Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 18, 2022
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This article includes discussion of Behcet disease, Behçet’s syndrome, silk route disease, triple symptom complex, multiple symptom complex of Behcet, Morbus Behcet, oculobuccogenital syndrome, Adamantiades-Behcet disease, neurobehçet, neurobehcet, neuro-Behçet, neuro-Behcet, vasculo-Behcet, entero-Behcet, incomplete Behcet disease, complete Behcet disease, mucocutaneous form of Behcet disease, and neuro-ocular form of Behcet disease. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Behcet disease is an idiopathic chronic relapsing multisystem vascular-inflammatory disease of unknown origin that can affect the nervous system. Clinical and imaging evidence suggests that primary neurologic involvement may be subclassified into 2 major forms. The first form, which is seen in the majority of patients, may be characterized by a vascular-inflammatory central nervous system disease with focal or multifocal parenchymal involvement. The other form is caused by isolated cerebral venous sinus thrombosis and intracranial hypertension. In this article, the author describes the various clinical manifestations, summarizes the diagnosis and differential diagnosis, and gives an update on the emerging views on its epidemiology, pathogenesis, suggested diagnostic MRI patterns, and other biomarkers as well as current management issues for the neurologic disease that include the use of anti-TNF-alpha agents.
• Behcet disease is a disorder of unclear pathogenesis. Several inflammatory markers and the association of Behcet disease with particular major histocompatibility complex antigens point to inflammatory mechanisms inducing the manifestations of the disease in a genetically predisposed host.
• Neurologic involvement, or Neuro-Behcet syndrome (NBS), is heterogeneous with 2 major clinical subtypes: a central nervous system inflammatory parenchymal disease and a less common nonparenchymal form that involves large extraparenchymal vascular structures, mainly venous dural sinuses. Dural venous sinus thrombosis is not uncommon in most cases of pediatric NBS. Peripheral nervous system involvement is extremely rare.
• NBS is a great mimicker of various central nervous system disorders. A history of oral and/or genital ulcers and uveitis should be sought in young patients who present with stroke-like syndromes or with symptoms involving the brainstem and corticospinal tracts, as well as increased intracranial pressure, or dural sinus venous thrombosis.
• New anti-inflammatory agents, in particular TNF-alpha inhibitors, currently are accepted to be the most efficient therapeutic alternative to conventional immunosuppressive drugs.
The earliest known observations of oral and genital ulcerations associated with uveitis are in Hippocrates' notes (33). The disease was named after Dr. Hulusi Behcet (14).
Since then, the manifestations of the disease have become more widely known and have been extended to include multiple systems.
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 (55), the major diagnostic criteria for Behcet disease are:
(1) oral ulcers recurring at least 3 times per year
Minor diagnostic criteria include arthritis or arthralgia, deep venous thromboses, subcutaneous thrombophlebitis, epididymitis, family history, and gastrointestinal, CNS, or vascular involvement.
Oral ulcers plus 2 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 (124). 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 heal more slowly and often result in scarring. The rarest type are the herpetiform ulcers, and these 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 (30).
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 (133; 30).
Eye involvement. This is 1 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 (133). 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, 2 cohorts of primary optic neuropathy in Behcet disease, 1 from China and the other 1 from Turkey, have been reported (03; 123). 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 (123). There were 25 cases in the Turkish cohort, but the gender distribution was almost equal, and in half of the patients the optic neuropathy had its onset before the development of the systemic signs of Behcet disease. Uveitis and disc edema weren’t uncommon 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 (133; 30).
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 1 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) (86). 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 Behcet disease patients (30). 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 (13).
Arthritis. Nonerosive, nonmigrating, oligoarticular involvement of large joints, especially knees, ankles, and wrists, is reported in 50% of patients. Sacroiliitis occurs rarely, if at all.
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 2 diseases (49). 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 the venous and arterial sides of the circulatory system 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 (30).
Cardiac involvement is rare, but when it occurs its manifestations include intracardiac thrombus, pericarditis, myocarditis, endocarditis, endomyocardial fibrosis, coronary arteritis, and valvular disease (74). Whether the prevalence of atherosclerosis is increased in Behcet disease patients remains a controversial issue (47; 78).
