Clinical manifestations

Presentation and course

Behcet disease is an idiopathic chronic relapsing multisystem vascular-inflammatory disease of unknown origin with complete or incomplete remission between attacks. The diagnosis is based on clinical findings. Various sets of diagnostic criteria have been published, with general agreement on the importance of mucocutaneous and ocular manifestations. Because symptoms appear asynchronously, the diagnostic criteria may not be met in many patients (75%) at the time of observation. According to the work of the International Study Group (67), the major diagnostic criteria for Behcet disease are:

Minor diagnostic criteria include arthritis or arthralgia, deep venous thromboses, subcutaneous thrombophlebitis, epididymitis, family history, and gastrointestinal, CNS, or vascular involvement.

Oral ulcers plus two other major criteria are required for the diagnosis. The terms "complete" and "incomplete" Behcet disease are based on the number of major criteria observed. The requirement for oral ulcers excludes the 3% of all patients who do not have this symptom.

Oral aphthae. The presence of recurrent oral ulcers is required for the diagnosis of Behcet disease. Most cases of NBS have a history of oral ulcers by the time they have developed neurologic symptoms. Although up to 3% of patients can develop other features of Behcet disease without ever having aphthae, its absence should strongly suggest another diagnosis (150). Aphthae are frequently the first manifestation of the syndrome, and it is not uncommon for some patients to only have oral ulcers for many years before other signs appear. Most oral ulcers in Behcet disease are indistinguishable from those seen in recurrent oral ulceration; however, they tend to be multiple and occur more frequently. These ulcers are categorized according to their size and shape as major, minor, and herpetiform ulcers. The most frequent type of oral ulcers are the minor ulcers, which are less than 1 cm in diameter. The major ulcers (> 1 cm in diameter) are less frequent but are more painful and deeper than the minor ulcers. These major ulcers heal more slowly and often result in scarring. The rarest types are the herpetiform ulcers, which are numerous, shallow, and small-pinpoint ulcers. The oral ulcers of Behcet disease may appear in the gingiva, tongue, palate, and buccal and labial mucosal membranes and have a tendency to decrease in frequency with aging (37).

Genital ulcers. External genital ulcers, which have the next highest sensitivity for the diagnosis of Behcet disease after oral ulcers, usually occur on the scrotum in men and on the labia in women. They are deep, very painful, and in about two thirds of patients leave scars, producing an objective sign even in the absence of active lesions. They are seen in 80% to 90% of patients with Behcet disease (159; 37).

Eye involvement. This is one of the most serious manifestations and a leading cause of morbidity in Behcet disease. The overall prevalence is about 50%, but it is more common and more severe in men and young patients, generally occurring within 3 years of disease onset (159). Eye disease is bilateral in 90% of patients and consists of a chronic relapsing posterior and anterior uveitis, and acute panuveitis. Blurred vision, decreased visual acuity, photophobia, pain in the eye, and conjunctival hyperemia are common symptoms. Intense inflammation (hypopyon) is seen in 20% of patients with eye disease. It is almost always associated with severe retinal disease and indicates a grave prognosis associated with blindness. Optic nerve involvement can occur but is rare. However, two cohorts of primary optic neuropathy in Behcet disease, one from China and the other one from Turkey, have been reported (03; 148). The Chinese had collected 61 such cases and observed that they frequently presented as isolated optic neuropathy, more in females, but men had a more severe visual outcome. The sunflower-like sign observed on MRI was likely to be a distinctive imaging feature. Short-term recurrence was very rare (148). There were 25 cases in the Turkish cohort, but the gender distribution was almost equal, and in half of the patients the optic neuropathy appeared before the development of the systemic signs of Behcet disease. Uveitis and disc edema were common findings (03).

Skin lesions. Skin lesions of different kinds are seen in up to 80% of patients with Behcet disease. These are folliculitis, papulopustular lesions and acneiform lesions, which occur more commonly in men, and erythema nodosum, which is more common in women. When present, erythema nodosum is localized symmetrically on lower extremities, as well as thighs and sacral region. All of these lesions represent various forms of vasculitis. Other skin lesions include leukocytoclastic vasculitis, necrotizing arteritis of the small and medium arteries, superficial thrombophlebitis, and unclassifiable papules and pustules (159; 37).

The pathergy test. The pathergy phenomenon, which is a nonspecific hypersensitivity reaction of the hyperirritable skin seen in Behcet disease, is produced by inserting a 20-gauge needle into the dermis of the forearm. The reaction is considered positive if a papule or pustule is formed at the site of the puncture within 48 hours. Despite being one of the diagnostic criteria for Behcet disease, its sensitivity varies in different ethnic and geographical groups, ranging between 20% and 80% (being higher in Far Eastern and Middle Eastern patients, but lower among Western patients) (101). It’s important to keep in mind that this pathergy phenomenon may also develop in sites other than the forearm skin, such as secondary to venipuncture and vascular surgery, because any trauma or injury may cause an exaggerated inflammatory response in tissues in patients with Behcet disease (37). This phenomenon is more strongly positive in male patients, may be seen in first-degree relatives of patients with Behcet disease, and has also been reported in up to 10% of patients with inflammatory bowel diseases (16).

Arthritis. Nonerosive, nonmigrating, oligoarticular involvement of large joints, especially knees, ankles, and wrists, is reported in 50% of patients. Sacroiliitis is very unusual.

Gastrointestinal disease. Constipation, diarrhea, abdominal pain, and vomiting are common symptoms (50%). Any part of the gastrointestinal tract, especially the distal ileum and caecum, may have ulcers, and at times it may be difficult to distinguish inflammatory bowel disease, mainly Crohn disease, from Behcet disease. However, the presence of other manifestations of Behcet disease will help in differentiating these two diseases (60). Perforations or massive bleeding are not uncommon, making gastrointestinal involvement another serious and difficult-to-treat complication of Behcet disease. Of note, gastrointestinal involvement in Behcet disease is relatively frequent in Japan but not in other geographic regions.

Cardiovascular involvement. Major vessel involvement is a serious cause of morbidity and mortality in Behcet disease. Both veins and arteries may be involved. Arterial disease is much less common (occurring in less than 5% of cases) but may have more severe consequences as it may manifest in the form of arterial aneurysms or occlusions, or as pulmonary artery aneurysms with a risk of fatal hemoptysis and death. Aortic regurgitation and aortic aneurysms may be life-threatening. Deep vein thrombosis and thrombophlebitis are among other large vessel complications, occurring in up to one third of the cases, with possibly a higher proportion having small vessel involvement. Deep vein thrombosis in the lower extremities is the most common first vascular event of Behcet disease and is likely to be seen in young male patients at disease onset. Budd-Chiari syndrome as well as superior vena cava thrombosis are also expected. It is essential to diagnose Behcet disease in a patient with Budd-Chiari syndrome or superior vena cava thrombosis because morbidity and mortality will be higher if these patients are treated with only anticoagulation without immunosuppressive treatment (37).

Cardiac involvement is rare, but when it occurs its manifestations include intracardiac thrombus, pericarditis, myocarditis, endocarditis, endomyocardial fibrosis, coronary arteritis, and valvular disease (88). Whether the prevalence of atherosclerosis is increased in patients with Behcet disease remains a controversial issue (58; 93).

Pulmonary symptoms. Among uncommon manifestations of Behcet disease, pulmonary findings occur, including mediastinal edema due to occlusion or stenosis of the superior vena cava, parenchymal infiltrations, obstructive lung disease, pulmonary hypertension, and pleural effusions. Hemoptysis due to arterial aneurysms and arteriobronchial fistulae occurs and can be fatal. Indeed, the most life-threatening manifestation of Behcet disease is the pulmonary artery aneurysm, which carries a 25% to 30% mortality. Studies have demonstrated that the pulmonary arterial aneurysm in Behcet disease is a manifestation of a more general pulmonary vascular disease. Furthermore, most of these patients are likely to have peripheral vascular disease, mainly in the form of thrombophlebitis.

Urinary system manifestations. Renal involvement is rare. Focal glomerulonephritis has been reported in a few cases. Sterile urethritis, orchitis, and especially epididymitis are rare but may occur.

Nervous system involvement. Neurologic manifestations have been reported in 1% to 49% of cases. In large series, their prevalence remains between 1.1% and 9% of all patients with Behcet disease (08; 128; 158; 29; 75). However, when patients with Behcet disease are followed for up to two decades, the frequency of neurologic involvement increases to 13% in males and to 5.6% in females (77).

