Abstract
Although Susac syndrome was first described in
1979, it remains an uncommon diagnosis. Advanced
imaging modalities have contributed to the
understanding of the pathology involved, however
many physicians remain unfamiliar with this
disorder. Imaging and autopsy exams suggest Susac
syndrome produces microangiopathic changes, the
result of a gradual destructive, likely auto-immune
process.
Abstract
Despite many patients having classic MRI findings it
remains difficult to diagnose prior to the onset of a
patient’s more severe symptoms. These symptoms,
seen as a clinical triad, include visual field deficits,
sensorineural hearing loss, and encephalopathy. Once
diagnosed, treatment regimens are inconsistent
throughout the literature with variable outcomes.
Below is an atypical presentation, one without
characteristic MRI or angiographic changes, but with a
significant response to a known therapeutic regimen.
Introduction
Susac syndrome, also known as
retinocochleocerebral vasculopathy, was originally
described by John Susac in 1979 and was first
characterized by encephalopathy, visual deficits,
and sensorineural hearing loss. Currently, clinical
evaluation with the support of imaging studies,
including fluorescein angiography and magnetic
resonance imaging (MRI), are used to make a
diagnosis.
Introduction
Pathognomonic MRI findings include T2-hyperintense deep
gray matter and supratentorial lesions involving the corpus
callosum, often described as “snowballs,” which may be
accompanied by parenchymal and leptomeningeal contrast
enhancement. Visual changes on imaging represent pauciinflammatory microangiopathy with infarction, sclerosis, and
or fibrin deposition in capillaries and arterioles. Further,
audiology examination reveals low frequency hearing loss.
While retinal fluorescein angiography shows sporadic
segmental retinal arterial occlusions.
Introduction
Limited clinical case reports exist on Susac
syndrome particularly among Neurology,
Ophthalmology, Pathology and Radiology.
Commonly the age of disease onset appears to be
between ages 20 to 40, although there have been
reported cases of Susac syndrome in patients as
young as 7 and as old as 72 years of age. Also
noted is a slight female predominance.
Introduction
The complex symptoms of this syndrome makes
distinguishing Susac syndrome from Multiple
Sclerosis (MS) and Acute Disseminated
Encephalomyelitis (ADEM) difficult as they have
much in common. In all three diseases, symptoms
can arise in rapid progression and patients can
experience symptom-free periods or remissions.
Headaches can be prodromal.
Introduction
However, unlike MS and ADEM, MRI findings
involving leptomeningeal enhancement, deep gray
matter, and “snowball” lesions in the central corpus
callosum are distinguishing features representative
of microangiopathy and not demyelination.1,2
Retinal fluorescein angiography in a Susac patient
will classically show non-perfused retinal arterioles
and hyperfluorescent walls consistent with retinal
artery branch occlusions with normal choroidal
circulation which is unlikely to be seen in either MS
or ADEM.3
Introduction
Despite unknown pathogenesis, there appears to
be an autoimmune connection leading to
microvasculature changes in the brain, retina, and
inner ear due to inflammation and possible
endotheliopathy. Anti-Endothelial Cell Antibodies
(AECAs) have been found to be present in the
disease although significance has yet to be
completely determined. It has been theorized that
AECAs may prove to be a “diagnostic biomarker.”4
Introduction
In addition to the classic retinal, inner ear, and neurological
findings, muscle aches and skin lesions can also be present
in Susac syndrome. Patient complaints of myalgias as well
as rashes, such as livedo reticularis, have been seen in prior
cases. Direct immunofluroescence of rashes show sparse
granular C3 component and IgA deposition. Biopsies reveal
endothelial cell swelling and lymphocytic and histiocytic
infiltrates within the upper dermal capillaries and
arterioles. Fibrin deposition could also be suggestive of a
procoagulopathic state, although this has not been
proven.3
Introduction
These findings suggest that Susac syndrome
may have the systemic manifestations of
inflammatory disease.2,4 With suspected
auto-immune pathophysiology and a rare
triad of symptoms, it is probable that the
Rheumatologist will encounter these patients
in the future for possible diagnosis as well as
management.
Clinical Case
A forty-four year old Caucasian female presented to
Rheumatology seven years after initial symptoms. In 2006,
this patient experienced sudden onset of severe vertigo
with loss of consciousness while seated during her night
shift as an ED nurse. Her past medical history at the time
was notable only for migraine headaches. Medications
were topiramate at 50mg tablets twice daily and
sumatriptan 100mg twice daily as needed. Also, at the time
of her symptoms, she was two months post partum after an
unremarkable delivery. CT results did not reveal
abnormality.
Clinical Case
Over the next few months she developed daily
headaches, confusion, difficulty ambulating, and
later tinnitus. She was subsequently seen by ENT
and diagnosed with benign paroxysmal positional
vertigo and treated unsuccessfully with physical
therapy. MRI 18 months later revealed
abnormalities suspicious for demyelination and
thus multiple sclerosis (MS).