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; however, when large series are studied, their prevalence remains between 1.1% and 9% of all Behcet disease patients (Al-Araji and Kidd 2009; Siva and Saip 2009; 132; 25; 63). However, when Behcet disease patients are followed for up to 2 decades, the frequency of neurologic involvement increases to 13% in males and to 5.6% in females (65).
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 (Uluduz et al 2011; 129) and when the onset age 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 (129). 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.
Primary neurologic involvement – neuro-Behçet syndrome (NBS) (neurologic involvement directly related to Behcet disease)
• Neuro-vascular Behcet syndrome – involvement of the extraparenchymal vessels (extraaxial NBS)
- Cerebral venous sinus thrombosis
- Extra-parenchymal large arterial involvement (ie, arterial dissection, large artery thrombosis, intracranial aneurysms)
• Parenchymal NBS – central nervous system involvement (intraaxial NBS)
- Involvement of parenchymal small veins (postcapillary venules)
- Involvement of parenchymal small arteries
- Atypical forms of parenchymal disease
• Neuro-psycho-Behcet syndrome (NPBS)
- With CNS parenchymal disease
- Without CNS parenchymal disease
• Cognitive changes
• Isolated headache syndrome (migraine-like nonstructural)
• Peripheral nervous system involvement
• Subclinical NBS
Secondary neurologic involvement (neurologic involvement indirectly related to Behcet syndrome)
• Neurologic complications secondary to systemic involvement of BS (ie, cerebral emboli from cardiac complications of BS, increased intracranial pressure secondary to superior vena cava syndrome)
• Neurologic complications related to BS treatments (ie, CNS neurotoxicity with cyclosporine, peripheral neuropathy secondary to thalidomide or colchicine, cerebral tuberculosis associated with anti-TNF-alpha agents)
• Somatoform neurologic symptoms associated with having a chronic disease
Coincidental – unrelated (non-BS) neurologic involvement
• Any coincidental neurologic disorders
BS: Behcet syndrome; NBS: neuro-Behcet syndrome; CNS: central nervous system
Modified and updated from (117)
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, and/or supported by neuroimaging findings (eg, MRI findings suggestive of NBS) or abnormal cerebrospinal fluid (CSF) findings consistent with NBS (Siva and Saip 2009). 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 (59). Probable NBS covers patients with either neurologic syndromes suggestive of definitive NBS, but in whom systemic features do not meet the International Study Group Behçet disease criteria, or patients with noncharacteristic neurologic syndromes within the context of Behçet disease supported by the International Study Group criteria. Clinical findings and neuroimaging demonstrate that there are 2 major forms of NBS.
• Central nervous system parenchymal involvement, also named CNS-NBS or “intra-axial-NBS.” This form is due to small vessel disease and causes a focal or multifocal CNS involvement seen in the majority of patients.
• Neuro-vascular Behcet syndrome: nonparenchymal disease pattern presenting with cerebral venous sinus thrombosis (CVST) or rarely due to extraparenchymal large arterial involvement, also named “extra-axial-NBS.” This most commonly seen form is due to large vessel disease presenting with thrombosis of the major cerebral venous dural sinuses. It has limited symptoms, a better neurologic prognosis, and generally an uncomplicated outcome. The more severe forms of extracerebral large arterial involvement such as arterial dissection, large artery thrombosis, and intracranial aneurysms are uncommon.
These 2 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 Behcet disease patients 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 during the acute stage a mild confusion may also be seen. 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 1 or 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 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 (127; 37; 24; 39; 115). 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) (Al-Araji and Kidd 2009; Siva and Saip 2009; 54; Hirohata et al 2012a; 84; 18; 63).
Non-parenchymal NBS. Cerebral venous sinus thrombosis (CVST) is seen in 10% to 20% of Behcet disease patients in whom neurologic involvement occurs (Siva and Saip 2009; 31). 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 (Hirohata et al 2012a).
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 violent 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 one; 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 (93; 02; 114).
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 (Uluduz et al 2011; 82).
