- Email: [email protected]
White matter relapsing remitting disease: “Susac’s syndrome”—An underdiagnosed entity
Multiple Sclerosis and Related Disorders (2013) 2, 349–354
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
White matter relapsing remitting disease: ‘‘Susac’s syndrome’’—An underdiagnosed entity Lucia V. Schottlaendera,1, Jorge Correaleb, Sebastian F. Amerisoc, Javier A. Moschinia, Lucia Crivellib, Francisco Melid, Marcela P. Fiola,n a
Department of Neurology, Institute for Neurological Research (FLENI) Dr. Ra´ ul Carrea, Montan ˜eses 2325, Belgrano, Ciudad de Buenos Aires, Argentina b Department of Neurology, Neuroimmunology Section, Institute for Neurological Research (FLENI) Dr. Ra´ ul Carrea, Montan ˜eses 2325, Belgrano, Ciudad de Buenos Aires, Argentina c Department of Neurology, Vascular Neurology Section, Institute for Neurological Research (FLENI) Dr. Ra´ ul Carrea, Montan ˜eses 2325, Belgrano, Ciudad de Buenos Aires, Argentina d Department of Neurology, Neuroimaging Section, Institute for Neurological Research (FLENI) Dr Ra´ ul Carrea, Montan ˜eses 2325, Belgrano, Ciudad de Buenos Aires, Argentina Received 13 November 2012; received in revised form 21 February 2013; accepted 27 February 2013
KEYWORDS
Abstract
Retina; Cochlea; Encephalopathy; Susac’s syndrome; White matter disease; Corpus callosum
Susac’s syndrome is a treatable microangiopathy of unknown etiology affecting arterioles of the brain, retina, and cochlea. The typical clinical manifestation is the triad of encephalopathy, visual loss, and sensorineural hearing loss. One or more of these features may not be present at onset and therefore Susac’s syndrome’s diagnosis may be difficult. We describe the clinical presentation, diagnostic tests, and treatment of three cases diagnosed and treated at our institution. & 2013 Elsevier B.V. All rights reserved.
1. n Corresponding author. Tel.: +54 1157773200x2704; fax: +54 1157773200. E-mail addresses: [email protected] (L.V. Schottlaender), jcorreale@fleni.org.ar (J. Correale), sameriso@fleni.org.ar (S.F. Ameriso), [email protected] (J.A. Moschini), lcrivelli@fleni.org.ar (L. Crivelli), fmeli@fleni.org.ar (F. Meli), mfiol@fleni.org.ar (M.P. Fiol). 1 Present affiliation: Department of Molecular Neuroscience, UCL, London, UK.
2211-0348/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2013.02.007
Introduction
Susac’s syndrome (SS) has been first described in 1979 (Susac et al., 1979). SS has also been called retinocochleocerebral vasculopathy and affects arterioles of the brain, retina and cochlea (Petty et al., 1998). Clinically, SS consists on the acute or subacute triad of encephalopathy, hypoacusia and visual deficit. The disease is more frequent in young women (Rennebohm et al., 2010). Two variants of SS have been described: the
350
L.V. Schottlaender et al.
encephalopathic form presents multifocal neurological manifestations, and the recurrent branch artery occlusions (BRAO) subset is characterized by visual disturbances with or without hypoacusia (Susac, 1994; Petty et al., 1998; Rennebohm et al., 2008, 2010). Susac’s syndrome can be a disabling disease. Early immunosuppression can impact on axonal integrity and thus, on patient’s prognosis and outcome. However, despite aggressive treatment, the immunological response can be different in each patient, and sometimes multiple regimens are needed (Home9SUSAC/University of Calgary, 2012). We report 3 SS cases that required different therapeutic management coordinated by a multidisciplinary team.
2. 2.1.
day) followed by oral tapering for 16 days. All symptoms were resolved, except the hypoacusia. Retinal fluorescein angiogram (RFA) showed a vasculitic pattern (Fig. 1C,D). SS was diagnosed and monthly cyclophosphamide (1 g/m2) was initiated. He presented 3 relapses characterized clinically by bilateral visual scotoma, new white-matter lesions, and right retinal ischemia in monthly intervals. Five methylprednisolone-pulses were administered for each exacerbation with minimal response. He later developed severe bilateral hypoacusia. He was treated with Intravenous immunoglobulin (IvIg) and hearing aids. Later treatment had to be switched to bi-monthly methylprednisolone-pulses, monthly IvIg and rituximab, as well as daily mycophenolate mofetil (3 g/day) in addition to 30 mg/ day of prednisolone. He remains stable with this scheme.
