12
CME ARTICLE Susac syndrome: clinical characteristics and treatment in 29 new cases F. J. Mateen a,b , A. Y. Zubkov c , R. Muralidharan a , J. E. Fugate a , F. J. Rodriguez d , J. L. Winters e and G. W. Petty a a Department of Neurology, Mayo Clinic, Rochester, MN; b Department of Neurology, Johns Hopkins Hospital, Baltimore, MD; c Minneapolis Clinic of Neurology, Edina, MN; d Division of Neuropathology, Department of Pathology, Johns Hopkins Hospital, Baltimore, MD; and e Division of Transfusion Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA Keywords: cochlea, encephalopathy, plasma exchange, retina, stroke, susac syndrome, treatment, vasculopathy, young adults Received 24 August 2011 Accepted 17 November 2011 Background and purpose: There are few clinical studies on the attempted treatments and outcomes in patients with Susac syndrome (SS) (retinocochleocerebral vasculopathy). Methods: A retrospective review was performed of all patients presenting with SS at the Mayo Clinic in Rochester, Minnesota, USA (1 January 1998–1 October 2011). Results: There were 29 cases of SS (24 women, mean age at presentation, 35 years; range, 19–65; full triad of brain, eye, and ear involvement, n = 16; mean follow-up time, 29 months). Thirty CSF analyses were performed in 27 cases (mean protein 130 mg/dl, range 35–268; mean cell count 14, range 1–86). MRI of the brain showed corpus callosal involvement (79%), T2-weighted hyperintensities (93%), and gado- linium enhancement (50%). Average lowest modified Rankin Scale score was 2.5 (median 2, range 0–5). Most patients (93%) received immunosuppressive treatment, with a mean time to treatment of 2 months following symptomatic onset. Treatments included intravenous methylprednisolone or dexamethasone (n = 23), oral corticos- teroids (n = 24), plasma exchange (PLEX) (n = 9), intravenous immunoglobulin (IVIg) (n = 15), cyclophosphamide (n = 6), mycophenolate mofetil (n = 5), aza- thioprine (n = 2), and rituximab (n = 1). Most patients also received an antiplatelet agent (n = 21). Improvement or stabilization was noted in eight of 11 cases treated with IVIg in the acute period (three experienced at least partial deterioration) and eight of nine cases of PLEX treatment (one lost to follow up). Conclusions: Susac syndrome may be severe, disabling, and protracted in some patients. PLEX may be an adjunct or alternative therapy for patients who do not experience symptomatic improvement following steroid treatment. Introduction Susac syndrome (SS) is a rare disorder of unknown pathogenesis that affects the pre-capillary arterioles of the brain, retina, and cochlea. The associated syndrome is a triad of hearing loss, branch retinal artery occlu- sions leading to visual loss, and cerebral symptoms that may include seizures, headaches, cognitive decline, and personality changes. Since its initial description in 1979 [1], more than two hundred cases have been reported, mostly involving young women [2]. Patients with SS usually experience discrete symp- tomatic episodes that can recur [3,4]. Although some episodes prove to be self-remitting without treatment, the clinical course cannot be readily predicted and pa- tients may experience sequelae of epilepsy, dementia, permanent deafness, and/or visual loss. The heteroge- neity and rarity of the disorder have prevented large clinical case series that include treatment. Because of a presumed autoimmune etiology, acute symptomatic treatment has justifiably centered on corticosteroids. There are no randomized trials on treatment efficacy to date. Anecdotal reports have suggested a therapeutic benefit from azathioprine, cyclophosphamide, myco- phenolate mofetil, infliximab, nimodipine, antiplatelet agents, intravenous immunoglobulin (IVIg), and/or plasma exchange (PLEX) in some patients [5–18]. We aim to expand the knowledge of the clinical course of patients with SS following various attempted treatments by qualitatively and, where possible, Correspondence: Farrah J. Mateen, Department of Neurology, Johns Hopkins Hospital, Pathology Building, Room 627, 600 North Wolfe Street, Baltimore, MD 21287, USA (tel.: +410 935 5181; fax: +410 502 6736; e-mail: [email protected]). This is a Continuing Medical Education article, and can be found with corresponding questions on the Internet at http://www.efns.org/EFNS Continuing-Medical-Education-online.301.0.html. Certificates for correctly answering the questions will be issued by the EFNS. 800 Ó 2012 The Author(s) European Journal of Neurology Ó 2012 EFNS European Journal of Neurology 2012, 19: 800–811 doi:10.1111/j.1468-1331.2011.03627.x

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CME ARTICLE

Susac syndrome: clinical characteristics and treatment in 29new cases

F. J. Mateena,b, A. Y. Zubkovc, R. Muralidharana, J. E. Fugatea, F. J. Rodriguezd, J. L. Winterse

and G. W. Pettya

aDepartment of Neurology, Mayo Clinic, Rochester, MN; bDepartment of Neurology, Johns Hopkins Hospital, Baltimore, MD; cMinneapolis

Clinic of Neurology, Edina, MN; dDivision of Neuropathology, Department of Pathology, Johns Hopkins Hospital, Baltimore, MD; andeDivision of Transfusion Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

Keywords:

cochlea, encephalopathy,

plasma exchange, retina,

stroke, susac syndrome,

treatment, vasculopathy,

young adults

Received 24 August 2011

Accepted 17 November 2011

Background and purpose: There are few clinical studies on the attempted treatments and

outcomes in patients with Susac syndrome (SS) (retinocochleocerebral vasculopathy).