Parenchymal CNS involvement in Behcet disease patients with CVST is unlikely (93; Siva and Saip 2009; 126; 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 (114). 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 (112). 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 2 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 (Al-Araji and Kidd 2009; Siva and Saip 2009), suggesting that arterial involvement may occur in a subgroup of NBS (Siva and Saip 2009). 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 (Siva and Saip 2009; 94).
Neuro-psycho-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 (Siva and Saip 2009). 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-psycho-BS may represent an intrinsic aspect of the disease (110).
Cognitive changes. Cognitive changes consistent with memory impairment in the form of delayed recall, abnormalities in verbal and/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 (85; 20). 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 (81; 91).
In a systematic review of neurocognitive functioning in Behcet disease Fisher and Bernard suggested that neurocognitive changes in Behcet disease/NBS may be on a continuum, being more prominent in patients with neurologic (parenchymal NBS) involvement than the Behcet disease patients without neurologic disease (34). They have also concluded that the neurocognitive profiles of neuro-Behcet disease and multiple sclerosis patients were largely comparable, with word fluency being the only cognitive construct where more than 25% of results suggested that neuro-Behcet disease performed significantly more poorly 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 (95; 12; 19; 58; 120). 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 Behcet disease patients 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 (95; 19). 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 (105; 12; 58; 35; 120).
Peripheral nervous system (PNS) involvement. PNS disease with clinical manifestations is extremely rare in Behcet disease (Akman-Demir et al 1999; 105; 16; Al-Araji and Kidd 2009; Siva and Saip 2009; 31). There are a limited number of case reports in which Behcet disease patients 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 (Akman-Demir et al 1999; Al-Araji and Kidd 2009; Siva and Saip 2009). 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 (128). The presence of cognitive dysfunction that is only apparent on testing is also suggestive of subclinical neurologic involvement (20). Subclinical CNS involvement was also detected by MRI and in SPECT studies, as well as with somatosensory evoked potentials (11).
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.
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. Neurologic involvement in Behcet disease is an important cause of morbidity, and approximately 50% of NBS patients are moderately to severely disabled after 10 years of disease (105).
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 (Akman-Demir et al 1999; 105). The presence of brainstem atrophy in the initial MRIs appears to be correlated with a progressive course in patients with NBS (32). 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 IL-6, correlates with a progressive course of NBS (62). 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 (84). 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.
Male sex and younger age of onset are associated with a worse prognosis because of the higher frequency of vascular, cerebral, and ocular symptoms.
Secondary amyloidosis may develop in Behcet disease patients; studies are needed to test the effect of colchicine in preventing this complication.
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.
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 too as discussed below.
Core histopathologic features of Behcet disease include a vasculitic involvement in some cases and a low-grade, chronic, nonspecific inflammation in others (96; 26). 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, supporting a proposed venous theory in pathology (08) confirmed by histopathology as well (21). 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 (43; 50; 26).
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 (133). 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 (73). 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 (Takeuchi et al 2015). 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 IL-17 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 (Takeuchi et al 2015; 133). 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 (29; 133). The results suggested that under Th17-stimulating conditions, T cells express both IL-17 and IFN-γ in Behcet disease; thus, more prominent IL-17 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 (46).
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 (94). The significance of these findings may vary among patient groups. One focus of cytokine studies has been directed to interleukin-6 (IL-6). Raised CSF levels of IL- 6 have been found in patients with acute parenchymal NBS (51; 36; 06; 53; 98). In addition, raised IL-6 levels, although to a lesser degree, have also been reported in some progressive parenchymal NBS cases (06; 52). Raised CSF IL-6 levels are usually associated with raised CSF cell count and protein, and these 3 parameters have been associated with disease activity and outcome. However, elevated CSF IL-6 levels have also been reported in the presence of normal CSF cells and protein (06; 52). A correlation between a decrease in CSF IL-6 levels in response to various treatments in NBS was reported in a number of studies, but all were from Japan (51; 36; 61; 52), and these studies involved only small numbers of patients. Collectively, these data indicate that IL-6 is not a reliable biomarker of NBS or Behcet disease, and the absence of IL-6 should not be viewed as the absence of disease activity. In another study, among a number of serum cytokines studied, including IL-6, only IL-8 was found to be significantly increased in patients with Behcet disease both with and without neurologic involvement, but there was no correlation between IL-8 levels and clinical severity (73); IL-8, 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 (22). 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 more recent work 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 (125). 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 (Sakane et al 1997; 42). 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 ineffectiveness of interleukin (IL)-1β treatments in Behcet disease and arguing against the autoinflammatory disease theory (133; 124). 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 (69), raising the probability that an adaptive immune response plays a role in the pathogenesis as one would expect in autoimmune diseases. Some have proposed that Behcet disease has the features of both autoimmune and autoinflammatory disorders (42; Takeuchi et al 2015), 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 (29). 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 (77; 42).
