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Article |Authors=David J Wilde MS |Additional contributors=Alexander Foster MD |Category=Neuro-ophthalmology/Orbit, Retina/Vitreous |Reviewer=Alexander.Foster |Date reviewed=August 12, 2019 |Meta description=Susac Syndrome (SS) is a rare neurological disorder characterized by the clinical triad of encephalopathy, vision loss and hearing loss. The syndrome’s etiology is unconfirmed, however, it is hypothesized that SS is an autoimmune microangiopathy. This theory is supported by the detection of anti-endothelial cell antibodies in some patients.

Disease Entity

ICD 11 8A45.2Y ICD 10 I67.7 Orphanet 838

Susac Syndrome (SS) is a rare neurological disorder characterized by the clinical triad of encephalopathy, vision loss and hearing loss. [1] [2] The syndrome’s etiology is unconfirmed, however, it is hypothesized that SS is an autoimmune microangiopathy. This theory is supported by detection of anti-endothelial cell antibodies in some patients. [3] [4] [5]

Disease

SS was originally described by John Susac in 1979 in two patients who presented with the classical clinical triad of symptoms. [1] This condition has had various designations over time, including: SICRET (small infarctions of cochlear, retinal and encephalic tissue), RED-M (microangiopathy with retinopathy, encephalopathy and deafness) Retinocochleocerebral vasculopathy, and Susac’s Syndrome. The term “Susac Syndrome” was established in 1994. [2]

Risk Factors

There are no current established risk factors for SS.

Pathophysiology

The pathophysiology of SS is under debate. Current evidence suggests that endothelial cells (EC) within capillaries and precapillary arterioles of the brain, cochlea, vestibular apparatus, and retina become immunologically injured, swell, and partially or completely occlude these vessels, leading to microischemia and microinfarction. [7] Anti-endothelial cell antibodies (AECA) have been detected in patients with SS, but this information is of limited value. Such antibodies may represent an epiphenomenon, rather than a primary cause of the EC injury, with other immunologic mechanisms being primarily responsible for the EC injury. To date, AECA have not proven to be adequately helpful in either diagnosis or follow-up management of patients. [5] The pathology of SS most closely resembles that observed in dermatomyositis, in which there is microinfarction of muscle and skin instead of the brain, retina and inner ear. [8]

Epidemiology

In data obtained from 304 published cases prior to 2013, the mean age of onset of SS is 31.6 years (range 8-65 years), with a male-to-female ratio of 1:3.5. [6] SS has no established ethnic prevalence. [7]

Diagnosis

Diagnosis based on history and physical exam alone is possible when the patient exhibits the classical clinical triad of symptoms, however, the individual manifestations may develop only as single events over a prolonged disease course, may be too subtle to be noticed or may be masked by severe encephalopathy. [12] Consequently, the complete triad is recognized in only 13% of patients at disease onset, with average time from onset to full clinical triad being 21 weeks. [6] This variability of presentation makes clinical recognition of SS difficult, and often leads to delay of diagnosis and initiation of appropriate treatment. [13]

History

Encephalopathy in SS is almost always accompanied by headache, which may be the presenting feature. Multifocal neurological signs and symptoms, psychiatric disturbances (behavioral changes, paranoia), cognitive changes, memory loss, and confusion may rapidly progress to dementia. [9] [10]

Vision loss in SS is typically experienced as partial and painless visual field loss in one or both eyes. Visual field loss, unfortunately, does not recover. The field defects are altitudinal and respect the horizontal meridian on visual field testing and infrequently involve the blind spot. [11]

Hearing loss is cochlear and presents in one or both ears and frequently coincides initially with roaring tinnitus. There are no clinical or audiometric findings that are diagnostic for SS. [11] Cochlear involvement may also lead to development of vestibular vertigo.

In a study of 20 patients diagnosed with Susac syndrome 72% of cases initially presented with encephalopathy, 20% with hearing loss, and 24% with visual disturbances. Of these, 64% had residual neurological deficits, 84% had residual auditory deficits, including hyperacusis and tinnitus, and 72% had residual visual impairment in the form of scotomas. [5]

Diagnostic criteria (Table 1) proposed by Kleffner et al. in 2016 indicate two categories of Diagnostic Accuracy:

1. Definite SS: Patients with an unequivocal clinical and/or paraclinical involvement of all three main organs (i.e., fulfilling the typical clinical triad).