Results Case 1
A 34 year-old, right-handed man had an upper respiratorytract infection. Two weeks later developed vertigo, vomiting and right lateropulsion. He also described transitory episodes of right and left-eye visual loss as well as intermittent hypoesthesia on his thorax. Upon admission his visual acuity was normal bilaterally. Fundoscopic examination showed threadlike arterioles and one BRAO. He had horizontal primary-gaze nystagmus and right hypoacusia; mild right hemiparesis and wide-based gait. His MRI showed multiple small white matter lesions. He was treated with 3 methylprednisolone-pulses (1gram/
2.2.
Case 2
A 37 year-old right-handed woman, developed progressive headache. Three days later, she complained of right eye visual loss. She became encephalopathic with emotional instability and gait impairment. On admission she was drowsy, inattentive and had global aphasia. She had a right supranuclear facial palsy and left-sided ataxia. Her MRI demonstrated multiple small white-matter lesions (Fig. 2A–E). RFA showed fluorescein leakage and diffuse BRAO (Fig. 2F,G). A diagnosis of SS was established and treatment with 5 methylprednisolone-pulses and cyclophosphamide was indicated. She recovered completely in
Fig. 1 MRI and Retinal fluoresein angiogram (RFA) images from Case 1. (A) Initial sagittal Flair MRI showing central callosal hyperintense lesions commonly described in Susac’s syndrome as ‘‘snow balls’’ and ‘‘icicles’’. (B) T1 MRI presenting hypointense central callosal lesions known as ‘‘black Holes’’. (C) RFA showing fluorescein leakage, ‘‘cotton wool spots’’ and arteriolar wall hyperfluorescence. (D) RFA showing schemia with hemorrhage due to a branch retinal artery occlusion.
‘‘Susac’s syndrome’’—An underdiagnosed entity
351
Fig. 2 MRI and Retinal fluorescein angiogram (RFA) images from Case 2. (A, B, C) Diffusion weighted MRI showing multifocal hyperintense lesions Arrow ‘‘string of pearls’’ in the internal capsule. (D) Sagittal Flair image showing a snow ball lesion in the splenium of the corpus callosum. (E) T1 MRI presenting central hypointense callosal lesions like ‘‘black holes’’. (F,G) RFA showing fluorescein leakage through retinal artery branches, multiple branch retinal artery occlusions and arteriolar wall hyperfluorescence.
6 months and remains on maintenance treatment with cyclophosphamide.
2.3.
Case 3
A 21 year-old right-handed man had a febrile syndrome 1 month before onset. He suddenly awoke with instability, vertigo, vomiting, right visual-loss and intense headache. His MRI showed multiple white-matter lesions, and with the suspicion of multiple sclerosis (MS), steroids and interferon b1a were prescribed. He developed progressive encephalopathy and ataxia. Five months later he was referred to our institution. He was aphasic, irritable and paranoid. He had bilateral visual loss, left supranuclear facial-palsy, quadriparesis and severe trunk ataxia. Frontal release signs were present.
His MRI showed multiple small white-matter lesions (Fig. 3A–E). RFA presented BRAO. SS was diagnosed and treatment was switched to 5 methylprednisolone-pulses plus cyclophosphamide during 8 months. He was then started on mycophenolate-mofetil. His gait, cognitive functions and behavior have improved but are still moderately affected. Table 1 summarizes complementary studies performed in the 3 patients.
3.
Discussion and review of the literature
Since the introduction of new MRI technology, faster and more acute neurologic diagnosis can be achieved. This is the case of SS, where brain MRI is the neuroimaging technique of choice (Do et al., 2004). Encephalopathy, hypoacusia and visual-loss are not always present at onset and Susac et al.
352
L.V. Schottlaender et al.
