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Clin Exp Med
DOI 10.1007/s10238-014-0328-z
REVIEW ARTICLE
Behcet syndrome: from pathogenesis to novel therapies
Gianluigi Mazzoccoli Angela Matarangolo
Rosa Rubino Michele Inglese Angelo De Cata
Received: 8 October 2014 / Accepted: 22 November 2014
Springer-Verlag Italia 2014
Abstract Behcet syndrome is a chronic disease hall-
marked by inflammation of the blood vessels that is related
to an autoimmune reaction caused by inherited suscepti-
bility due to specific genes and environmental factors,
probably components of infectious microorganisms, which
turn on or get going the disease in genetically susceptible
subjects. The more common clinical expression of the
disease is represented by a triple-symptom complex of
recurrent oral aphthous ulcers, genital ulcers, and uveitis,
sometimes associated with inflammatory arthritis, phlebitis,
iritis, as well as inflammation of the digestive tract, brain,
and spinal cord. The treatment strategies used to manage
the manifestations of Behcet syndrome have gradually
progressed, and a number of new therapeutic resources
have been implemented in recent years, allowing better
control of pathogenic mechanisms, reducing symptoms and
suffering, and ameliorating patients outcome.
Keywords Behcet
Vasculitis
Arthritis
Aphthae

Uveitis
Immunosuppression
G. Mazzoccoli (&)
R. Rubino
Division of Internal Medicine and Chronobiology Unit,
Department of Medical Sciences, IRCCS Scientific Institute and
Regional General Hospital Casa Sollievo della Sofferenza, more important are the association with HLA genotype of
San Giovanni Rotondo, FG, Italy
e-mail: g.mazzoccoli@operapadrepio.it
A. Matarangolo
M. Inglese
A. De Cata (&)
Division of Internal Medicine and Rheumatology Unit,
Department of Medical Sciences, IRCCS Scientific Institute and
Regional General Hospital Casa Sollievo della Sofferenza,
San Giovanni Rotondo, FG, Italy
e-mail: a.decata@operapadrepio.it
Introduction
Behcets disease (BD) is a vasculitis that affects the arteries
and veins of all sizes, resulting in an alteration of the
endothelial function [15], which comes out from the
clinical point of view in the appearance of organic lesions
at various levels [6]. There are no real diagnostic criteria
for BD; nevertheless, the International Team for the
Revision of the International Criteria for Behcets Disease
(ITR-ICBD) established purely classifying criteria, fre-
quently used as clinical guidance from doctors who suspect
the pathology (Table 1) [7, 8]. BD has a higher incidence
in the countries located along the ancient Silk Road,
stretching from Asia to the Mediterranean countries. It is
therefore very common in Turkey (80370 cases per
100,000 inhabitants), but also in Japan, Korea, and China
[9]. The prevalence in the USA and in Europe ranges from
0.12 to 7.5 patients per 100,000 inhabitants [10]. BD
affects young patients aged between 20 and 40 years,
generally of female gender in countries of northern Europe,
and of male gender in the eastern Mediterranean region [9].
Pathogenesis
The pathogenesis of BD is still not well known, and there
are many possible mechanisms implicated. Among the
the patients, bacterial cross-reactivity with human peptides,
cellular secretion of some clusters of cytokines, presence of
autoantibodies and circulating immune complexes, hyper-
coagulability, and activation of the vascular endothelium
[11]. Although some studies seem to show an influence
equal to only 20 % on the pathogenesis of the disease [12],
the increased risk of developing BD is associated with the
123

Table 1 International criteria Signs/symptoms
for Behcets disease diagnosis
Ocular lesions
Oral aphthae
Genital aphthae
Cutaneous lesions
Neurological
manifestations
Vascular events
Positive pathergy test
presence of a particular HLA antigen pattern. In this
regard, a recent meta-analysis showed that subjects with
HLA-B51/B5 have an increased risk of developing BD
compared to non-carriers of HLA-B51/B5 [13]. Other
studies also show the prevalence of HLA-B51 in Italy,
Germany, and Asia, HLA-B52 in Israel and HLA-B57 in
England, HLA-B5101 and HLA-B5108 in the countries
along the ancient Silk Road [1419]. Other evidences also
seem to show the existence of a correlation between the
presence of HLA-B51 and the severity of BD [2022].
