Neuro-Behçet Syndrome

Aksel Siva and Sabahattin Saip

Department of Neurology, Cerrahpaşa School of Medicine, Istanbul University, Cerrahpaşa, Turkey

Introduction

Behçet disease (BD), originally described in 1937 by Hulusi Behçet as a distinct disease with orogenital ulceration and uveitis known as the triple-symptom complex, is an idiopathic chronic relapsing multisystem vascular inflammatory disease of unknown origin. The disease affects many organs and systems, causing mucocutaneous lesions, uveitis sometimes resulting in blindness, nervous system involvement and major vessel disease that may be fatal, musculoskeletal problems, gastrointestinal involvement, and others.

Epidemiology

The epidemiology of the disease shows a geographical variation, seen more commonly along the Silk Route, extending from the Mediterranean region to Japan. This is coupled by a similar variation in HLA-B51 association, which is strongly associated with the disease in high prevalence areas such as Middle and Far East.

Its prevalence has been reported to be less than 0.5/10⁵ in the USA and between 0.5 and 1/10⁵ in Northern and Central Europe and goes up to 2.5/10⁵ in northwestern Mediterranean region and increases further in the eastern Mediterranean region. Prevalence rates up to 400/10⁵ have been found in population-based studies in Turkey, and rates between 10 and 20/10⁵ have been reported in Japan, China, and Korea, countries at the other end of the ancient trade routes of Silk Road.

The usual onset of the BD is in the third or fourth decade. Although rare, onset in children has also been reported. The gender distribution is almost equal. However, the reported increased tendency to affect men more than women may be explained by the higher incidence of systemic complications and more severe disease in men, possibly bringing them to earlier medical attention.

Diagnosis and systemic manifestations of Behçet disease

Currently the diagnosis of BD is clinical. The most widely used diagnostic criteria are the International Study Group’s classification criteria, according to which a definitive diagnosis requires recurrent oral ulcerations plus two of the following: recurrent genital ulcerations, skin lesions, eye lesions, or a positive pathergy test (Table 18.1).

Table 18.1 Criteria for diagnosis of Behçet’s disease^a

Source: International Study Group for Behçet’s Disease (1990). Criteria for diagnosis of Behçet’s disease. Lancet, 335:1078–1080. Reproduced with permission of Elsevier.

Finding	Definition
Recurrent oral ulceration	Minor aphthous, major aphthous, or herpetiform ulcers observed by the physician or reliably described by the patient, which recurred at least three times over a 12-month period
Recurrent genital ulceration	Aphthous ulceration or scarring observed by the physician or reliably described by the patient
Eye lesions	Anterior or posterior uveitis or cells in the vitreous body on slit-lamp examination or retinal vasculitis detected by an ophthalmologist
Skin lesions	Erythema nodosum, pseudofolliculitis, papulopustular lesions, or acneiform nodules not related to glucocorticoid treatment or adolescence
Positive pathergy test^b	Test interpreted as positive by the physician at 24–48 h

^a For a definite clinical diagnosis of BD, the patient must have recurrent oral ulceration plus at least two of the other findings, in the absence of any other clinical explanations.

^b The pathergy phenomenon is a nonspecific skin hypersensitivity that is almost specific for BD. It is performed by inserting an 18 g needle into the dermis of the forearm. The reaction is considered positive if a papule or a pustule forms at the puncture site within 48 h. Presence of erythema only is considered negative.

Oral aphthae

The presence of recurrent oral ulcers is required for the diagnosis of BD, and it is quite unlikely to see cases without oral ulcers. However, 1–3% of patients can have several of the other features of the syndrome without ever having aphthae. Aphthae are frequently the first manifestation of the syndrome, and it is not uncommon for some patients to have only oral ulcers for many years before other signs appear.

Genital ulceration

External genital ulcers, which have the next highest sensitivity for the diagnosis of BS, usually occur on the scrotum in men and on the labia in women.