Fig. 3 MRI images from Case 3. (A) Diffusion weighted MRI showing one hyperintense cerebellar lesion. (B, C) T2 MRI images presenting hyperintense lesions compromising the basal ganglia. (D, E) T1 MRI images showing hypointense callosal lesions as ‘‘black holes’’ and also on lesion in the posterior region of the pons (E).
proposed that a diagnosis of SS can be made with certainty in an encephalopathic patient when the pathognomonic corpus callosum (CC) findings are present; even in the absence of BRAO and hearing loss (Rennebohm et al., 2010). MRI is always abnormal in the encephalopathic form of the disease but may be normal in the recurrent BRAO subset. The most frequent MRI abnormalities are small lesions that affect the periventricular white matter, centrum semiovale and subcortical areas. The central portion of the CC is usually predominantly affected, as a consequence of the occlusion of pre-capillary arterioles. Four different patterns of callosal lesions have been described: round lesions known as ‘‘snow balls’’ that evolve into ‘‘black holes’’, and when the roof of the CC is affected, the microinfarcts can adopt the ‘‘icicle’’ and ‘‘spoke’’ configurations. All these findings are typical of SS. The CC’s ventricular surface is usually not affected and this helps to differentiate SS from MS (Rennebohm et al., 2010). Graymatter involvement, infra-tentorial and gadoliniumenhanced lesions have been described, and can be also useful to differentiate SS from other demyelinating diseases (Susac et al., 2003; Do et al., 2004). Internal capsule microinfarcts can look like a ‘‘string of pearls’’. The combination of central callosal lesions and ‘‘string of pearls’’ is strongly suggestive of SS (Rennebohm et al., 2010). RFA should be performed in all patients were SS is suspected. If the initial RFA is unremarkable, it should be
repeated during follow-up. The characteristic findings are BRAO and fluorescein leakage. Other observations are arteriolar wall hyperfluorescence (AWH) and gass plaques (Susac, 1994; Egan et al., 2010). AWH or BRAO’s presence is evidence of active retinopathy (Rennebohm et al., 2010). The cochlear apex infarction produces low-frequency hearing-loss (Papo et al., 1998), which can be associated with tinnitus and vertigo. Patients may need cochlear implants (Rennebohm et al., 2008). Susac syndrome’s etiology is unknown. As in our cases 1 and 3, patients may present a precedent viral infection (Petty et al., 1998, 2001). Findings on brain biopsies such as endothelial cell swelling, degeneration and necrosis, suggest that SS is a primary autoimmune endotheliopathy. Capillary destruction, basal membrane thickening, reduplication and lamellation, complement deposition and perivascular lymphocytic infiltration support the autoimmune etiology of SS. These findings resemble to those of juvenile dermatomyositis (Home9SUSAC/University of Calgary, 2012) and the vast experience on juvenile dermatomyositis patients has been used as a guide for SS’s immunosuppressant treatment (Rennebohm et al., 2008). Differential diagnoses include primary and secondary vasculitis, MS and ADEM. Other pathologies such as thrombophilic states, infections and Meniere’s disease should also be considered (Petty et al., 1998; Rennebohm et al., 2008).
‘‘Susac’s syndrome’’—An underdiagnosed entity
Table 1
353
Complementary studies performed in Susac’s syndrome patients.
Brain MRI
Spinal cord MRI RFA
Digital subtraction angiography Brain biopsy
Case 1
Case 2
Case 3
Multiple white matter lesions affecting predominantly the central CC, medial cerebellar peduncles, and periventricular areas. They were hyperintense in T2 and FLAIR sequences. Some of the lesions showed restriction DWI. No gadolinium enhancement was observed. Normal Multiple BRAO and AWH. Later, he presented a right retinal ischemia Normal
Multiple small supra and infratentorial lesions predominantly affecting the central CC. They were hyperintense in DWI, Flair and T2. Both lesion and leptomeningeal gadoliniumenhancement were recorded.
Multiple small supra and infratentorial lesions predominantly affecting the central CC and the basal ganglia. They were hyperintense in DWI, Flair ant T2. Some gadolinium enhanced lesions were registered.