Although most of the cases of BD are sporadic, examples
of increased incidence of BD have been reported within
some families, in which the presence of the disease in a
first-degree relative increased the risk of developing the
disease. This figure also would agree with the increased
presence of HLA-B51 in patients with familial forms
compared to patients with sporadic forms [23, 24]. In
addition to HLA genotype, according to some studies, in
the pathogenesis of BD, the cross-reactivity between bac-
terial antigens and self-antigens of the host could have an
important role, by virtue of their structural homology.
Among the antigens in question, for example, have been
implicated the so-called heat shock proteins (HSPs), pro-
teins produced by many organisms in response to stress. T
cells and/or B cells would recognize exposed bacterial and
human epitopes, determining the start or perpetuation of
the disease. In confirmation, in patients with BD were
isolated high levels of IgG and IgA antibodies directed
against HSPs of mycobacteria, which showed significant
sequence homology with human mitochondrial HSPs [25],
while another study also mentions the involvement of T
cells in response to exposure to HSPs of mycobacteria [26].
The increase in circulating levels of autoantibodies could
then match the exacerbation of the uveitis manifestations
typical of BD [27]. Mycobacteria, however, were not the
only bacteria implicated in the pathogenesis of BD. Several
evidences would show a possible pathogenic role of
Streptococci: increased salivary bacterial colonization by
the Streptococcus mutans in patients with BD compared
with healthy controls [28], a higher antibody titer directed
toward the Streptococcus sanguinis in patients with BD
123
Clin Exp Med
Score compared with healthy controls [29, 30], and the preva-
lence of antibodies against streptococcal HSPs in patients
2 with mucocutaneous manifestations [31]. Streptococcal
2 antigens in the infected organism seem to increase the
2 production by T lymphocytes of IL-6 and INFc, as well as
1 the concentrations of IL-8 and TNFa [3234]. These
1 findings are confirmed by another study, in which the
improvement in mucocutaneous lesions was analyzed in
1 two groups of patients, one of which consisted of 94
1 patients with BD treated with colchicine and benzathine
penicillin, the other group composed of 60 patients with
BD who underwent only colchicine therapy. This study
showed a significantly higher improvement in the muco-
cutaneous lesions in the first group when compared to that
obtained in the group of patients treated only with colchi-
cine [35]. Another study instead calls into question anti-
bodies directed against a cytotoxin of Helicobacter pylori,
responsible for the vascular damage typical of BD through
a mechanism of cross-reaction on endothelins. Such evi-
dence seems demonstrated by the decrease in disease
activity upon eradication of the bacterium [36]. Lastly,
some studies suggest a virus-related etiopathogenesis of
BD. The trigger role of the herpes simplex type 1 virus,
found in the nuclei of the cells of some patients with BD,
but according to other studies, not present in the saliva of
patients with BD tested with polymerase chain reaction
(PCR) method, remains controversial. Besides, the effec-
tiveness of the therapy with acyclovir in a randomized trial
conducted in patients with BD was not evidenced [37]. A
different role would play the parvovirus B19, found in
patients with BD but without ulcerative lesions of the skin
in greater amounts than in healthy controls or patients with
BD and with ulcerative cutaneous lesions [38]. In the
pathogenesis of BD, a reduced function of innate immunity
has been called into question, since in patients with BD
have been found low levels of mannose binding lectin
(MBL), a protein capable of activating the complement
cascade upon binding to the mannose of the bacterial sur-
face. Such low concentrations not only would correlate
with the appearance of BD after infections and with the
severity of disease, but would also be present in other
autoimmune diseases, such as rheumatoid arthritis and
lupus erythematosus systemicus [39, 40]. As part of innate
immunity, an alteration in the expression of Toll-like
receptors on lymphocytes of patients suffering from BD
was recently evidenced [4143], as well as an increased
expression of Toll-like receptors 2 and 4 on monocytes of
patients with the active form of BD [44, 45]. In BD, there is
an alteration in the number and activation of T cells [46], as
demonstrated for example by the aforementioned HSPs
[26] or by activation of adenosine deaminase, an enzyme
involved in the proliferation and differentiation of T cells
[4749]. In BD, there seems to be an involvement of both
Clin Exp Med
T-helper 1 (Th1) and Th2 cells [5052]. In many studies of
patients with BD, in fact there were high levels of Th1
lymphocytes [5359], normally responsible for the secre-
tion of cytokines such as IL2, IL6, IL8, IL12, IL18, TNFa,
