Introduction

Behçet’s disease (BD) is a multisystemic inflammatory disease of unknown etiology. It was first described by the Turkish dermatologist Hulusi Behçet in 1937, as a tri-symptom complex including recurrent oral aphthous ulcers, genital ulcers, and uveitis. The disease affects many organs and systems, causing mucocutaneous lesions, eye inflammation, musculoskeletal problems, and major vessel disease; there is cardiac, pulmonary, and gastrointestinal involvement as well as nervous system involvement. As a result of this multisystemic involvement, a wide range of clinical manifestations and presentations may occur, and some of these may result in severe disability or death.

The International Study Group’s classification criteria are widely used to establish the diagnosis of BD [1]. According to these criteria, a diagnosis of BD requires recurrent oral aphthous ulcerations plus two of the following: genital ulcerations, skin lesions, eye lesions, or a positive pathergy test (Table 1).

Table 1 Criteria for diagnosis of Behçet diseasea
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The etiology of BD is unknown, but clinical and laboratory data suggest that there is dysfunction of both innate and adaptive immune systems, resulting in an exaggerated response to viral or bacterial insults [2••]. Debate is ongoing about whether this hyperreactivity is an autoimmune phenomenon, or—as suggested by more recent data—an autoinflammatory phenomenon [3]. The core histopathologic phenomenon seems to be a vasculitic involvement in some cases and a low-grade, chronic, nonspecific inflammation in others [4, 5•].

Neurologic involvement

Various types of neurologic presentation of BD patients are listed in Table 2. The most common neurologic symptom in BD patients is headache; however, most of these represent primary headache syndromes such as migraine, tension-type headache, and probably disease-related migraine-like headaches [6, 7]. These patients are not considered to have neurologic BD, and there is rarely a need for further radiologic studies if the patient has no neurologic symptoms or signs other than headache.

Table 2 The neurologic spectrum of Behçet’s disease
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On the other hand, serious neurologic involvement of BD also presents with headache, but in the presence of other neurologic findings. Neurologic involvement in BD was seen in about 5% of two large BD cohorts from Turkey [6, 8], and the rate is known to increase with prolonged follow-up, up to 13% within 20 years [9]. Males are more commonly affected than females; the average age at onset of BD is about 25 years, with neurologic onset at about 30 years of age [10–12••, 13••]. Table 2 lists a number of neurologic syndromes, of which the most common two, parenchymal CNS involvement and dural venous sinus thrombosis, are summarized here.

The majority of patients with neurologic involvement due to BD present with parenchymal CNS involvement, most commonly affecting the brainstem-diencephalic region. This pattern of involvement is seen in up to 70% to 80% of the patients with neurologic involvement and is termed “parenchymal neuro-Behçet’s disease” (NBD) or “intra-axial NBD.” These patients present with a subacute (or rarely, acute) onset of severe headache, dysarthria, ataxia, and hemiparesis. Cognitive-behavioral involvement is also seen in some, and sphincter problems in others. A minority of these patients may present with a spinal cord syndrome [10–12••, 13••]. Some patients may have only a single attack, with or without residual neurologic deficits, but most will have recurrences with further sequelae, and some will have secondary progression. A few may have a primary progressive course. The suggested diagnostic criteria for NBD in a patient who fulfills the international diagnostic criteria for BD [1], is the occurrence of neurologic symptoms not otherwise explained by any other known systemic or neurologic disease or treatment, and in whom objective abnormalities are detected either on neurologic examination or by imaging (such as MRI), laboratory investigations (cerebrospinal fluid [CSF] examination), or both [13••].

Lymphocytic or polymorphonuclear pleocytosis (up to a few hundred cells per microliter) is seen in the CSF, with slightly elevated protein levels and normal glucose levels; CSF oligoclonal IgG is rarely present. Cranial MRI shows an almost stereotypical lesion involving brainstem, mainly the midbrain and upper pons, and extending to the diencephalon and basal ganglia; it appears hyperintense on T2 sections and hypo/iso-hypointense in T1 sections (Fig. 1); usually there is a much smaller area of enhancement, and occasionally small hemorrhages can be seen [14]. After steroid treatment, the lesion regresses to punctate T2 hyperintensities and brainstem atrophy [15]. Rarely, instead of the typical brainstem-diencephalic lesion, subcortical or periventricular white matter lesions can be seen, which may be difficult to distinguish from other vasculitic lesions or multiple sclerosis [16]. When there is spinal cord involvement, it may tend to be longitudinally extensive [17].

Fig. 1
figure 1

Parenchymal neuro-Behçet’s disease. a and b Axial T2-weighted MR images show a large edematous lesion extending from the midbrain to the diencephalic and basal ganglia regions on the right, consistent with an acute parenchymal neuro-Behçet attack. c A coronal fluid-attenuated inversion recovery (FLAIR) image and d axial T1-gadolinium image display ring-like enhancement in the center of the lesion.