2. Probable SS: Patients with an unequivocal clinical and/or paraclinical involvement of two of the three main organs.

Note: In patients with some of the typical features of SS, in whom SS could not be established as the most probable diagnosis because they do not fulfil even two of the necessary items, the diagnosis of SS should be considered as possible. These patients need careful and frequent follow-up since the diagnosis could evolve in the future. [12]

Clinical Workup & Diagnosis

Patients in whom SS is a suspected diagnosis based on thorough history and physical exam should have a combination of the following clinical tests to establish or rule out the diagnosis: MRI of the brain, DFE, FA, OCT, and audiogram.

MRI findings

-White Matter Lesions (100%) [12] [14]

-Grey Matter Lesions (70%) [14]

-Leptomeningeal Enhancement (33%) [14]

Typical “Snowball” lesions are hyperintense, multifocal, round brain lesions with at least one located in the corpus callosum, best appreciated on T2/Flair. [12] [14] These lesions, when located in the central corpus callosum eventually evolve into pathognomonic “holes” which are best appreciated on sagittal T1. [11] [15] The roof of the corpus callosum is also frequently affected. SS lesions in this location take the form of “spokes” or “icicles.” [15]

Fundoscopy

Typical fundoscopic findings in a patient with SS include Gass Plaques and Branch Retinal Artery Occlusion (BRAO). Gass Plaques (previously know as Retinal Artery Wall Plaques; RAWP) are yellow-white refractile lesions, simulating emboli, presumably caused by a localized immune reaction in the retinal artery wall. Unlike true emboli, Gass plaques are located randomly, rather than at arterial bifurcations. [16] (16.1; Heng 2019) Anecdotal evidence suggests Gass plaques are common in the acute phase of the disease although their presence fluctuates with disease progression. [11] (11.4; Egan 2019) BRAO in SS may be isolated or multiple and may occur in one or both eyes. Lesions can cause scotoma or photopsia or be asymptomatic if peripheral arteries are involved. [17] (17.1; Garcia-Carrasco 2011)

Fluorescein Angiography

Fluorescein angiography (FA) typically reveals an unusual pattern of Arterial Wall Hyperfluorescence (AWH), occurring remotely from arteriole occlusions or in normal vessels. [16] The presence of AWH located away from a BRAO is pathognomonic. Retinal Arterio-Arterial collaterals can form in approximately the same location of AWH and this finding is strongly suggestive of SS. [11] FA can also show characteristic non-perfusion of retinal arteries in BRAO. [17]

Optical Coherence Tomography

Optical coherence tomography (OCT) in patients with SS reveals scattered reduction of inner retinal layers from the mRNFL to the OPL, which accumulates over the disease course. OCT provides complementary diagnostic information to FA, particularly later in the disease course when acute findings such as BRAO and AWH may not be found. [18] Challenging for current OCT, however, is the spatial distribution of microangiopathy in Susac syndrome. BRAO and AWH often occur in peripheral arterioles and routine OCT usually covers a macular window of 20° · 20°, meaning that disease activity outside this area is missed. [3] Nevertheless, OCT is a noninvasive, safe, and highly precise diagnostic tool, and will likely be a key component of future diagnostic workup of SS. [18]

Audiogram

Audiogram in SS demonstrates low or mid-frequency hearing loss. Caloric testing of the vestibular organ or Vestibular Evoked Myogenic Potential (VEMP). These tests can confirm and quantify vestibular organ damage seen in SS.