and IFNc. Other studies seem to show a correlation
between high levels of IL8, IL12, and TNFa and disease
activity [6064], for example in terms of exacerbation of
ocular involvement [65] or new onset of posterior uveitis
[66], as well as the presence of high levels of IL6 in
patients with neurological involvement in the course of
active disease [67]. In BD, however, have been demon-
strated not only changes in the Th1 subpopulation, but also
of Th2 lymphocytes, as demonstrated by the increase in the
soluble portion of CD30, released by Th2 cells as effect of
their activation and activity of BD itself. An important role
is also played by the Th17 subpopulation, normally
secreting IL-17, which seems to be increased and activated
in active BD [6873]. Also the soluble fraction of CD28,
an important regulator of the activation of T lymphocytes,
seems to be increased in patients with active BD, corre-
lating also with the activity of disease [7476]. Elevated
levels of IL2, IL6, and TNFa were found in patients with
active uveitis in the course of BD subsequently treated with
benefit with infliximab [77] and, although at lower con-
centrations than in patients with rheumatoid arthritis, even
in the synovial fluid of patients with BD have been reported
increased concentrations of IL2 and IL8, but lower con-
centrations of TNFa [78]. B lymphocytes also appear to
play a prominent role in the pathogenesis of BD, consid-
ering that an increased level of antigen-driven circulating B
lymphocytes have been demonstrated in patients with BD
[79, 80]. Autoantibodies to numerous self-antigens were in
fact described [81, 82], such as mucosal proteins, endo-
thelial cells, and oxidized LDL, and as regards uveitis,
autoantibodies directed against the a-tropomyosin antigen
[83, 84], localized in the endoplasmic reticulum, which,
after immunization induced in the laboratory, induced the
appearance of cutaneous and uveitic lesions in rats very
similar to those of patients suffering from BD, were also
described. A number of factors play a role in the patho-
genesis of vascular damage in patients with BD. The
thrombotic risk is certainly increased for the vascular
damage induced by vascular inflammation [85]; neverthe-
less, the presence of endothelial dysfunction has been
demonstrated in these patients, in terms of endothelial
activation with increased levels of nitric oxide (NO) and its
metabolites in the plasma, synovial fluid and humor
aqueous [8690]. Some studies also show an increase in
plasma concentrations of vascular endothelial growth fac-
tor (VEGF) in patients with elevated activity of BD [91]
and in the cerebrospinal fluid of patients with neuro-Behcet
[92]. A generalized state of hypercoagulability is also
demonstrated by the finding in patients with BD of high
levels of thrombin with reduction in physiological fibri-
nolysis, low concentrations of activated protein C [93, 94],
increase in platelet activation [95], and lower plasma levels
of tissue plasminogen activator tPA [96]. In BD patients,
activation of polymorphonuclear (PMN) leukocytes, or
neutrophil granulocytes also seems to be present, as a result
of increased plasma concentrations of cytokines, such as
IL8 and TNFa [97, 98]. Such PMN cells present increased
motility and adhesion to endothelial cells in vitro, also in
virtue of the increased expression of cell surface receptors,
including CD11, CD18, ICAM1, and E-selectin [99]. This
fact favors the migration and adhesion of neutrophils to
inflamed vessel walls [100], as well as an increase in
granulocyte colony stimulating factor (G-CSF), leukocyte
growth factor, and increased apoptosis of neutrophil gran-
ulocytes [101]. In patients with neurological involvement,
a pathogenic role of matrix metalloproteinase (MMP)-9
was also demonstrated in leukocyte invasion of the central
nervous system (CNS) and cerebro-spinal fluid (CSF) of
patients with BD compared to healthy controls [102]. In
summary, therefore, the pathogenesis of BD could roughly
be traced back to the intervention of an infectious antigen
(viral or bacterial?), able to determine the activation and
exposure of HLA class II antigens on antigen-presenting
cells (APC), such as Langerhans cells, dendritic cells, B
lymphocytes, and macrophages. Such cells, assisted by the
presence of numerous circulating cytokines, such as IL6
and IL1, would present antigen to CD4? T lymphocytes
(Th1), determining proliferation and activation, with con-
sequent release into the circulation of IFNc, IL-2, and
TNFb, cytokines that are able to determine in turn the
activation of B lymphocytes, which, by secreting antibod-
ies, determine the formation of circulating immune com-
plexes and subsequent activation of complement and
neutrophil granulocytes [103]. Among other cytokines,
IFNc also impinges on macrophages, stimulating the pro-
duction of IL1, TNF, IL8, and IL12 [104]. IL8 instead
leads to the expression of adhesion molecules on endo-
thelial cells and the subsequent chemotaxis and hyperac-
tivation of neutrophils [105].
