Rare disease

Case report

Delirium as presentation of late-onset and relapsing
Susac syndrome
Romain Betend,1 Andrea M Humm,1,2 Friedrich Medlin1,3
1

Department of Internal
Medicine, Unit of Neurology,
HFR Fribourg Hopital Cantonal,
Fribourg, Switzerland
2
Department of Neurology,
Inselspital Universitatsspital
Bern, Bern, Switzerland
3
Department of Clinical
Neurosciences, Centre
Hospitalier Universitaire
Vaudois, Lausanne, Switzerland
Correspondence to
Dr Romain Betend,
​romain_​betend@​hotmail.​com
Accepted 23 July 2017

Summary
A 67-year-old patient, only known for bilateral
presbycusis, presented with subacute onset of delirium.
Clinical examination showed multifocal neurological
deficits, all together suggesting subcortical frontal
dysfunction together with cerebellar and corpus callosum
involvement.
Cerebral MRI demonstrated supratentorial and
infratentorial subcortical and periventricular T2hyperintense lesions with cerebellar gadolinium
enhancement and multiple central lesions of the
corpus callosum (snowball lesions). The diagnosis of
Susac syndrome was made and the patient treated
with intravenous methylprednisolone, followed by a
prednisone maintenance dose over 8 weeks. After a clinical
improvement, a relapse was noticed during corticosteroid
tapering. The patient was again treated with intravenous
methylprednisolone followed by a prednisone maintenance
therapy with simultaneous introduction of mycophenolate
mofetil acid and one cycle of intravenous rituximab. The
patient recovered rapidly. At 11-month follow-up, only mild
executive dysfunction and persistent right postural tremor
was noted, MRI showed partial regression of subcortical
and juxtacortical lesions.

seeking evaluation in the emergency department of
our institution. He had a history of relevant for bilateral presbycusis, a recent episode of vertigo and transient blurred vision of the right eye.
On admission, vital signs were normal and there
was no fever. A lumbar puncture was done in the
emergency department and, given the results, intravenous acyclovir was empirically introduced waiting
for herpes simplex virus (HSV) analysis. Neurological assessment at 48 hours after admission revealed
psychomotor slowing, emotional lability, attentional deficits with temporal and spatial disorientation, marked executive and anterograde amnestic
disturbances (Montreal Cognitive Assessment
(MoCA) score at 14/30) as well as left ear suppression on dichotic listening test. Furthermore, right
central facial palsy, left upper limb and gait ataxia,
right-sided predominant postural tremor and leftsided predominant rigidity and bradykinesia of the
upper limbs were noted. The clinical picture with
multifocal neurological deficits suggested subcortical frontal dysfunction together with cerebellar
and corpus callosum involvement.

Investigations
Background
We report a well-documented case of Susac
syndrome, which is a rare, and probably under
recognised disease. The diagnosis was suggested
given the full clinical triad of subacute encephalopathy, multiple branch retinal arterial occlusions
(BRAOs) and bilateral sensorineural hearing deficits
(SNHL), together with the presence of characteristic snowball lesions of the corpus callosum on
MRI. The full clinical triad is uncommon at disease
onset and therefore missing components should be
screened for when diagnosis is suspected.
Treatment for Susac syndrome is empiric with
corticosteroids and immunosuppressive therapy.
We noticed a relapse during prednisone tapering,
highlighting the importance of early-sustained
aggressive and multimodal immunosuppressive
therapy.

Case presentation
To cite: Betend R,
Humm AM, Medlin F. BMJ
Case Rep Published Online
First: [please include Day
Month Year]. doi:10.1136/
bcr-2017-220494

A 67-year-old retired teacher was hospitalised in our
institution for subacute onset of delirium with initial
suspicion of meningoencephalitis. His wife noticed a
progressive deterioration over 2 months characterised by cognitive decline with behaviour disturbance
followed by a delirium with visual hallucinations

Contrast enhanced brain CT was normal. Cerebrospinal fluid (CSF) analysis revealed a lymphocytic pleocytosis (12 leucocytes/mm3) and elevated
protein (2.64 g/L). Oligoclonal bands were absent.
PCR for HSV type 1 and type 2 returned negative
and acyclovir was stopped. PCR for EBV was also
negative. Electroencephalography showed diffuse
slowing. Cerebral MRI demonstrated multiple supratentorial and infratentorial subcortical and periventricular T2-hyperintense lesions (figures 1A, B and
E), with modest cerebellar gadolinium enhancement
(not shown) and multiple central lesions of the corpus
callosum (snowball lesions). Spinal MRI and thoracoabdominal CT scan were normal. Laboratory analysis revealed a slightly elevated erythrocyte sedimentation rate (13 mm/hour), elevated rheumatoid factor
(357 U/mL), mixed non-infectious cryoglobulinaemia
and modest vitamin D deficit (43 nmol/L). Routine
laboratory analysis, thyroid-stimulating hormone,
angiotensin converting enzyme, antinuclear antibody, lupus anticoagulant, protein electrophoresis,
anti-NMO antibodies titre and testing for Lyme, HIV,
hepatitis C and tuberculosis were negative.
Retinal fluorescein angiography (RFA) showed
BRAO (figure 1G and figure 1H) and tone audiometry revealed bilateral, left predominant pantonal
SNHL (figure 1I).