Skin lesions

Skin lesions of different kinds are seen in up to 80% of patients with BS. These are folliculitis, papulopustular lesions, and acneiform lesions, which occur more commonly in men, and erythema nodosum, which are more common in women.

Eye involvement

This is one of the most serious manifestations and a leading cause of morbidity in BD. The overall prevalence is about 50%, being more common and more severe in men and young patients. It’s bilateral in 90% and consists of a chronic relapsing posterior and anterior uveitis and acute panuveitis, with blurred vision, decreased visual acuity, photophobia, pain in the eye, and conjunctival hyperemia being the common ocular symptoms. Optic nerve involvement can occur but is rare.

The pathergy phenomenon

The pathergy phenomenon, a nonspecific hypersensitivity reaction of the skin, is one of the diagnostic tests that are almost specific to BD, but its sensitivity varies largely between different ethnic and geographical groups (range, 20–80%). It is produced by inserting a 20 gauge needle into the dermis of the forearm of the patients. The reaction is considered positive if a papule or pustule is formed at the site of the puncture within 24–48 h. Erythema alone is considered negative.

Musculoskeletal involvement

A nonerosive, nonmigrating monoarthritis or oligoarthritis, involving the large joints, either in the form of arthritis or arthralgia is reported in about 50% of patients. Another musculoskeletal manifestation associated with BD is aseptic necrosis of the bone. This is possibly related to vasculitis and not necessarily to steroid use.

Gastrointestinal involvement

Although most common in the ileocecal region, ulcers can be seen all along the digestive tract with various clinical symptoms. Gastrointestinal involvement is relatively frequent in Japan, but not in other geographic areas.

Cardiovascular involvement

Major vessel involvement is another serious cause of morbidity and mortality in BD. BD is one of the few vasculitides that can involve both the venous and arterial sides of the circulatory system. Arterial disease is less common (occurring in <5% of cases), but it is of high most importance, as it may manifest itself in the form of arterial aneurysms or occlusions or as pulmonary artery aneurysms with the risk of fatal hemoptysis and death. Deep vein thrombosis and thrombophlebitis are among other large-vessel complications, and all are expected to be seen in 25–30% of the cases, while a possibly higher proportion do have small-vessel involvement, mostly affecting postcapillary venules. In BD, there is also a tendency to develop venous thrombosis after venipunctures. Although rare, myocardial ischemia associated with coronary vasculitis or with inflammation such as endocarditis, myocarditis, and pericarditis may all occur.

Other systems

Other systems reported to be involved through the course of the disease are pulmonary, urinary, and the central nervous system (CNS). Unlike many other systemic vasculitides, glomerulonephritis is uncommon. Amyloidosis of the AA type is seen sporadically.

Laboratory investigations

There are no laboratory findings specific for BS. The moderate anemia of chronic disease and leukocytosis can be seen in some patients. The erythrocyte sedimentation rate is only mildly elevated, as is the C-reactive protein. None of these correlates with disease activity. Autoantibodies are absent, whereas complement levels may be high. However, HLA testing can support the diagnosis in populations where the disease is associated with HLA-B51 phenotype and may help in the differential diagnosis.

Pathology and etiopathogenesis of Behçet syndrome

The core histopathologic phenomenon seems to be a vasculitic involvement in some cases and a low-grade, chronic, nonspecific inflammation in others. Histopathologic changes consistent with vasculitis involving both arterial and venous systems have been shown. However, vascular involvement in BD is predominantly venous in contrast to what is seen in most other systemic vasculitides. Other than vasculitis, involved tissues may show various types of histopathological lesions varying with the age of the lesion according to the time of examination, a nonspecific inflammatory reaction with neutrophilic predominance in early lesions is expected, whereas as lesions age lymphocytes become more predominant. Interestingly, usually a clear-cut vasculitic process cannot be demonstrated in the CNS, and studies on pathology of the CNS involvement indicate that neuro-Behçet syndrome (NBS) may not a cerebral vasculitis, but rather be a perivasculitis.

