Clinical Neurology and Neurosurgery 191 (2020) 105680

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Clinical Neurology and Neurosurgery
journal homepage: www.elsevier.com/locate/clineuro

Case Report

Recurrent intracranial hemorrhage and cerebral venous sinus thrombosis: an
atypical case of Neuro-Behçet’s Syndrome

T

Fabrizio Giammelloa, Cristina Dell’Aeraa, Francesco Grilloa, Masina Cotroneoa,*,
Carmela Casellaa, Maria Carolina Fazioa, Paolino La Spinaa, Isabella Francalanzaa,
Alessia Fiorenzab, Antonio Toscanoa, Fabiola Atzenib, Rosa Fortunata Musolinoa
a
b

Department of Clinical and Experimental Medicine, AOU Policlinico G. Martino, University of Messina, Messina, Italy
Rheumatology Unit, University of Messina, Italy

A R T I C LE I N FO

A B S T R A C T

Keywords:
Neurobehçet
PACNS
CVST
anti-TNF-α

We report the case of a 22-year-old man with an history of headaches, seizures, cognitive impairment associated
with recurrent intracranial hemorrhage (ICH), acute ischemic stroke (AIS), worsened over the last eighteen
months for a new onset of uveitis and cerebral venous sinus thrombosis (CVST). After excluding common causes
of lobar ICH, and some rare ones according to the diagnostic protocol proposed by Beuker et al, in the suspicion
of Primary Angiitis of the Central Nervous System (PACNS), the gradual development of a low-grade fever, a
cutaneous rash, and a papulopustular manifestation on lower back after rachicentesis (pathergy phenomenon),
allowed us to make a diagnosis of Neuro-Behçet's Syndrome (NBS) without oral/genital aphthous ulcerations,
according to the International Study Group for Behçet’s Disease classification criteria for BD (ICBD).

1. Introduction
Behçet disease (BD) is an idiopathic, chronic relapsing, multisystem,
vascular-inflammatory disease with unknown etiology, more common
in men and usually seen in the third decade with recurrent buccal
aphthosis, genital ulcer and uveitis with hypopyon [1].
Neurologic involvement or Neuro-Behçet's Syndrome (NBS) occurs
in about 4-49% of patients with BD and may be caused by either primary parenchymal lesions or vascular damage. NBS is classified in two
major forms: parenchymal-NBS (P-NBS) and nonparenchymal-NBS (NPNBS). P-NBS, which is caused by parenchymal pathology, accounts for
the majority of NBS (75% of NBS cases). Parenchymal-NBS is featured
by diffuse brainstem, cerebral, optic, and spinal cord symptoms. On the
other hand, NP-NBS, which is usually caused by occlusion or hemorrhage of the main vascular structures is relatively rare, with a frequency
reported 10 to 20% of all NBS patients. Cerebral venous sinus thrombosis (CVST), pseudo-tumor like intracranial hypertension and acute
meningeal syndrome revealed for MRI imaging, intra-extracranial aneurysms are common forms of NP-NBS [2]. NBS should be considered in
the differential diagnosis of stroke in young adults, neoplastic and
paraneoplastic syndromes, multiple sclerosis, central nervous system
(CNS) vasculitides, sarcoidosis, CNS infections and other neurologic
syndromes [3]. Among NBS mimics, primary angiitis of the central

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nervous system (PACNS) is a rare and severe disease, responsible for
approximately 3–5% of cerebrovascular events in patients aged < 50
years. In PACNS, inflammation affects the blood vessels supplying the
brain parenchyma, spinal cord and leptomeninges and less frequently
veins and venules, resulting in poor blood circulation, blood vessel
ruptures and intracranial haemorrhage [4].
2. Case report
We report the case of S.G, a 22-year-old man with a history of recurrent ICH, associated with headaches, seizures, cognitive impairment.
The patient received multiple anti-epileptic drugs (AED) treatment and
had several hospitalization from December 2017 to June 2019 without
a diagnosis. The patient was admitted to Stroke Unit of University
Hospital “G. Martino” in April 2019. Neurological examination showed:
ideomotor slowdown, impaired spatial and temporal orientation, ataxic
gait, unilateral ptosis with ipsilateral miotic and poor reactive pupil
associated with conjunctival injection in the left eye, asymmetry of
deep tendon reflexes with right-side prevalence, postural and intention
tremors in right hand. Neurocognitive assessment found memory, attention, and frontal executive functions impairment with Mini-Mental
State Examination (MMSE) of 19.19 (normal > 23). Laboratory routine
tests, acute phase reactants, rheumatoid factor, antinuclear antibodies,

Corresponding author.
E-mail address: cotroneomasina@gmail.com (M. Cotroneo).

https://doi.org/10.1016/j.clineuro.2020.105680
Received 3 December 2019; Received in revised form 10 January 2020; Accepted 13 January 2020
Available online 15 January 2020
0303-8467/ © 2020 Elsevier B.V. All rights reserved.