Betend R, et al. BMJ Case Rep 2017. doi:10.1136/bcr-2017-220494

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Rare disease

Figure 1 Composite figure showing fluid-attenuated inversion recovery T2 axial (A, C, E and F) and sagittal T2 (B and D) cranial MRI at presentation
(A, B and E) and at 11 months (C, D and F). (A), (B) and (E) show diffuse subcortical white and grey matter lesions and characteristic lesions of the
corpus callosum (snowball lesions) and one right caudate nucleus lesion (large yellow arrow). (G) and (H) are retinal fluorescein angiography at
presentation. Thin yellow arrows show multiples branch retinal arterial occlusions (BRAOs) on the right (G) and left (H) eyes. (I) is the tone audiometry
at presentation. Left ear is depicted in blue, right ear in red. Horizontal axis shows the frequency in kilohertz, vertical axis show the decibel level at
which the frequency is perceived. (J) is RFA at 3 months (right eye) demonstrating zones of focal ischaemia (cross), new BRAOs (large arrows) and
leakages (thin arrow).

Differential diagnosis

The clinical presentation fulfilling the diagnostic criteria for
Susac syndrome with all components of the clinical triad
together with the pathognomonic snowball lesions on MRI
narrows the differential diagnosis and leaded straightforward to the diagnosis.1 Still, important differential diagnosis
include multiple sclerosis, acute disseminated encephalomyelitis (ADEM), neurosarcoidosis, primary cerebral nervous
2

system lymphoma (PCNSL) and primary angiitis of the central
nervous system (PACNS).
In the presented case, clinical history lacking prior vaccination
or infection before clinical onset, the older age and the relapsing
course argue against ADEM.
Likewise, age at onset, the lesion pattern on MRI with characteristic snowball lesions and multifocal lesions involving both
white and grey matter, the absence of oligoclonal bands and the
Betend R, et al. BMJ Case Rep 2017. doi:10.1136/bcr-2017-220494

Rare disease
high protein level in CSF make the diagnosis of multiple sclerosis
unlikely.
Absence of systemic symptoms, meningeal or orbital involvement without signs of uveitis or chorioretinitis, the normal
thoracoabdominal CT scan, normal ACE assay argue against
neurosarcoidosis. Furthermore, BRAOs are usually not seen in
neurosarcoidosis neither in multiple sclerosis.
Again, absence of systemic symptoms and leptomeningeal
involvement, the results of CSF analysis including negative PCR
for EBV and finally the above-mentioned lesion pattern on MRI
lowers the likelihood for PCNSL. Hence, a stereotaxic biopsy
was not performed.
Finally, PACNS or systemic vasculitis with CNS involvement
as challenging differential diagnoses have been initially considered but were ruled out mainly because of the absence of distal
vasculopathy on CT/MRI angiography, and once more the characteristic snowball lesions of the corpus callosum.

Learning points
►► Susac syndrome is a rare and probably under recognised

disease. Given the fact that the full clinical triad is
uncommon at disease onset, missing components should be
actively screened for.
►► The presence of snowball lesions on MRI in a patient with
encephalopathic is highly suggestive of Susac syndrome.
►► Until today, there is no diagnostic blood analysis to confirm
Susac syndrome. The exact pathophysiological role of antiendothelial cell antibodies is still unknown.
►► Empirical treatment for Susac syndrome is mainly based on
long-term corticosteroid and immunosuppressive therapy
and requires close clinical follow-up when tapering because
of the risk of relapse.

His cognitive functions improved rapidly and at 6-week
follow-up, he remained stable with moderate executive
dysfunction as assessed by comprehensive neuropsychological testing (MoCA score at 20/30), without new lesions and
no contrast enhancement on brain MRI. Neurological status
was unchanged. Given the favourable clinical and radiological course as well as important steroid side effects (insomnia,
impulsivity, glucose intolerance due to weight gain), corticosteroids were further tapered and stopped 3 months after
onset. Two-weeks later, he was rehospitalised for delirium with
psychotic decompensation and visual hallucinations requiring
transient administration of atypical neuroleptics (haloperidol and olanzapine). Clinical examination at this time did
not reveal new focal neurological signs. However, brain MRI
showed new subcortical and callosal T2-hyperintense lesions
without contrast enhancement. Audiometry was repeated,
showing a pronounced pantonal bilateral hearing deficit. RFA
demonstrated new BRAOs with zones of focal ischaemia and
vascular leakages (figure 1J), whereas repeated CSF analysis
showed mild neutrophilic pleocytosis (19 leucocytes/mm3) and
still elevated protein (1.64 g/L).
Intravenous methylprednisolone 500 mg/day was repeated for
3 days, followed by a prednisone maintenance therapy (1 mg/
kg) with simultaneous introduction of mycophenolate mofetil
acid and administration of one cycle of intravenous rituximab
(2×1 g at the 14-days interval). The patient recovered rapidly
from delirium. At 11-months follow-up, only mild executive
dysfunction (MoCA score at 26/30) and persistent right postural
tremor was noted, MRI showed partial regression of subcortical
and juxtacortical lesions (figure 1F).