Clinical Case
Findings on the MRI included many small foci by increased
T2 and FLAIR signal within the subcortical and deep white
matter bilaterally. One lesion in particular was found near
the genu of the corpus callosum. The lesions were nonenhancing. Additional opinions from Neurology determined
that these were not consistent with MS. Clinically her
symptoms continued to worsen despite a rigorous therapy
of ondansetron 4mg tablets every eight hours, famotidine
20mg daily, diazepam 5mg four times daily, levetiracetam
500mg nightly, and clonazepam 0.5mg nightly.
Clinical Case
The patient was seen nearly seven years after her
initial symptoms at the Cleveland Clinic by a Susac
specialist. Her cranial nerves, deep tendon reflexes,
and mental status examinations were
unremarkable, despite a wobbly gait, confusion,
and hearing loss. She was seen by Ophthalmology
who reported no evidence of retinal vasculopathy
on fluorescein angiography. Audiology examination
revealed a ten decibel sensorineural hearing loss on
the right at high frequencies between 2-8,000 Hz.
Clinical Case
A repeat MRI revealed few punctuate T1, T2 and
FLAIR hyperintensities scattered through the
subcortical white matter of the frontal lobes
bilaterally with periventricular nonenhancing white
matter hyperintensities surrounding, and possibly
involving, the corpus callosum. Her cerebral spinal
fluid did not reveal oligoclonal bands nor elevated
protein. After seven years a clinical diagnosis of
Susac syndrome was made despite inconclusive,
but suggestive, imaging and angiography studies.
Clinical Case
The patient received pulse corticosteroids and was
placed on prednisone along with mycophenolate
mofetil titrated to1000mg twice daily. Although
symptoms began to improve, there was a dramatic
response once monthly IVIG was added seven
weeks later. She remains on IVIG every 4 weeks as
well as mycophenolate mofetil and a tapering dose
of steroids, currently at 12.5mg daily, to fully
control her symptoms.
Clinical Timeline
Imaging
Left: Sagittal T1 weighted MR image of the brain. Middle: Axial T1
weighted MR image with small punctate white matter lesions.
Right: Axial T2 weighted MR image with peri-genuic corpus
callosum hyperintense white matter lesion.
Discussion
Susac syndrome is commonly seen as a clinical triad
of encephalopathy, sensorineural hearing loss and
visual deficits with supportive imaging. The
presented case was noted to have sensorineural
hearing loss on audiology examination. However,
her inconclusive imaging studies and fluorescein
angiography left much to be explained in terms of
diagnosis.
Discussion
Clinically, she met the originally described triad, but we
were not able to qualify her symptoms with further
testing. It is possible that her peri-genuic corpus
callosum lesion represents a new finding for Susac
syndrome. The lesion could also have direct corpus
callosum involvement that is not fully appreciated on
MRI. Other known etiologies had been eliminated. The
patient was treated clinically and has improved with
immunosuppressive therapy, which further supports
her Susac syndrome diagnosis.
Discussion
Prior to this patient’s diagnosis, years were spent
with worsening symptoms and no successful
treatment regimen. Factors complicating this
syndrome are the difficulty establishing a diagnosis
and a non-standardized treatment protocol.
Discussion
Acute improvement with pulsed steroids and IVIG
suggest an autoimmune pathogenesis. One case
study report described a post-partum patient
whose disease was initially treated with steroids
then escalated to cyclophosphamide, aspirin, IVIG,
and is now controlled on azathioprine and
infliximab.2 To the best of our knowledge, this
appears to be the first described clinical case with
treatment with anti-tumor necrosis factor alpha
agents which further suggests an autoimmune
component.
Discussion
Another case report details a patient with Susac
syndrome being treated successfully with rituximab,
an anti-CD 20 antibody.5 In addition to our patient’s
successful therapeutic regimen, she presented early
post-partum which, like other autoimmune diseases
such as Rheumatoid Arthritis, further suggests
inflammatory pathogenesis. Further studies are
ongoing to determine the most appropriate
treatment therapies for these patients and to
determine symptom pathogenesis.
Conclusion
Susac syndrome is a complex, likely autoimmune
derived disease process. Patients benefit from
aggressive and long-term therapies but only after
accurate diagnosis which can often take years to
establish. To reach a level of early detection and
successful treatment regimen for Susac syndrome
patients we will require an informed base across
multiple disciplines and a coordinated approach to
integrated patient care.
References
1. Wuerfel, J, Sinnecker, T., Ringelstein, E. “Lesion Morphology at 7 Tesla MRI differentiates
Susac Syndrome from Multiple Sclerosis”. Multiple Sclerosis Journal. 18(11) 1592-1599
2012
2. Hardy, T., Garsia, R., Halmagyi G., Lewis S., “Tumor Necrosis Factor (TNF) Inhibitor
Therapy in Susac’s Syndrome” Journal of Neurological Sciences. 302(2011) 126-128
3. Lohmann, H. “A Brief Review of Susac Syndrome” Journal of Neurological Sciences.
322(2012) 35-40
4. Magro, C., Poe, J., Lubow, M., Susac, J., “Susac Syndrome - An Organ-Specific
Autoimmune Endotheliopathy Syndrome Associated with Anti-Endothelial Cell Antibodies”
Am J Clin Pathol 2011; 136:903-912.
5. Lee M, Amezcua I. “Treatment of Susac’s syndrome with Rituximab: a case report.”
Neurology 2009; 10:67-74