Methods: A retrospective review was performed of all patients presenting with SS at

the Mayo Clinic in Rochester, Minnesota, USA (1 January 1998–1 October 2011).

Results: There were 29 cases of SS (24 women, mean age at presentation, 35 years;

range, 19–65; full triad of brain, eye, and ear involvement, n = 16; mean follow-up

time, 29 months). Thirty CSF analyses were performed in 27 cases (mean protein

130 mg/dl, range 35–268; mean cell count 14, range 1–86). MRI of the brain showed

corpus callosal involvement (79%), T2-weighted hyperintensities (93%), and gado-

linium enhancement (50%). Average lowest modified Rankin Scale score was 2.5

(median 2, range 0–5). Most patients (93%) received immunosuppressive treatment,

with a mean time to treatment of 2 months following symptomatic onset. Treatments

included intravenous methylprednisolone or dexamethasone (n = 23), oral corticos-

teroids (n = 24), plasma exchange (PLEX) (n = 9), intravenous immunoglobulin

(IVIg) (n = 15), cyclophosphamide (n = 6), mycophenolate mofetil (n = 5), aza-

thioprine (n = 2), and rituximab (n = 1). Most patients also received an antiplatelet

agent (n = 21). Improvement or stabilization was noted in eight of 11 cases treated

with IVIg in the acute period (three experienced at least partial deterioration) and

eight of nine cases of PLEX treatment (one lost to follow up).

Conclusions: Susac syndrome may be severe, disabling, and protracted in some

patients. PLEX may be an adjunct or alternative therapy for patients who do not

experience symptomatic improvement following steroid treatment.

Introduction

Susac syndrome (SS) is a rare disorder of unknown

pathogenesis that affects the pre-capillary arterioles of

the brain, retina, and cochlea. The associated syndrome

is a triad of hearing loss, branch retinal artery occlu-

sions leading to visual loss, and cerebral symptoms that

may include seizures, headaches, cognitive decline, and

personality changes. Since its initial description in 1979

[1], more than two hundred cases have been reported,

mostly involving young women [2].

Patients with SS usually experience discrete symp-

tomatic episodes that can recur [3,4]. Although some

episodes prove to be self-remitting without treatment,

the clinical course cannot be readily predicted and pa-

tients may experience sequelae of epilepsy, dementia,

permanent deafness, and/or visual loss. The heteroge-

neity and rarity of the disorder have prevented large

clinical case series that include treatment. Because of a

presumed autoimmune etiology, acute symptomatic

treatment has justifiably centered on corticosteroids.

There are no randomized trials on treatment efficacy to

date. Anecdotal reports have suggested a therapeutic

benefit from azathioprine, cyclophosphamide, myco-

phenolate mofetil, infliximab, nimodipine, antiplatelet

agents, intravenous immunoglobulin (IVIg), and/or

plasma exchange (PLEX) in some patients [5–18].

We aim to expand the knowledge of the clinical

course of patients with SS following various attempted

treatments by qualitatively and, where possible,

Correspondence: Farrah J. Mateen, Department of Neurology, Johns

Hopkins Hospital, Pathology Building, Room 627, 600 North Wolfe

Street, Baltimore, MD 21287, USA (tel.: +410 935 5181;

fax: +410 502 6736; e-mail: [email protected]).

This is a Continuing Medical Education article, and can be found with

corresponding questions on the Internet at http://www.efns.org/EFNS

Continuing-Medical-Education-online.301.0.html. Certificates for

correctly answering the questions will be issued by the EFNS.

800� 2012 The Author(s)

European Journal of Neurology � 2012 EFNS

European Journal of Neurology 2012, 19: 800–811 doi:10.1111/j.1468-1331.2011.03627.x

quantitatively presenting our experience of the diag-

nosis, assessment, and management of a large series of

patients with SS at a high-volume referral center.

Methods

The Mayo Clinic Institutional Review Board approved

this study. A retrospective medical record review was

performed of all patients with the diagnosis of SS be-

tween 1 January 1998 and 1 October 2011 at the Mayo

Clinic in Rochester, Minnesota, USA. Keyword search

terms included �Susac Syndrome� and �retinocochleoce-rebral vasculopathy�, �cerebral vasculopathy�, �cerebro-retinovasculopathy�, and �other encephalopathy�. The

institutional experience of SS prior to this time has been

reported [3]. None of the patients included in the pre-

vious report were included in this study.

