EXPERIENCE AND REASON |
Microangiopathy of Brain, Retina, and Inner Ear (Susac’s Syndrome) in an Adolescent Female Presenting as Acute Disseminated Encephalomyelitis
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* Departments of Neurology
Pediatrics, Stanford University School of Medicine, Stanford, California
Lucile Packard Children’s Hospital, Palo Alto, California
|| Lucile Packard Children’s Hospital, Redding, California
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ABSTRACT |
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 TOP ABSTRACT CASE REPORTSDISCUSSIONCONCLUSIONSREFERENCES |
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Susac’s syndrome is a rare disorder that consists of microangiopathy of the brain, retina, and inner ear and usually affects young women in young adulthood. The triad of clinical manifestations consists of acute encephalopathy with neurologic signs, branch retinal artery occlusion (BRAO), and sensorineural hearing loss. We present a case of an adolescent female who presented at age 16 years with clinical and neuroimaging features of acute disseminated encephalomyelitis (ADEM). The full triad did not develop until 2.5 years after the initial neurologic presentation.
Abbreviations: BRAO, branch retinal artery occlusion • ADEM, acute disseminated encephalomyelitis • MRI, magnetic resonance image • CSF, cerebrospinal fluid • WBC, white blood cell • LPCH, Lucile Packard Children’s Hospital • SLE, system lupus erythematosus • MS, multiple sclerosis • CNS, central nervous system • FLAIR, fluid-attenuated inversion recovery
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CASE REPORTS |
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TOPABSTRACTCASE REPORTSDISCUSSIONCONCLUSIONSREFERENCES |
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A previously healthy, 16-year-old, right-handed female presented in August 2000 with a 10-day history of headache, lethargy, fatigue, and a low-grade fever. She developed vomiting and became confused and unsteady in her gait. On admission to a local hospital, she was disoriented, ataxic, and hyperreflexive. A magnetic resonance image (MRI) revealed multiple signal hyperintensities in the corpus callosum, frontal and parietal white matter, cerebellum, and left cerebellar peduncle without significant enhancement (Fig 1A–C). Cavitary lesions of the corpus callosum were noted. Cerebrospinal fluid (CSF) revealed 1 white blood cell (WBC) per µL, 1 red blood cell per µL, a protein level of 156 mg/dL, and a glucose level of 67 mg/dL. CSF IgG index was normal, and oligoclonal bands were absent. She was thought to have ADEM and was treated with intravenous methylprednisolone (500 mg for 4 days). Because her neurologic status did not improve, she was transferred to Lucile Packard Children’s Hospital (LPCH) at Stanford, California. On examination, she was awake but had a blunted affect and was difficult to engage. She was able to answer simple questions and would inconsistently follow simple 1-step commands. Cranial nerve, motor, and sensory examinations were normal. Hearing was intact to speech. She had gait ataxia, hyperreflexia in the lower limbs, and extensor plantar responses. A second MRI revealed no significant changes, although some lesions showed contrast enhancement (Fig 1D). Diffusion-weighted images did not show evidence of acute infarcts, and magnetic resonance angiography of the circle of Willis was unremarkable. She was treated with IVIg (400 mg/kg per day for 5 days), with rapid improvement of her mental status and ataxia.
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One month later, she developed recurrence of neurologic symptoms including memory problems, slurred speech, headaches, and gait imbalance. She received another 2 g/kg of IVIg but did not improve. An MRI revealed new lesions of the base of the right basal ganglia and left caudate nucleus (Fig 2). She was readmitted to LPCH in late October 2000 for a 3-day course of methylprednisolone pulse (1 g/kg per day). She had a good response, with marked improvement in her symptoms. She was discharged on an oral prednisone taper and interferon ß 1a injections (30 µg/wk).
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Two weeks later, she was readmitted to LPCH with recurrence of symptoms including confusion, altered level of consciousness, memory problems, headaches, vomiting, and ataxia. An MRI revealed new, large white matter lesions in the splenium of corpus callosum (Fig 3). She was treated with plasmapheresis (alternate-day therapy for 2 weeks followed by twice-a-week therapy for 2 weeks) with partial improvement.