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The second most common form of neurologic involvement is cerebral venous sinus thrombosis (CVST), which may be seen in up to 20% of the patients with CNS involvement. This is termed “vascular-NBD” or “extra-axial NBD” [10–12••, 13••]. These patients also present with severe headache, which in general develops over a few weeks. They usually have papilledema, and occasionally palsy of cranial nerve VI on neurologic examination. Hemiparesis, impairment of consciousness, or epileptic seizures are seen much more rarely in these patients than in patients with dural sinus thromboses due to other causes [18, 19••]. Similarly, venous hemorrhagic infarcts are not expected to occur in people with CVST due to BD. Cranial MRI usually shows occluded dural sinus, but otherwise is normal. MR venography will confirm the diagnosis and the extent of the CVST. The CSF is also normal except for elevated opening pressure. Interestingly, parenchymal neurologic involvement and CVST are unlikely to occur in the same individual [10, 11, 13••]. Moreover, CVST occurs at a much younger age than parenchymal NBD, and its prognosis is far better than that of parenchymal CNS involvement, although recurrences of CVST are possible [10, 11, 19••]. These differences suggest that these two types of NBD may have different pathogenetic bases [13••].

Parenchymal neurologic involvement is usually associated with a poor prognosis; about 50% of the patients are severely disabled within 10 years. However, long-term follow-up of patients with BD gives the impression of a better course in recent years when compared with earlier cases [20], which may suggest some treatment effect.

Treatment

  • Neurologic involvement in BD is heterogeneous, and it is difficult to predict its course and prognosis. In a similar review in this journal about 10 years ago, we emphasized that it will not be possible to reach a conclusion regarding the efficacy of any treatment until properly designed, double-masked, placebo-controlled studies are carried out [21]. Since then, there have been a few attempts to initiate such studies, but none could be completed because the number of new NBD cases each year is limited even in large centers. Most studies that report some efficacy for various treatments have not included uniform cases, did not follow patients for long periods, and did not include controls. Currently, we have no Class I evidence for any form of treatment for NBD. Empiric impressions are the guidelines for management.

  • The lack of randomized controlled trials is not limited only to the treatment of neurologic involvement in BD. A recent review of the literature on the management of various types of systemic involvement in BD revealed few randomized controlled trials. There was good evidence only to support the use of azathioprine and cyclosporine A in eye involvement and interferon alfa in mucocutaneous involvement. There were no controlled data for the management of vascular, gastrointestinal, and neurologic involvement, and the task force commissioned by the European League Against Rheumatism (EULAR) concluded that properly designed, controlled studies, both new and confirmatory, are needed to guide management of BD [22]. In a separate work, the same task force developed evidence-based EULAR recommendations for the management of BD, supplemented where necessary by expert opinion [23•]. One of us (AS) served on this EULAR Committee. Management of neurologic involvement was based largely on expert opinion and uncontrolled evidence from open trials to observational studies. It was concluded that there were no controlled data to guide the management of CNS involvement in BD. For parenchymal involvement, agents to be tried would be corticosteroids, interferon alfa, azathioprine, cyclophosphamide, methotrexate, and tumor necrosis factor (TNF)-α antagonists. For dural sinus thrombosis, corticosteroids were recommended. It was also emphasized that cyclosporine should not be used in BD patients with CNS involvement unless necessary for intraocular inflammation.

  • Glucocorticoids are used to treat acute CNS involvement in BD, but their effects are not long-lasting, and they do not prevent further relapses or progression. We usually treat attacks of CNS involvement with high-dose intravenous methylprednisolone (IVMP) for 5 to 10 days, which is followed by either a slow oral tapering or weekly/monthly pulses. There are also some centers preferring oral high-dose prednisone (1 mg/kg per day) for up to 4 weeks, followed by a slow oral taper (Fig. 2). It should be noted that early discontinuance of steroids is often followed by a severe relapse.

    Fig. 2
    figure 2

    Treatment algorithm for parenchymal neuro-Behçet’s disease. CNS central nervous system; IV intravenous; MP methylprednisolone. (Adapted from Akman-Demir to Serdaroglu [73]).

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  • Many drugs have been shown to be effective in various systemic manifestations of BD. Colchicine, azathioprine, cyclosporine, cyclophosphamide, methotrexate, chlorambucil, thalidomide, interferon alfa, and anti-TNF agents could be listed. Some newer drugs, such as anti-IL-1β and anti-IL-17A, are being investigated in BD, but none of these drugs have been shown to be effective in CNS involvement of BD in a properly designed study.

  • Azathioprine was tested in a group of patients with BD uveitis in 1991, and was found to be effective in preventing blindness [24, Class I]. It was also effective in long-term follow-up, regardless of other future therapies [25, Class II]. Based on these observations, azathioprine has become a drug that commonly has been used for long-term control of systemic findings in BD. Recent observations on 350 consecutive patients with NBD conducted by the Istanbul School of Medicine suggest that patients with parenchymal NBD who were initially seen before 1991 fared much worse than those who were seen more recently and who received azathioprine, regardless of disease duration [20], consistent with the earlier observation [25]. This indirect observation suggests that azathioprine may have a role in controlling the disease activity in NBD to a certain extent. Our current approach is to consider starting azathioprine at the first neurologic attack, together with high-dose steroid treatment. The severity of the initial neurologic event, as well as the systemic manifestations of BD, influence our treatment decision, which we decide together with the patient’s treating rheumatologist. Because azathioprine becomes effective over 5 to 6 months, it is advisable to keep the patient on low-dose steroid maintenance therapy or on monthly pulses of IVMP for the first 6 months of treatment. When a quicker clinical response is required, or if the patient cannot tolerate azathioprine, the use of monthly pulses of cyclophosphamide may be considered as an option, though the effect of cyclophosphamide in NBD is controversial. For some patients, mycophenolate mofetil may be considered as an alternative. One of us (GAD) used mycophenolate mofetil in five patients with azathioprine intolerance; the result was disease stabilization and cessation of attacks. However, four of those patients had a relapse after they prematurely discontinued mycophenolate mofetil, so prolonged treatment is recommended.