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 (122). This antibody, as well as another autoantibody against annexin-V in Behcet disease (38), 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 (47). 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 (80). 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 (92). Another genome-wide association study from Japan also showed an association with IL10, and IL23R and IL12RB2 (79). IL10 is a potent suppressor of many proinflammatory cytokines and also reduces T-cell and NK-cell activation by macrophages. IL10 receptor mutations have been indicated 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 Behcet disease patients and 1779 controls it was confirmed that HLAB51 was associated with susceptibility to Behcet disease, and in addition some other associations were found between IL1A-IL1B, IRF8, and CEPBP-PTPN1, and also a probable role of ADO-EGR2 and IRF8 (109). 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” (76). However, this is not a widely accepted proposal and debates are ongoing regarding this issue (124).
In a Turkish cohort of 207 Behcet disease patients without any symptoms and family history for familial Mediterranean fever, the 5 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 (111). 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 (56).
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.
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 (96). In 1 study, 185 patients of Italian origin with Behcet disease were studied by using an anthropological evolutionary genetics approach (99). 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 (66; 124). However, in a number of studies higher rates in some U.S. and European populations have been reported (83; Villiger et al 2019). In 1 study from the Southwestern United States, the estimated the prevalence was reported to be up to 10.9 per 100,000 (83). On the other hand, prevalence rates up to 420/105 have been reported from population-based studies in Turkey. 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 (66; 124). However, in a metaanalysis 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 (72). 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 (60). 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. Such prevalence studies among immigrants give important clues regarding the role of genetics versus 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 1 explanation for the reason for less severe symptoms, as Behcet disease tends to be more severe in men (66).
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 (Hirohata et al 2012a; 132). 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 (Siva and Saip 2009).
The symptoms of Behcet disease 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 (124). Although environmental factors may influence clinical manifestations, the prevalence of Behcet disease among immigrants matches the rate of the country of origin and is independent of the age of immigration, pointing to a role of constitutional factors (71).
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 (23). 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 (107).
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 (124).
Sarcoidosis can be confused with Behcet disease due to uveitis, arthritis, central nervous system disease, and increased globulins. Rate 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 (104). 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 (68), 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 (104). 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 (97), 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 (104).
Neurologic findings in Behcet disease can be confused with multiple sclerosis when patients present with symptoms and signs suggestive of multifocal CNS involvement and/or with multiple white matter lesions (Siva and Saip 2009). 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 (64; Siva and Saip 2009; 104; 104). 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 2 to 3 vertebral segments. In Behcet disease they are uncommon, but when present, they are likely to extend longitudinally more than 3 segments. Finally, 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 multiple sclerosis patients and in less than 20% of NBS patients (Siva and Saip 2009). 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 and/or immunosuppressive treatments.
Although Behcet disease has been suggested to be among the autoinflammatory disorders, as already discussed above 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.
There is no diagnostic laboratory test for Behcet disease. The moderate anemia of chronic disease and leucocytosis 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 (96; 133). 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 1 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 (59).
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 (64). 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 (89; 75; 100; 39; 10). The presence of brainstem atrophy, particularly of the midbrain tegmentum and pons, has been reported to correlate with a progressive form of the disease (62). 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 (131), it is not clear whether this finding is within the spectrum of NBD 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 (130).
Work had confirmed that the “central vein sign” can accurately differentiate multiple sclerosis of from other diseases that mimic this condition, and mainly the inflammatory CNS vasculopathies, including Behcet disease (70).