Not performed Fluorescein leakage and BRAO
Not performed BRAO
Normal
Normal
Unspecific (i.e.: retracted neurons with acidophil nucleus and cytoplasm) Elevated proteins Not performed Not performed
Not performed
Not performed
CSF OCB Auditory evoked potentials Visual evoked potentials Audiometry
Normal Negative Prolonged central conduction on the left side. Axonal loss on the left side Low frequency bilateral sensorineural hearing loss
Videonystagmography
Not performed
Anticochlear antibodies General blood tests (thyroid, colagenopaties, thrombophilic states) Neuropsychological assessment
Negative Normal
Right canalparesia in caloric test Not performed Normal
Normal (May 2011)
Normal (July 2011)
Not performed Normal
Elevated proteins Not performed Bilateral low amplitude Low amplitude 1st: Not evaluable 2nd control: low frequency mild hypoacusia (asymptomatic) Not performed Not performed Normal
Executive, attentional, memory and verbal fluency deficits. Visual reasoning affected possibly due to visual impairment (July 2011)
DWI, diffusion weighted MRI; CC, copus callosum; CSF, cerebrospinal fluid; OCB, oligoclonal bands; RFA, retinal fluorescein angiogram; BRAO, branch retinal artery occlusions; AWH, arteriolar wall hyperfluorescence.
Table 2
Specific findings in our SS cases that differentiate them from MS. Case 1
Case 2
Clinical course MRI
Bilateral hypoacusia Headache, encephalopathy, Aphasia Affection of the central portion of Affection of the central portion of the CC. the CC Leptomeningeal gadolinium enhancement and string of pearls lesions.
RFA OCB Audiometry and auditory evoked potentials Treatment
BRAO. Right retinal ischemia Negative Abnormal
BRAO Not performed Normal (only audiometry performed).
Required high doses of steroids and an escalating and persistent regimen of immunotherapy
Required persistent immunotherapy
Case 3 Encephalopathy, Aphasia. Affection of the central portion of the CC. Compromise of the basal ganglia BRAO Not performed Abnormal
Required persistent immunotherapy
DWI, diffusion weighted MRI; CC, copus callosum; OCB, oligoclonal bands; RFA, retinal fluorescein angiogram; BRAO, branch retinal artery occlusions.
354
L.V. Schottlaender et al.
Susac’s syndrome can be disabling. Treatment must be early, and sustained. Relapses usually occur with reduction of steroid’s doses. Independently of the clinical presentation, SS usually responds to immunosuppression with steroids. In order to control long-term disease’s progression, cyclophospamide, rituximab, IvIg and micofenolate can be considered (Rennebohm et al., 2008). Treatment must be monitored with a multidisciplinary approach and RFA can be used during follow-up for the early detection of subclinical retinopathy (Rennebohm et al., 2008). Prognosis depends on the presence of encephalopathy. When it is present in the first 2 years, the course might be self-limited (Rennebohm et al., 2008). A case of recurrence after 18 years has been reported (Petty et al., 2001).
4.
Conclusion
We report 3 cases of SS with atypical gender distribution and variable responses to treatment in order to exemplify the variable manifestations that this autoimmune disorder may present (Table 2). SS can be largely under-diagnosed. We aim to alert neurologists, ophthalmologists and otology specialists of this treatable but potentially disabling disease.
Disclosures and conflicts of interest Dr. Correale is a board member of Merck-Serono Argentina, Biogen-Idec Argentina, and member of Merck-Serono LATAM. Dr. Correale was also paid for the development of educational presentations by Merck-Serono LATAM and TEVATuteur Argentina. Professional travel/accommodations stipends have been awarded to Dr. Correale by Merck-
Serono. Dr. Fiol was paid for educacional presentations by Merck Serono and Bayer, and travel/accomdations stipends by Merck Serono, Bayer and Novartis. The rest of the authors have nothing to disclose.