Laboratory Test

A role for anti-endothelial cell antibodies (AECA) in SS has been proposed. In one study, it was found that 25% of patients with definite SS had elevated AECA titers. However, seropositive and seronegative patients did not differ in any clinical parameters. [5]

Differential Diagnosis

-Inflammatory demyelinating CNS disease: Multiple sclerosis, acute disseminated encephalomyelitis, neuromyelitis optica (Devic disease)

-Cerebrovascular disease: Stroke, transient ischemic attack, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

-Vasculitis, connective tissue disease or other autoimmune diseases: Primary CNS vasculitis, limbic encephalitis, polyarteritis nodosa, Wegener granulomatosis, Churg–Strauss syndrome, systemic lupus erythematosus, sarcoidosis, Sjögren syndrome, Behçet disease, antiphospholipid antibody syndrome, Cogan syndrome, Eales disease, autoimmune inner-ear disease

-Infectious CNS disease: Lyme disease, syphilis, tuberculosis, viral encephalitis

-Malignancy: Primary CNS lymphoma, CNS metastases, paraneoplastic syndrome

-Others: Migraine, encephalopathy, lactate acidosis and stroke-like episodes (MELAS), Menière disease, psychotic disorders (including drug-related psychosis), isolated branch retinal artery occlusion [6] (6.3; Dorr 2013)

Management

There have been no randomized controlled trials to establish treatment guidelines in SS. Various published case reports have proposed empirical treatment algorithms. There is agreement amongst experts that high dose corticosteroids should be the first line therapy and early, aggressive, sustained immunosuppressive treatment may markedly improve outcomes. However, it remains unclear as to how much immunosuppressive medication is required and for how long. [19] In addition to high-dose corticosteroids, immunosuppressive agents typically used in the treatment of SS include IVIG, Cyclophosphamide, Mycophenolate Mofetil, Tacrolimus, and Rituximab. [20] [11]

Based on a review of literature and expert opinion, Robert A. Egan proposed the following treatment guidelines: All patients with active SS should be started on corticosteroids and IVIG. Corticosteroids may be given as prednisone orally at 80 mg a day or intravenous methylprednisolone 1,000 mg a day and then switched to oral prednisone after several days of intravenous treatment. IVIG should be started initially at 2 g/kg over several days and then given monthly at 0.4 mg/kg every month for a total of 6 months before a decision is made to consider cessation of treatment.

Both medications are ideal due to rapid onset of action. Lack of treatment with IVIG in the first 6 months tends to allow for relapses especially when the retina is primarily affected. If a patient is breaking through on this initial dual therapy, mycophenolate mofetil and/or rituximab should be added.

Mycophenolate mofetil typically is dosed at 500 mg twice a day for a week and then increased to 1,000 mg twice a day. Rituximab is initiated as a single dose of 500 mg given once and then repeated in 6 months. Some practitioners may give rituximab 250 mg once then repeated in 2 weeks followed by 500 mg every 6 months and some may treat with slightly higher doses. [11]

A similar treatment algorithm for SS with primarily Ophthalmological findings suggests use of IVIG as third-line treatment and the option of plasma exchange for intractable cases. Co-management with neurology and ENT is suggested. [16]

Prognosis

The clinical course in SS may be monocyclic, polycyclic or chronic continuous. SS has a good prognosis when treatment is initiated early. Recovery may be almost complete despite significant encephalopathy at presentation in patients in whom early diagnosis has led to early administration of immunosuppressive therapy. However, the diagnosis is usually delayed, resulting in sequelae. Approximately 50% of patients have ongoing cognitive impairment. [10] Unfortunately, visual field deficits do not resolve with treatment.

References

1. Susac JO, Hardman JM, Selhorst JB. Microangiopathy of the brain and retina. Neurology. 1979;29:313–316.

2. Susac, John O., 1994. Susac's syndrome: The triad of microangiopathy of the brain and retina with hearing loss in young women. Neurology 44 (4), 591-593.

3. Brandt AU, Oberwahrenbrock T, Costello F, Fielden M, Gertz K, Kleffner I, Paul F, Bergholz R, Dörr J. RETINAL LESION EVOLUTION IN SUSAC SYNDROME. Retina. 2016 Feb;36(2):366-74.

4. Magro CM, Poe JC, Lubow M, Susac JO. Susac syndrome: an organ-specific autoimmune endotheliopathy syndrome associated with anti-endothelial cell antibodies. Am J Clin Pathol. 2011 Dec;136(6):903-12.