When the frequency of perivenular lesions in multiple sclerosis patients was compared with other inflammatory vasculopathies it was found that NBS patients 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% (70). In our experience, in most parenchymal-NBS patients the MRI findings are distinct from multiple sclerosis and don’t require the central vein sign for distinction. 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 (104). 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.
Spinal cord involvement can affect the spinal cord with myelitis-like inflammatory lesions that in most patients are longitudinally extensive involving more than 3 segments (37; 24; Uygunoglu et al 2014; 67). When the lesion is in the cervical cord it may extend to the brainstem (64; 40). Although the long spinal cord lesions are similar to those seen in patients with neuromyelitis optica spectrum disorder, Behcet disease patients do not fulfill the clinical criteria for neuromyelitis optica spectrum disorder and the anti-aquaporin 4 antibody is negative. Single or multiple cervical and/or dorsal lesions, gadolinium enhancement, and spinal cord atrophy developing following the acute episode also have been noted.
Uygunoglu and colleagues described 2 distinct patterns of spinal cord involvement in parenchymal-NBS based on T2-weighted axial MRI scans, 1 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 (118).
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 104).
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 (98). An elevated concentration of IL-6 in the CSF of patients with both acute and chronic progressive NBS that correlates with disease activity has also been reported (51; 06; 52). In 2 separate studies it was suggested that an increase of CSF IL-10 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 (09; 15). CSF in patients with CSVT can be under increased pressure; however, the cellular and chemical composition is usually normal (105).
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 (41). 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 (59).
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 (Hatemi et al 2009). However, in the updated recommendations of EULAR the medical management of mucocutaneous, joint, eye, vascular, neurologic, and gastrointestinal involvement of Behcet disease were modified (44).
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 (44). In the completed phase 3 trial of apremilast for oral ulcers in Behcet syndrome, its efficacy in reducing oral ulcers was confirmed (45).
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 (44). 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; Hirohata et al 2012a).
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 (Akman-Demir et al 2011; 44). 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 (44). 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 (Akman-Demir et al 2011). 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 (84); however, this has not been the author’s experience.
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 (59; Ozguler and Hatemi 2016). 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 (102). 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 (Zeydan et al 2016). 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 (57). 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 (28). Currently it is recommended that monoclonal anti-TNF antibodies should be considered in severe CNS disease as first-line or in refractory patients (44).
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. Further, reinitiation of biologics after the development of tuberculosis under anti‑TNF therapy may be considered, but because the risk of redevelopment of tuberculosis infection is possible, patients should be followed-up closely (88). 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 (101). 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 (104). 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 use of interferon alpha or beta agents 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 IL-6 concentrations with inflammation in NBS, an anti-IL-6 receptor antibody, tocilizumab, a humanized IL-6 receptor blocking agent, seems to be promising for refractory central nervous system involvement (103; 01; 27).
The pathogenic, clinical, and therapeutic data supporting the use of IL-1 inhibition in Behcet disease have been discussed, with the suggestion that anti-IL-1 agents may be considered promising in managing Behcet disease. As a result, therapeutic trials have been mounted involving the IL-1 receptor antagonist anakinra, the anti-IL-1beta monoclonal antibody canakinumab, and the recombinant humanized anti-IL-1beta, gevokizumab (Ozguler and Hatemi 2016). Rituximab, alemtuzumab, ustekinumab, and apremilast are other drugs reported to show some efficacy in Behcet disease, including cases with neurologic involvement (121). However, whether these drugs will become a therapeutic option in NBS is currently not 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 (Akman-Demir et al 2011). The addition of anticoagulant medication to steroids was 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 (Hatemi et al 2009). 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” (44). 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 (126). As these patients also have a higher risk of developing other types of vascular involvement (112), long-term immunosuppressive therapy with azathioprine has been suggested in NBS patients with CVST (Akman-Demir et al 2011).
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 3 defined major clinical phenotypes (17). 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 1 of the other 2 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 (17). These therapeutic strategies for the patients with the neurologic phenotypes as mentioned above are our clinical practice.