References Do TH, Fisch C, Evoy F. Susac syndrome: report of four cases and review of the literature. American Journal of Neuroradiology 2004;25:382–8. Egan RA, Hills WL, Susac JO. Gass plaques and fluorescein leakage in Susac Syndrome. Journal of the Neurological Sciences 2010;299:97–100. Home9SUSAC/University of Calgary [WWW Document]. URL /http://www.ucalgary.ca/susac/S; 2012. Papo T, Biousse V, Lehoang P, Fardeau C, N0 Guyen N, Huong DL, et al. Susac syndrome. Medicine (Baltimore) 1998;77:3–11. Petty GW, Engel AG, Younge BR, Duffy J, Yanagihara T, Lucchinetti CF, et al. Retinocochleocerebral vasculopathy. Medicine (Baltimore) 1998;77:12–40. Petty GW, Matteson EL, Younge BR, McDonald TJ, Wood CP. Recurrence of Susac syndrome (retinocochleocerebral vasculopathy) after remission of 18 years. Mayo Clinic Proceedings 2001;76:958–60. Rennebohm R, Susac JO, Egan RA, Daroff RB. Susac’s syndrome— update. Journal of the Neurological Sciences 2010;299:86–91. Rennebohm RM, Egan RA, Susac JO. Treatment of Susac’s syndrome. Current Treatment Options in Neurology 2008;10:67–74. Susac JO. Susac’s syndrome: the triad of microangiopathy of the brain and retina with hearing loss in young women. Neurology 1994;44:591–3. Susac JO, Hardman JM, Selhorst JB. Microangiopathy of the brain and retina. Neurology 1979;29:313–6. Susac JO, Murtagh FR, Egan RA, Berger JR, Bakshi R, Lincoff N, et al. MRI findings in Susac’s syndrome. Neurology 2003;61: 1783–7.
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
White matter relapsing remitting disease: ‘‘Susac’s syndrome’’—An underdiagnosed entity Lucia V. Schottlaendera,1, Jorge Correaleb, Sebastian F. Amerisoc, Javier A. Moschinia, Lucia Crivellib, Francisco Melid, Marcela P. Fiola,n a
Department of Neurology, Institute for Neurological Research (FLENI) Dr. Ra´ ul Carrea, Montan ˜eses 2325, Belgrano, Ciudad de Buenos Aires, Argentina b Department of Neurology, Neuroimmunology Section, Institute for Neurological Research (FLENI) Dr. Ra´ ul Carrea, Montan ˜eses 2325, Belgrano, Ciudad de Buenos Aires, Argentina c Department of Neurology, Vascular Neurology Section, Institute for Neurological Research (FLENI) Dr. Ra´ ul Carrea, Montan ˜eses 2325, Belgrano, Ciudad de Buenos Aires, Argentina d Department of Neurology, Neuroimaging Section, Institute for Neurological Research (FLENI) Dr Ra´ ul Carrea, Montan ˜eses 2325, Belgrano, Ciudad de Buenos Aires, Argentina Received 13 November 2012; received in revised form 21 February 2013; accepted 27 February 2013
KEYWORDS
Abstract
Retina; Cochlea; Encephalopathy; Susac’s syndrome; White matter disease; Corpus callosum
Susac’s syndrome is a treatable microangiopathy of unknown etiology affecting arterioles of the brain, retina, and cochlea. The typical clinical manifestation is the triad of encephalopathy, visual loss, and sensorineural hearing loss. One or more of these features may not be present at onset and therefore Susac’s syndrome’s diagnosis may be difficult. We describe the clinical presentation, diagnostic tests, and treatment of three cases diagnosed and treated at our institution. & 2013 Elsevier B.V. All rights reserved.
1. n Corresponding author. Tel.: +54 1157773200x2704; fax: +54 1157773200. E-mail addresses: [email protected] (L.V. Schottlaender), jcorreale@fleni.org.ar (J. Correale), sameriso@fleni.org.ar (S.F. Ameriso), [email protected] (J.A. Moschini), lcrivelli@fleni.org.ar (L. Crivelli), fmeli@fleni.org.ar (F. Meli), mfiol@fleni.org.ar (M.P. Fiol). 1 Present affiliation: Department of Molecular Neuroscience, UCL, London, UK.
2211-0348/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2013.02.007
Introduction
Susac’s syndrome (SS) has been first described in 1979 (Susac et al., 1979). SS has also been called retinocochleocerebral vasculopathy and affects arterioles of the brain, retina and cochlea (Petty et al., 1998). Clinically, SS consists on the acute or subacute triad of encephalopathy, hypoacusia and visual deficit. The disease is more frequent in young women (Rennebohm et al., 2010). Two variants of SS have been described: the
350
L.V. Schottlaender et al.
encephalopathic form presents multifocal neurological manifestations, and the recurrent branch artery occlusions (BRAO) subset is characterized by visual disturbances with or without hypoacusia (Susac, 1994; Petty et al., 1998; Rennebohm et al., 2008, 2010). Susac’s syndrome can be a disabling disease. Early immunosuppression can impact on axonal integrity and thus, on patient’s prognosis and outcome. However, despite aggressive treatment, the immunological response can be different in each patient, and sometimes multiple regimens are needed (Home9SUSAC/University of Calgary, 2012). We report 3 SS cases that required different therapeutic management coordinated by a multidisciplinary team.