Diagnoses were confirmed by review of the laboratory

tests, imaging studies, and treating clinicians� diagnoses.Demographic and clinical data included age, sex, and

details of the symptomatic presentation, methods of

diagnostic evaluation, treatment course, and any evi-

dence of recurrence. Dates of birth, symptomatic onset,

first treatment, first signs of improvement, and last fol-

low-up were collected. A modified Rankin Scale score

[19] was assigned retrospectively by the authors, based

on detailed clinical notes. Magnetic resonance images of

the brain were analyzed for the following: (i) evidence of

lesions consistent with SS, notably punctuate T2 hy-

perintense lesions in the cerebral parenchyma and sub-

cortical structures, (ii) T2 hyperintense lesions involving

the corpus callosum thought to be highly characteristic

of SS, and (iii) gadolinium enhancement of the T2

hyperintense lesions noted in (i) and (ii).

Patient therapy was determined by the treating neu-

rologist(s) at the time of evaluation in conjunction with

a consultant rheumatologist, ophthalmologist, and/or

otolaryngologist when appropriate. Use of PLEX was

determined by the treating physician without any pre-

treatment criteria. These were not necessarily more se-

vere cases. There are no standard algorithms for the use

of steroids, IVIg, or PLEX in SS at our institution.

Treatment course was assessed by the presence of

symptomatic improvement documented in the medical

records, corroborated by audiogram, retinal examina-

tion, and brain imaging when performed. PLEX is an

extracorporeal technique for removing humoral factors

such as immunoglobulins, complement, or cytokines

from the blood. At our institution, the usual course of

PLEX for SS consisted of a one-volume PLEX

administered every other day for a planned course of

five treatments. Replacement fluid was 5% albumin

with the anticoagulant consisting of either acid citrate

dextrose solution A (ACDA) or heparin and ACDA.

All procedures were performed on the COBE Spectra

(CaridianBCT; Roundlake, CO, USA).

Results

Search results and patient characteristics

There were 43 case records retrieved that had SS within

the differential diagnosis. A total of 29 patients (24

women (83%), mean age at symptomatic presentation

35 years, range 19–65) had a diagnosis of SS. All

patients were diagnosed or had the diagnosis confirmed

by a neurologist. All patients underwent an extensive

workup to exclude other diagnoses that may mimic SS.

Patients were seen as an inpatient (n = 10), outpatient

(n = 15), or both (n = 4). One patient was diagnosed

during pregnancy.

Patients included in this series had at least two of the

three retinal, cochlear, or cerebral symptoms charac-

teristic of SS, including 16 (55%) with the full triad of

brain, vestibulocochlear, and eye involvement at the

time of first assessment. Hearing was involved in 24

cases (83%), vision in 24 cases (83%), and cerebral

symptoms in 26 cases (90%) (Table 1). Follow-up

ranged from a single visit with further treatment and

care by local physicians to more than 10 years of ex-

tended follow-up at this institution (mean 29 months

(2.4 years), median 13 months, range < 1–

128 months). Average lowest modified Rankin Scale

score reported was 2.5 (mRS 2 = slight disability, able

to look after own affairs without assistance but unable

to carry out all previous activities) [median 2, range 0

(no symptoms) to 5 (severe disability, incontinent,

bedridden, and requiring constant attention for care)].

No patient is known to have died.

Twenty-four additional patients had SS within the

differential diagnosis of their condition but had a dif-

ferent final diagnosis. These alternative diagnoses were

confirmed by the treating physicians to be multiple

sclerosis, central nervous system lymphoma, primary

central nervous system vasculitis, probable central ner-

vous system vasculitis, Wegener�s granulomatosis, Co-

gan�s syndrome, retinal vasculitis, cerebral autosomal

dominant arteriopathy with subcortical infarcts and

leukoencephalopathy (CADASIL), cerebroretinal vas-

culopathy, episodic vertigo with sensorineural hearing

loss, conversion syndrome, or indeterminate symptoms

that lacked at least two features of the triad of SS.

Investigations

The diagnostic evaluation of patients with SS is sum-

marized in Table 1. There were 30 CSF analyses in 27

individuals with an average CSF protein of 130 mg/dl

Susac syndrome 801

� 2012 The Author(s)European Journal of Neurology � 2012 EFNS European Journal of Neurology

Table

1Investigationsanddem

ographic

featuresofpatients

withsusacsyndrome

Age/sex

Presenting

symptoms/

clinical

findings/first

symptom(s)

Involvem

ent

ofbrain

(B),

hearing

(H),and

vision(V

)

Inpatient/

outpatient

evaluation

(episode#)

CSF

protein

CSF

cellcount

Oligoclonal

bands

Audiogram

Other

findings

MRI

corpus

callosum

involvem

ent

(y/n)

MRIT2

hyperintensities

(y/n)