Clinical manifestations
The most common and frequent clinical feature of BD is
certainly the presence of unsightly and painful oral aphthae
and mucocutaneous ulcers, usually of magnitude more
severe in male patients. More than two-thirds of the
patients also present ocular involvement, more than a third
vascular pathologies and finally roughly 1020 % of
patients present with involvement of the central nervous
system. Less common instead is the involvement of joints,
kidney, and peripheral nervous system [106]. The majority
123

of BD patients at onset of disease present recurrent oral
aphthae, histologically similar to the aphthae present in
recurrent oral stomatitis, but more extensive, multiple,
painful, round-bottomed, yellowish-white, with well-rec-
ognized border and surrounded by an erythematous halo.
These ulcers are often the first clinical manifestations to
appear and the last to disappear during the course of the
disease. They are defined minor ulcers when the size is less
than 1 cm, and major when the size is more than 1 cm. The
latter can sometimes cause residual scars. The ulcers are
usually recurrent and typically heal spontaneously in a
period ranging from 7 to 20 days, becoming less common
after 20 years or so of disease [107]. Genital ulcers affect
approximately three-quarters of patients with BD. They are
usually localized to the scrotum in males and the vulva in
women. They are painful, sometimes evolving in scars and
are less recurrent than oral ulcers, of which, however,
retain the same morphological characteristics. Epididymitis
and salpingitis, although rare, can occur in patients with
BD [108, 109]. Also skin lesions are often present and
recurrent in patients with BD. They consist of acneiform
lesions, erythema nodosum, papulopustular lesions, nod-
ules, pseudofolliculitis, and pyoderma gangrenosum-like
lesions. They are present in more than 75 % of patients.
Acneiform lesions are similar to the lesions of acne vul-
garis, are often associated with articular involvement of
arthritic type [110, 111], and are not sterile, since they are
often colonized by Staphylococcus aureus and Prevotella
[112]. Typical of BD is also the erythematous-papular or
pustular reaction approximately 2 mm in diameter at
pathergy test, i.e., 2448 h after inoculation intradermally
for at least 5 mm deep with a 20-gauge needle [113]. The
ocular involvement in BD affects from 25 to 75 % of
patients and, if not adequately treated, can lead to blind-
ness. A typical expression of the disease is uveitis. It is
characteristically episodic and bilateral and may affect the
entire uvea (panuveitis). The hypopyon is instead a puru-
lent anterior uveitis of severe entity that affects approxi-
mately 20 % of patients. Other ocular manifestations in
patients with BD include posterior uveitis, retinal vasculi-
tis, retinal vein thrombosis, and optic neuritis. These dis-
eases are to be treated with immunosuppressive therapy
quickly to avoid an irreversible reduction in visual acuity
up to blindness. It can also cause the appearance of sec-
ondary cataract, glaucoma, conjunctival ulcers [114, 115],
episcleritis, and sicca syndrome, which fortunately seem to
be less common manifestations. Many clinical manifesta-
tions of BD are the obvious consequence of the involve-
ment of the vessels (arterial and venous) of all calibers and
are more common in male patients. The involvement of the
arteries is more common at the level of small vessels;
nevertheless, the involvement of medium and large caliber
vessels is not uncommon. In fact, in one-third of patients,
123
Clin Exp Med
there is involvement of the carotid artery, pulmonary
artery, iliac arteries, aorta, and femoral and popliteal
arteries [116], while less frequent is the involvement of the
cerebral and renal arteries [117, 118]. The histological
feature is the presence of a peri- and intra-vascular
inflammatory infiltrate provoking stenosis, bleeding, blood
clots, and aneurysms. From a clinical point of view, these
histological changes translate into increased risk of acute
myocardial infarction due to the involvement of the coro-
nary arteries (however, a rare event) and carotid athero-
sclerosis [111]. The involvement of the pulmonary artery
clinically leads to the onset of hemoptysis, accompanied by
fever, cough, pleuritic chest pain, and dyspnea [119, 120].