The usual onset age of Behcet disease is later in the third or earlier within the fourth decade; however, although rare, onset in children has also been reported (137; 155). When the age of onset of the initial symptoms (most likely oral aphthous ulcers) are considered, then in up to one fourth of patients the disease starts under the age of 16 (155). Behcet syndrome shows equal frequency among males and females. However, there is a difference in disease expression between genders, and males have a more severe course due to the morbidity of pulmonary vascular diseases. Neuro-Behcet syndrome generally presents in individuals in their late 30s, about 5 years after the onset of the established systemic disease and is more common in males (3:1).

The neurologic involvement and manifestations seen in patients with Behcet disease are heterogenous and may be subclassified as either primary or secondary, leading to a number of neuropsychiatric syndromes summarized in Table 1.

Table 1. The Neuropsychiatric Spectrum of Behcet Disease

Primary involvement of the nervous system in Behcet disease is referred to as “neuro-Behcet syndrome” (NBS) and is defined as the occurrence of neurologic symptoms in a patient with Behcet disease that cannot be explained by another systemic or neurologic disease or treatment and in which objective abnormalities are detected either on neurologic examination or supported by neuroimaging (eg, MRI suggestive of NBS) or cerebrospinal fluid (CSF) findings consistent with NBS (128). This diagnostic definition of NBS was adopted by the international consensus group and recommended for the diagnosis and management of Neuro-Behcet disease with the addition of the “probable NBS” subcategory (71). Probable NBS covers patients with either neurologic syndromes suggestive of definitive NBS, but in whom systemic features do not meet the International Study Group Behcet disease criteria, or patients with noncharacteristic neurologic syndromes within the context of Behcet disease supported by the International Study Group criteria. Clinical findings and neuroimaging demonstrate that there are two major forms of NBS.

These two types of involvement very rarely occur in the same individual and presumably have a different pathogenesis.

Parenchymal CNS involvement. Parenchymal NBS is seen in up to 80% of patients with Behcet disease in whom neurologic involvement occurs. Clinically, neurologic manifestations are usually related to brainstem or corticospinal tract syndromes, with the most common presentation being a subacute brainstem syndrome that includes ophthalmoparesis and other cranial nerve findings, dysarthria, and corticospinal tract signs with or without weakness and ataxia. The presentation may include all or some of these symptoms and signs, and mild confusion may also be seen during the acute stage. Most commonly, the patient is a young man, and if he is also of Mediterranean (or Middle Eastern or Asian) origin, the probability of NBS should be strongly considered. A history of systemic findings of Behcet disease should be questioned in these patients. In the case of Behcet disease, one is very likely to obtain a past or present history for oral aphthous ulcers and other systemic manifestations of the disease. Many patients may have never consulted a physician because of the mild nature of their systemic symptoms of Behcet disease, or they may be missed because of not reporting a full-blown picture of the disease. It is unusual to see NBS cases without at least oral ulcers.

The MRI findings of parenchymal-NBS are almost pathognomonic and provide additional support for the diagnosis. However, it should be kept in mind that parenchymal NBS does not always present with brainstem signs and symptoms. Although rare, a self-limited or progressive pattern can be seen, and cases with longitudinally extensive myelitis have been reported (153; 45; 28; 49; 139). The neuroimaging findings of Behcet disease are discussed in detail below.

Cognitive-behavioral changes, emotional lability, a self-limited or progressive myelopathy, urinary sphincter dysfunction, and, to a much lesser extent, other CNS manifestations such as extrapyramidal signs and seizures have been reported. There are also a few cases reported with isolated progressive ataxia with cerebellar atrophy on MRI, isolated optic neuritis, and recurrent peripheral facial paresis. However, optic neuritis is extremely rare in Behcet disease, and most visual symptoms in Behcet disease are due to ocular involvement.

The course of CNS parenchymal involvement may be limited to a single attack, may show relapses with a subgroup showing secondary progression, or may be progressive from the onset (chronic progressive NBS) (08; 128; 66; 63; 99; 21; 75).

Non-parenchymal NBS. Cerebral venous sinus thrombosis (CVST) is seen in 10% to 20% of patients with Behcet disease in whom neurologic involvement occurs (128; 39). However, this form of involvement rarely occurs in Japanese patients, suggesting the importance of ethnic differences that may be related to genetic factors in susceptibility to CVST. Of note, ethnic differences might also be at play with respect to intestinal involvement, which is much more common in the Japanese population (64).

Thrombosis of the venous sinuses may cause increased intracranial pressure with severe headache, mental changes, and ocular cranial nerve palsies; however, the only manifestation in some patients may be a moderately severe headache. The clinical manifestations resulting from thrombosis of the intracranial venous system vary according to the site and rate of venous occlusion and its extent. Experience suggests that the CVST in Behcet disease evolves gradually so that a fulminating syndrome with severe headache, convulsions, paralysis, and coma is uncommon. Papilledema and sixth nerve paresis are the most common signs reported. The superior sagittal sinus is the most commonly involved; however, a substantial number of these patients also have a lateral sinus thrombosis, which have been reported to be the most common involved site in female patients with Behcet disease (110; 02; 138).

There is a tendency for CVST to occur earlier in the disease course than the parenchymal type of CNS disease, and this difference is significant in male patients. In the pediatric age group affected with Behcet disease, the neurologic involvement is mostly in the form of CVST, and rarely, CNS-parenchymal disease (137; 97).

Parenchymal CNS involvement in Behcet disease patients with CVST is unlikely (110; 128; 152; 02), as the extension of the clot into the cerebral veins causing focal venous hemorrhagic infarction is uncommon. In addition, the occurrence of CVST with primary CNS involvement is extremely rare. In a multicenter study of cerebral venous sinus thrombosis (VENOST) due to all causes, Behcet disease was found to be the underlying cause in 9.4% of all collected 1144 patients in Turkey (138). Patients with Behcet disease were younger, showed a male predominance, and had a better functional outcome compared with cerebral venous sinus thrombosis due to all other causes. The authors as in previous series also didn’t observe hemorrhagic infarcts and intracerebral hemorrhage in the Behcet disease group. The authors concluded that Behcet disease should be considered first as a causative factor for cerebral venous sinus thrombosis among 18- to 36-year-old men, at least in countries and among ethnic groups in whom Behcet disease is relatively common.

In all series it was observed that the neurologic disease in the form of CVST had a better neurologic prognosis than parenchymal NBS. However, a close association between CVST and systemic major vessel disease in Behcet disease has been reported (136). Because patients with major vessel disease can have a high rate of morbidity and mortality, a diagnosis of CVST in a patient with Behcet disease may not always be associated with a favorable outcome.

All these observations that include CVST occurring at a much earlier age, being less likely to have recurrences, and more likely to be associated with systemic major vessel disease when compared with the parenchymal form, and that it is extremely rare for both forms of neurologic involvement to be seen in the same patient are suggestive that these two major forms of neurologic disease in Behcet disease may have different pathogenic mechanisms. A number of other primary or secondary neurologic problems may be seen in patients with Behcet disease, and these are summarized below.

Arterial NBS. Arterial involvement resulting in CNS vascular disease is rare, as are cases with systemic arterial involvement. However, cases have been described with bilateral internal carotid artery occlusion, vertebral artery thrombosis, vertebral artery dissection, intracranial aneurysms, and intracranial arteritis, with their corresponding neurologic consequences (08; 128), suggesting that arterial involvement may occur in a subgroup of NBS (128). It is noteworthy that the arterial involvement affects mostly large arteries located at extracerebral sites of the craniocervical arterial tree, suggesting that an extra-axial arterial pattern of NBS may exist in addition to an intra-axial arterial NBS pattern related to intracranial arteritis and intra-axial small arterial occlusions (128; 112).

Neuropsychiatric-Behcet syndrome. Some patients with Behcet disease develop a neurobehavioral syndrome, which consists of euphoria, loss of insight, disinhibition, indifference to their disease, psychomotor agitation or retardation with paranoid attitudes, and obsessive concerns unrelated to glucocorticosteroid or any other therapy. These psychiatric manifestations may be observed in association with other neurologic symptoms of NBS or independently and are named as neuro-psycho-BS (128). Work by Talarico and colleagues, who found a higher frequency of psychiatric disorders represented by bipolar disorders and a significant correlation between systemic disease activity and mood disorders in patients with Behcet disease, confirms that neuro-psychiatric-BS may represent an intrinsic aspect of the disease (132).

Cognitive changes. Cognitive changes consistent with memory impairment in the form of delayed recall, abnormalities in verbal or visual modalities, impairment in the process of acquisition and storage, in addition to attention deficit and deficits of executive function of the frontal system have been observed in Behcet disease (100; 23). Neuropsychological status can deteriorate insidiously unrelated to the neurologic attacks. The presence of cognitive decline is not directly related to detectable lesions on neuroimaging at early stages of the disease. The observation that cognitive and psychological impairments were not restricted to cases with NBS and can be detected in patients with the systemic disease without neurologic manifestations was confirmed in a number of studies (96; 108).