  • A growing number of case reports in recent years have suggested that anti-TNF agents (e.g., infliximab) may be an effective alternative in NBD [26, 27]. A recent multicenter observational work suggested that infliximab may be somewhat effective in controlling relapses and progression in NBD if first-line immunotherapies fail [28•].

  • In a small retrospective study, chlorambucil was reported to be beneficial in meningoencephalitis of BD [29, Class IV]. This study was performed before the MRI era, so we have no information on neuroimaging correlates of treatment, but lessening of the CSF pleocytosis was documented in patients treated. Our experience with chlorambucil is limited to only a few cases. It seems that the drug is somewhat (but temporarily) effective, but it does not merit widespread use because of its tolerability problems and long-term risks.

  • Methotrexate is not a commonly used drug at our practice, but Japanese data suggest that methotrexate could be somewhat beneficial in progressive NBD and in lowering CSF IL-6 levels [30, 31]. The number of cases is limited, however, and the results are not conclusive and have not been confirmed.

  • Although cyclosporine is an effective drug for BD uveitis, there are accumulating data concerning its causative role in neurologic involvement in BD [32–34]. Therefore, the use of cyclosporine in NBD is not recommended, and if the patient is already under cyclosporine treatment at the time of neurologic attack, cyclosporine should be immediately discontinued.

  • Venous thrombosis of BD is usually treated with either high-dose or medium-dose steroids because it is accepted that the clot formation in the veins is caused by a low-grade endothelial inflammation rather than by hypercoagulability [4, Class IV]. The addition of anticoagulant medication to steroids is highly controversial. Although one of our centers (SS & AS) previously used a combination of subcutaneous low-molecular-weight heparin with glucocorticoids [21], this is no longer our routine protocol. Extreme caution is needed, as BD patients with CVST are more likely to have systemic large vessel disease, including pulmonary and peripheral aneurysms that carry a high risk of bleeding [23•]. Therefore the use of anticoagulation should be considered only after such possibilities have been ruled out.

  • Our current practice is to give a 5-day course of IVMP, with an oral taper in addition to aspirin. Recurrences of CVST are possible in BD [19••], and these patient are also at a higher risk of developing other types of vascular involvement [35]. Therefore, long-term azathioprine is also recommended in patients with CVST.

Diet and lifestyle

  • There are no known dietary or lifestyle interventions effective in the management of NBD. However, hot and spicy food is known to aggravate oral aphthae, whereas smoking seems to alleviate them. Therefore, BD patients tend to abuse tobacco. Stressful life events also seem to aggravate systemic symptoms of BD.

Pharmacologic treatment

Glucocorticoids

Prednisone, prednisolone, and methylprednisolone are widely used by clinicians experienced in the management of BD. They are reported to be used as first-line drugs for both acute and chronic progressive CNS involvement, for aggressive gastrointestinal lesions and arteritis, for venous thrombosis and uveitis, and as alternative agents in the treatment of persistent mucocutaneous symptoms and arthritis [36, 37, Class IV]. There is a single randomized controlled trial with corticosteroid treatment (40 mg intramuscular methylprednisolone depot injections); it showed an effect only on nodular lesions [38, Class I]. No controlled trials have evaluated the efficacy of glucocorticoids in NBD. High-dose IVMP is currently the preferred initial treatment for acute CNS involvement in BD. This is followed by an oral taper of prednisone over months, which is then maintained at a minimum effective dose.

Standard dosage :

High-dose IVMP: 1,000 mg/d for 5 to 10 consecutive days is used in the management of active CNS involvement. This dosage is followed by either an oral taper starting from 1 mg/kg per day or alternatively weekly 1,000-mg pulses, with 16 to 32 mg of oral methylprednisolone in the days in between pulses. After 1 month, IVMP pulses could be reduced to monthly pulses for 6 months. Prednisone 5 to 20 mg daily could be used to treat refractory mucocutaneous lesions or arthritis, or as neurologic maintenance treatment when needed. If azathioprine is also started concomitantly, steroid treatment should be maintained for at least 6 months after an effective daily dose of azathioprine has been reached.

Contraindications :

High-dose IVMP is contraindicated in patients with systemic fungal infection, tuberculosis, or known hypersensitivity to the product. Special consideration should be given to patients with diabetes mellitus, severe hypertension, or active peptic ulcer; monitoring of arterial blood pressure and serum glucose levels is required. Infected oral or genital ulcers or urinary tract infections in patients with bladder involvement should be treated before or concomitantly with glucocorticoid treatment.