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After discharge, she developed bilateral hearing loss and tinnitus. Audiologic testing revealed severe bilateral sensorineural hearing loss (low frequencies in right ear and low to medium frequencies in the left ear). Speech discrimination was poor in the right ear and fair in the left ear.
As an outpatient, she had intermittent headaches, balance problems, and mental status changes. She required continued therapy of plasmapheresis followed by IVIg boluses of 20 to 30 g every 2 weeks. She also was treated with interferon ß 1a and mycophenolate mofetil. She was stable with this regimen for >2 years and had no attacks requiring admission. She had regained most of her neurologic function except for hearing.
In early March 2003, she developed a sudden loss of vision in her right eye without pain. On ophthalmologic evaluation, her visual acuities were "count fingers" OD and 20/20 OS. Fundoscopic examination revealed a BRAO in the right eye temporal to the disk, with a large cotton-wool infarct involving the nasal macula (Fig 4). Fluorescein angiography confirmed BRAO with a larger affected segment temporal to the disk (Fig 4). Numerous areas of sheathing and apparent platelet-fibrin aggregation were present. She received intravenous methylprednisolone (1 g/kg per day for 3 days), with only a slight improvement of her eyesight. She also was started on aspirin (81 mg daily). Two months before the visual problem, she had started oral contraceptives (Ortho Tri-Cyclen). This was discontinued immediately.
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She was admitted to Stanford University Hospital on March 19, 2003, because of a complaint of blurriness of vision in her left eye. She was alert and oriented and had normal speech. Her visual acuities were unchanged. Ophthalmologic examination revealed no vascular occlusions in the left eye and no acute changes in the right eye. She had decreased hearing bilaterally, but speech discrimination was good. Her motor examination was normal. She had mild difficulty with tandem gait. She was hyperreflexive throughout, with several beats of ankle clonus.
An MRI of her brain and spine showed no new or acute lesions. There were some residual signal hyperintensities in the corpus callosum, deep white matter, and cerebellum, but they appeared much improved from her previous MRIs. Laboratory evaluation for thrombophilia was negative. This evaluation included normal international normalized ratio, prothrombin time, partial thromboplastin time, lupus anticoagulant, anticardiolipin antibodies, antiphospholipid antibodies, protein C and protein S, antithrombin III, rapid plasma reagin, and dilute Russell’s viper venom time. Factor V Leiden and prothrombin gene 20210 mutation analyses were normal. A methylenetetrahydrofolate reductase (MTHFR) mutation study revealed compound heterozygous mutation with 1 copy of MTHFR 677C
T and 1 copy of MTHFR 1298AC mutation. Plasma homocysteine levels were normal. Other laboratory tests for system lupus erythematosus (SLE) and other vasculitides were normal, including fluorescent antinuclear antibody, C3 and C4, CH50, coarse granular anti-neutrophil cytoplasmic antibodies, perinuclear anti-neutrophil cytoplasmic antibodies, and anti-double-stranded DNA antibodies.
She was treated with intravenous cyclophosphamide (10 mg/kg) and methylprednisolone pulse (1 g/day for 5 days). She was discharged on a prednisone taper and cyclophosphamide and intravenous methylprednisolone every 2 weeks. She was also maintained on aspirin and plasmapheresis every 2 weeks followed by IVIg. Six months after the onset of visual loss, she still has severely reduced visual acuity in the right eye but has not had any new neurologic symptoms or signs.
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DISCUSSION |
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TOPABSTRACTCASE REPORTSDISCUSSIONCONCLUSIONSREFERENCES |
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Susac’s syndrome consists of microangiopathy of the brain, retina, and inner ear. The clinical triad is composed of acute encephalopathy, BRAO, and sensorineural hearing loss. The disorder has also been referred to as SICRET syndrome (small infarctions of cochlear, retinal, and encephalic tissue), RED-M syndrome (retinopathy, encephalopathy, deafness associated microangiopathy), and retinocochleocerebral vasculopathy.