There may be the onset of pulmonary artery aneurysms,
usually involving the larger branches of the artery, and
pulmonary embolism with possible fatal outcome if treated
only with anticoagulants, not recognizing and quickly
addressing the underlying inflammatory vascular etiology
[121]. Pulmonary infarction seems to be less common. In
contrast, the involvement of the venous vessels is more
frequent, resulting clinically in the presence of occlusion of
the superior and inferior vena cava, BuddChiari syn-
drome, thrombosis of the dural venous sinuses, superficial
and deep venous thrombosis of the legs, often early in the
course of disease [122]. In a study conducted on 493
patients with BD, about fifty-three patients had venous
thrombosis, fourteen of which thrombosis of the portal
vein, eight patients thrombosis of the inferior vena cava,
and two patients thrombosis of the portal vein, and the
inferior vena cava concomitantly [123]. BD can also show
joint involvement, histologically apparent for inflammation
evidenced by synovial biopsies [124], and clinically char-
acterized by asymmetric arthritis, non-deforming and non-
erosive, which particularly affects the medium and large
joints (knees, elbows, and hips) of variable duration from 7
to 20 days, but causing aches and functional limitation
similar to those that affect patients suffering from rheu-
matoid arthritis, as demonstrated by a study that evaluated
by means of the Multidimensional Health Assessment
Questionnaire (MHAQ) the functional limitation of
patients with BD and arthritic involvement [125]. Renal
involvement in BD is less common and severe than in other
types of vasculitis and may present with proteinuria,
hematuria and renal failure usually mild. In a study con-
ducted on 159 BD patients with renal involvement, 51 of
them had glomerulonephritis, 4 interstitial nephritis, 35
renal artery aneurysm, and 69 patients secondary amyloi-
dosis [126]. Also the cardiac involvement is uncommon in
BD patients and is characterized by the appearance of
pericarditis, endocarditis, myocarditis, coronary arteritis,
and aneurysms, with or without acute myocardial infarc-
tion, mitral valve prolapse, valvular insufficiency [127
130]. Regarding the involvement of the gastrointestinal
Clin Exp Med
tract, BD patients may have anorexia, nausea, vomiting,
diarrhea, abdominal pain, and oral and bowel ulcerations,
particularly at the level of the terminal ileum and the
ascending colon. These ulcers are often indistinguishable
from those that affect patients with Crohns disease, which
therefore should be considered in the differential diagnosis
of BD.