Main drug interactions :

Methylprednisolone may increase cyclosporine levels. Inducers of hepatic enzymes such as phenytoin and phenobarbital may increase the clearance of glucocorticoids. Because glucocorticoids have variable effects on oral anticoagulants, the coagulation indices should be monitored closely when these two drugs are used concomitantly.

Main side effects :

Dyspepsia, insomnia, anxiety, mood and personality changes, acute psychotic reaction, fluid retention, elevated blood glucose levels, hypertension, and a metallic taste in the mouth. Additional side effects with prolonged use of glucocorticoids are weight gain, acne, hirsutism, osteoporosis, aseptic necrosis of the hip, cataracts, increased intraocular pressure, increased tendency toward bruising and myopathy, cushingoid state, and opportunistic infections.

Special points :

Our practice is to prescribe prophylactic treatment with proton pump inhibitors regardless of the duration and form of glucocorticoid treatment. We have shown that glucocorticoid therapy augments gastroduodenal permeability and that high doses are associated with macroscopic mucosal lesions [39, Class II]. Patients who will be receiving long-term glucocorticoid therapy need to be referred for bone densitometry studies and should receive prophylactic therapy to minimize osteopenia, when needed. Steroid treatment should not be stopped abruptly in patients with neuro-Behçet.

Cost/cost-effectiveness :

These drugs are relatively inexpensive, even when used as high-dose IVMP or orally for long periods, but there are no formal studies on their cost-effectiveness.

Colchicine

Colchicine is an antimitotic agent that acts primarily by binding to the microtubular proteins and interfering with the function of the mitotic spindles. It inhibits the migration of granulocytes into inflamed areas and interferes with the inflammatory response. It has been used for almost all the manifestations of BD, but controlled studies proving its efficacy are rare. It was shown to be superior to placebo in managing arthritis and erythema nodosum [40, Class I]. Another placebo-controlled, masked trial showed that it was equally effective in males and females for arthritis and erythema nodosum, but it was effective for aphthous and genital ulcerations mainly in females [41, Class I]. This drug is commonly used in BD, but it has shown no efficacy in the prevention and management of CNS involvement.

Standard dosage :

It is usually administered as 0.5 to 1.5 mg/d orally. Oral glucocorticoids such as prednisone (5–20 mg/d) or azathioprine (2.5 mg/kg per day) may be added if the mucocutaneous symptoms are refractory. The drug can be administered on a life-long basis.

Contraindications :

Colchicine should not be given in the presence of combined renal and hepatic disease.

Main drug interactions :

Colchicine has been shown to induce malabsorption of vitamin B12 reversibly by altering the function of the ileal mucosa.

Main side effects :

Nausea, vomiting, diarrhea, abdominal pain, amenorrhea or dysmenorrhea, oligospermia, general malaise, and hair loss are the most common adverse effects, but they can be reduced by decreasing the dose of the drug. Neurologic adverse effects such as myopathy, neuropathy, and disturbances of smell and taste also have been reported. Granulocytopenia, agranulocytosis, thrombocytopenia, and aplastic anemia have occurred in patients receiving colchicine, but fortunately, they are rare. Complete blood counts must be performed every 2 months in patients receiving colchicine.

Cost/cost-effectiveness :

Colchicine is an inexpensive drug that is cost-effective.

Azathioprine

Azathioprine is a purine analogue that is converted in the liver to its active metabolite, 6-mercaptopurine. It exerts its immunosuppressive effect by incorporating dividing cells into the DNA, where it inhibits purine nucleotide synthesis and function of RNA.

It has been reported to be of use in the treatment of retinal vasculitis, arthritis, and oral ulcers of BD and as an alternative therapy for arteritis, venous thrombosis, and progressive CNS involvement [4, 37, Class IV]. There are no controlled studies evaluating its efficacy in either parenchymal NBD or CVST of BD. The only controlled study of azathioprine in BD demonstrated that at a dose of 2.5 mg/kg per day, it was superior to placebo in preventing the spread of unilateral eye disease to the second eye, in preserving vision that had previously been affected, and in reducing the need for additional glucocorticoids [24, Class I]. Patients who received azathioprine had better long-term outcomes than the group receiving placebo, independent of subsequent and additional treatments [25, Class II]. The number of patients in these studies with neurologic involvement was so small that no conclusions could be drawn regarding the efficacy of azathioprine in NBD. Although there are no proper, controlled clinical trials for the use of azathioprine in CNS involvement, our observations suggest a beneficial effect, when we compare the prognosis of patients treated in the pre-azathioprine era versus those in the post-azathioprine era [20]. Therefore we recommend that every patient with parenchymal NBD should receive azathioprine for at least 5 years. Patients with CVST should also be considered for azathioprine therapy, given the probability of recurrence and the high risk of other concurrent vascular events resulting from the systemic disease.