Our patient fits the clinical triad of Susac’s syndrome. She developed first symptoms at 16 years of age, when she presented with an acute encephalopathy. She then had a 3-month period during which her encephalopathy had a multiphasic course. Her initial course was consistent with ADEM, but she had multiple attacks of encephalopathy during the first few months that resembled multiphasic disseminated encephalomyelitis or multiple sclerosis (MS). She developed sensorineural hearing loss 3 months after initial symptoms. Two-and-a-half years after the onset of her initial symptoms, she developed BRAO and was given the diagnosis of Susac’s syndrome. The BRAO may have been precipitated by the addition of oral contraceptives. Oral contraceptives have been noted to precipitate BRAO in other cases of Susac’s syndrome,1 presumably by promoting a hypercoagulable state, thus exacerbating the underlying vasculopathy.
The clinical triad of encephalopathy, BRAO, and deafness was reported by Susac in 1979.2 The syndrome predominantly affects women in their third and fourth decades of life, predominantly between ages 18 and 42 years.1,3 In a review of 46 patients with Susac’s syndrome, the mean age was 28 years, with a range of 8 to 59 years.4 Of these cases, 85% have been women.4 Our patient is one of the youngest reported patients with Susac’s syndrome. The vast majority of the cases reported in literature reviews have been 
18 years at onset.4–6 Currently, the youngest reported case is an 8-year-old girl who had progressive hearing loss and monocular visual loss but no encephalopathy.7 On fluorescein angiography, she had BRAO in the affected eye. On cerebral angiography, she had occlusion of distal branches of the middle cerebral artery. These 2 cases indicate that Susac’s syndrome can occur during childhood, although it remains exceedingly rare.
During the encephalopathy phase various neurologic manifestations occur, including acute mental status changes and memory impairment. Personality changes, including paranoia and depression, are often early manifestations and are followed by memory loss, dementia, and abnormal neurologic signs.1 Headaches are common.5 There is often a chronic relapsing and remitting course. Over time, patients often develop dementia, long-tract signs, and brainstem signs.8
The neuroimaging study of choice is the MRI. During the acute encephalopathy, MRIs show numerous high signal intensities on T2-weighted images in the white and gray matter. There is a predilection for corpus callosal involvement. Brainstem and cerebellum are often involved. These lesions show inconsistent contrast enhancement. White matter lesions are more prominent than gray, and hence the lesions are often misinterpreted as being caused by MS.4 However, the involvement of gray matter would differentiate Susac’s syndrome from MS (which is limited to white matter involvement) but not from ADEM (which can involve both white and gray matter). These lesions most likely represent small vascular infarcts, although diffusion-weighted imaging studies have not consistently demonstrated these lesions as being acutely ischemic. In patients who have serial imaging, resolution of some of the lesions without development of infarcts has been noted.6 Hence, some of the lesions in the central nervous system (CNS) may be immune-mediated in nature rather than ischemic.
Electroencephalograms usually show diffuse slowing.4 CSF shows a variable degree of leukocytosis, with a mean cell count of 9 WBC/µL (range: 0–37 WBC/µL) and elevation of protein in the vast majority of patients.4 CSF oligoclonal bands are absent.4
The hearing loss is usually bilateral but asymmetric.3,4 Tinnitus and vertigo are common symptoms also.3,4 The hearing loss most commonly involves low and medium frequencies.4 The location of the lesion that causes sensorineural hearing loss in Susac’s syndrome is thought to be the apical portions of the cochlea.4 Our patient had typical audiologic features of Susac’s syndrome, including bilateral low- and medium-frequency hearing loss and tinnitus.