2. 2.1.
day) followed by oral tapering for 16 days. All symptoms were resolved, except the hypoacusia. Retinal fluorescein angiogram (RFA) showed a vasculitic pattern (Fig. 1C,D). SS was diagnosed and monthly cyclophosphamide (1 g/m2) was initiated. He presented 3 relapses characterized clinically by bilateral visual scotoma, new white-matter lesions, and right retinal ischemia in monthly intervals. Five methylprednisolone-pulses were administered for each exacerbation with minimal response. He later developed severe bilateral hypoacusia. He was treated with Intravenous immunoglobulin (IvIg) and hearing aids. Later treatment had to be switched to bi-monthly methylprednisolone-pulses, monthly IvIg and rituximab, as well as daily mycophenolate mofetil (3 g/day) in addition to 30 mg/ day of prednisolone. He remains stable with this scheme.
Results Case 1
A 34 year-old, right-handed man had an upper respiratorytract infection. Two weeks later developed vertigo, vomiting and right lateropulsion. He also described transitory episodes of right and left-eye visual loss as well as intermittent hypoesthesia on his thorax. Upon admission his visual acuity was normal bilaterally. Fundoscopic examination showed threadlike arterioles and one BRAO. He had horizontal primary-gaze nystagmus and right hypoacusia; mild right hemiparesis and wide-based gait. His MRI showed multiple small white matter lesions. He was treated with 3 methylprednisolone-pulses (1gram/
2.2.
Case 2
A 37 year-old right-handed woman, developed progressive headache. Three days later, she complained of right eye visual loss. She became encephalopathic with emotional instability and gait impairment. On admission she was drowsy, inattentive and had global aphasia. She had a right supranuclear facial palsy and left-sided ataxia. Her MRI demonstrated multiple small white-matter lesions (Fig. 2A–E). RFA showed fluorescein leakage and diffuse BRAO (Fig. 2F,G). A diagnosis of SS was established and treatment with 5 methylprednisolone-pulses and cyclophosphamide was indicated. She recovered completely in
Fig. 1 MRI and Retinal fluoresein angiogram (RFA) images from Case 1. (A) Initial sagittal Flair MRI showing central callosal hyperintense lesions commonly described in Susac’s syndrome as ‘‘snow balls’’ and ‘‘icicles’’. (B) T1 MRI presenting hypointense central callosal lesions known as ‘‘black Holes’’. (C) RFA showing fluorescein leakage, ‘‘cotton wool spots’’ and arteriolar wall hyperfluorescence. (D) RFA showing schemia with hemorrhage due to a branch retinal artery occlusion.
‘‘Susac’s syndrome’’—An underdiagnosed entity
351
Fig. 2 MRI and Retinal fluorescein angiogram (RFA) images from Case 2. (A, B, C) Diffusion weighted MRI showing multifocal hyperintense lesions Arrow ‘‘string of pearls’’ in the internal capsule. (D) Sagittal Flair image showing a snow ball lesion in the splenium of the corpus callosum. (E) T1 MRI presenting central hypointense callosal lesions like ‘‘black holes’’. (F,G) RFA showing fluorescein leakage through retinal artery branches, multiple branch retinal artery occlusions and arteriolar wall hyperfluorescence.
6 months and remains on maintenance treatment with cyclophosphamide.
2.3.
Case 3
A 21 year-old right-handed man had a febrile syndrome 1 month before onset. He suddenly awoke with instability, vertigo, vomiting, right visual-loss and intense headache. His MRI showed multiple white-matter lesions, and with the suspicion of multiple sclerosis (MS), steroids and interferon b1a were prescribed. He developed progressive encephalopathy and ataxia. Five months later he was referred to our institution. He was aphasic, irritable and paranoid. He had bilateral visual loss, left supranuclear facial-palsy, quadriparesis and severe trunk ataxia. Frontal release signs were present.
