by Aksel Siva
Behçet’s disease (BD), originally described in 1937 by the Turkish dermatologist Hulusi Behçet, as a distinct disease with oro-genital ulceration and uveitis known as the “triple-symptom complex”, is an idiopathic chronic relapsing multisystem vascular-inflammatory disease of unknown origin. The disease affects many organs and systems, causing mucocutaneous lesions, eye inflammation, musculoskeletal problems, and major vessel disease; there is cardiac, pulmonary, and gastrointestinal involvement as well as nervous system involvement.
Due to the lack of specific laboratory, radiologic, or histologic findings of BD, accurate diagnosis of BD depends only on clinical findings. According to the International Study Group’s classification 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.
The epidemiology of the disease shows a geographical variation, seen more commonly among the Silk Route countries that extend from the Mediterranean region to Japan. This is coupled by a similar variation in HLA-B51, which is strongly associated with the disease in high prevalence areas. The prevelance of BD is highest in Turkey (1/250). Its prevalence has been reported to be less than 1/105 in Northern and Central Europe and the US, and goes up to 2.5/105 in the north-western Mediterranean region, and then increases considerably in the Eastern Mediterranean region.
The usual onset of the BD is in the third or fourth decade; however, although rare, onset in children has also been reported. BD shows equal frequency among males and females. However males have a more severe course due to the morbidity of pulmonary vascular diseases.
The etiology of BD is unknown, but clinical and laboratory data suggest that there is dysfunction of both innate and adaptive immune systems, resulting in an exaggerated response to viral or bacterial insults. Debate is ongoing about whether this hyperreactivity is an autoimmune phenomenon, or — as suggested by more recent data — an autoinflammatory phenomenon. The core histopathologic phenomenon seems to be a vasculitic involvement in some cases and a low-grade, chronic, nonspecific inflammation in others.
NEURO-BEHÇET SYNDROME
Primary neurological involvement is named as Neuro-Behcet’s Syndrome (NBS) and occurs approximately in 5-10% in all patients with BD. The onset of neurologic involvement is about 3-6 years after the diagnosis of the systemic disease and NBS is 3–4 times more frequent in males than women. However, although extremely rare, onset with neurological involvement prior to the systemic features of BD have been reported.
The suggested diagnostic criteria for NBS in a patient that fulfills the International Diagnostic Criteria for Behçet’s Syndrome is the occurrence of neurological symptoms not otherwise explained by any other known systemic or neurological disease or treatment, and in whom objective abnormalities consistent with NBS are detected either on neurological examination, and/or with neuroimaging studies (magnetic resonance imaging) and/or abnormal cerebrospinal fluid examination.
Parenchymal syndrome – Intra-axial NBS: The majority of patients with neurologic involvement due to BS 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 Syndrome” (pNBS) or “intra-axial NBS.” These patients present with a subacute (or rarely, acute) onset of severe headache, dysarthria, ataxia, and hemiparesis. Cognitive-behavioral changes, emotional lability, a self limited or progressive myelopathy, urinary sphincter dysfunction and to a lesser extent other CNS manifestations such as extrapyramidal signs and seizures have been reported. Isolated optic neuritis are rare in BS, and most visual symptoms in BS are due to ocular inflamation. Onset of pNBS is usually associated with a flaring of the systemic features of BD. Some patients may have only a single attack, with or without residual neurologic deficits, but most will have recurrences and some will have secondary progression. pNBS is usually associated with a poor prognosis, with approximately 50% of the patients becoming severely disabled within 10 years.
Cranial MRI will show an almost stereotypical edematous 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; usually there is a much smaller area of enhancement, and occasionally small hemorrhages can be seen. These lesions regress overtime but enlargement of the third ventricule and brainstem atrophy may develop. Rarely, subcortical or periventricular white matter lesions can be seen, which may be difficult to distinguish from other vasculitic lesions or multiple sclerosis. When there is spinal cord involvement, it may tend to be longitudinally extensive but the AQP4 antibodies are absent.