MRI

gadolinium

enhancement

Cerebral

angiogram

orMRA

findings

134/F

Headaches,

numbnessand

tinglingof

handsandface,

visualfield

defect,hearing

loss,tinnitus

B,H,V

In101

2n/a

n/a

Symptoms

during3rd

trim

esterof

pregnancy

YY

NNorm

al

232/F

Vertigo,diplopia,

visualloss,

tinglingof

handsandfeet,

andamnestic

episodes

B,V

Out

161

11

0Low-to

mid-frequency

hearingloss

Symptoms

began

postpartum

YY

YNorm

al

336/F

Tongue

numbness,

TIA

-like

episodes

of

upper

extrem

ity

numbness,

tingling,and

weakness,

photosensitivity,

HA

B,V

Out

105,76

86,6

<2

n/a

PositiveFTA

·2(negative

RPR);elevated

IgG

synthesis

rate

YY

NNorm

al

435/F

Unilateraltinnitus,

hearingloss,unilateral

visualloss,

disequilibrium

mem

ory

loss,

uncontrollable

laughter

B,H,V

Out

47

20

Bilateral

asymmetric

hearingloss,

particularlyin

lower

frequencies

EEG:diffuse

abnorm

alities

VEP:

abnorm

al

prolongation

bilaterally

YY

NNorm

al

551/F

Segmentalvisual

loss,vertigo

H,V

Out

Norm

al

5n/a

Low-frequency

hearingloss

ANA

mildly

positive

NY

NNorm

al

626/F

Diplopia,

stroke-like

episodes

of

righthem

iparesis,

hearingloss,

episodic

gait

instability,

slurred

speech,

numbnessin

UE

B,H,V

Both

185

70

0Bilateral

hearingloss;

rightat40DB

(250–1000Hz,

80dBat

1000–6000Hz)

Rheumatoid

factormildly

positive;

mild

diffuse

lymph

adenopathy

(biopsy

negativefor

malignant

cells)

NY

NNorm

al

802 F. J. Mateen et al.

� 2012 The Author(s)European Journal of Neurology � 2012 EFNS European Journal of Neurology

Table

1(C

ontinued

)

Age/sex

Presenting

symptoms/

clinical

findings/first

symptom(s)

Involvem

ent

ofbrain

(B),

hearing

(H),and

vision(V

)

Inpatient/

outpatient

evaluation

(episode#)

CSF

protein

CSF

cellcount

Oligoclonal

bands

Audiogram

Other

findings

MRI

corpus

callosum

involvem

ent

(y/n)

MRIT2

hyperintensities

(y/n)

MRI

gadolinium

enhancement

Cerebral

angiogram

orMRA

findings

730/M

Confusion,cognitive

difficulty,

new

headaches,

unilateralhearing

loss,andtinnitus

H,B

In188

16

1n/a

None

YY

YNorm

al

846/M

Vertigo,numb

hands,vision

loss,hearingloss,

cognitivedecline,

agitation

B,V,H

In�slightly

elevated�

8n/a

n/a

Brain

biopsy:

scant

perivascular

chronic

inflammation,

microglial

activationand

mildnon-

specificgliosis

YY

NNorm

al

923/F

Episodes

ofvisual

loss,hearingloss,

disorientation,

imbalance,

mem

ory

loss,

hallucinations,

lethargy

B,H,V

Both

133

10

n/a

n/a

EEG:

generalized

slowing

Yn/a

n/a

Norm

al

10

50/F

Headaches,unilat

eralvisualloss,

imbalance,

vertigo,

hem

iparesis

B,H,V

Out

171,157

12,6

n/a

Sensorineural

hearingloss

(250–2000Hz

rangeonone

ear,all

frequencies

other

ear)

ANA

positive

1:80,

CK

=5000,

LDH

338,

ESR

24.

YY

NNorm

al

11

36/F

Gaitataxia,uni

lateralhearing

loss,confusion,

pseudobulbar

affect,urinary

incontinence

B,H

In106

21

n/a

None

YY

YNorm

al

12

20/F

Intractable

HA,

unilateralhearing

loss,progressive

cognitivedecline,

scintillating

scotoma,

photophobia,

N&V

B,H,V

In170

20

n/a

50%

reduced

hearingleft

ear

None

YY

Yn/a

Susac syndrome 803

� 2012 The Author(s)European Journal of Neurology � 2012 EFNS European Journal of Neurology

Table

1(C

ontinued

)

Age/sex

Presenting

symptoms/

clinical

findings/first

symptom(s)

Involvem

ent

ofbrain

(B),

hearing

(H),and

vision(V

)

Inpatient/

outpatient

evaluation

(episode#)

CSF

protein

CSF

cellcount

Oligoclonal

bands

Audiogram

Other

findings

MRI

corpus

callosum

involvem

ent

(y/n)

MRIT2

hyperintensities

(y/n)