Standard dosage :

Azathioprine is administered orally at a dose of 2.5 mg/kg per day with food, in divided doses. The average daily dose for adults ranges between 150 and 200 mg, which is reached over a period of no less than 4 weeks. The complete blood count and liver function tests should be obtained before starting therapy and should be monitored biweekly for the first month, then monthly for the next 2 months, and later bimonthly.

Contraindications :

Pregnancy and lactation (Category D). Infections should be controlled before starting the drug. Severe leukopenia (white blood cell count <1.0 × 109/L) and thrombocytopenia (platelet count <50 × 109/L) are contraindications to starting or continuing the drug. Patients who are hypersensitive to azathioprine (manifesting as fever, rash, nausea, vomiting, or urticaria) should not be re-exposed to this therapy.

Main drug interactions :

Concomitant administration of allopurinol and azathioprine entails an overdose hazard because oxidation of mercaptopurine to inactive metabolites by xanthine oxidase is greatly reduced by allopurinol. Reduction of the normal dose of azathioprine by 65% to 75% is recommended for patients who are also receiving allopurinol. Patients who are receiving other immunosuppressants, angiotensin-converting enzyme inhibitors, or hepatic enzyme inducers should be monitored more carefully for bone marrow suppression and hepatotoxicity.

Main side effects :

There is a risk of idiosyncratic agranulocytosis in the first few weeks of therapy. Leukopenia and thrombocytopenia may occur initially or at some point during the course of therapy. The dose of azathioprine should be modified when such hematologic toxicity is observed. An acute hypersensitivity reaction can also occur in the first weeks of treatment and may include severe nausea, vomiting, diarrhea, fever, rash, urticaria, malaise, myalgia and arthralgia. Other side effects are hepatotoxicity, pancreatitis, reduced resistance to infection, and teratogenesis. As was shown in patients with multiple sclerosis treated with azathioprine [42, Class II], an increased risk of malignancy is possible, especially after about 10 years of continuous therapy. Temporary or permanent sterility is another concern.

Special points :

It should be kept in mind that azathioprine needs 5 to 6 months to be fully effective when first started. In patients with BD, it would be advisable to cover that period with steroids.

Cost/cost-effectiveness :

Azathioprine is relatively inexpensive. There is no formal analysis evaluating its cost-effectiveness, but it does have beneficial effects on eye disease, with a resultant decrease in morbidity.

Cyclosporine

Cyclosporine is an immunosuppressive drug that affects T-cell–mediated responses and therefore spares most humoral immune responses not requiring T cells. It selectively inhibits helper T-cell activation, thus resulting in inhibition of the production of several cytokines (e.g., IL-2, IL-3, or IL-4; granulocyte-macrophage colony-stimulating factor; TNF-α; and gamma interferon. It is used in BD for the management of retinal vasculitis and was reported to be more effective than azathioprine, chlorambucil, and colchicine in suppressing ocular inflammation [43, Class II]. Furthermore, it was found to be superior to monthly pulses of cyclophosphamide in a single masked study conducted in a limited number of patients [44, Class II]. In addition, it was shown to be effective in the management of the mucocutaneous lesions [45, Class I]. Cyclosporine has been reported to have some efficacy in CNS involvement, but the number of cases studied was small and the inclusion of patients with migraine-like headaches (i.e., patients without neurologic involvement) limits the conclusions [46, Class IV]. However, cyclosporine is a drug with known neurotoxicity, and accumulating data suggest that cyclosporine can cause CNS neurologic involvement in itself, mainly in the form of posterior reversible leukoencephalopathy syndrome (PRES) [47]. However, when BD patients using cyclosporine develop neurologic symptoms, the resulting picture may mimic parenchymal CNS involvement of BD or it may present as PRES with epileptic seizures and cortical hyperintensities that are unexpected in NBD [34]. There are many retrospective cohorts in which patients with BD receiving cyclosporine for their systemic symptoms developed CNS involvement much more frequently than those that did not receive cyclosporine [32, 33, Class III]. Our observations also support this idea [34]. The EULAR task force recommends that cyclosporine should not be started in patients with neuro-Behçet, and if neurologic symptoms occur during cyclosporine treatment, it should be immediately discontinued [22, 23•].

Standard dosage :

5 mg/kg per day orally. It has a rapid onset of action, but its efficacy gradually declines with time. It is sometimes combined with azathioprine in managing severe uveitis, and unpublished data show that baseline visual acuity improves under this regimen, with no additional toxicity attributable to the combination. Because of the known adverse effects of renal dysfunction and hypertension, serum creatinine values and arterial blood pressure should be regularly monitored.

Contraindications :

Pregnancy and lactation are absolute contraindications. Infections should be brought under control before starting the drug. The drug should not be used in patients with hypertension or renal failure, or in patients with a past history of hypersensitivity reaction. Neurologic involvement of BD is also considered a contraindication.