The systemic arterial involvement is infrequent in BD, and so is cranio-cervical arterial involvement, but there are a number of case reports with bilateral internal carotid artery occlusion, vertebral artery dissection, intracranial aneurysms and intracranial arteritis.
A neurobehavioral syndrome, which consists of euphoria, loss of insight, disinhibition, psychomotor agitation or retardation, with paranoid attitudes and obsessive concerns may develop in some patients with or without other neurological symptoms of NBS which is named as “Neuro-Psycho-Behçet Syndrome”.
Non-parenchymal syndrome – extra-axial NBS: 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 neurologic involvement. This is termed “vascular- NBS” or “extra-axial NBS”. Clinical manifestations resulting from thrombosis of the intracranial venous system vary according to the site and rate of venous occlusion and its extent.
CVST in BD 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. Interestingly, in the pediatric age group affected with BD, the neurologic involvement is early and mostly in the form of CVST. A close association between CVST and systemic major vessel disease in BD has been reported. Neurologic disease in the form of CVST has a better neurologic prognosis than pNBS. CVST is often visible on MRI and MRV and cerebral angiography is not indicated. A spinal tap will reveal increased cerebrospinal fluid (CSF) pressure, but the cellular and chemical composition mostly is normal.
These two types of involvement occur in the same individual very rarely, and presumably have a different pathogenesis.
Headache: Headache is the most common neurologic symptom seen in BD and may be a manifestation of both forms of NBS, or may be in association with ocular inflammation. The prevalence of co-exiting primary headaches are no less than the general population. However, a paroxysmal migraine-like pain occurring with exacerbation of the systemic features of the disease may also be seen, which may be explained by a vascular headache triggered by the immunomediated disease activity in susceptible individuals.
Peripheral nervous system involvement: Primary peripheral nervous system (PNS) involvement is extremely rare in BD and when seen secondary polyneuropathy as a side effect of treatment should be considered.
Treatment of parenchymal NBS: There are no controlled data for the management of neurologic involvement and treatment strategies mostly currently depends on reports based on the clinical experience of neurologists.
High-dose intravenous methylprednisolone (IVMP) for up to 10 days, which is followed by either a slow oral tapering, is the first choice for treating acute relapses. In pNBS azathioprine is the most commonly used agent in the long-term treatment, however with limited efficacy but better risk/benefit profile than many other immunosuressants. Currently a growing number of case reports are suggestive that infliximab alone or combined with immunosuppressive therapies could be useful in preventing disease progression and providing clinical improvement in NBS patients who are resistant to conventional immunosuppressive treatment.
CVST 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. The use of anticoagulation in CVST however, remains controversial.
Aksel Siva is Professor of Neurology at the Department of Neurology, Istanbul University, Cerrahpaşa School of Medicine Cerrahpaşa in Istanbul, Turkey.
Together with Ugur Uygunoglu, MD and Sabahattin Saip, MD Prof he leads the neurology team of the I.U.Cerrahpaşa School of Medicine Behçet’s Disease Research Center Study Group.
Currently (May 2014) there are records of about 10.000 patients with BS who are registered at the multidisciplinary outpatient clinic at Cerrahpasa Medical Faculty. This dedicated clinic was founded in 1977 by Prof. Hasan Yazici and had been the first of its kind both locally and internationally. The clinic has been held once a week every Monday since its inception. All patients are initially evaluated by a rheumatologist, dermatologist, and ophthalmologist. The patients are referred to the departments of neurology, pulmonary disease, gastroenterology, and vascular surgery when necessary, and all management problems are discussed in a joint meeting of the various disciplines during the same day the patients are seen.
The information presented in this article is based on the following chapter:
Saip S, Akman-Demir G, Siva A. Neuro-Behçet syndrome. Handb Clin Neurol. 2014;121:1703-23.