Therapy
The autoimmune pathogenesis of BD advocates the con-
sequent use of immunosuppressive drugs. The glucocorti-
coids are used for BD of mediumhigh severity and in
particular are used at initial high dosage in the acute forms
and subsequently reduced to maintenance dose or discon-
tinuation of the administration, in relation to the clinical
needs of the patient [131, 132]. Generally, the intravenous
bolus of methylprednisolone (1 g) administered for 3 days
is reserved for patients with severe and progressive organ
disease. Although trials that have studied colchicine use
have shown contradictory results [133137], this drug is
widely used in the treatment of BD, in particular in the
treatment of the signs and symptoms of skin and mucosa,
such as genital ulcers and erythema nodosum, but also in
the reduction in arthritic symptoms sometimes associated
with BD [134]. Also azathioprine is among the immuno-
suppressive drugs mainly evaluated over time in several
studies of patients with BD. Among them, a randomized,
double-blind, placebo-controlled study compared in the
two arms BD patients treated with glucocorticoids and
azathioprine versus patients treated with placebo and glu-
cocorticoids [138]. This study showed that patients without
initial ocular involvement in therapy with azathioprine
showed a low incidence of new onset of ocular pathology,
as well as patients with initial ocular involvement treated
with azathioprine showed lower incidence of occurrence of
hypopyon compared to patients in therapy with glucocor-
ticoid and placebo. Patients treated with azathioprine also
had a lower incidence of occurrence of oral and genital
ulcers and arthritic manifestations [138]. Azathioprine has
been shown to be effective even in 157 patients with
posterior uveitis, and panuveitis associated with BD. After
azathioprine treatment, 52 % of them showed complete
remission of ocular disease and 41 % of them responded
partially [139]. Cyclophosphamide, on the contrary, has
shown in the few studies carried out a good control of
neurological and vascular involvement, but not of the
ocular pathology [140]. In the only trial comparing
cyclophosphamide and cyclosporine in 23 patients with
uveitis, the latter improved visual acuity in contrast to what
happened in patients treated with cyclophosphamide [141].
The effectiveness of cyclosporine has been demonstrated
instead in many trials, in particular in the therapeutic
management of patients with BD and ocular mucocutane-
ous and articular involvement [141143]. It is usually used
in combination with glucocorticoids [144] and, in more
severe cases, in combination with other immunosuppres-
sants, such as azathioprine [135]. The effectiveness of the
drug is confirmed by reports of reactivation of the disease
after the temporary suspension of the administration of
cyclosporine [144]. Although it is very effective in the
treatment of ocular involvement of BD, even compared to
chlorambucil in a randomized trial of 40 patients [145],
cyclosporine should be used with caution in the treatment
of neuro-Behcet, as also highlighted in a retrospective
study of 117 patients in which cyclosporine showed a
lower efficacy compared with other immunosuppressive
drugs [146], in spite of an increased risk of occurrence of
side effects, such as hypertension, increased serum creati-
nine [147], and neurotoxicity, sometimes indistinguishable
from the one linked to the primary disease [148]. Also anti-
TNFa biological drugs have shown to be effective in the
treatment of patients with BD, in particular infliximab and
etanercept [149, 150]. As for infliximab, in a prospective
study the drug was administered at a dose of 5 mg/kg i.v.,
in addition to the usual therapy, in BD patients with
relapses of ocular pathology. The majority of patients
improved rapidly, and all of them improved anyway within
28 days of the administration. In particular, 100 % of
patients attained resolution of reduced visual acuity, as
well as vitritis and retinitis, and 94 % of patients attained
resolution of retinal vasculitis [151]. In a retrospective
study of 28 patients, infliximab has been shown to be
effective even in BD patients with intestinal involvement,
maintaining the efficiency even during a median patients
follow-up of 30 months [152]. Among the anti-TNFa
agents, also etanercept has been studied in a randomized
trial conducted for 4 weeks in 40 BD patients with
mucocutaneous lesions and/or arthritis. In this study, eta-
nercept has been shown to be more effective than placebo
in maintaining the patient free from skin lesions and oral
ulcers, but not from genital ulcers [153]. Similarly, in a
trial study, also adalimumab was effective in improving the
ocular involvement of patients suffering from BD [154].
Interferon (IFN)-a2a and IFN-a2b showed also in several
trials [155165] a good therapeutic efficacy in the control
of neurological, mucocutaneous, and arthritic and ocular
manifestations of BD. IFN was effective in the treatment of
uveitis and mucocutaneous manifestations unresponsive to
other immunosuppressive drugs, with the appearance of
reactivation of disease after discontinuation of the therapy
[166]. Mycophenolate, despite some case reports of
effectiveness [167], has not been shown to be beneficial in
BD patients with mucocutaneous involvement [168].