Clinical Neurology and Neurosurgery 191 (2020) 105680

F. Giammello, et al.

Fig. 1. Cerebral vascular alterations. (A) An axial contrast enhanced T1 MRI with gadolinium demonstrating a filling defect at the right sigmoid sinus (withe arrow)
and (B) TOF MRI showing CSVT (white arrow); (C-D) DSA showing diffuse arterial stenosis and dilatation (black arrows).

prednisolone (1 mg/kg for 4 weeks) plus azathioprine (2 mg/kg/ day)
with tapering oral steroids as maintenance therapy reported in literature [5]. One month after the dosage of corticosteroid was reduced, the
patients develop right hemiparesis (National Institutes of Health Stroke
Scale – NIHSS: 8) due to a new AIS with HT (Fig. 2). Because the clinical
findings were corticosteroid-dependent and refractory, the patient was
begun on infliximab, an anti-TNF-α monoclonal antibody. He received
intravenous injections of infliximab at a dose of 5 mg/kg in week 0, 2, 6
and then every 8 week. Before started infliximab, we found a positive
Quantiferon Tuberculosis (TB) gold - test and treatment for latent TB
infection (LTBI) has been administered. The cutaneuous and ocular
symptoms resolved soon after the initiation of infliximab. The patient
showed a significant clinical improvement in cognitive functions and in
ocular and motor symptoms (NIHSS: 3). No meaningful adverse effects
of infliximab were observed during follow ups.

antineutrophil cytoplasmic antibodies, antiphospholipid antibodies,
HIV tests, viral antibodies for CMV, EBV, VZV, Herpes Simplex 1-2,
measles, parotitis and hepatotropic virus, tumor markers were normal,
with the exception of serum beta 2-microglobulin levels (4327.50 ng/
ml; normal range 900.00–2700.00). Cerebrospinal fluid (CSF) showed
18 cell/ml (range 0–5), total protein concentration 150 mg/dL (range
20–50) and the presence of oligoclonal bands in serum and CSF. Serial
magnetic resonance tomography (MRI) exams showed multiple lobar
intracranial hemorrhage (ICH) and acute ischemic stroke (AIS) with
hemorrhagic transformation (HT) in long TR sequences in the cortical
and subcortical structure of the frontal and parietal lobes, associated
with cerebral venous sinus thrombosis (CVST) and leptomeningeal enhancement after somministration of gadolinium. Digital subtraction
angiography (DSA) showed diffuse, bilateral and alternating areas of
arterial stenosis and dilatation (beading) and multifocal venous occlusions (Fig. 1). 11C-Pittsburgh compound B positron emission tomography (PiB-PET) showed no rise in amyloid tracer uptake. CSF biomarkersβ-amyloid (Aβ)42, Aβ40, total tau (t-tau) and phosphorylated
tau (p-tau) did not show alterations. Cerebral biopsy has not been
performed.The ophthalmologic examination showed plastic and exudative iridocyclitis in the left eye with potato-like keratic precipitates
with a positive Tyndall test. The rheumatological assessment found
Human leucocyte antigen (HLA)-B51 positive and a papulo pustular
rash on the lower back. Nail fold videocapillaroscopy found enlargement and tortuosity of the capillaries, with sub- and peri-ungual oedema. During hospitalization corticosteroid pulse therapy with methylprednisolone (1 g/day for 5 days) was initiated, followed by oral

3. Discussion
After excluding common causes of lobar ICH, we considered some
rare ones and, in the suspicion of PACNS, we applied the diagnostic
protocol proposed by Beuker et al., which includes the analysis of
clinical features, laboratory tests, CSF, MRI, DSA and brain biopsy. We
have satisfied 5 to 6 criteria of Beuker et al. for PACNS diagnosis (in the
absence of tissue confirmation), but the association with uveitis is very
rare in this disease [4]. The previous findings drove us to investigate for
the presence of NBS without oral aphthous ulcerations, according to the
International Study Group for Behçet’s Disease classification criteria for
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Clinical Neurology and Neurosurgery 191 (2020) 105680

F. Giammello, et al.

Fig. 2. New AIS. (A-B) FLAIR and (C) SWI MRI imaging; (D) DSA showing CSVT (black arrows).

4. Conclusion

BD (ICBD) [1]. The second most common form of neurologic involvement in BD is CVST (12–20%), localizing in superior sagittal sinus,
transverse sinuses, deep cerebral veins, and cavernous sinuses. The
papulo-pustular rash on lower back was observed one day after rachicentesis around the same site of lumbar puncture. After the first intravenous injections of infliximab, the patient presented an analogous
rash on trunk. It could be considered as pathergy phenomenon, a nonspecific skin hypersensitivity that is almost specific for BD, when induced by inserting an 18-G into the dermis of the forearm. The reaction
is considered positive if either a papule, a pustule, or an ulcer forms at
the puncture site within 48 hours [2]. According to the ICBD classification criteria, the presence of eye and skin lesions associated with
CVST and AIS is highly suggestive of NP-NBS [1]. Interesting that our
patient has a LTBI and recent laboratory and clinical findings include
the discovery of antibodies to human and mouse neuro-fibrils showing
cross-reactivity with Streptococcus spp. and Mycobacterium tuberculosis heat shock proteins (HSP) in NBS [2]. NBS attacks can be treated
with glucocorticoids alone or in combination with azathioprine. For
patients with relapsing-remitting or progressive courses, shifting to
more potent immunosuppressive drugs such as mycophenolate, methotrexate, cyclophosphamide, or targeted therapy is warranted. Administration of cyclosporine has been reported to be associated with the
development of acute neurological attacks and accordingly should not
be advocated in NBS patients. For NBS and CVST, immunosuppressive
drugs with or without anticoagulation are suggested [3]. At present,
after multiple AED, corticosteroid immunosuppressive and infliximab
therapy the patient hasn’t had other relapses from June 2019 up to sixmonth follow-up.

The identification of NBS mimics is often challenging in clinical
practice, but crucial to avoid far-reaching treatment decisions and to
demonstrate the effectiveness of immunosuppressive therapies in a refractory case of NBS.
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