MRI

gadolinium

enhancement

Cerebral

angiogram

orMRA

findings

13

35/F

Headaches,blurry

vision,hearing

loss,confusion,

mem

ory

loss,gait

instability

B,H,V

Out

177

n/a

n/a

n/a

PositiveIgM

andIgG

anticardiolipin

antibody,V

Leiden

heterozygous

YY

Nn/a

14

23/F

Headaches,R

vi

sualloss,R

hearingloss,

cognitive

difficulty,gait

ataxia,R

facial

sensory

disturbance,

confusion,

pseudobulbar

affect

B,H,V

Out

59

4n/a

n/a

None

YY

YNorm

al

15

37/F

Segmentalvisual

loss,dizziness,

weakandnumb

UE

V,B

Out

n/a

n/a

n/a

Norm

al

None

NN

NNorm

al

16

44/F

Episodic

loss

of

consciousness,

transientvisual

disturbance,

progressive

cognitivedecline,

andmem

ory

loss

B,H,V

Both

131

00

10%

word

recognitionin

left

ear

None

YY

YNorm

al

17

19/F

Headache,

hearing

loss,blurry

vision,

disorientation,

personality

change,

and

cognitivedecline

B,H,V

In126

3n/a

n/a

None

YY

YNorm

al

18

24/F

Vertigo,tinnitus,

bilateralhearing

loss,segmental

visualloss

B,H,V

Out

n/a

n/a

n/a

Moderate

left

hearingloss

250–1000Hz

range

Prothrombin

20210A

mutation

heterozygote

NN

NNorm

al

804 F. J. Mateen et al.

� 2012 The Author(s)European Journal of Neurology � 2012 EFNS European Journal of Neurology

Table

1(C

ontinued

)

Age/sex

Presenting

symptoms/

clinical

findings/first

symptom(s)

Involvem

ent

ofbrain

(B),

hearing

(H),and

vision(V

)

Inpatient/

outpatient

evaluation

(episode#)

CSF

protein

CSF

cellcount

Oligoclonal

bands

Audiogram

Other

findings

MRI

corpus

callosum

involvem

ent

(y/n)

MRIT2

hyperintensities

(y/n)

MRI

gadolinium

enhancement

Cerebral

angiogram

orMRA

findings

19

46/F

Scotomatousvi

sualloss,vertigo,

worseninggait,

tinnitus,

headache,

paresthesiasof

face

and

extrem

ities

B,H,V

Both

83,57

0,0

n/a

Low-frequency

hearingloss

left,low-and

high-frequency

loss

right

ANA

(1:40)

YY

Yn/a

20

28/F

Hearingloss,

headache,

blurred

vision

H,V

Out

35

10

Unilateral6000

and8000Hz

loss

None

NY

NNorm

al

21

27/M

Hearingloss,

headache,

vertigo,left

numbness,gait

unsteadiness

B,H

In164

50

MildR

and

moderate–

severeleft

sensorineural

hearingloss,

allfrequencies

None

YY

Yn/a

22

43/F

Righteardiscomfort,

gaitinstability,

disorientation

B,H

,VOut

>200

50

0Mostly

norm

al

butloss

at

1500Hzleft

and2000Hz

rightear

None

YY

YNorm

al

23

20/F

Visualloss,

hearingloss,

headache

H,V

Out

84

20

n/a

None

YY

N*Norm

al

24

33/F

Disorientation,

visualloss,

headache

B,V

Out

84

11

n/a

Norm

al

None

YY

NNorm

al

25

57/F

Disorientation,

hearingloss

B,H

Out

248

n/a

n/a

n/a

None

YY

n/a

Norm

al

26

39/M

Disorientation,

urinary

retention,

gaitinstabliity

B,V

In79

40

Notdonebut

hadabnorm

al

brainstem

evoked

potentials

None

YY

n/a

Norm

al

27

25/F

Headache,

nausea,

vomiting,

tinnitus,hearing

loss,dizziness,

short-term

mem

ory

loss

B,H

Out

147

14

0Sensorineural

hearingloss

bilaterally

(1000–8000Hz

range)

None

YY

Y*Norm

al

Susac syndrome 805

� 2012 The Author(s)European Journal of Neurology � 2012 EFNS European Journal of Neurology

(median 129, range 35–268, normal range 15–45 mg/dl)

and an average cell count of 14 cells/ml (median 5,

range 0–86, normal range 0–5 cells/ml). MRI was per-

formed in all cases (Fig. 1). Corpus callosal involve-

ment of lesions was noted in 23/29 cases (79%).

Punctate T2-weighted hyperintense lesions were seen in

26 individuals (absent in two cases, not available in one

case, 93%). Gadolinium enhancement of lesions oc-

curred in 13 cases (available in 26 cases, 50%). One

patient had the diagnosis confirmed by brain biopsy

(Fig. 2).