In a systematic review of neurocognitive functioning in Behcet disease Fisher and Bernard suggested that neurocognitive changes in Behcet disease/NBS may be a continuum, being more prominent in patients with neurologic (parenchymal NBS) involvement than the Behcet disease patients without neurologic disease (42). They have also concluded that the neurocognitive profiles of patients with neuro-Behcet disease and multiple sclerosis were largely comparable, with word fluency being the only cognitive construct where more than 25% of results suggested that neuro-Behcet disease performed significantly worse than multiple sclerosis. They have also raised the probability of the contributing role of neurocognition on the higher rates of depression and anxiety seen in both Behcet disease and NBS.

Headache. Headache is the most common neurologic symptom seen in patients with Behcet disease and is due to various causes (113; 15; 22; 70; 145). It may be the presenting symptom of NBS, either due to parenchymal CNS involvement or CVST. It can be seen as an accompanying symptom in some Behcet disease patients with ocular inflammation. Some patients with Behcet disease report a bilateral, frontal, moderately severe paroxysmal migraine-like pain, which is not true migraine, starting after the onset of the systemic disease; this headache commonly accompanies the exacerbations of systemic findings such as oral ulcerations or skin lesions, though this is not always the rule (113; 22). It may be explained by a vascular headache triggered by the immunomediated disease activity in susceptible individuals and may be seen in up to one fifth of Behcet disease patients. Coexisting primary headaches, such as migraine and tension-type headache, in patients with Behcet disease are also seen.

Patients with Behcet disease who report a severe headache of recent onset without any neurologic deficit and not consistent with any coexisting primary headache require further evaluation because this symptom may indicate early onset of NBS (127; 15; 70; 43; 145).

Peripheral nervous system (PNS) involvement. PNS disease with clinical manifestations is extremely rare in Behcet disease (06; 127; 19; 08; 128; 39). There are a limited number of case reports in which patients with Behcet disease manifest clinical and electrophysiological findings consistent with mononeuritis multiplex, poly-radiculoneuritis, sensorimotor axonal neuropathy, or recurrent episodes of myositis. It should be kept in mind that the neuropathy may develop secondary to a drug used in the treatment of Behcet disease, such as thalidomide or colchicine, or may be coincidental.

Subclinical NBS. The incidental finding of neurologic signs in patients with Behcet disease without neurologic symptoms was reported in some series, with a minority of these patients developing mild neurologic attacks later (06; 08; 128). It was suggested that this group of patients represents a milder form of the disease as the mortality and disability rate was found to be significantly low when the patients were followed prospectively (154). The presence of cognitive dysfunction that is only apparent on testing is also suggestive of subclinical neurologic involvement (23). Subclinical CNS involvement was also detected by MRI and in SPECT studies, as well as with somatosensory evoked potentials (14).

Secondary neurologic involvement. Neurologic complications secondary to systemic involvement of Behcet disease, such as cerebral emboli from cardiac complications of Behcet disease or increased intracranial pressure secondary to superior vena cava syndrome, are indirect neurologic problems seen in Behcet disease. CNS neurotoxicity with cyclosporine and peripheral neuropathy secondary to thalidomide or colchicine use are neurologic complications related to Behcet disease treatments. With the increased use of anti-TNF-alpha agents in treatment of Behcet disease and NBS, the increased risk of tuberculosis including cerebral tuberculosis should be kept in mind, mainly in endemic regions.

Prognosis and complications

Behcet disease is a recurrent disease. Its activity tends to subside over years as attacks become less frequent and less severe.

Morbidity and mortality depend on the systems involved. Eye disease is the main cause of morbidity. Cataracts due to the disease or glucocorticoid treatment, glaucoma, and optic atrophy are common complications. Without immunosuppressive treatment, involvement of the second eye usually occurs within 2 years, and vision is lost within a few years.

Mortality is often due to cardiovascular, pulmonary, or gastrointestinal involvement, which can create serious complications, mostly secondary to aneurysmal rupture or intestinal perforation. Secondary amyloidosis may develop in Behcet disease patients; studies are needed to test the effect of colchicine in preventing this complication. Neurologic involvement in Behcet disease is an important cause of morbidity, and approximately 50% of patients with NBS are moderately to severely disabled after 10 years of disease (127).

Parenchymal CNS disease may be progressive or relapsing, with incomplete recovery. Neurologic outcome is worse in the presence of progressive symptoms, dysarthria, cerebellar and motor signs, as well as an abnormal CSF; however, a single episode of disease and headache at onset are associated with a favorable prognosis (06; 127). The presence of brainstem atrophy in the initial MRIs seems to correlate with a progressive course in patients with NBS (40). In another study it was suggested that early demonstration of brainstem atrophy, particularly of the midbrain tegmentum and pons, together with elevated CSF levels of IL6, correlates with a progressive course of NBS (74). However, these findings need to be confirmed and their practical implication is not clear.

In a retrospective analysis of 115 patients with parenchymal NBS and a mean follow-up of 73 months, one third of patients had a progressive course from onset with or without further relapses, and 25.2% of all patients became dependent or died (99). Factors independently associated with poor outcome were paresis at onset and the location of inflammatory lesions in the brainstem on MRI. A positive HLA-B51 status, which was detected in 49% of patients, was independently associated with the risk of NBS relapse and a worse outcome.

Younger age at diagnosis of Behcet disease is associated with serious involvement of the systemic disease, but some of these manifestations subside over time (77). The association between age and prognosis specific to NBS is controversial. In a study, it was shown that younger age at diagnosis of Behcet disease and cranial nerve dysfunction at NBS onset were independent predictors of relapses (111). Higher initial disability scores and the progressive type of parenchymal NBS were predictors of poor outcome. However, the correlation between relapse frequency and severity with the outcome wasn’t clear. In another study, patients with pyramidal tract involvement and late-onset NBS were more likely to have a progressive course and developed more severe disability contrary to patients with systemic Behcet disease without neurologic involvement in whom disease activity decreases with age (34). The likely explanation for this difference in age of onset was attributed to the decreased regeneration capacity of the central nervous system with advanced age.

Aggressive treatment may be considered in patients with NBS who present with or develop poor prognostic factors early even though there is no evidence that this approach will prevent progression and severe neurologic disability.

Clinical vignette

A 29-year-old man presented with uveitis in the left eye followed by diplopia, dysarthria, ataxia, and a behavioral disorder. His medical history was significant for recurrent oral ulcers for a number of years and genital ulcers and skin lesions within the last year; however, due to the mild nature of his symptoms he didn’t seek medical care and was not seen by any physician until he developed uveitis. Based on his past medical history and current findings, he received a diagnosis of Behcet disease. The neurologic symptoms and signs, which could not be attributed to any other primary neurologic disorder or systemic disease, led to a diagnosis of NBS. The neurologic examination revealed an abducens paralysis on the left, dysarthria, and cerebellar ataxia. An MRI of the brain showed an upper pontine and midbrain hyperintense lesion consistent with inflammation, more prominent on the left where there was extension to the diencephalic region. He was treated with high-dose intravenous methylprednisolone followed by an oral taper. He was maintained on low-dose prednisolone and monthly pulses of intravenous cyclophosphamide at another center. He initially had neurologic improvement; however, a couple of months after stopping oral steroids he developed worsening of his prior neurologic symptoms and then a new right-sided hemiparesis with new MRI lesions. The neurologic worsening occurred while he was receiving cyclophosphamide pulses. It was then decided to stop cyclophosphamide and switch to infliximab therapy. Since treatment with infliximab, the patient has stabilized without further events.

Biological basis

Etiology and pathogenesis

Despite increased understanding of this disease, the etiology is unknown. Three major pathophysiologic changes have been reported in Behcet disease: an abnormal enhanced activity of neutrophils, endothelial injury with vasculitis, and autoimmune responses. It was suggested that Behcet disease may belong to a newly designated group of autoinflammatory diseases; however, this is controversial.

Core histopathologic features of Behcet disease include a vasculitic involvement in some cases and a low-grade, chronic, nonspecific inflammation in others (114; 30). Vessel wall changes and perivascular mononuclear cell infiltration consistent with vasculitis of both arterial and venous systems have been demonstrated in histopathologic studies. However, in contrast to what is seen in most other systemic vasculitides, the major vascular involvement in Behcet disease is predominantly venous, including the CNS involvement. When studied with susceptibility weighted imaging (SWI), parenchymal lesions are significantly larger than seen with conventional MRI, and most are hemorrhagic. This supports the proposed venous theory (09), which has also been confirmed by histopathologic studies (24). It has also been shown that lesions with occlusion of venous and collateral venous structures are present. Interestingly, in NBS, a clear-cut vasculitic process cannot be demonstrated in the CNS in most cases. Studies of the CNS pathology indicate that NBS may not be a true cerebral vasculitis, but rather a perivasculitis (54; 61; 30).