The etiology of BD is unknown, but clinical and laboratory data suggest that there is dysfunction of both innate and adaptive immune systems, resulting in an exaggerated response to viral or bacterial insults. Debate is ongoing about whether the hyperreactivity reaction seen in BD is an autoimmune phenomenon or as suggested by more recent data an autoinflammatory phenomenon. Autoinflammatory diseases indicate a relatively rare group of heritable disorders that are characterized by seemingly unprovoked episodes of inflammation and relative lack of an obvious autoimmune pathology (i.e., pathogenic high-titer autoantibodies or antigen-specific T cells). These disorders arise from various genetic disorders, which result in a chronic low-grade inflammatory activity with overlapping recurrent inflammatory attacks. However, along with immunological and genetic factors, fibrinolytic defects have been implicated as well (Table 18.1 and Table 18.2).

Table 18.2 Suggested Diagnostic Criteria for NBS^a

Source: Siva, A. and Saip, S. (2009) Journal of Neurology, 256, 513–529. Adapted with permission from Dr. Dietrich Steinkopff Verlag.

Fulfilling the International Diagnostic Criteria for BD

Onset of neurological symptoms not otherwise explained by any other known systemic or neurological disease or treatment

Presence of at least two of the following:

Objective abnormalities on neurological examination (clinical evidence)
Abnormal neuroimaging findings suggestive of NBS (imaging evidence)
Abnormal CSF findings suggestive of NBS (laboratory evidence)

^a Diagnosis of NBS is confirmed when all above criteria are fulfilled.

Nervous system involvement in Behçet disease: Neuro-Behçet syndrome

NBS is defined as the occurrence of neurological symptoms in a patient with BD that is not better explained by any other well-known systemic or neurological disease. The prevalence of NBS in BD is between 3% and 9% in large series. However, when BD patients are followed for up to two decades, the frequency of neurological involvement increases to 13.0% in males and 5.6% in females. In a Japanese autopsy series of patients with BD, it was reported that 20% had pathological evidence for neurological involvement.

The mean onset age of BD is about mid-third decade, and neurological involvement occurs after a mean of 5 years. Despite the gender difference being insignificant in BD, neurological involvement occurs more commonly in men, with a male to female ratio of up to 4:1. Such a significant male predominance has also been noted for other severe vascular complications of BS. However, once NBS develops, the severity doesn’t show a gender difference.

BD is rare in the pediatric population. About 3% of BD patients present at or before 16 years of age; however, neurological involvement may be seen in up to 10% of them.

Although neurologic involvement is relatively uncommon in BD, when it occurs, it presents with numerous and different neurological problems that are related either directly or indirectly to the disease (Table 18.3). Cerebral venous sinus thrombosis (CVST), parenchymal–CNS involvement secondary to vascular inflammation, and the neuro-psycho-Behçet variant, in which an organic psychotic syndrome is prominent, are considered direct effects. As all demonstrate neurological manifestations, they will be reviewed here as NBS.

Table 18.3 The Neurological Spectrum of Behçet Disease

Source: Siva, A. and Saip, S. (2009) Journal of Neurology, 256, 513–529. Adapted with permission from Dr. Dietrich Steinkopff Verlag.

Primary Neurological Involvement (Neurological Involvement Directly Related to BD)

CVST (extra-axial NBS)

CNS involvement (intra-axial NBS)

Neuro-psycho-Behçet syndrome

Isolated headache syndrome (migraine-like, nonstructural)

PNS involvement

Subclinical NBS

Secondary Neurological Involvement (Neurological Involvement Indirectly Related to BD)

Neurologic complications secondary to systemic involvement of BD (i.e., cerebral emboli from cardiac complications of BD, increased intracranial pressure secondary to superior vena cava syndrome)

Neurologic complications related to BD treatments (i.e., CNS neurotoxicity with cyclosporine, peripheral neuropathy secondary to thalidomide or colchicine)

Somatoform neurologic symptoms related to psychogenic factors of having a chronic disease

Coincidental: Unrelated (Non-BD) Neurological Involvement

Primary headaches and any other coincidental neurological problem

BD, Behçet disease; CNS, central nervous system; CVST; Cerebral venous sinus thrombosis; NBS, neuro-Behçet syndrome.