5. Jarius et al.: Clinical, paraclinical and serological findings in Susac syndrome: an international multicenter study. Journal of Neuroinflammation 2014 11:46.

6. Dörr J, Krautwald S, Wildemann B, Jarius S, Ringelstein M, Duning T, Aktas O, Ringelstein EB, Paul F, Kleffner I. Characteristics of Susac syndrome: a review of all reported cases. Nat Rev Neurol. 2013 Jun;9(6):307-16.

7. Marrodan M, Correale J, Alessandro L, Amaya M, Fracaro ME, Köhler AA, Fiol M. Susac Syndrome: A differential diagnosis of white matter lesions. Mult Scler Relat Disord. 2017 Jul;15:42-46.

8. Greco A, De Virgilio A, Gallo A, Fusconi M, Turchetta R, Tombolini M, Rizzo MI, de Vincentiis M. Susac's syndrome--pathogenesis, clinical variants and treatment approaches. Autoimmun Rev. 2014 Aug;13(8):814-21.

9. Susac JO, Egan RA, Rennebohm RM, et al. Susac's syndrome: 1975–2005 microangiopathy/autoimmune endotheliopathy. J Neurol Sci Jun 15 2007;257(1–2): 270–2.

10. García-Carrasco M, Mendoza-Pinto C, Cervera R. Diagnosis and classification of Susac syndrome. Autoimmun Rev. 2014 Apr-May;13(4-5):347-50.

11. Egan RA. Diagnostic Criteria and Treatment Algorithm for Susac Syndrome. J Neuroophthalmol. 2019 Mar;39(1):60-67.

12. Kleffner I, Dörr J, Ringelstein M, Gross CC, Böckenfeld Y, Schwindt W, Sundermann B, Lohmann H, Wersching H, Promesberger J, von Königsmarck N, Alex A, Guthoff R, Frijns CJ, Kappelle LJ, Jarius S, Wildemann B, Aktas O, Paul F, Wiendl H, Duning T; European Susac Consortium (EuSaC).. Diagnostic criteria for Susac syndrome. J Neurol Neurosurg Psychiatry. 2016 Dec;87(12):1287-1295.

13. Rennebohm RM, Egan RA, Susac JO. Treatment of Susac's Syndrome. Curr Treat Options Neurol. 2008 Jan;10(1):67-74.

14. Susac JO, Murtagh FR, Egan RA, Berger JR, Bakshi R, Lincoff N, Gean AD, Galetta SL, Fox RJ, Costello FE, Lee AG, Clark J, Layzer RB, Daroff RB. MRI findings in Susac's syndrome. Neurology. 2003 Dec 23;61(12):1783-7.

15. Rennebohm R, Susac JO, Egan RA, Daroff RB. Susac's Syndrome--update. J Neurol Sci. 2010 Dec 15;299(1-2):86-91.

16. Heng LZ, Bailey C, Lee R, Dick AD, Ross A. A review and update on the Ophthalmic implications for Susac Syndrome. Surv Ophthalmol. 2019 Jan 28. pii: S0039-6257(18)30261-3.

17. García-Carrasco M, Jiménez-Hernández C, Jiménez-Hernández M, Voorduin-Ramos S, Mendoza-Pinto C, Ramos-Alvarez G, Montiel-Jarquin A, Rojas-Rodríguez J, Cervera R. Susac's syndrome: an update. Autoimmun Rev. 2011 Jul;10(9):548-52.

18. Ringelstein M, Albrecht P, Kleffner I, et al. Retinal pathology in Susac syndrome detected by spectral-domain optical coherence tomography. Neurology 2015;85:610-8.

19. Rennebohm RM, Lubow M, Rusin J, Martin L, Grzybowski DM, Susac JO. Aggressive immunosuppressive treatment of Susac's syndrome in an adolescent: using treatment of dermatomyositis as a model. Pediatr Rheumatol Online J. 2008 Jan 29;6:3.

20. Rennebohm RM, Asdaghi N, Srivastava S, Gertner E. Guidelines for treatment of Susac syndrome - An update. Int J Stroke. 2018 Jan 1:1747493017751737.