The frequency of clinical vascular involvement is high among patients with Behcet disease and is seen in up to 40%, with high rates of recurrences that vary between 30% and 50% (135). It is well known that vascular involvement with inflammation-induced thrombosis is an early manifestation that leads to diagnosis of the disease in a significant number of patients. Vascular involvement is also one of the major causes of morbidity and mortality of the systemic disease.

The mean vein wall thickness of proximal deep and superficial lower extremity veins was found to be increased among patients with Behcet disease without any clinical and radiologic vascular involvement, suggesting that subclinical disease is more widespread than clinically detected (119). This observation might be useful in the management and further exploration of disease mechanisms, and it may shed light on the pathogenesis of inflammatory thrombosis in vascular Behcet disease. It has also been demonstrated that thickness measurement with ultrasonography at common femoral veins can be a diagnostic tool for Behcet disease and serve to differentiate it from other inflammatory diseases, such as Crohn disease (11).

The cause of Behcet disease is unknown. Initially, infectious agents were suspected to cause Behcet disease by several investigators, including Behcet himself; however, this hypothesis remains unproven. Many immunologic abnormalities due to stimulation by an infectious agent or activation of immune mechanisms against autoantigens, such as microvascular endothelial cells, have been reported in Behcet disease. Several studies have associated Behcet disease with infections, in particular streptococcal infections and herpes simplex virus type I, but a direct link has not been shown (159). In a study in which the role of infections in Behcet disease and neuro-Behcet syndrome was studied, some evidence for a polyclonal immune activation rather than a specific virus effect in the sera of individuals with Behcet disease and NBS was shown (87). However, in none of these studies could a clear role for antibodies and autoreactive cells be established.

The immunogenetic findings are providing clues that both innate and adaptive immunity are involved in the pathogenesis of Behcet disease and confirming the importance of the predominant polarization towards helper T cell (Th) 1 versus Th2 cells, and the involvement of Th17 cells (130). In addition, the contribution of an HLA class I-peptide presentation-based mechanism to this complex disease has been also shown. Although a Th1-predominant cytokine profile and elevated IL17 levels are examples in favor of the adaptive system, the primed state of neutrophils, circulating polyclonal gamma delta T cells in the serum, and the decreased mannose-binding leptin levels are in favor of the action of the innate immune system (130; 159). It is likely that the dysfunction of both the innate and adaptive immune systems result in an exaggerated response to nonspecific viral or bacterial infections (33; 159). The results suggested that under Th17-stimulating conditions, T cells express both IL17 and IFN-γ in Behcet disease; thus, more prominent IL17 and IFN-γ production by all lymphocyte subsets in Behcet disease might be associated with the increased innate responses, early tissue neutrophil infiltrations, and late adaptive immunity in Behcet disease. A number of studies on the immunological profile of Behcet disease had further confirmed the role of TH1 and TH17 related proinflammatory activity, whereas the limited studies on B cell abnormalities had not yet disclosed a significant role of B cells in this disease (57).

A nonspecific hyperreactivity as exemplified by the pathergy phenomenon constitutes an important feature of Behcet disease. The spontaneous or induced overproduction of proinflammatory cytokines from mononuclear cells in Behcet disease may also constitute an aspect of this non-specific hyperreactivity.

The cytokine profile (especially interleukin 6), lymphocyte subsets, immune complexes, complement levels, polyclonal activation of B lymphocytes, apoptotic mechanisms, neutrophil chemotactic functions, and aberrant immune responses against self-antigens including heat shock protein, oral mucosal antigens, retinal cells, endothelial cells, myelin, and cardiolipin have been studied (112). The significance of these findings may vary among patient groups. One focus of cytokine studies has been directed to interleukin 6 (IL6). Raised CSF levels of IL6 have been found in patients with acute parenchymal NBS (62; 44; 07; 64; 116). In addition, raised IL6 levels, although to a lesser degree, have also been reported in some progressive parenchymal NBS cases (07; 63). Raised CSF IL6 levels are usually associated with raised CSF cell count and protein, and these three parameters have been associated with disease activity and outcome. However, elevated CSF IL6 levels have also been reported in the presence of normal CSF cells and protein (07; 63). A correlation between a decrease in CSF IL6 levels in response to various treatments in NBS was reported in a number of studies, but all were from Japan (62; 44; 73; 63), and these studies involved only small numbers of patients. Collectively, these data indicate that IL6 is not a reliable biomarker of NBS or Behcet disease, and the absence of IL6 should not be viewed as the absence of disease activity. In another study, among a number of serum cytokines studied, including IL6, only IL8 was found to be significantly increased in patients with Behcet disease both with and without neurologic involvement, but there was no correlation between IL8 levels and clinical severity (87); IL8, in particular, attracts and activates neutrophils and other leukocytes and is thought to mediate endothelial damage in Behcet disease.

In a gut microbiome study, a peculiar dysbiosis of the gut microbiota and a significant decrease of butyrate production were shown to be present in patients with Behcet disease, suggesting that mainly a defect of butyrate production is present in these patients, which may lead to both reduced T-regulatory responses and an activation of immunopathological T-effector responses (25). This finding needs to be confirmed, and whether the experimental laboratory evidence that oral administration of butyrate favors T-regulatory cells differentiation would play any therapeutic role in Behcet disease remains a hypothetical question. In a study by Ye and colleagues, the association of gut microbiome composition with Behcet disease as well as its possible roles in the pathogenesis of the disease has been studied, and based on their results, the authors concluded that Behcet disease seems to be associated with considerable gut microbiome changes (151). However, the considerable gut microbiome changes found in this study require a diseased control group in order to be confirmed as specific for Behcet disease.

It is not clear whether the hyperreactivity reaction seen in Behcet disease is an autoimmune phenomenon or, as suggested by more recent data, an autoinflammatory phenomenon (114; 52). Autoinflammatory diseases are a relatively rare group of heritable disorders that are characterized by seemingly unprovoked episodes of inflammation and a relative lack of an obvious autoimmune pathology (ie, pathogenic high titer autoantibodies or antigen-specific T cells). These disorders arise from various genetic conditions that result in a chronic low-grade inflammatory activity with overlapping recurrent inflammatory attacks. Although most of these entities begin in infancy, Behcet disease is not frequent in the pediatric age group. On the other hand, the extensive vasculitis, hypercoagulability, and more severe disease among males are features of Behcet disease that are not characteristic of the autoinflammatory conditions, reducing that probability as well as controversial responses of interleukin (IL)-1β treatments in Behcet disease and arguing against the autoinflammatory disease theory (159; 150; 119). On the other hand, there are some clinically important differences between Behcet disease and other autoimmune diseases, including sex differences in disease expression and a lack of comorbidities with other autoimmune diseases. Interestingly, antibodies to human and mouse neurofibrils that crossreact with Streptococcus spp. and M tuberculosis heat shock proteins have been shown in Behcet disease (84), raising the probability that an adaptive immune response plays a role in the pathogenesis as one would expect in autoimmune diseases. Some authors have proposed that Behcet disease has the features of both autoimmune and autoinflammatory disorders (52; 130; 119), but it’s clear that it’s not specific for either.

In addition to the suggested immunological and genetic factors, fibrinolytic defects have also been suggested to play a role in the etiology of Behcet disease (33). Hypercoagulability resulting from increased platelet aggregation, decreased prostacyclin synthesis and fibrinolytic activity, and higher levels of homocysteine have all been implicated in the pathogenesis of the thrombotic complications. However, no specific defect in the coagulation system has been demonstrated. Currently, it is thought that the thrombosis seen in Behcet disease is due to immune-mediated endothelial dysfunction, which increases in the presence of other risk factors that are associated with Behcet disease (92; 52).

A group of researchers from Italy have identified a unique ci-miRNA profile that segregates patients with Behcet disease from healthy subjects, active versus inactive disease, as well as Behcet disease from other disease (systemic lupus erythematosus and giant cell arteritis) control groups (35). The identified ci-miRNA profile potentially controls pathways related to thrombo-inflammation, which may serve as a candidate biomarker in the diagnosis of the syndrome and may lead to the development of novel therapeutic strategies in Behcet disease.