Peripheral nervous system (PNS) involvement is extremely rare, despite that neurophysiological and histopathological studies may demonstrate nonspecific findings in some patients without related symptoms.

Neurologic complications of various BD treatments and neurologic complications secondary to systemic involvement of the disease are among indirect neuropsychiatric consequences of the disease.

The suggested diagnostic criteria for NBS in a patient that fulfills the International Diagnostic Criteria for BD is the occurrence of neurological symptoms not otherwise explained by any other known systemic or neurological disease or treatment, and in whom objective abnormalities are detected either on neurological examination, and/or on neuroimaging studies (magnetic resonance imaging (MRI) disclosing findings suggestive of NBS) and/or abnormal cerebrospinal fluid (CSF) findings consistent with NBS (Table 18.2).

The two major forms of neurological involvement in BD are parenchymal–CNS involvement and CVST. Neurological manifestations clinically are related commonly to brainstem or corticospinal tract syndromes in the former one and to increased intracranial pressure in the second form.

Clinical and neuroimaging evidence also confirms this subclassification of NBS. CNS NBS or intra-axial NBS is due to small-vessel disease and causes the focal or multifocal CNS involvement manifested in the majority of patients. The second form, CVST or extra-axial NBS, which is due to large-vessel disease presenting with thrombosis of the major cerebral venous sinuses, has limited symptoms, a better neurological prognosis, and generally an uncomplicated outcome. These two types of involvement occur in the same individual very rarely and presumably have a different pathogenesis. Many of the CNS NBS patients with small-vessel inflammation have a relapsing–remitting course initially, with some ultimately developing a secondary progressive course later, and a few will have a progressive CNS dysfunction from the onset.

Extra-axial NBS

CVST is seen in 10–20% of BD patients in whom neurologic involvement occurs. Thrombosis of the venous sinuses may cause increased intracranial pressure with severe headache, mental changes, and oculomotor cranial nerve palsies. In some patients, the only manifestation may be a moderate headache. It is well known that the clinical presentation resulting from thrombosis of the intracranial venous system varies according to the site and rate of venous occlusion and its extent. Experience suggests that the CVST in BD evolves gradually and a fulminating syndrome with violent headache, convulsions, paralysis, and coma is unlikely. Papilledema and sixth nerve paresis are the most common signs reported, and hemiparesis may develop in some.

There is a tendency for CVST to occur earlier in disease course compared to the parenchymal type of CNS disease, and this difference is significant in male patients. In the pediatric age group affected with BD, the neurologic involvement is mostly in the form of CVST. Any of the sinuses may be affected, but the superior sagittal sinus is the most commonly thrombosed, with a substantial number of these patients also disclosing lateral sinus thrombosis. Intracranial hypertension without any obvious neuroimaging abnormality initially has been reported, with some of these patients developing neuroimaging findings consistent with CVST in further attacks later.

Parenchymal–CNS involvement in BS patients with CVST is unlikely. The extension of the clot into the cerebral veins causing focal venous hemorrhagic infarction is uncommon, and also the occurrence of CVST with primary CNS involvement (coexistence of intra- and extra-axial NBS) is extremely rare. Extra-axial NBS occurs earlier in the disease course compared with the parenchymal–CNS type of neurological involvement. A close association between CVST and systemic major vessel disease in BD has been reported. It is also well established that neurological disease in the form of CVST has a better neurological prognosis. However, since patients with major vessel disease have a higher rate of morbidity and mortality, CVST in a patient with BD may not be associated always with a favorable outcome.

It’s likely that the two major forms of neurological disease (intra- and extra-axial involvement) in BD might have different pathogenic mechanisms.