Main drug interactions :

The main mechanism of interaction between other drugs and cyclosporine is an effect on cytochrome P450, resulting in reduced or elevated blood concentrations. All major antiepileptic drugs (e.g., phenytoin, phenobarbital, carbamazepine, and valproate), ticlopidine, and the antimicrobials trimethoprim-sulfamethoxazole and rifampin accelerate the clearance of cyclosporine, resulting in reduced blood levels. Decreased clearance and increased levels of cyclosporine have been associated with concurrent administration of methylprednisolone, the calcium channel blockers diltiazem and verapamil, and the antimicrobials erythromycin, ketoconazole, fluconazole, and amphotericin B. Histamine blockers and nonsteroidal anti-inflammatory drugs may potentiate nephrotoxicity. Cyclosporine should not be used with digoxin (or should be used very cautiously), because it may increase the risk of digoxin toxicity.

Main side effects :

The major toxic manifestations of cyclosporine are renal, and nephrotoxicity occurs in 25% to 75% of patients treated with the drug. Renal dysfunction is usually reversible with discontinuation of the drug or reduction in dose. Hypertension is seen in more than 30% of patients, and opportunistic infections, hepatotoxicity, headache, hirsutism, gingival hyperplasia, tremor, fluid retention, encephalopathy, and anaphylaxis may also occur. The risk of malignancy secondary to cyclosporine therapy is up to fivefold greater than in the normal population; its combination with other immunosuppressives further increases the risk.

Cost/cost-effectiveness :

Cyclosporine is more expensive than azathioprine, but less expensive than interferon alfa and TNF-α antagonists. There are no formal studies evaluating its cost-effectiveness.

Cyclophosphamide

Cyclophosphamide is an alkylating agent that is structurally related to nitrogen mustard. It exerts its effect by acting on rapidly dividing cells, including B cells and T cells. It is recommended as an alternative therapy for retinal vasculitis in BD [4, Class IV]. It has been a relatively common practice to use it in NBD, as BD is considered to be a form of vasculitis. However, its use in BD is empirical, as there are no randomized controlled trials regarding this indication. In an open study, intravenous pulsed cyclophosphamide was given to 17 patients, of whom 7 had CNS involvement [48, Class III]. One died of undetermined causes, two showed no response, and four with recent onset of neurologic involvement showed some improvement. Our observations with cyclophosphamide vary: some patients are unresponsive to it and some others have developed CNS involvement while undergoing cyclophosphamide therapy for the systemic disease. However, the use of cyclophosphamide is common when there is systemic arterial involvement in BD, so it may be considered as an alternative for selected patients with CNS arterial involvement.

Standard dosage :

Several protocols have been proposed for the use of cyclophosphamide in BD. The recommended oral dose is 2 to 3 mg/kg daily. An alternative regimen, recommended for patients with severe ocular inflammation or CNS involvement, consists of intravenous cyclophosphamide administered monthly at a dose of 700 to 1,000 mg/m2 body surface area in combination with glucocorticoids for 12 to 24 months. Pulsed cyclophosphamide is generally administered with antiemetics, intravenous hydration and with continuous bladder irrigation, or infusion of mesna for the prevention of hemorrhagic cystitis. Dosage adjustment to maintain a WBC count of 2,500 to 4,000 cells/microliter or a relative lymphocyte count of 10% is usually recommended for the long-term use of this drug.

Contraindications :

Pregnancy and lactation are absolute contraindications. The use of cyclophosphamide should be avoided in patients with severe bone marrow depression or those who have ongoing infections.

Main drug interactions :

Cyclophosphamide increases the inhibition of cholinesterase activity by succinyl chloride, especially in the first 10 days of administration. Phenobarbital and phenytoin increase its rate of metabolism and the leukopenic effect.

Main side effects :

The most severe side effects are reduced resistance to infection, bone marrow suppression, hemorrhagic cystitis (which can be prevented by the concurrent administration of the acrolein inhibitors), and an increased risk of bladder cancer. Cyclophosphamide has teratogenic effects, and also causes nausea and vomiting, diarrhea, fatigue, alopecia, and amenorrhea. It may cause infertility in both sexes.

Cost/cost-effectiveness :

Cyclophosphamide is relatively inexpensive, but there are no analyses of its cost-effectiveness.

Interferon alfa

Interferons are naturally occurring glycoproteins that are produced by lymphocytes, macrophages, fibroblasts, and certain other human cells. They are named for their ability to interfere with viral RNA and protein synthesis. There are three types of interferon (interferon alfa, interferon-β, and interferon-γ), which are synthesized by different cell types. The structures of the α and β types are similar. Interferon alfa possesses antiviral, immunomodulating, and antiproliferative effects, and on viral stimulation it is primarily synthesized in macrophages. Although its mode of action in BD is unknown, interferon alfa was originally considered for BD because of its antiviral activity [49, Class IV]. It is more likely, however, that its immunomodulatory effects, such as its influence on proinflammatory cytokines, are responsible for the responses observed in BD. Interferon alfa-2a and alfa-2b are the two forms reported to be used in BD; the interferon alfa-2a regimen was found to be more effective [50, Class IV].