When patients with Behcet disease and with and without neurologic involvement along with healthy controls were screened using a protein macro array and then with confirmatory immunohistochemistry and immunoblotting studies, the mitochondrial carrier homolog 1 (Mtch1) autoantibody was detected and appeared to be highly sensitive and specific for NBS and Behcet disease (147). This antibody, as well as another autoantibody against annexin-V in Behcet disease (48), have targets that are associated with apoptosis. Furthermore, levels of these antibodies were shown to be correlated with disease severity, raising the probability that these antibodies might be involved in pathogenic mechanisms of NBS. Further studies on the immunology and genetics of Behcet disease have been conducted. A number of different polymorphisms were found to be associated with the syndrome, and some risk loci were identified (58). Although some of these findings add limited explanations to understand the syndrome, none are astounding.

The incidence of Behcet disease among family members is higher than in the general population. An autosomal recessive mode of inheritance has been suggested for pediatric disease (95). Certain major histocompatibility complex class I chain-related protein alleles are more frequent in these patients; however, the HLA B5, particularly B51 association, is the most significant. The association between Behcet disease and HLA appears to be lower in the United States and United Kingdom than in the Middle East and Japan. Genetic polymorphisms of various cytokines, their regulators, and promoters are being studied. In a genome-wide association study in Behcet disease, the most significant association was found with the MHC region in chromosome 6, mostly due to HLA-B51. Other associations were with CPLX1 and IL10, and IL23R and IL12RB2 (109). Another genome-wide association study from Japan also showed an association with IL10, and IL23R and IL12RB2 (94). IL10 is a potent suppressor of many proinflammatory cytokines and also reduces T-cell and NK-cell activation by macrophages. A number of meta-analyses confirmed the role of associations between interleukin-10 polymorphisms and susceptibility to Behcet disease. The -819 T>C and the -592 A>C, as well as rs1518111 and rs1554286, polymorphisms of IL10 were found to be associated with a decrease in Behcet disease risk, whereas the -1082 A>G was not associated with a change in risk (80; 124; 81). IL10 receptor mutations have been indicated not only in Behcet disease but in various autoimmune and autoinflammatory disorders. However, the implication of these findings and the genetic basis of the immune hyper-reactivity in Behcet disease are still unclear.

In a study in which a dense genotyping of immune-related loci was performed among 1900 Turkish patients with Behcet disease and 1779 controls, HLAB51 was associated with susceptibility to Behcet disease; in addition, other associations were found between IL1A-IL1B, IRF8, and CEPBP-PTPN1 as well as a probable role of ADO-EGR2 and IRF8 (131). These findings extended the list of susceptibility genes shared with Crohn disease and leprosy and implicate the role of mucosal factors and the innate immune response to microbial exposure in the pathogenesis of Behcet disease.

Given that HLA-B51 is an MHC class allele, and that Behcet disease shares some features (ie, acne, arthritis) with ankylosing spondylitis and psoriatic arthritis, it was suggested that Behcet disease may be considered as an “MHCI-opathy” (91). However, this is not a widely accepted proposal and debates are ongoing regarding this issue (150).

In a Turkish cohort of 207 Behcet disease patients without any symptoms and family history for familial Mediterranean fever, the five common Mediterranean fever (MEFV) gene mutations were studied. Thirty-six percent of these patients were found to carry a single MEFV mutation, a result that was statistically significant from the healthy control group. This finding is suggestive that MEFV mutations may have a role in the pathogenesis of Behcet disease (133). In another study from Japan, MEFV gene mutations were studied in a smaller cohort of 17 NBS cases in whom such an association was also found, and it was concluded that MEFV gene mutations may act as disease modifiers in NBS and correlate with particular clinical findings and lesion sites on MRI (68).

In summary, despite a large number of studies, the etiopathogenesis of Behcet disease remains unknown. It is accepted as a multifactorial disease with a strong genetic background, in which the wide spectrum of disease manifestations is considered to be triggered by various environmental factors in genetically susceptible individuals.

Epidemiology

The epidemiology of Behcet disease shows a geographical variation. It is more common along the Silk Route, which extends from the Mediterranean region to Japan. This distribution is associated with a similar variation in HLA-B51, which correlates with disease high prevalence areas such as the Middle East and Far East (114). In a study, 185 patients of Italian origin with Behcet disease were studied by using an anthropological evolutionary genetics approach (117). Characterization of Behcet disease variation at ancestry, informative mitochondrial DNA control region, and haplogroup diagnostic sites of these 185 patients revealed that they were more closely related with some middle eastern and central Asian populations settled along the ancient Silk Road rather than with healthy Italians. This study is important as it provides some genetic evidence for the longstanding hypothesis that Behcet disease had spread over centuries through the ancient Silk Road trade route.

The prevalence of Behcet disease has been reported to be between 0.5 to 5/10⁵ in the United States, between 0.5 to 3/10⁵ and 1/10⁵ in northern and central Europe, 2.5 to 7.1/10⁵ in the northwestern Mediterranean region, and increases further in the eastern Mediterranean and Middle Eastern regions (78; 150). However, in a number of studies higher rates in some U.S. and European populations have been reported (98; 144). In a study from the Southwestern United States, the estimated prevalence rate was reported to be up to 10.9 per 100,000 (98). A study from the U.K. found a prevalence rate of 14.61/10⁵ in 2017, a much higher rate than the one reported in the 1990s (134), suggesting that an increase in the incidence of the disease was likely. On the other hand, prevalence rates up to 420/105 have been reported in population-based studies from Turkey, where the disease is most prevalent globally. Rates reported in Japan, China, and Korea, countries at the other end of the ancient trade routes of Silk Road, are between 10 and 20/10⁵ (78; 150). However, in a meta-analysis the pooled estimates of prevalence proportions expressed as cases/100,000 inhabitants were reported to be 10.3 (95% CI 6.1 - 17.7) for all studies and 119.8 for Turkey, 31.8 for the Middle East, 4.5 for Asia, and 3.3 for Europe (86). It was concluded that the differences reported in various studies on Behcet disease prevalence proportions likely reflect a combination of true geographic variation and methodological artefacts.

In a multihospital-based prevalence study from the Netherlands, patients with Behcet disease from different ethnic backgrounds living in the Rotterdam area were recorded and compared to the number of people with the same ethnic background living in the same area (72). A prevalence rate for Behcet disease was calculated to be 1/10⁵ among Dutch-Caucasians, 71/10⁵ among Turks, and 39/10⁵ among Moroccans. These rates are consistent with the prevalence among Turks to what was reported from Western Turkey and for the Moroccons to what was reported from Morocco. However, further studies from Europe revealed that the prevalence of Behcet syndrome among immigrants is lower than that reported in their countries of origin but higher than that among native Germans, Dutch, and French (149). Such prevalence studies among immigrants give important clues regarding the role of genetics and environment in the pathogenesis of a disease.

There is emerging evidence that Behcet disease in nonendemic regions may be less severe, suggesting potential environment agents in determining the severity of the disease. However, the observation that women seem to be overrepresented in nonendemic areas has been suggested to be one explanation for the reason for less severe symptoms, as Behcet disease tends to be more severe in men (78).

In most reported series the onset of Behcet disease is in the third or fourth decade; however, the onset in the Asian population tends to be a decade later (64; 158). Pediatric Behcet disease has rarely been reported. Although the gender distribution in Behcet disease is almost equal, in Behcet disease there is a reported slight increase in males; this increase may be explained by the higher incidence of systemic complications and more severe disease in males, which is likely to bring them to medical attention earlier (128).

The symptoms of Behcet disease also show geographical and ethnic variation, with severe eye involvement and inflammatory bowel disease being more common in the Far East than in the Mediterranean basin. Mucocutaneous forms are more common in Western countries, and the pathergy reaction is less frequent in patients from Northern Europe and the United States than the Mediterranean region and Japan (150).

Several studies related to specific organ involvement in Behcet syndrome have identified four major clusters: (1) oral ulcers, genital ulcers, and erythema nodosum; (2) superficial and deep vein thrombosis; (3) uveitis; and (4) papulopustular skin lesions and joint involvement (119). In addition to these, gastrointestinal and central nervous system involvement may emerge as further separate subgroups of the syndrome. These clinical findings reveal important heterogeneity across patients as well as disease severity, showing a large variety based on the geographical and ethnic background of individuals with the disease. This variety makes trial design and disease assessment complicated.

Prevention

An increased risk of Behcet disease has been observed in association with cold sores, large sibship size, late birth order, and first sexual intercourse before 16 years of age (26). Certain ethnic groups carrying HLA B5, particularly B51 and B52, are at increased risk, and family members with the same HLA phenotype are prone to recurrent oral lesions. No specific methods are known to prevent the disease in those at risk.

Avoidance of oral trauma and some food items may decrease the recurrence rate of aphthae in some patients. Cessation of smoking appears to activate mucocutaneous symptoms, especially oral aphthous lesions (129).