His MRI showed multiple small white-matter lesions (Fig. 3A–E). RFA presented BRAO. SS was diagnosed and treatment was switched to 5 methylprednisolone-pulses plus cyclophosphamide during 8 months. He was then started on mycophenolate-mofetil. His gait, cognitive functions and behavior have improved but are still moderately affected. Table 1 summarizes complementary studies performed in the 3 patients.
3.
Discussion and review of the literature
Since the introduction of new MRI technology, faster and more acute neurologic diagnosis can be achieved. This is the case of SS, where brain MRI is the neuroimaging technique of choice (Do et al., 2004). Encephalopathy, hypoacusia and visual-loss are not always present at onset and Susac et al.
352
L.V. Schottlaender et al.
Fig. 3 MRI images from Case 3. (A) Diffusion weighted MRI showing one hyperintense cerebellar lesion. (B, C) T2 MRI images presenting hyperintense lesions compromising the basal ganglia. (D, E) T1 MRI images showing hypointense callosal lesions as ‘‘black holes’’ and also on lesion in the posterior region of the pons (E).
proposed that a diagnosis of SS can be made with certainty in an encephalopathic patient when the pathognomonic corpus callosum (CC) findings are present; even in the absence of BRAO and hearing loss (Rennebohm et al., 2010). MRI is always abnormal in the encephalopathic form of the disease but may be normal in the recurrent BRAO subset. The most frequent MRI abnormalities are small lesions that affect the periventricular white matter, centrum semiovale and subcortical areas. The central portion of the CC is usually predominantly affected, as a consequence of the occlusion of pre-capillary arterioles. Four different patterns of callosal lesions have been described: round lesions known as ‘‘snow balls’’ that evolve into ‘‘black holes’’, and when the roof of the CC is affected, the microinfarcts can adopt the ‘‘icicle’’ and ‘‘spoke’’ configurations. All these findings are typical of SS. The CC’s ventricular surface is usually not affected and this helps to differentiate SS from MS (Rennebohm et al., 2010). Graymatter involvement, infra-tentorial and gadoliniumenhanced lesions have been described, and can be also useful to differentiate SS from other demyelinating diseases (Susac et al., 2003; Do et al., 2004). Internal capsule microinfarcts can look like a ‘‘string of pearls’’. The combination of central callosal lesions and ‘‘string of pearls’’ is strongly suggestive of SS (Rennebohm et al., 2010). RFA should be performed in all patients were SS is suspected. If the initial RFA is unremarkable, it should be
repeated during follow-up. The characteristic findings are BRAO and fluorescein leakage. Other observations are arteriolar wall hyperfluorescence (AWH) and gass plaques (Susac, 1994; Egan et al., 2010). AWH or BRAO’s presence is evidence of active retinopathy (Rennebohm et al., 2010). The cochlear apex infarction produces low-frequency hearing-loss (Papo et al., 1998), which can be associated with tinnitus and vertigo. Patients may need cochlear implants (Rennebohm et al., 2008). Susac syndrome’s etiology is unknown. As in our cases 1 and 3, patients may present a precedent viral infection (Petty et al., 1998, 2001). Findings on brain biopsies such as endothelial cell swelling, degeneration and necrosis, suggest that SS is a primary autoimmune endotheliopathy. Capillary destruction, basal membrane thickening, reduplication and lamellation, complement deposition and perivascular lymphocytic infiltration support the autoimmune etiology of SS. These findings resemble to those of juvenile dermatomyositis (Home9SUSAC/University of Calgary, 2012) and the vast experience on juvenile dermatomyositis patients has been used as a guide for SS’s immunosuppressant treatment (Rennebohm et al., 2008). Differential diagnoses include primary and secondary vasculitis, MS and ADEM. Other pathologies such as thrombophilic states, infections and Meniere’s disease should also be considered (Petty et al., 1998; Rennebohm et al., 2008).
‘‘Susac’s syndrome’’—An underdiagnosed entity
Table 1
353
Complementary studies performed in Susac’s syndrome patients.
Brain MRI
Spinal cord MRI RFA
Digital subtraction angiography Brain biopsy
Case 1
Case 2
Case 3
Multiple white matter lesions affecting predominantly the central CC, medial cerebellar peduncles, and periventricular areas. They were hyperintense in T2 and FLAIR sequences. Some of the lesions showed restriction DWI. No gadolinium enhancement was observed. Normal Multiple BRAO and AWH. Later, he presented a right retinal ischemia Normal
Multiple small supra and infratentorial lesions predominantly affecting the central CC. They were hyperintense in DWI, Flair and T2. Both lesion and leptomeningeal gadoliniumenhancement were recorded.