Thalidomide monotherapy instead showed, in a
123

randomized placebo-controlled trial, discreet effectiveness
after 4 weeks of treatment of oral ulcers and after 8 weeks
of therapy of genital ulcers and cutaneous lesions [169].
Besides, in a randomized trial in which patients treated
with rituximab in combination with methotrexate and
prednisolone were compared to patients treated with
cyclophosphamide in combination with azathioprine and
prednisolone, the first group showed greater efficacy in the
treatment of retinal vasculitis [170]. There are instead
limited studies regarding the use of tocilizumab, pentox-
ifylline, plasmapheresis, and intravenous immunoglobulin
in the treatment of BD [171, 172].
Neuro-Behcet: anatomical pathology,
neuroimmunology, and therapy
The neurological involvement, when present, usually
appears after an average of about 5 years after diagnosis of
the disease and affects 5 % of patients with BD [173175],
although prospective studies evaluating neuro-Behcet
patients with follow-up of about 20 years reported a fre-
quency of cerebral involvement of 13 % in male patients
and 5.6 % in female patients [176]. A similar gender-
related difference has also been reported in some vascular
complications of BD [176]. The most common form of
neurological involvement in BD affects the brain paren-
chyma, is due to vasculitis of small vessels (intra-axial
form), or can be linked to the presence of venous sinus
thrombosis and, therefore, defined by some authors as
vascular-Behcet(extra-axial form) [177, 178]. In recent logical point of view, the intra-axial form of neuro-Behcet
years, the number of clinical cases of patients suffering
from silent neuro-Behcet, characterized by the presence of
alterations in neuroimaging, which does not correspond to
a clear clinical manifestation, is also increased. These cases
are defined subclinical neurological involvement [179].
The parenchymal involvement of the intra-axial form is
most frequently characterized by the presence of focal or
multifocal abnormalities, accompanied or not by headache,
and consisting in pyramidal, cerebellar and cognitive def-
icits, including memory deficit [180] and behavioral dis-
orders [179]. Less common are seizures and signs of
involvement of the spinal cord, as well as isolated optic
neuritis, aseptic meningitis, and extrapyramidal syndrome
[179, 181, 182]. Some patients may also experience a form
of psycho-neuro-Behcet characterized by the presence of
emotional lability, euphoria, disinhibition, agitation, and
obsessive behavior, not attributable to treatment with glu-
cocorticoids or other drugs [183]. Headache is one of the
most common symptoms of BD, is typically migrant, and is
not associated closely with brain intraparenchymal alter-
ation [176, 184], but rather to the systemic inflammation
that accompanies exacerbations of BD [184]. The
123
Clin Exp Med
neuromuscular involvement instead is considered rare and
includes multiple mononeuritis, distal sensorimotor neu-
ropathy, and myositis with focal or generalized involve-
ment [175, 178, 181, 185188]. Neuromuscular
involvement may be coincidental or secondary to certain
drugs used in the treatment of BD [7], such as thalidomide
and colchicine, and is sometimes diagnosed only by elec-
troneuromyography in patients with silent clinical symp-
tomatology [178, 188]. The clinical course of neuro-Behcet
can be acute in many cases [173175] or be characterized
by periods of relapse or subtly progress toward a chronic
phase, leading to progressive and untreatable changes in
behavior and ataxia, in anticipation of a neurological
deterioration resulting in a significant disability [173175].
In some cases, it may appear as a quite progressive form
from the beginning [189191]. The extra-axial form affects
approximately 1020 % of patients with neuro-Behcet
[173, 175, 181, 192, 193] and, often being secondary to
venous sinus thrombosis, can determine intracranial
hypertension with papilledema and paresis of the cranial
nerves (especially trochlear nerve), although fortunately for
the majority of patients the main symptom is constituted by
a slight intensity headache [173, 175, 181, 192, 193]. The
arterial involvement in neuro-Behcet is generally rather
rare and can determine occlusion of the carotid arteries,
vertebral artery dissection or thrombosis, aneurysm, and
intracranial arteritis [182, 194199]. The evolution of the
extra-axial form is generally slow, although there are cases
reported in the scientific literature of acute onset epilepsy
and focal neurological signs [177]. From a neuropatho-
in the acute phase is characterized by the presence of
perivascular infiltration of T lymphocytes and monocytes,
and few B cells, resulting in apoptosis of some neurons
[200]. This figure would lead, according to some authors,
to consider neuro-Behcet as a perivasculitis [200202].