Differential diagnosis

In countries with a high incidence of Behcet disease, all chronic recurrent uveal inflammations, especially panuveal inflammations, need to be differentiated from Behcet disease. The patients should be examined and followed-up for other manifestations of this symptom complex.

Herpes simplex lesions should be considered in the differential diagnosis of genital ulcers, and cytological or virological examination should be performed as necessary. Tuberculosis may resemble Behcet disease because of its similar multisystem involvement, including subacute or chronic meningitis. However, hilar lymphadenopathy and pulmonary cavities are rare in Behcet disease. Microbiological and pathological examination of body fluids or tissue specimens should be able to clarify whether the disease is tuberculosis. Some of the systemic features helpful in the differential diagnosis of Behcet disease are discussed in detail in a review by Yazici and colleagues (150).

Sarcoidosis can be confused with Behcet disease due to uveitis, arthritis, central nervous system disease, and increased immunoglobulins. The frequency of neurologic involvement is also around 5% to 10% in sarcoidosis, with facial nerve palsy, optic neuropathy, headache, and seizures being the most common symptoms. The clinical, cerebrospinal fluid, and imaging features of neurosarcoidosis may mimic NBS; however, meningeal involvement is extremely rare in NBS and when seen is more likely to be associated with neurosarcoidosis (126). Hilar lymph nodes on chest x-ray, serum angiotensin converting enzyme levels, Kveim skin test, and pathological examination of the granulomatous lesions of sarcoidosis help in the differential diagnosis.

Rheumatoid arthritis and systemic lupus erythematosus may have skin, eye, joint, and multisystem manifestations similar to those of Behcet disease. Rheumatoid factor, antinuclear antibodies, and anti-DNA antibodies are negative in Behcet disease, although serum complement levels are usually elevated in all of these diseases. Vasculitis is the predominant finding in erythema nodosum of Behcet disease, whereas histiocytic infiltration is typical in others.

Reactive arthritis, formerly known as “Reiter syndrome” disease (83), may superficially mimic Behcet disease, with urethritis, arthritis, and ocular inflammation. In reactive arthritis, conjunctivitis is more common than uveitis, and genital lesions are painless. Sacroiliitis and HLA B27 are rare in Behcet disease, features that help in the differential diagnosis with seronegative spondylarthritides.

Stevens-Johnson syndrome presents with mucosal ulcers, rash, and conjunctival injection as a hypersensitivity reaction to drugs or microorganisms. The skin lesions are more acute, disseminated, and superficial than in Behcet disease; a mixture of erythema, vesicles, and pustules and a "target" or "iris" lesion are typical. Mucosal lesions are extensive with irregular borders. Eye findings can usually be differentiated clinically.

Hyper IgD syndrome is characterized by periodic fever, arthritis, and rash. However, it usually starts during childhood, and mucosal or ocular lesions are not part of its symptomatology.

An acute stroke-like onset is not common in NBS, and MRI lesions compatible with classical arterial territories are also not expected. The absence of systemic symptoms and signs will serve to differentiate the primary CNS vasculitic disorders from NBS, and the difference in the systemic symptoms and signs from the secondary CNS vasculitides, as well as the MRI findings (126). The inflammatory large brainstem lesions occasionally extending to the deep hemispheric and diencephalic regions seen in most acute CNS-NBS patients are unlikely to be seen in other systemic vasculitic disorders.

In primary CNS vasculitis, cerebral angiography is reported to be abnormal in up to 90% of patients, and MRI can detect multiple infarcts, mostly involving cortical areas (115), which are unusual in NBS. There is no systemic involvement, and the MRI lesions in primary CNS vasculitis are more likely to be hemispheric with subcortical and cortical or juxtacortical involvement, not common in NBS (126).

Neurologic findings in Behcet disease can be confused with multiple sclerosis when patients present with symptoms and signs suggestive of multifocal CNS involvement or with multiple white matter lesions (128). However, aphthous or ocular findings can be observed or elicited from the history in Behcet disease. Multiple sclerosis is more common in females, whereas NBS is seen primarily in men. Some common symptoms at onset of multiple sclerosis are optic neuritis, internuclear ophthalmoplegia (INO), and myelopathy, which rarely occur in NBS. Brainstem findings are more common in NBS, mainly in the form of multiple cranial nerve involvements, with INO being rare. Headache is a common symptom at the onset of NBS but not in multiple sclerosis. Neuroimaging can also disclose differences in patients with multiple sclerosis versus parenchymal NBS (further discussed in the neuroimaging section below). The posterior fossa lesions of multiple sclerosis are small and discrete, whereas parenchymal NBS brainstem lesions are large, diffuse, may have mass effect, and involve the diencephalon, thalamus, and basal ganglia and only rarely the optic nerves (76; 128; 126; 126). Periventricular, juxtacortical, and corpus callosum lesions are common in multiple sclerosis, but rare in parenchymal NBS. Hemispheric subcortical regions are rare in NBS, and when present, they are usually small and asymptomatic, whereas coalescent periventricular lesions are more supportive of multiple sclerosis. Spinal cord lesions are common in multiple sclerosis and are usually small, spanning less than two to three vertebral segments. In Behcet disease they are uncommon, but when present, they are likely to extend longitudinally more than three segments.

Prominent inflammatory changes with CSF pleocytosis and mild to moderate elevation of protein in the CSF are more common in parenchymal NBS than in multiple sclerosis. Oligoclonal bands are found in more than 90% of patients with multiple sclerosis and in less than 20% of patients with NBS (128; 116; 140). NBS can present with cranial sinus thrombosis and, therefore, should be considered in the differential diagnosis of benign intracranial hypertension. Rare cases of Behcet disease with tumor-like lesions could initially be confused with an intracranial mass, and infiltrative lesions of Behcet disease may mimic gliomatosis cerebri.

Gastrointestinal symptoms in Behcet disease may resemble Crohn disease or chronic ulcerative colitis; however, eye disease and genital ulcers are rare in inflammatory bowel diseases. Arthritis associated with enteropathies is axial and erosive. The diagnosis of a primary gastrointestinal disorder can be confirmed by intestinal biopsy.

Chronic uveitis and meningoencephalitis occur in Vogt-Koyanagi-Harada syndrome; however, this syndrome's unusual features (eg, alopecia, vitiligo, and deafness) can be differentiated from Behcet disease on clinical grounds.

Neurologic complications of treatment should also be considered in a patient with Behcet disease who is under immunomodulatory or immunosuppressive treatments.

Although Behcet disease has been suggested to be among the autoinflammatory disorders, it lacks the characteristic paroxysmal attacks that last hours to days with fever and frequent serosal involvement that are seen in autoinflammatory disorders. On the other hand, recurrent oral aphthous ulcers, the extensive vascular inflammation and hypercoagulability, and that the disease is more severe among males in Behcet disease are not characteristic of the monogenic autoinflammatory disorders.

Diagnostic workup

There is no diagnostic laboratory test for Behcet disease. 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 (114; 159). HLA testing can support the diagnosis in populations in which the disease is associated with the HLA-B51 phenotype and may help in the differential diagnosis. Despite being one of the diagnostic criteria, the pathergy test has a low sensitivity. According to the International Neuro Behcet’s Advisory Group’s Consensus Recommendations, a positive pathergy test in a patient with suspected Behcet disease and systemic Behcet disease features contributes significantly towards the diagnosis; however, a negative test does not exclude NBS (71).

Neuroimaging. Magnetic resonance imaging (MRI) is the primary imaging modality to diagnose NBS. It is sensitive in demonstrating the reversible inflammatory parenchymal lesions of parenchymal NBS as well as CVST of the non-parenchymal disease. Parenchymal lesions are generally located within the brainstem, occasionally extending to the diencephalon, and less often they are within the periventricular and subcortical white matter (76). The nature of the lesions in acute stages, and their resolution with the occurrence of silent lesions on follow-up studies, are consistent with the inflammatory nature of CNS MRI lesions seen in NBS. There are also a number of reports of NBS cases in which MRI images have shown mass lesions that mimicked brain tumors, some necessitating histological diagnosis (105; 89; 118; 49; 12). The presence of brainstem atrophy, particularly of the midbrain tegmentum and pons, has been reported to correlate with a progressive form of the disease (74). Heterogenous enhancement with gadolinium may be seen in acute parenchymal lesions. MRI abnormalities can be found in the absence of neurologic symptoms.

Although hypertrophic pachymeningitis has been reported in Behcet disease (157), it is not clear whether this finding is within the spectrum of NBS or unrelated to the disease. In a nationwide survey of hypertrophic pachymeningitis in Japan, a country where Behcet disease is frequent, there was not a single case with Behcet disease (156).

Work had confirmed that the “central vein sign” can accurately differentiate multiple sclerosis from other diseases that mimic this condition, mainly inflammatory CNS vasculopathies, including Behcet disease (85).