Treatment and outcomes

Two patients (cases 4 and 20) were untreated. Mean

time to treatment was 2 months (median 1 month)

amongst the 27 cases who received immunosuppressive

therapy (Table 2). PLEX was used in nine cases (range

of 3–10 exchanges). Symptomatic improvement was

observed in six cases, stabilization was in two cases, and

one case was lost to follow up. No patient continued to

worsen. Amongst the patients treated with IVIg, there

were 11 cases who received initial treatment with IVIg

(cases 6, 9, 10, 11, 14, 17, 22, 24, 26, 28, and 29) and

three cases who were observed whilst receiving main-

tenance monthly IVIg (cases 21, 23, and 25). Amongst

the 11 cases who were evaluated in the acute symp-

tomatic treatment phase and treated with IVIg,

improvement was noted in six cases, stability or modest

improvements in two cases, deterioration in symptoms

in two cases, and mixed results (both improvement and

deterioration) in one case. Additional treatments

included intravenous methylprednisolone or dexa-

methasone (n = 23), oral corticosteroids (n = 24),

mycophenolate mofetil (n = 5), cyclophosphamide

(n = 5), azathioprine (n = 2), and rituximab (n = 1).

Most patients also received an antiplatelet agent: aspi-

rin (n = 18), clopidogrel (n = 2), and aspirin and

dipyridamole (n = 1). Nimodipine was taken by five

individuals.

Discussion

Given the variable course and rarity of SS, there are no

prospective studies on the best treatment of patients.

Retrospective studies are also challenging given the

wide range of symptomatic manifestations of SS, delay

to diagnosis in many cases, lack of diagnostic biomar-

kers, and limited literature on the natural history of the

disease. In our experience, which is subject to referral

bias, not all patients with SS have a symptomatic re-

sponse to corticosteroids. Most patients were treated

with additional immunosuppressive therapy with the

goal of achieving symptomatic remission in the acuteTable

1(C

ontinued

)

Age/sex

Presenting

symptoms/

clinical

findings/first

symptom(s)

Involvem

ent

ofbrain

(B),

hearing

(H),and

vision(V

)

Inpatient/

outpatient

evaluation

(episode#)

CSF

protein

CSF

cellcount

Oligoclonal

bands

Audiogram

Other

findings

MRI

corpus

callosum

involvem

ent

(y/n)

MRIT2

hyperintensities

(y/n)

MRI

gadolinium

enhancement

Cerebral

angiogram

orMRA

findings

28

32/F

Acute

unilateral

hearingloss,

visualloss,

disorientation

B,H,V

In268

19

0n/a

None

YY

NNorm

al

29

65/M

Headache,

disori

entation

B,H,V

In96

20

Moderate–se

verebilateral

sensorineural

hearingloss

None

NY

NNorm

al

*Digitalsubtractionangiography;ANA,antinuclearantibody;

B,brain;EEG,electroencephalogram;FTA,fluorescenttreponem

alantibodyabsorption;H,hearing;HA,headache;MRI,magneticresonance

imagingstudy

ofthebrain;L,left;N,no;N&V,nauseaandvomiting;n/a,notdone;

R,right;VEP,visualevoked

potentials;V,vision;Y,yes.

806 F. J. Mateen et al.

� 2012 The Author(s)European Journal of Neurology � 2012 EFNS European Journal of Neurology

period. This is especially true for patients with severe

presentations, including dementia, recurrent seizures,

and recurrent visual loss despite treatment with corti-

costeroids.

There are several reports of refractory cases of SS

treated with IVIg in the acute period [7,8,10–12].

Rarely, IVIg may cause additional ischaemic changes in

the microvasculature [20,21], which is a theoretical

concern in SS, given the arteriolar distribution of the

disease. By contrast, reports of patients with SS treated

with PLEX are exceptional. Five patients with SS are

reported to have been treated with PLEX [3,5–8]. The

positive therapeutic effects probably involve removal of

humoral factors from the patient�s blood including

immunoglobulins, complement, and/or cytokines [22].

The putative pathogenic antibody or antibodies are

probably removed or reduced in this process.

Many cases of SS are treated with antiplatelet agents

including aspirin and clopidogrel given the arteriolar

involvement seen under fluorescein angiography of the

retina and cerebral pathology [3,4]. Possible arteriolar

vasospasm has prompted the use of the calcium channel

blocker nimodipine, which is almost always an adjunct

treatment. These treatments are difficult to assess for

efficacy independently of immunosuppressive treat-

ment.

These findings are not definitive evidence for the use

of PLEX in the treatment of SS. Our observations are

rather intended to be foundational for prospective

studies on the treatment of patients with SS. Based on

our data alone, we cannot confirm that any treatment

improved the course of patients with Susac syndrome.

There are only occasional cases of untreated individu-

als, including just two in this series, some of whom

experience spontaneous resolution of symptoms with-

out immunosuppressive treatment. It is unclear whether

the currently employed treatments hasten symptomatic

recovery. The appropriate duration of treatment

requires proper study and presently is anecdotal.

Our study had limitations. This was a retrospective,

observational study and, at times, had incomplete data.

Follow-up was not consistent amongst patients, and

not all patients received their complete care for SS at

this institution. There are no defined criteria for SS.

Therefore, we considered cases to have SS if they had at

least two of the three features of the triad of retinal,

cochlear, or brain involvement during our observation

period. Deficits from SS are difficult to quantify with

standard functional outcome scales, such as the modi-

fied Rankin Scale; therefore, the degree of cognitive and

functional deficits can be underestimated.