The retinopathy in Susac’s syndrome consists of arteriolar branch occlusions with patchy areas of retinal infarcts. These BRAOs cause sudden onset of impaired vision. Arterioles are often occluded by long segments of white material.8 The cause of retinal arteriolar occlusions is unknown, because there is no evidence of vasculitis in most patients with Susac’s syndrome. The microangiopathy that is the underlying problem in Susac’s syndrome is thought to affect small branches of the retinal artery.
Although the time to develop the full triad of Susac’s syndrome can range from a few weeks to 2 years, the vast majority of patients in one large review series developed the full triad within 1 year.6 Our patient developed encephalopathy and hearing loss within 3 months, but the BRAO did not occur until >30 months after her initial neurologic symptoms.
Susac’s syndrome usually begins with neurologic abnormalities and mental status changes before the onset of visual or hearing loss.1,3 Therefore, it is not uncommon for patients with Susac’s syndrome to carry other diagnoses before the syndrome is recognized. These diagnoses include MS, ADEM, vasculitis, SLE, transient ischemic attacks, and complicated migraines.4,9 If a patient with a history of acute encephalopathy (with an MS- or ADEM-like picture) also develops hearing loss or acute visual loss due to BRAO, Susac’s syndrome should be considered. In rare circumstances, BRAO may be a presenting sign, although a careful history will often reveal earlier neurologic symptoms or signs.1,6 Otolaryngologists and ophthalmologists must be aware of this syndrome, because they may the first ones to evaluate patients with Susac’s syndrome. Furthermore, neurologist who treat MS patients should be aware of this syndrome, because MS is often the initial diagnosis considered when patients present with the encephalopathy phase. Careful history and examination with regard to hearing loss or visual abnormalities may provide hints to this diagnosis.
Etiology and Pathogenesis
The nature of the cerebral lesions has not been entirely clear. Cerebral arteriography has suggested arteriolar vasculitis in a few cases.2,4 Cases usually show occlusion or stenosis of 1 or 2 small vessels. No autopsy cases have been reported. Several brain biopsies have been reported, describing multiple microinfarcts with minimal periarteriolar inflammatory changes.2,4,6,8,10 The arterioles may show thickening with sclerosis of the media and adventitia. Neither necrotizing vasculitis nor fibrinoid necrosis was seen. Although these biopsies indicate that the CNS lesions are caused by microinfarcts, the underlying cause of the arteriolar occlusion remains elusive. The loss of low and moderate tones on pure-tone audiometry is thought to be compatible with damage to the apical portions of the cochlea.8 These regions are supplied by end arterioles of the inner ear.
Differential diagnosis of Susac’s syndrome includes demyelinating diseases, systemic vasculitis, thrombophilic disorders, and mitochondrial encephalopathy. Extensive differentials are available in reviews.5,6 Because of the predominant white matter lesions seen on an MRI, the syndrome frequently is misdiagnosed as MS. However, the retinal occlusive disease and hearing loss are atypical of MS. The involvement of deep gray matter in Susac’s syndrome is also not typical of MS. Other conditions to consider include a hypercoagulable state, vasculitis, and other vascular causes of CNS lesions and BRAO.
BRAO may be caused by embolic phenomenon, but embolic sources are rarely identified in these patients.4 Furthermore, the hyperfluorescence on fluorescein angiography commonly seen in Susac’s syndrome is not a typical finding in embolic occlusions.1,4 BRAO may occur rarely in SLE. Some cases of Susac’s syndrome have been attributed initially to SLE. However, these patients do not usually meet the criteria for SLE, and most have normal antinuclear antibody titers. Gass11 reported a series of otherwise healthy patients with idiopathic recurrent BRAO, which he believes to be part of a spectrum of disease including Susac’s syndrome. However, both sexes were affected equally in his series.
Granulomatous angiitis generally affects older people of both genders and is not usually associated with hearing loss or psychiatric symptoms.8 It can also cause vasculitis of the retina, but the central artery and vein of the retina are typically involved, whereas in Susac’s syndrome the branch retinal arteries are affected.