When the frequency of perivenular lesions in patients with multiple sclerosis was compared with other inflammatory vasculopathies it was found that patients with NBS had the highest median frequency of such perivenular lesions among other inflammatory vasculopathies; however, when a threshold of 50% for perivenular lesions was applied, central vein sign discriminated multiple sclerosis from inflammatory vasculopathies including NBS (in which this rate was 34%) with a diagnostic accuracy of 100% (85). The MRI findings are different from multiple sclerosis in most parenchymal-NBS patients, and the central vein sign is not required for the differential diagnosis with multiple sclerosis. As already mentioned, the major involvement in NBS is the brainstem-diencephalic region with lesions being large, extending vertically, quite different than the smaller discrete brainstem lesions of multiple sclerosis. Besides, although subcortical lesions may be seen in both, ovoid shape isn’t observed in NBS and there is a relative absence of multiple sclerosis-diagnostic periventricular and juxtacortical/cortical lesions in NBS (126). However, it should be kept in mind that a subgroup of Behcet disease patients with neurologic complaints may have multiple sclerosis-like lesions on MRI, and these may even fulfill radiological criteria for multiple sclerosis, or more likely they may be in fact multiple sclerosis patients with comorbid systemic Behcet disease (126).

In recent years, patients with NBS have begun presenting with atypical CNS lesions. They are mostly within the cerebral hemispheres with some mimicking tumefactive lesions or in the form of scattered small nodular lesions. It is hypothesized that with the introduction of biological and other new treatments and the changing of treatment algorithms in Behcet disease, the immune response of the disease may be further manipulated, resulting in unusual disease presentations.

Spinal cord involvement can affect the spinal cord with myelitis-like inflammatory lesions that in most patients are longitudinally extensive involving more than three segments (45; 28; 139; 79). When the lesion is in the cervical cord it may extend to the brainstem (76; 50). Although the long spinal cord lesions are similar to those seen in patients with neuromyelitis optica spectrum disorder, patients with Behcet disease do not fulfill the clinical criteria for neuromyelitis optica spectrum disorder and the anti-aquaporin 4 antibody is negative. Single or multiple cervical or dorsal lesions, gadolinium enhancement, and spinal cord atrophy developing following the acute episode also have been noted.

Uygunoglu and colleagues described two distinct patterns of spinal cord involvement in parenchymal-NBS based on T2-weighted axial MRI scans, one of them being the “Bagel sign” pattern, which is characterized by a central lesion with a hypo-intense core and hyper-intense rim, with or without contrast enhancement, and the “motor neuron” pattern, which is characterized by symmetric involvement of anterior horn cells (143).

In Behcet disease patients with cranial sinus thromboses the occluded dural sinus is often visible on MRI with the relative lack of venous infarcts that are expected to be seen with dural sinus thrombosis of other causes. Cerebral angiography is not indicated but performing MR venography to confirm the diagnosis and extent of CVST is recommended (Uygunoglu and 126).

Cerebrospinal fluid (CSF). If performed during the acute stage, CSF studies usually show inflammatory changes in most cases of NBS with parenchymal involvement. An increased number of cells, up to a hundred and sometimes more per ml, with modestly elevated protein levels are expected in most parenchymal cases. When the spinal tap is performed in the acute stage, the increased cells are likely to show a neutrophilic predominance, but this is not always the rule, and a lymphocytic prominence may also be seen. In later stages, cells decrease and lymphocytes are almost always the prominent cell type. Oligoclonal bands can be detected, but this is an infrequent finding and is seen in less than 20% of NBS cases (116). An elevated concentration of IL6 in the CSF of patients with both acute and chronic progressive NBS that correlates with disease activity has also been reported (62; 07; 63). In two separate studies it was suggested that an increase of CSF IL10 and CSF/serum matrix metallopeptidase-9 ratio (increased in serum and decreased in CSF compared to multiple sclerosis) could serve to discriminate between NBS and multiple sclerosis, respectively (10; 18). CSF in patients with CSVT can be under increased pressure; however, the cellular and chemical composition is usually normal (127).

Tissue biopsy is usually not indicated because Behcet disease has no specific diagnostic appearance; however, findings compatible with perivasculitis may help in the diagnosis and differential diagnosis (51). The International Neuro Behcet’s Advisory Group recommends considering nervous tissue biopsy only when all other diagnostic procedures have failed and especially for tumor-like presentations (71).

Management

A systematic review of the literature by a multidisciplinary group from the European League Against Rheumatism (EULAR) in 2008 demonstrated that azathioprine and cyclosporine A were effective for eye involvement and interferon alpha for mucocutaneous involvement. It was noted that there were no controlled studies have been carried out related to the management of vascular, gastrointestinal, and neurologic disease (59). However, in the updated recommendations of EULAR the medical management of mucocutaneous, joint, eye, vascular, neurologic, and gastrointestinal involvement of Behcet disease were modified (55).

Natural history and longitudinal studies have shown that patients with Behcet disease tend to manifest most symptoms either at presentation or within the first 5 years of diagnosis, with the condition getting milder with time. Therefore, it has been suggested that the treatment approach should involve a more aggressive therapy early in the disease course based on the body system and the severity of involvement as well as on the age and sex of the patient (149). In addition, informing patients that they may not require lifelong treatment can also help with compliance with given therapies. However, whether the case for Behcet disease patients with neurologic involvement is the same is not clear.

The management of mucocutaneous involvement include topical measures such as steroids that are used for the treatment of severe oral and genital ulcers. Colchicine is the initial drug of choice for the prevention of recurrent mucocutaneous lesions, especially when the dominant lesion is erythema nodosum or genital ulcer. Papulopustular or acne-like lesions are treated with topical or systemic measures as used in acne vulgaris. In selected cases azathioprine, thalidomide, interferon-alpha, TNF-alpha inhibitors, or apremilast may be considered (55). In the completed phase 3 trial of apremilast for oral ulcers in Behcet syndrome, its efficacy in reducing oral ulcers was confirmed (56).

Flares of uveitis are treated with cycloplegia and topical glucocorticoids. Anti-tumor necrosis factor (TNF)-alpha treatment is beneficial in uveitis refractory to standard immunosuppressive treatment. Current recommendations for any Behcet disease patient with inflammatory eye disease affecting the posterior segment include a treatment regime with either azathioprine, cyclosporine-A, interferon alpha, or monoclonal anti-TNF antibodies (55). Systemic glucocorticoids should be used only in combination with azathioprine or other systemic immunosuppressives. The purpose of treatment is to decrease the frequency of attacks and prevent irreversible visual deterioration.

Glucocorticoids are widely used to suppress most manifestations of Behcet disease but are not sufficient to prevent blindness, onset of the neurologic disease, or death. Chlorambucil, azathioprine, cyclophosphamide, cyclosporine, and methotrexate have been used in combination with low doses of prednisone. This form of treatment is effective in suppressing and preventing both ocular and extraocular manifestations. However, it should be kept in mind that cyclosporine may increase the risk of neurologic involvement in Behcet disease (04; 64).

Venous thrombosis in Behcet syndrome mainly presents as deep vein thrombosis of the lower extremities, but other vascular territories, such as pulmonary artery and vena cava as well as cerebral venous sinuses, are also affected. Because deep vein thrombosis is induced by inflammation, it should be treated with glucocorticoids and immunosuppressants in patients with Behcet disease; the role of anticoagulation remains controversial (135).

Initial studies published in the early days of the COVID-19 pandemic were based on limited case series and suggested that patients with Behcet disease were younger and appeared to have an increased risk for severe outcome when infected with COVID-19 compared to the general population (160; 27). However, later studies based on larger case series showed no increased risk for patients with Behcet disease compared to the normal population with respect to the frequency of SARS-CoV-2 infection, length of hospital stay, lung involvement, ICU admission, and mortality (38; 36; 90; 104; 106; 123). The effect of different forms of treatments received in patients with Behcet disease for COVID-19–related clinical outcomes were not clear, but the possibility of a correlation between TNF inhibitors and a worse outcome as well as a possible protective role of colchicine were suggested.