The influence of pregnancy on the clinical course is variable between patients. Postpartum reactivation of uveitis is not uncommon (90). A few cases of transient neonatal Behcet disease in babies of affected mothers, presumably due to a factor transferred placentally, have been reported.
No information is available. However, no particular complications of anesthesia have been reported in patients who underwent surgery.
Aksel Siva MD
Dr. Siva of the Istanbul University Cerrahpasa School of Medicine received honorariums from Bayer-Schering AG, Biogen/Gen Ilac of Turkey, Genzyme, Merck-Serono, and Roche for consulting, fees from Novartis as a consultant and advisory committee member, travel and registration reimbursements from Genzyme, and honorariums from Teva for speaking engagements.See Profile
Francesc Graus MD PhD
Dr. Graus, Emeritus Professor, Laboratory Clinical and Experimental Neuroimmunology, Institut D’Investigacions Biomédiques August Pi I Sunyer, Hospital Clinic, Spain, has no relevant financial relationships to disclose.See Profile
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Jan. 18, 2022
Movement disorders are prominent in the clinical presentation of many autoimmune disorders. These abnormal motor phenomena include faciobrachial dystonic seizures, neuromyotonia, chorea, myorhythmia, stereotypies, dystonia, tremor, parkinsonism, ataxia, and stiff-person-like phenomena. Each type of autoimmune encephalitis presents with a different profile of abnormal movements, and a therapeutic response to immunomodulatory therapy suggests that these motor phenomena also have an autoimmune pathogenesis.
Dec. 30, 2021
Acquired sensory neuronopathies depend on a primary involvement of sensory neurons in dorsal root ganglia leading eventually to a definitive and irreversible degeneration of the cell body. They include toxic, infectious, and dysimmune mechanisms, although an important proportion remains idiopathic after an extensive workup. The loss of large sensory neurons results in ataxia that usually predominates in the lower limbs, resulting in ataxic gate and Romberg sign.
Dec. 02, 2021
Hashimoto encephalopathy is a poorly understood syndrome of reversible cognitive impairment in the setting of antithyroid autoantibodies. There are no validated criteria for the diagnosis of the disease, but proposed diagnostic criteria include: (1) encephalopathy with seizures, myoclonus, or stroke-like episodes; (2) subclinical or mild overt thyroid disease; (3) normal or nonspecific abnormalities on brain MRI; (4) positive serum anti-TPO or anti-TG antibodies; (5) absence of well-characterized neuronal antibodies in CSF and serum; (6) reasonable exclusion of alternative causes.
Oct. 28, 2021
Clinically isolated syndrome is a first symptomatic episode of central nervous system dysfunction due to inflammatory demyelination, which may indicate the onset of multiple sclerosis, or may be an isolated incident. Patients may show accelerated brain atrophy and mild cognitive impairments.
Oct. 25, 2021
Motor and multifocal motor neuropathy is characterized by weakness with muscle wasting and fasciculations, and may resemble motor neuron disease. Sensory symptoms are notably absent, with only the occasional complaint of paresthesias. Motor weakness typically occurs in the distribution of individual motor nerves rather than the segmental distribution seen in amyotrophic lateral sclerosis. Compared with amyotrophic lateral sclerosis, motor neuropathies have a favorable prognosis and a prolonged course.
Oct. 18, 2021
Bell palsy is an acute, usually unilateral mononeuropathy of the seventh cranial nerve. The disorder is presumed to be inflammatory and associated with one of several different viral etiologies, usually herpes simplex virus-1. Features of Bell palsy include impairment of voluntary movement of facial and platysmal muscles, facial muscles pulled to the opposite side on smiling, saliva and food collected on the paralyzed side, and on attempting to close the eye, the eyeball is diverted upward and slightly outwards to avoid corneal exposure (Bell phenomenon).
Oct. 18, 2021
Initial symptoms of progressive multifocal leukoencephalopathy include alterations in personality, changes in intellect, focal weakness, difficulty with motor skills, visual abnormalities, or sensory loss. It is an opportunistic demyelinating infection of the central nervous system that primarily affects immunosuppressed patients.
Oct. 17, 2021