Treatment and Management
Although the pathogenesis of the syndrome is unknown, the response to immunosuppressive agents has suggested an immunologic basis for this syndrome. Many of the patients have been empirically treated with various immunomodulatory agents including intravenous methylprednisolone, oral prednisone, and cyclophosphamide.4 Plasmapheresis has been used also.12 For acute attacks, one group recommends the use of intravenous methylprednisolone (1 g/day) for 3 days followed by prednisone (80 mg daily) with a gradual taper.4 If the patient fails to respond, cyclophosphamide is then recommended. Anticoagulation has been used, but it is not clearly effective, because 1 patient continued to have recurrences despite therapeutic anticoagulation.1 Aspirin, clopidogrel, and calcium channel blockers have also been used empirically.12,13 Treatment options are summarized in Table 1.
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As in our case, oral contraceptives and estrogen-replacement therapy have been noted to exacerbate Susac’s syndrome.1,12 The thrombophilic effects of these hormones may act in concert with preexisting microangiopathy to trigger additional vascular occlusion. We recommend avoiding these hormonal treatments whenever possible.
Outcome and Prognosis
The course of the disorder is variable. Some authors have reported spontaneous remission after 1 month, whereas others have reported recurrences despite immunomodulatory treatments.1,13 Most cases seem to stabilize without additional attacks after 2 years.4 Our case exemplifies the more severe course in which the patient continued to have recurrent attacks despite treatment with several immunomodulatory modalities. She had a stable period of 2.5 years on a regimen of plasma exchange, until she developed BRAO. Recurrence of Susac’s syndrome after a remission of 18 years has been reported in a 51-year-old woman.12 In this case, the recurrence occurred after initiation of estrogen-replacement therapy.
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CONCLUSIONS |
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TOPABSTRACTCASE REPORTSDISCUSSIONCONCLUSIONSREFERENCES |
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When evaluating patients (including children) with an acute encephalopathy and multiple MRI signal hyperintensities of the brain, Susac’s syndrome should be considered. Careful history and examination for hearing loss or visual disturbances may yield important clues toward the possibility of this syndrome. When there is a consideration of Susac’s syndrome, MRI, ophthalmologic evaluation with fluorescein angiography, and audiometry are recommended to confirm the diagnosis. Early recognition and treatment may prevent neurologic and ophthalmologic sequelae that can result from delayed treatment with immunomodulatory therapies.
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ACKNOWLEDGMENTS |
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We thank Leia Nghiemphu, MD, for assistance with the manuscript.
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FOOTNOTES |
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Received for publication Jul 11, 2003; Accepted Nov 4, 2003.
Address correspondence to Jin S. Hahn, MD, Department of Neurology, A343, 300 Pasteur Drive, Stanford, CA 94305-5235. E-mail: jhahn{at}stanford.edu
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REFERENCES |
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TOPABSTRACTCASE REPORTSDISCUSSIONCONCLUSIONSREFERENCES |
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- Susac JO, Hardman JM, Selhorst JB. Microangiopathy of the brain and retina.
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- Heiskala H, Somer H, Kovanen J, Poutiainen E, Karli H, Haltia M. Microangiopathy with encephalopathy, hearing loss and retinal arteriolar occlusions: two new cases. J Neurol Sci. 1988;86 :239 –250[CrossRef][Web of Science][Medline]
- Gass JDM. Stereoscopic Atlas of Macular Diseases: Diagnosis and Treatment. 4th ed. St Louis, MO: Mosby; 1997:458–462
- Petty GW, Matteson EL, Younge BR, McDonald TJ, Wood CP. Recurrence of Susac syndrome (retinocochleocerebral vasculopathy) after remission of 18 years. Mayo Clin Proc. 2001;76 :958 –960[Abstract]
- Marie II, Guegan-Massardier E, Levesque H, Favennec L, Cailleux N, Courtois H. Susac’s syndrome or retinocochleocerebral vasculopathy: a misdiagnosed and overlooked disorder. Eur J Intern Med. 2000;11 :108 –111[CrossRef][Medline]
PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics
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