There are no controlled studies to guide the management of CNS involvement. Corticosteroids are recommended for acute episodes of parenchymal involvement and dural sinus thrombosis. Acute attacks of parenchymal NBS are treated with high-dose intravenous methylprednisolone (IVMP 1g/day) for up to 10 days, or by oral prednisolone (1 mg/kg for up to 4 weeks, or until improvement is observed). Both forms of treatment should be followed with an oral tapering dose of glucocorticoids over 2 to 3 months in order to prevent early relapses along with the initiation of an immunosuppressant such as azathioprine (05; 55). The initiation of long-term treatment with immunosuppressive agents is recommended because in patients with parenchymal CNS involvement the probability of having a relapsing or secondary progressive course that may result in significant physical and cognitive deficits leading to neurologic disability is high (55). A common clinical practice is to add an immunosuppressant drug, such as azathioprine or monthly pulses of cyclophosphamide, to steroids in patients who present with a neurologic episode or who are diagnosed with progressive NBS; however, the efficacy of such a combination has not been demonstrated. Although there is no rigorous evidence-based support, treatment with azathioprine together with oral steroids may be considered as a first-line preventive therapy in patients with NBS who experience relapses. In patients who cannot tolerate azathioprine, mycophenolate mofetil may be an option; however, there is also no information regarding the potential effect of this drug in preventing CNS involvement or new neurologic attacks. The severity of the initial neurologic event, as well as the systemic manifestations of Behcet disease, influence treatment decisions, which should be decided together with the patient’s treating rheumatologist. Other agents that can be tried for parenchymal disease are interferon alpha, azathioprine, cyclophosphamide, methotrexate, and tumor necrosis factor-alpha antagonists (05). In a single study, a trend toward longer event-free survival was observed in patients with severe NBS receiving intravenous cyclophosphamide compared with those receiving azathioprine (99); however, this has not been the author’s experience. A study confirmed that infertility and malignancies were experienced by 30% and 8% of Behcet syndrome patients, respectively, underlining the need for safer treatment modalities (53).

A growing number of case reports have suggested that anti-TNF-alpha agents may be an effective alternative in NBS and also suggested that infliximab may be somewhat effective in controlling relapses and progression in NBS if first-line immunotherapies fail (71; 102). A panel of experts reviewed anti-TNF-alpha therapy in the management of Behcet disease and recommended that infliximab or etanercept could be used as an add-on therapy for selected patients with Behcet disease, including those with CNS involvement, who are refractory or intolerant to traditional immunosuppressive regimens (122). In a large, published case series, it was shown that in patients with NBS who had ongoing clinical relapses on single or multiple immunosuppressants, a switch to infliximab prevents further relapses and stabilizes disability (161). It is of interest that in the same center none of the 74 patients with Behcet disease and without NBS who were put on infliximab for either arterial or eye involvement because of failure of other immunosuppressants developed NBS at the time of last follow-up. When compared to the expected prevalence of 5% NBS within the larger Behcet disease population, this observation suggests that early use of infliximab can even be beneficial in prevention of NBS. However, there is a single case report of a woman with Behçet disease in whom longitudinal extensive transverse myelitis occurred 5 years after the initiation and while receiving anti-TNF-alpha therapy despite inhibition of TNF-alpha activity, suggesting that anti-TNF-alpha therapy does not necessarily prevent the onset of acute NBS (69). However, the anti-TNF-alpha therapy was continued without worsening of the neurologic deficit and it’s difficult to reach a conclusion with this single case report.

The efficacy of TNF blockade for patients with severe NBS and resistance to standard immunosuppressive regimens was also shown in another case series (32). Currently it is recommended that monoclonal anti-TNF antibodies should be considered in severe CNS disease as first-line or in refractory patients (55).

It should be kept in mind that the use of monoclonal anti-TNF antibodies carries the risk of activating latent tuberculosis and, therefore, tuberculosis screening should be conducted prior to the administration of infliximab, and isoniazid prophylaxis (300 mg/day) should be prescribed for up to 9 months in patients with latent tuberculosis. Interestingly, the risk of tuberculosis is further increased in Behcet disease compared to other rheumatological disorders after anti-TNF alpha treatments (47). Despite this, reinitiation of biologics after the development of tuberculosis under anti-TNF therapy may be considered in selected cases because of their efficacy. Because the risk of redevelopment of tuberculosis infection is possible, patients should be followed closely (103). One other issue regarding infliximab treatment is when to stop the treatment. It was reported that long-term remission may be achieved following the discontinuation of infliximab after a minimum use of 2 years (121). In our practice, we tend to use infliximab for at least 2 years and thereafter use neurologic response based on clinical-neuroimaging (MRI) findings as well as the outcome of the systemic disease to guide further dosing of infliximab (126). Finally, because the probability of developing neutralizing antibodies against the drug is possible, these antibodies should be monitored in patients who continue to progress.

The Japanese National Research Committee for Behcet disease has published their recommendations for the management of NBS (65). They suggest initiating and continuing colchicine for up to 5 years after an acute attack of NBS following early management with glucocorticoids. Their recommendation for the treatment of progressive disease is to start methotrexate and, if unresponsive, to add or switch to infliximab. The response to therapy is based on controlling CSF IL6 and keep it at a low level, no progression of symptoms, and no progression in atrophy of the brainstem on MRI (65). However, there is currently no convincing evidence on the efficacy of colchicine in NBS nor the role of CSF IL6 levels as a marker for treatment responsiveness. The authors also emphasized that their recommendations were based on the results of uncontrolled evidence from open trials, retrospective cohort studies, and expert opinions due to a lack of randomized clinical trials.

The use of alpha or beta interferons in NBS is more theoretical and may only be considered as an option for second-line treatment in patients who cannot receive anti-TNF alpha antibody treatment. Due to the studies noted above, which found a correlation of elevated CSF IL6 concentrations with inflammation in NBS, an anti-IL6 receptor antibody, tocilizumab, a humanized IL6 receptor blocking agent, seems to be promising for refractory central nervous system involvement (125; 01; 31; 82; 13).

The pathogenic, clinical, and therapeutic data supporting the use of IL1 inhibition in Behcet disease have been discussed, with the suggestion that anti-IL1 agents may be considered promising in managing Behcet disease. As a result, therapeutic trials have been mounted involving the IL1 receptor antagonist anakinra, the anti-IL1beta monoclonal antibody canakinumab, and the recombinant humanized anti-IL1beta, gevokizumab (102). Rituximab, alemtuzumab, ustekinumab, and apremilast are other drugs reported to show some efficacy in Behcet disease, including cases with neurologic involvement (146). There have been additional case reports on the efficacy of rituximab in refractory NBS (46; 162), suggesting that it may be considered as an alternative option for this condition. However, whether these drugs will become a therapeutic option in NBS is not yet clear.

Dural venous sinus thrombosis is usually treated with either high-dose or medium-dose steroids because it is believed that the clot formation in the veins is caused by a low-grade endothelial inflammation rather than hypercoagulability (05). The addition of anticoagulant medication to steroids is controversial, as Behcet disease patients with CVST are more likely to have systemic large vessel disease, including pulmonary and peripheral aneurysms that carry a high risk of bleeding (59). Therefore, the use of anticoagulation should be considered only after such possibilities have been ruled out, and in the EULAR 2018 recommendations this issue was modified as “the first episode of CVST should be treated with high-dose glucocorticoids followed by tapering and anticoagulants may be added for a short duration. Screening is needed for vascular disease at an extracranial site” (55). Our current practice is to give a 5- to 7-day course of IV methylprednisolone, with an oral taper in addition to aspirin. Recurrence of CVST, although uncommon, is possible in Behcet disease (152). As these patients also have a higher risk of developing other types of vascular involvement (136), long-term immunosuppressive therapy with azathioprine has been suggested in NBS patients with CVST (05).

To summarize current treatment approaches in Behcet disease we may refer to a review in which it was suggested that therapeutic strategies in Behcet disease should be tailored according to the three defined major clinical phenotypes (20). The first is the “mucocutaneous and articular” phenotype in which patients should be started treatment with colchicine, alone or in combination with corticosteroids as a first line, and that azathioprine may be reserved for patients resistant or intolerant to colchicine and anti-TNF-alpha or IFN only in truly refractory or severe forms. In one of the other two phenotypes in which there is also neurologic involvement—patients presenting the “extraparenchymal and peripheral vascular phenotype”—use of immunosuppressants, mainly AZA and additional anticoagulants in well-selected patients, should be recommended. Anti-TNF-alpha agents or IFN-alpha should be considered as a second-line treatment. Finally, for patients who present with the “parenchymal neurologic and ocular phenotype,” AZA is the first-line therapeutic option following an induction therapy with high-dose steroids, and in patients with more severe forms or in those who are intolerant or refractory to AZA, anti-TNF-alpha drugs should be started without delay (20). These therapeutic strategies for the patients with the neurologic phenotypes as mentioned above are our clinical practice.

Special considerations

Pregnancy

The influence of pregnancy on the clinical course is variable between patients. Postpartum reactivation of uveitis is not uncommon (107). A few cases of transient neonatal Behcet disease in babies of affected mothers, presumably due to a factor transferred placentally, have been reported.

Anesthesia

No information is available. However, no particular complications of anesthesia have been reported in patients who underwent surgery.