However, our findings report the largest series of SS

to date including the careful evaluation and confirma-

tion of this diagnosis in a large referral center over the

Figure 1 Axial view of a T1-weighted MRI of the brain with

gadolinium contrast, demonstrating involvement of the cochlea in

a patient with diagnosed Susac syndrome.

(a) (b)

Figure 2 Pathologic features of Susac

syndrome in brain biopsy of case 21.

Histologic sections demonstrate aggre-

gates of macrophages representing a

subacute microinfarct (arrowheads)

associated with a small vessel (large

arrow). Rare isolated acute ischaemic

neurons are also present (small arrows)

(a). Distinct microthrombi were also

identified within leptomeningeal vessels

(arrow) (b).

Susac syndrome 807

� 2012 The Author(s)European Journal of Neurology � 2012 EFNS European Journal of Neurology

Table

2Treatm

entandclinicalcourseofpatients

withsusacsyndrome

Age

(years

/sex)

Durationof

symptoms

priorto

treatm

ent

months)

Antiplatelet

medication

Oral

steroids

(Y/N

)

IV steroids

Other

treatm

ents

IVIg

(#ofdays)

PLEX

Lowest

modified

rankin

scale

score

Improvem

ent

following

treatm

ent

Outcome

No.of

monthsof

follow-up

available

134/F

2ASA

YN

––

Everyother

day

·5

0Stabilized

symptoms

postpartum

Recurrence

after

oral

steroid

taper

9

232/F

0.25

ASA

YY

––

Everyother

day

·5

0Im

proved

Laterepisodes

ofvisualand

hearingloss

128

336/F

1ASA

2pills

only

YNim

odipine

–Daily

·3

0Weaknessim

proved

withIV

steroids

butlaterhadvisual

changes

(halos

aroundobjects),

earpressure,and

objectivehearing

loss

Recommended

tohave

PLEX

but

LFU

13

435/F

5ASA

NN

––

–5

Initialepisode

resolved

without

treatm

ent;later

episodetreated

withIV

Ig

Improvem

ent

without

treatm

ent

then

recurrenteye

symptoms

6years

later

88

551/F

1ASA-D

ipyri

damole

NY

––

Everyother

day

·5

0Im

proved

hearing

andsight

Norecurrent

symptoms

62

626/F

Uncertain

Clopidogrel

YY

–3

–2

Improved

n/a

95

730/M

1–

YY

––

–2

Improved

following

IVsteroidson2

occasions

Improved

32

846/M

3–4

ASA

NY

Cyclophosphamide

––

5Stable

Stable

but

poorbaseline

9

923/F

6ASA

NY

Nim

odipine,

recommended

to

have

cyclophosphamide

2mg/kgPO

daily

·6months

Daily

·5days

Daily

·5,then

1month

later

4more

doses

5Initiallyreturned

to

baselinewithIV

Ig

maintained

on

monthly

IVIg

and

Solu-M

edrol;

recurrence

1year

laterwithsome

improvem

entwith

PLEX

butdid

not

return

tobaseline

Some

improvem

ent

withIV

Ig

andPLEX

butcontinually

worsening

baselineover

15months

15

808 F. J. Mateen et al.

� 2012 The Author(s)European Journal of Neurology � 2012 EFNS European Journal of Neurology

Table

2(C

ontinued

)

Age

(years

/sex)

Durationof

symptoms

priorto

treatm

ent

months)

Antiplatelet

medication

Oral

steroids

(Y/N

)

IV steroids

Other

treatm

ents

IVIg

(#ofdays)