first report with a disease onset beyond 65 years.2 The most
common manifestation at disease onset is encephalopathy but
importantly, the presence of the full clinical triad at disease
onset is uncommon and present in only about a quarter of
patients, underlining the need to screen for all components by
MRI, RFA and audiometry, as illustrated in this case.2 3 The
presence of snowball lesions in an patient with encephalopathic is highly suggestive of Susac syndrome and should hasten a
search for BRAO and SNHL.4 These are small corpus callosum
lesions (3–7 mm) involving more frequently the central fibres,
that look like snowballs on sagittal T2 and fluid-attenuated
inversion recovery sequences.5 6
The exact pathophysiological mechanisms of the disease are
still unclear, but an immune-mediated inflammatory endotheliopathy seems to be a key element, causing micro infarcts of
brain, retina and inner ear and sharing histologically similarities
with juvenile dermatomyositis. In Susac syndrome, complement
activating antiendothelial cell antibodies (AECA) are inconsistently found, although its exact pathophysiological role needs to
be further addressed.3 7 Unfortunately, testing for AECA was not
available in our institution. Interestingly, our patient had non-infectious mixed cryoglobulinaemia that might argue for a cryoglobulinaemia vasculitis. However, the lack of association with
malignant haemopathy or systemic connective tissue disorder
makes this assumption in our opinion less likely.
Treatment recommendations for Susac syndrome are
empiric, but there is agreement for early, high dose corticosteroid therapy and sustained multimodal immunosuppressive therapy as well as intravenous immunoglobulin as firstline treatment. Plasmapheresis and alternative drugs such as
rituximab are mostly proposed in refractory cases.8 Aspirin
is frequently added to reduce procoagulopathic state and is
recommended by some authors.9
In conclusion, we report a well-documented and relapsing case
of late-onset Susac syndrome successfully treated with multimodal immunosuppressive therapy. We noticed an acute relapse
due to rapid tapering of corticoids emphasising the importance
for a close clinical follow-up and if necessary an aggressive and
sustained immunosuppression.

Discussion

Acknowledgements Beknazar E., Chouiter L., Colombo-Thuillard F., Hennion D.

Treatment
Consequently, the patient was treated with intravenous methylprednisolone 1 g/day for 3 days, followed by a prednisone
maintenance dose (1 mg/kg) over 8 weeks. Aspirin was also
added.

Outcome and follow-up

Susac syndrome is a rare disease characterised by the clinical
triad of encephalopathy, BRAO and SNHL. Until today, as
few as 304 cases with Susac syndrome were reported in the
literature.2 It affects preferentially young women in their 20s
or 30s at disease onset with disease onset between 8 and 65
years having been reported, but to our knowledge, this is the
Betend R, et al. BMJ Case Rep 2017. doi:10.1136/bcr-2017-220494

Contributors RB: Study concept and design, analysis and interpretation of data,
drafting of the manuscript. AMH: Critical revision of the manuscript. FM: Study
concept and design, data collection and interpretation, drafting and critical revision
of the manuscript, supervised the study.
Competing interests None declared.
Patient consent Obtained.
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Rare disease
Provenance and peer review Not commissioned; externally peer reviewed.
© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article)
2017. All rights reserved. No commercial use is permitted unless otherwise expressly
granted.

References

1 Kleffner I, Dörr J, Ringelstein M, et al. European Susac Consortium (EuSaC).
Diagnostic criteria for Susac syndrome. J Neurol Neurosurg Psychiatry
2016;87:jnnp-2016-314295.
2 Dörr J, Krautwald S, Wildemann B, et al. Characteristics of Susac syndrome: a review of
all reported cases. Nat Rev Neurol 2013;9:307–16.
3 Greco A, De Virgilio A, Gallo A, et al. Susac's syndrome--pathogenesis, clinical variants
and treatment approaches. Autoimmun Rev 2014;13:814–21.

4 Rennebohm R, Susac JO, Egan RA, et al. Susac's Syndrome — Update. J Neurol Sci
2010;299:86–91.
5 Susac JO, Murtagh FR, Egan RA, et al. MRI findings in Susac's syndrome. Neurology
2003;61:1783–7.
6 Garg N, Reddel SW, Miller DH, et al. The corpus callosum in the diagnosis of multiple sclerosis
and other CNS demyelinating and inflammatory diseases. JNNP 2015;86:1374–82.
7 Jarius S, Kleffner I, Dörr JM, et al. Clinical, paraclinical and serological findings
in Susac syndrome: an international multicenter study. J Neuroinflammation
2014;11:46.
8 García-Carrasco M, Mendoza-Pinto C, Cervera R. Diagnosis and classification of Susac
syndrome. Autoimmun Rev 2014;13:347–50.
9 Kleffner I, Duning T, Lohmann H, et al. A brief review of Susac syndrome. J Neurol Sci
2012;322:35–40.

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Betend R, et al. BMJ Case Rep 2017. doi:10.1136/bcr-2017-220494