Interferon alfa is usually administered in BD for the management of retinal vasculitis and arthritis. Recent studies have shown that the drug was effective in the control of uveitis [51, 52]. In an open-label study in which patients with neurologic involvement were excluded, interferon alfa was associated with a reduction in the number of oral and genital ulcers, cutaneous lesions, and articular symptoms [50, Class IV]. A meta-analysis revealed that the drug was also beneficial in treating mucocutaneous lesions, arthritis, and gastrointestinal symptoms [49, Class IV]. These results should be interpreted with caution, because these data are derived mainly from uncontrolled studies to case reports. There is no consensus on the dose to be used, and exacerbations are frequent when the drug is discontinued. There is only a single case report of beneficial effect in NBD [53]. We have treated a few patients with parenchymal CNS involvement or dural sinus thrombosis and observed that the disease stabilized and did not relapse during treatment or after treatment cessation. We also have limited experience with interferon-β in combination with azathioprine in cases with BD and MS-like disorders, and have the impression that the disease is stabilized with this treatment [54].

Standard dosage :

There is no consensus on the standard dosage of the drug. For its usual application in eye involvement, starting therapy consists of 6 million IU subcutaneously three times a week, maintained with 3 million IU subcutaneously three times a week.

Contraindications :

Interferon should not be administered in the presence of depression or bipolar disorder. Pregnancy and lactation are also contraindications.

Main drug interactions :

There are no known drug interactions.

Main side effects :

Influenza-like symptoms such as fever, chills, headache, sweating, myalgias, and profound fatigue, and gastrointestinal symptoms such as anorexia, abdominal pain, nausea, vomiting, and diarrhea are relatively common. Injection site reactions and mild alopecia may occur. Bone marrow suppression with granulocytopenia and thrombocytopenia, neurotoxicity manifested as an encephalopathy, electroencephalographic changes, myopathy, and seizures are more serious effects that have been reported.

Cost/cost-effectiveness :

Interferons are expensive. No formal cost-effectiveness analysis has been performed.

Thalidomide

Thalidomide is a nonbarbiturate hypnotic drug that also has anti-inflammatory, immunomodulatory, and antitumor properties. It has recently received considerable attention because of its beneficial effects in various autoimmune diseases and malignancies. Its mechanism of action in autoimmune disorders may be related to its selective inhibition of certain cytokines. It appears to be highly specific for the suppression of TNF-α. Probable overall stimulation of Th2 cells and inhibition of Th1 subpopulations have also been suggested. It is not routinely used in clinical practice, but a randomized, double-blind, placebo-controlled trial has shown that the drug is effective in treating the oral and genital ulcers and follicular lesions of BD in the short term in male patients [55, Class I]. However, relapses are common when it is discontinued. Mild polyneuropathy was a major adverse effect, which developed in 6.3% of patients. In three patients, the neuropathy occurred within a year following trial completion, and CNS involvement developed in one patient after the trial.

Standard dosage :

In BD, the drug is administered orally at a daily dose of 100 to 300 mg.

Contraindications :

The drug is contraindicated in pregnant women and in women capable of becoming pregnant because of its well-established teratogenic effects.

Main drug interactions :

None.

Main side effects :

Teratogenicity and peripheral neuropathy are the major adverse effects of the drug. Sedation, fatigue, constipation, weight gain, transient rash, and decrease in libido are some of its other effects.

Cost/cost-effectiveness :

Because thalidomide is well known for its high risk of teratogenicity and other adverse effects, in many countries it can be prescribed only by licensed and registered prescribers. Its cost varies from country to country, and in many places only the generic form is affordable. There are no formal studies on the cost-effectiveness of this drug.

TNF-α antagonists

TNF-α antagonists directly neutralize soluble TNF and prevent its binding to its receptors. They may also induce complement-dependent and antibody-dependent cytotoxicity, and may be involved in programmed cell death of inflammatory cells. The three TNF-α antagonists that have been available since the late 1990s are infliximab, a chimeric monoclonal anti-TNFα antibody; adalimumab, a human recombinant monoclonal anti-TNFα antibody; and etanercept, a TNF-α receptor antagonist. There are two newer drugs, certolizumab pegol and golimumab, but the experience with them is very limited, and they will not be discussed here. Only infliximab is approved in Japan for BD uveoretinitis [56••]. Infliximab was shown to produce a rapid and effective response in small cohorts with refractory inflammatory eye disease due to BD in open-label studies [57–59, Class III], but only small observational series or case presentations reporting beneficial effects pertain to CNS involvement [26, 27, Class IV]. A recent multicenter, case-control study including our limited experience with infliximab in CNS involvement of BD suggests that the TNF-α antagonists may be beneficial in refractory cases [28•].

Standard dosage :

Because the use of anti-TNF drugs in CNS involvement of BD is limited to case reports, there is no standard dosage. For approved indications such as rheumatoid arthritis, infusions of 3 to 5 mg/kg of infliximab are usually given at week 0, 2, 6, and every 6 to 8 weeks thereafter. Adalimumab is recommended at a dose of 40 mg given subcutaneously every other week, and etanercept is recommended at a weekly dose of 50 mg given subcutaneously [56••]. The most common agent used in neuro-Behçet disease is infliximab, given using the regimen just mentioned. However, it should be noted that the dose could be increased up to 10 mg/kg, and the intervals could be decreased to every 4 to 6 weeks. Although the data are limited for BD, infliximab seems to be the most efficacious of the anti-TNF agents [56••].