PLEX

Lowest

modified

rankin

scale

score

Improvem

ent

following

treatm

ent

Outcome

No.of

monthsof

follow-up

available

10

50/F

<1

–Y

NCyclophosphamide

5doseson2

different

occasions

–0

Symptomatic

response

toIV

Ig

reported

inpast

Continued

progression

then

LFU

<1

11

36/F

2–

YY

–Everyother

day

·5

–4

Noresponse

toIV

/

PO

steroids,

4weekslaterhad

response

toIV

Ig

Improvem

ent

3

12

20/F

1.25

ASA

YY

––

Everyother

day

·5

4Im

proved

objective

gaitspeedand

coordination

LFU

<1

13

35/F

0.5

ASA

YY

Nim

odipine

––

2Im

proved

Nonew

symptoms

76

14

23/F

1.5

ASA

YY

Mycophenolate

mofetil,Nim

odipine

5everyother

daythanweekly

–4

Deteriorated

n/a

73

15

37/F

1ASA

YN

––

Everyother

day

·5

0Im

proved

Nonew

symptoms

9

16

44/F

3ASA

YN

––

Everyother

day

·5,then

relapse

then

2

more

doses

4Im

proved

following

PLEX,then

cognitiveandgait

deficits

relapsed

andthen

repeat

treatm

ent

Cognitive

improvem

ent

butrequired

wheelchairat

7months

15

17

19/F

1ASA

YY

Nim

odipine

2doses,then

relapse

then

5

everyother

daywith

improvem

ent,

then

3·per

week

–2

Improved

Nonew

symptoms

43

18

24/F

3.5

Clopidogrel

YY

Azathioprine

–Everyother

day

·5;2

separate

occasion

0Stable,unclear

whether

improvem

ent

occurred

Visualchanges

off

immuno

suppression

nearly

2years

later

treatedwith

repeatPLEX

24

19

36/F

3ASA

YY

Cyclophosphamide

100mgdaily

––

1Onerelapse

while

ona15-m

onth

courseof

cyclophospha

mide,

treatedwith

steroids

Norecurrent

symptomsfor

nearly5years,

persistent

mildvisual

loss

59

Susac syndrome 809

� 2012 The Author(s)European Journal of Neurology � 2012 EFNS European Journal of Neurology

Table

2(C

ontinued

)

Age

(years

/sex)

Durationof

symptoms

priorto

treatm

ent

months)

Antiplatelet

medication

Oral

steroids

(Y/N

)

IV steroids

Other

treatm

ents

IVIg

(#ofdays)

PLEX

Lowest

modified

rankin

scale

score

Improvem

ent

following

treatm

ent

Outcome

No.of

monthsof

follow-up

available

20

28/F

No Treatm

ent

ASA

NN

––

–1

Improved

Hearingloss

andvision

improved

8

21

27/M

4–

YY

Azathioprine

Maintained

on

once

monthly

dose

–2

Cognition

significantly

improved

Slightresidual

mem

ory

deficits

24

22

43/F

1.75

–Y

Y–

5dosesdaily,

then

once

weekly

–4

Stable

Persistent

mem

ory

problems,

improved

gait

3

23

20/F

�months�

ASA

YY

Mycophenolate

mofetilwhen

symptomsremitted

Maintained

on

2g/kgmonthly

–1

Improved

vision

andhearingloss

Norm

al

examination

3

24

33/F

0.25

–Y

Y5dosesdays,then

weekly

·3

–4

Improved

Gait

improvem

ent,

cognitive

gainsto

nearly

norm

al

11

25

57/F

0.25

–Y

YMycophenolate

mofetilwhen

symptomsremitted

Maintained

on

0.25g/kgevery

3weeks

–4

Improved

cognition

Markedly

improved

cognition,

legsweak,

walker

dependent

13

26

39/M

0.75

ASA

YY

Cyclophosphamide,

laterrituxim

ab

Daily

·7

–5

Stable

––

27

25/F

0.25–0.5

ASA

YY

Mycophenolate

mofetil

––

3Im

proved

Mild

improvem

ent

inhearing

loss

and

headaches

9

28

32/F

0.5

ASA

YY

Cyclophosphamide

recommended

post-dismissal

Daily

·5

–4

Cognitionsubtly

improved

––

29

65/M

0.5

–Y

YMycophenolate

mofetil

Daily

·5,then

once

monthly

–4

Cognition

improved,hearing

loss

worsened

Persistent

cognitivedef

icits

8

ASA,aspirin;F,female;LFU,lost

tofollow

up;IV

,steroids;

IVIg,intravenousim

munoglobulins;

M,male;mRS,modified

Rankin

Scale

score;N,no;n/a,notavailable;PLEX,plasm

aexchange;

PO,bymouth;Y,yes.

810 F. J. Mateen et al.

� 2012 The Author(s)European Journal of Neurology � 2012 EFNS European Journal of Neurology

course of nearly 14 years. Our findings help establish

the clinical spectrum of SS, including a depiction of the

treated history of the disease. Our qualitative analysis

also suggests that PLEX is worthy of further evalua-

tion, perhaps in a matched case control design com-

pared to IVIg. Given that SS may rarely be fatal and is

often disabling and severe [8,13], we propose that

PLEX should be considered as an adjunct or alternative

treatment to steroids in patients who do not improve

with IVIg.

Our clinical cohort underscores the value and

necessity of prospective studies of this rare condition.

Such studies would be most effectively achieved

through an international collaboration of researchers,

so that patients can participate in the acute symptom-

atic period from multiple centers. The use of stan-

dardized and uniform clinical assessment tools – where

possible, also including audiogram and visual testing –

will further help clarify the degree of impairment and

long-term disability. Such tests must be carried out at

sufficiently timed intervals to capture the fluctuating

and occasionally recurrent nature of the disorder. In the

longer term, outcome studies of the degree of disability

and recovery through proposed international registries

will provide valuable new information to the growing

number of patients diagnosed with SS.

Acknowledgements

Dr. Mateen is supported by the American Academy of

Neurology Practice Research Fellowship grant.

Disclosure of conflict of interests

The authors declare no financial or other conflict of

interests.

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Susac syndrome 811

� 2012 The Author(s)European Journal of Neurology � 2012 EFNS European Journal of Neurology