Multiple small supra and infratentorial lesions predominantly affecting the central CC and the basal ganglia. They were hyperintense in DWI, Flair ant T2. Some gadolinium enhanced lesions were registered.
Not performed Fluorescein leakage and BRAO
Not performed BRAO
Normal
Normal
Unspecific (i.e.: retracted neurons with acidophil nucleus and cytoplasm) Elevated proteins Not performed Not performed
Not performed
Not performed
CSF OCB Auditory evoked potentials Visual evoked potentials Audiometry
Normal Negative Prolonged central conduction on the left side. Axonal loss on the left side Low frequency bilateral sensorineural hearing loss
Videonystagmography
Not performed
Anticochlear antibodies General blood tests (thyroid, colagenopaties, thrombophilic states) Neuropsychological assessment
Negative Normal
Right canalparesia in caloric test Not performed Normal
Normal (May 2011)
Normal (July 2011)
Not performed Normal
Elevated proteins Not performed Bilateral low amplitude Low amplitude 1st: Not evaluable 2nd control: low frequency mild hypoacusia (asymptomatic) Not performed Not performed Normal
Executive, attentional, memory and verbal fluency deficits. Visual reasoning affected possibly due to visual impairment (July 2011)
DWI, diffusion weighted MRI; CC, copus callosum; CSF, cerebrospinal fluid; OCB, oligoclonal bands; RFA, retinal fluorescein angiogram; BRAO, branch retinal artery occlusions; AWH, arteriolar wall hyperfluorescence.
Table 2
Specific findings in our SS cases that differentiate them from MS. Case 1
Case 2
Clinical course MRI
Bilateral hypoacusia Headache, encephalopathy, Aphasia Affection of the central portion of Affection of the central portion of the CC. the CC Leptomeningeal gadolinium enhancement and string of pearls lesions.
RFA OCB Audiometry and auditory evoked potentials Treatment
BRAO. Right retinal ischemia Negative Abnormal
BRAO Not performed Normal (only audiometry performed).
Required high doses of steroids and an escalating and persistent regimen of immunotherapy
Required persistent immunotherapy
Case 3 Encephalopathy, Aphasia. Affection of the central portion of the CC. Compromise of the basal ganglia BRAO Not performed Abnormal
Required persistent immunotherapy
DWI, diffusion weighted MRI; CC, copus callosum; OCB, oligoclonal bands; RFA, retinal fluorescein angiogram; BRAO, branch retinal artery occlusions.
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Susac’s syndrome can be disabling. Treatment must be early, and sustained. Relapses usually occur with reduction of steroid’s doses. Independently of the clinical presentation, SS usually responds to immunosuppression with steroids. In order to control long-term disease’s progression, cyclophospamide, rituximab, IvIg and micofenolate can be considered (Rennebohm et al., 2008). Treatment must be monitored with a multidisciplinary approach and RFA can be used during follow-up for the early detection of subclinical retinopathy (Rennebohm et al., 2008). Prognosis depends on the presence of encephalopathy. When it is present in the first 2 years, the course might be self-limited (Rennebohm et al., 2008). A case of recurrence after 18 years has been reported (Petty et al., 2001).
4.
Conclusion
We report 3 cases of SS with atypical gender distribution and variable responses to treatment in order to exemplify the variable manifestations that this autoimmune disorder may present (Table 2). SS can be largely under-diagnosed. We aim to alert neurologists, ophthalmologists and otology specialists of this treatable but potentially disabling disease.
Disclosures and conflicts of interest Dr. Correale is a board member of Merck-Serono Argentina, Biogen-Idec Argentina, and member of Merck-Serono LATAM. Dr. Correale was also paid for the development of educational presentations by Merck-Serono LATAM and TEVATuteur Argentina. Professional travel/accommodations stipends have been awarded to Dr. Correale by Merck-
Serono. Dr. Fiol was paid for educacional presentations by Merck Serono and Bayer, and travel/accomdations stipends by Merck Serono, Bayer and Novartis. The rest of the authors have nothing to disclose.
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