p-ANCA, anti cardiolipin, anti-beta 2-gp, LA and ANA: neg
New T2 hyperintense lesions with mild Gd-enhancement
cART: TDF, FTC, ATV (3 weeks)
IV MEP 1 g qd (6 days), then oral PDN 75 mg qd
Third relapse May 2008
Worsening of previous symptoms
New Gd-enhancing lesions (brain and brain stem) (Figure 1c)
cART: TDF, FTC, ATV (6 weeks). Oral PDN 75 mg qd (5 days)
IV Ig 15.5 g qd (5 days). IV MEP 40 mg bid (6 days)
Third relapse, follow-up May 2008
Persistence of symptoms
cART: TDF, FTC, ATV (8 weeks). IV MEP 40 mg bid (6 days)
IV MEP 1 g qd (3 days), then oral PDN 150 mg qd, tapered to 5 mg in 16 weeks. IV GCV 5 mg/Kg bid (14 days), then oral V-GCV 450 mg qd (4 weeks). IV ACV 15 mg/Kg tid (14 days), then oral ACV 800 mg q5h (3 weeks)
Proteins: 172 g/dL
Fourth relapse November 2008
Vertigo, visus deficit
New small Gd-enhancing lesions (cerebellum) ( Figure 1d)
cART: TDF, 3TC, ABV. Oral PDN 5 mg
IV MEP 1 g qd (3 days). IV ACV 15 mg/Kg tid (14 days), then oral ACV 400 mg bid (4 weeks)
Improvement and subsequent stabilization
In April 2008, three weeks after discharge, the patient was readmitted for new neurological symptoms and contrast-enhancing brain lesions at MRI (second relapse). She received high dose i.v. methylprednisolone, tapered with oral prednisone, followed by mild clinical improvement. A third relapse with new MRI contrast-enhancing lesions occurred in May 2008, while patient was still on maintenance oral prednisone (Figure 1c). She received i.v. immunoglobulin followed by 40 mg bid of i.v. methylprednisolone, with no improvement. High dose i.v. methylprednisolone was then started. I.v. gancyclovir and acyclovir were also administered for the presence of CMV pp65 antigen in plasma (5 nuclei) and suspecting a reactivation of a viral infection of the CNS, in view of the response to gancyclovir during the first episode in 2002. Patient conditions improved substantially and she was discharged with oral maintenance prednisone, acyclovir and valgancyclovir. Acyclovir was continued for 3 weeks and valganciclovir was stopped after 4 weeks for hematologic toxicity. In August 2008 cART was switched to lamivudine, tenofovir and abacavir. A fourth relapse occurred seven months later, with new MRI contrast enhancing cerebral and cerebellar lesions (Figure 1d). Patient was treated with i.v. methylprednisolone and i.v. acyclovir for 14 days, followed by clinical and MRI improvement with no further relapses.
During the following years the patient continued cART and oral prednisone maintenance at 2.5-5 mg per day, increased to 12.5-25 mg for short periods, for worsening of vertigo. She experienced no new neurological episodes, but was left with severe neurological sequelae, iatrogenic diabetes and severe osteoporosis with vertebral fractures. At last visit in January 2013 the patient had mild cognitive impairment by neuropsychological evaluation, walked with a cane and suffered from severe visual and earing loss. There was no evidence of disease activity at MRI (Figure 1e), CD4+ were 574 cells/μL and HIV-RNA <50 c/mL.
This is, to our knowledge, the first case of SS described in an HIV-infected person. Our patient met all the diagnostic criteria for SS, i.e., MRI findings of corpus callosum microinfarctions, leptomeningeal enhancement and grey matter involvement, evidence of branch retinal artery occlusion at retinal fluorangiography and abnormal brainstem auditory evoked potentials . In agreement with what often reported , diagnosis was achieved only years after onset, when the classical triad of cerebral, ocular and auditory involvement was documented, along with exclusion of other etiologies.
In our case, symptoms occurred in the peculiar context of immune reconstitution, which was apparently spontaneous at the onset of SS and associated with cART in the subsequent relapses, providing the criteria for IRIS . IRIS consists of a broad spectrum of inflammatory diseases that present after starting an effective cART, leading to CD4+ cells increase and, more importantly, plasma HIV-RNA reduction.  IRIS reflects a paradoxycal inflammatory response to opportunistic pathogens, such as Cryptococcus spp, mycobacteria , JC virus , or also to auto-antigens [10, 11]. Indeed, autoimmune diseases like Graves thyroiditis, pulmunary sarcoidosis, rheumatoid arthritis, systemic lupus erythematosus and polymiositis have been reported as IRIS manifestations . The recent finding of anti-endothelium cell autoantibodies in some SS patients  and the usually good response to immunosuppressive therapy support the autoimmune pathogenesis of SS. Thus our case suggests that SS might represent an additional manifestation of “autoimmune IRIS”.
Our patient did not show a long-lasting response to high dose i.v. steroids or i.v. immunoglobulins alone in three attempts (first and second relapses), whereas a substantial and durable improvement was achieved both times steroids were combined with antiviral drugs, i.e., acyclovir, active on herpes simplex virus type 1 and type 2 and varicella-zoster virus (VZV), and gancyclovir, also active on CMV and Epstein-Barr virus. It is known that the response to steroids in SS can not persist over time  and that SS can be characterized by spontaneous attenuation of the immunopathological process . However, the temporal relationship between antiviral treatment and clinical improvement was strong and consistent in our case, suggesting that reactivation of an herpesvirus in the CNS might have contributed to disease pathogenesis.
We did not find evidence of herpesviruses in CSF (Table 1), but this does not exclude possible low level replication in CNS tissue . We can speculate on a pathogenic model by which an herpesvirus reactivated in the context of immune reconstitution and, by replication in vascular cells  and consequent exposure of either viral or auto-antigens, lead to immune mediated damage of cerebral vessels. According to this model, antiviral therapy could have initially contributed to switch off the inflammatory stimulus by control of viral replication. A potential candidate herpesvirus is VZV. VZV can cause direct damage of CNS vessels of all calibres and indirect damage of CNS cells  and it is a well known cause of CNS vasculitis and ocular infections in HIV-infected subjects [17, 18]. In addition, herpes zoster, resulting from peripheral VZV reactivation, is a frequent IRIS manifestation and cases of VZV CNS-IRIS have recently been reported [19, 20].
In conclusion, our case shows that SS may occur within a dysimmune context that is possibly sustained by HIV infection, cART-associated immune reconstitution, or both. The clinical and neuroradiological remission observed when antiviral drugs were added to corticosteroids support a potential pathogenetic role of herpes virus reactivations in SS in our case.
Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
The authors thank the medical and nursing staff at the Department of Infectious Diseases of San Raffaele Hospital for their assistance in the care of this patient. We also wish to thank the patient and her family for their collaboration.
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