Contraindications :

Advanced congestive heart failure, preexisting multiple sclerosis, any active infection, lymphoma, and solid tumors pose contraindications to the use of anti-TNF drugs; pregnancy is a relative contraindication.

Main drug interactions :

These agents do not have serious drug interactions. They should not be used together with the anti-IL-1 agent anakinra, as the immunosuppressive effect could be heightened. Vaccines may not be effective during anti-TNF therapy, so all necessary vaccinations should be completed prior to treatment with anti-TNF agents.

Main side effects :

Allergic reactions can be seen in about 5% of infliximab infusions. Rates of infections may increase, especially for tuberculosis. Rare adverse events include aplastic anemia, psoriasis, systemic lupus erythematosus, and vasculitis. Demyelinating CNS disease and peripheral neuropathies have been associated with the use of TNF-α antagonists [58, 60], but these effects have not yet been reported with their use in BD.

Special points :

Prior to the use of anti-TNF agents, patients must be screened for latent tuberculosis, hepatitis B and C, and HIV.

Cost/cost-effectiveness :

Anti-TNF agents are expensive drugs, with a yearly cost well over $10,000 US. However, there is no formal cost-effectiveness analysis in BD.

Surgery

  • The only neurologic manifestation of BD that may require surgical intervention is the formation of an arterial aneurysm. The causative association of classic Willis aneurysms with BD is not established; most probably, they represent chance concurrence. However, when the aneurysm is at an atypical intracranial or extracranial location, the possibility of vasculitic aneurysm formation should be considered. In that case, medical treatment with pulsed cyclophosphamide should be the initial step, as dramatic improvement of aneurysms has been reported with this treatment [61, 62]. Successful surgical interventions also have been reported [63]. However, in the case of classic Willis aneurysms, interventional neuroradiology and coil insertion should hypothetically be the procedure of choice [64, 65, Class IV]. Pretreatment with low-dose glucocorticoids can be recommended to prevent the so-called “vascular pathergy reaction,” as the puncture of arteries and veins in BD could be complicated by thrombosis and pseudoaneurysm formation.

Physical/speech therapy and exercise

  • Some patients with CNS involvement who have substantial residual sequelae or a progressive course may end with upper motor neuron or cerebellar impairment or cognitive dysfunction that can interfere with functioning. When indicated, assistive appliances such as canes, walkers, ankle-foot orthoses, or knee braces, as well as other rehabilitation devices, could be used. Physical therapy and rehabilitation may be very beneficial, along with cognitive rehabilitation when indicated.

Other treatments

  • We have used intravenous immunoglobulins (IVIg) in four patients with progressive NBD, based on its reported use in some forms of vasculitis, but none of these patients showed improvement [66, Class IV]. Our limited experience does not warrant the use of IVIg in NBD, with the possible exception of BD cases with well-documented inflammatory peripheral neuropathy unresponsive to other treatments.

  • Tacrolimus is a macrolide, and its mechanism of action is similar to that of cyclosporine in that it inhibits T-cell activation and the synthesis of several cytokines. It has been used to treat ocular inflammation in BD. As with cyclosporine, tacrolimus has been implicated in possible association with CNS toxicity or enhancement of neurologic involvement [67].

  • Immunomodulators such as pentoxifylline, the antihelminthic levamisole, and the antiplatelet agents aspirin and dipyridamole have been used in uncontrolled studies in NBD without any significant result [4, 21].

  • In a few case reports, patients with severe progressive NBD were treated successfully with autologous or allogeneic stem cell transplantation following severe immunosuppression [68–70••]. However, as this procedure is a very aggressive form of treatment with significant mortality in autoimmune disorders and the experience is limited in NBD, it may be considered only in very severe forms of the disease [70••].

Emerging therapies

  • Anti-IL-17A has been studied in a large group of patients with ocular BD, but the results are discouraging [71].

  • Anti-IL-1β was used in seven patients with severe BD who had eye involvement resistant to cyclosporine and azathioprine. The results seem to be promising [72].

  • Monoclonal antibody therapies such as alemtuzumab, daclizumab, and rituximab were used in small studies or single cases of non-neurologic BD, without conclusive results [70••].

Pediatric considerations

  • Although the first systemic symptoms of BD can emerge during childhood, usually in the form of recurrent oral aphthae, it is uncommon to have the complete disease in childhood. The prevalence rates of pediatric cases with both BD and NBD are very low, and the rate of pediatric neurologic involvement occurring before age 16 was 3.6% in our combined cohort of 728 patients with NBD (submitted for publication). Interestingly, childhood NBD cases almost exclusively present with CVST (80%).

  • As with adult NBD, there is no Class I evidence for any beneficial treatment in pediatric cases. Our usual approach is to give high-dose intravenous steroids (i.e., 20 mg/kg per day of methylprednisolone) for 5 consecutive days, and either an oral or pulsed taper over a prolonged period [73]. It is very important for the care of these children to be supervised by a pediatric endocrinologist to prevent developmental and growth delay due to steroids. Because most cases present with CVST, the usual approach is not to give any initial immunosuppressive therapy unless there is other major vascular involvement or recurrence. When necessary, the choice is azathioprine.