From the purely neuroimmunological point of view in the
intra-axial form instead, analysis of cerebrospinal fluid,
when performed, showed the presence of leukocytosis and
proteinorrachia [173175], as well as high concentrations
of IL6, that many studies have shown to have a central role
in determining the neuronal damage, up to apoptosis of the
cell [203205]. In neuro-Behcet patients with intra-axial
pattern, brain magnetic resonance imaging (MRI) is usually
diagnostic and shows lesions most often localized to
diencephalon, basal ganglia, and, less frequently, at the
level of the periventricular area and subcortical white
matter [206]. As mentioned, much less common is the
involvement of the spinal cord and, if this occurs, MRI
shows a particular involvement in the cervical area [6].
Besides, in the extra-axial pattern, the more frequent
involvement of the post-capillary venules makes arteriog-
raphy a little useful imaging technique to finalize the
Clin Exp Med
diagnosis [6]. The neurological involvement in BD is
considered a major cause of disability, since about 50 % of
patients experience moderate-to-severe disability during
the 10 years following the diagnosis [175]. The cerebellar
involvement, the chronic rather than acute course and
pleocytosis accompanied by proteinorrachia are considered
unfavorable prognostic factors [173, 179], whereas patients
with headache, acute onset, and extra-axial form are con-
sidered to be at lower risk [179]. The treatment of the intra-
axial form is different depending on whether it is acute
episodical or chronic progressive. In the first case, gluco-
corticoids are preferentially used, although their use does
not prevent the possible progression of the pathology.
Generally, oral prednisolone (1 mg/kg for at least 4 weeks
or until clinical improvement) or high-dose intravenous
methylprednisolone (1 g/day for at least 5 days) is used
and then scaled appropriately and kept in the next
23 months in order to prevent early flares [207, 208]. For
the chronic progressive form, several immunosuppressive
agents (colchicine, azathioprine, cyclophosphamide,
methotrexate, IFN) have been used, and although each of
them has led patients to a clinical benefit, none of them
have been part of a study design adequately powered [207
210]. Typically, such patients are treated with the addition
of an immunosuppressant (azathioprine or cyclophospha-
mide) to corticosteroids. We advise against the use of
cyclosporine because of its possible neurotoxicity [211
213], while there are reports of clinical efficacy in patients
treated with methotrexate (515 mg/week) [214] and,
recently, also in patients treated with anti-TNFa biological
drugs, such as infliximab [215220]. The pattern of extra-
axial neuro-Behcet, as already mentioned, is treated with
the use of anticoagulants and glucocorticoids [177, 192,
207], although some authors prefer to use only glucocor-
ticoids [193].
Conclusions
The chronic vasculitis underlying the clinical manifesta-
tions that characterize Behcet syndrome is provoked by
environmental triggers, in all probability bacterial or viral,
which set out or stimulate an autoimmune response in
genetically susceptible subjects. Oral aphthous ulcers,
genital ulcers, and uveitis typically wax and wane,
occasionally occurring with inflammatory arthritis, phle-
bitis, iritis, as well as inflammation of the digestive tract,
brain, and spinal cord. In recent times, innovative thera-
peutic strategies have advanced management of patho-
genic mechanisms, enhanced control of clinical
manifestations, and improved patients outcome and life
expectancy.
Acknowledgments The study was supported by the 5 9 1,000
voluntary contribution and by a Grant (GM) from the Italian Ministry
of Health (RC1201ME04, RC1203ME46, RC1302ME31, and
RC1403ME50) through Department of Medical Sciences, Division of
Internal Medicine and Chronobiology Unit, IRCCS Scientific Institute
and Regional General Hospital Casa Sollievo della Sofferenza,
Opera di Padre Pio da Pietrelcina, San Giovanni Rotondo (FG), Italy.
Conflict of interest The authors declare that there are no conflicts
of interest with respect to the authorship and/or publication of this
article.
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