Behçet's syndrome and the nervous system

PURPOSE OF REVIEW: Beh?et's syndrome (BS) is a multi-system, vascular-inflammatory disease of unknown origin, involving the nervous system in a subgroup of patients. The syndrome is rare, but as patients with BS are young and frequently present with an acute or subacute brainstem syndrome or hemiparesis, as well as with other various neurological manifestations, the syndrome is often included in the differential diagnosis of multiple sclerosis, stroke of the young adult, and another wide range of neurological disorders. The present review summarizes the neurological involvement in BS, and emphasizes recent clinical concepts and ethiopathogenetic findings. RECENT FINDINGS: Over the last years the growing clinical and imaging evidence had suggested that neurological involvement in BS may be subclassified into two major forms: one, which is seen in the majority of patients, may be characterized as a vascular-inflammatory CNS disease, with focal or multifocal parenchymal involvement; the other, which has few symptoms and a better neurological prognosis, may be caused by isolated cerebral venous sinus thrombosis and intracranial hypertension. These two types rarely occur in the same individual, and their pathogenesis is likely to be different. A nonstructural vascular type headache is relatively common, whereas isolated behavioral syndromes and peripheral nervous system involvement are rare. SUMMARY: The involvement of the nervous system in BS is heterogeneous as clinical and imaging data reveal. Currently it is unknown which factors determine or have a role in the development of neurological involvement, but some progress has been achieved in understanding the neurological spectrum of the syndrome, which may lead to a better management of these patients.     

Optic neuropathy in Behçet’s syndrome

This paper presents the clinical features, investigation results and response to treatment of four cases of primary optic neuropathy in Behçet’s syndrome, with a comprehensive literature search for all other published cases. A total of 20 cases has been identified; the clinical syndrome is a unilateral or bilateral optic neuropathy of inflammatory type in which pain arises in 20 % and optic disc swelling seen in 45 % of cases. The condition was relapsing in four cases, and a progressive optic neuropathy was seen in one case. All but the progressive case responded to steroids with or without additional immunosuppression. The nadir visual acuity was the only determinant of visual outcome. 67 % of cases reported a return to normal acuity following treatment.     

Neurological complications of Behçet’s syndrome

In this review of the neurological complications of Behçet’s syndrome, the clinical features and epidemiology of the systemic disease are summarised before a discussion of the neurological syndromes which may develop is made. Neurological involvement occurs in 9% of cases, and is equally prevalent in each geographical area. Vascular complications occur in 14%, in whom thrombosis of the venous sinuses or cerebral veins occurs, and intracranial hypertension, venous infarction and parenchymal haemorrhage may develop. There is a correlation with the prevalence of peripheral venous thrombosis. Concurrent inflammatory disease of the brain is most uncommon. Inflammation may affect any part of the central nervous system, but most commonly involves a subacute meningoencephalitis of the brainstem and diencephalon. Inflammatory lesions elsewhere in the brain and in the spinal cord may occur, and tumefactive lesions may arise from the diencephalon. Cognitive dysfunction and affective symptoms, including psychosis, may occur, and there are high levels of anxiety and fatigue which are related to the severity of the systemic disease, all of which are more severe in those with neurological involvement. Imaging shows enhancing lesions which often disappear after treatment, but atrophy is common. The CSF is active when there is a meningoencephalitis, and oligoclonal bands do not occur. Treatment is with steroids and immunosuppression. Those with treatment resistant disease respond to biological agents, including TNF alpha, IL-1 and IL-6 antagonists.     

The spectrum of Susac’s syndrome

We report a series of four patients with Susac’s syndrome, which is characterized by the triad of visual loss due to branch retinal artery occlusions, sensorineural hearing loss due to cochlear involvement, and encephalopathy due to cerebral microangiopathy. However, as we describe in this series, the clinical triad may not be apparent for years, resulting in delays in diagnosis. We also report the variable cerebrospinal fluid and brain magnetic resonance imaging findings, and treatment using a combination of steroids and intravenous immunoglobulin, followed by mycophenolate mofetil.     

Histopathology of central nervous system lesions in Behçet's disease

Central nervous system (CNS) involvement in Beh?et's disease, usually called neuro-Beh?et's syndrome (NB), is one of the most serious complications of the disease. In the present study, we carried out immunohistological examination of biopsied or autopsied brain tissues from 3 patients with different types of NB, acute NB, chronic progressive NB, and NB in a long-term remission. Histopathology of mass lesion in acute NB revealed infiltration of mononuclear cells around small vessels, consisting of CD45RO+ T lymphocytes and CD68+ monocytes with few CD20+ B lymphocytes. Of interest, TUNNEL staining disclosed that most neurons were undergoing apoptosis in the inflammatory lesion. In chronic progressive NB, similar histopathological changes were noted in pons, cerebellum, medulla, internal capsule, and midbrain, although the degree of mononuclear cell infiltration was modest. There were also scattered foci of neurons undergoing apoptosis with formation of a few binucleated neurons. The most prominent feature of NB in a long-term remission was atrophy of basal pons with formation of cystic or moth-eaten lesions, consisting of isomorphic gliosis with viable neurons. There were still scattered foci of perivascular cuffing of T lymphocytes and monocytes. These results emphasize the common features throughout the courses of NB, perivascular cuffing of T lymphocytes and monocytes, irrespective of the clinical phenotypes. More importantly, it is suggested that soluble factors produced by infiltrating cells, including IL-6, might play a role in the induction of apoptosis of neurons in NB.     

Cerebrovascular manifestations of Behçet’s disease

Behçet’s disease (BD) is a systemic inflammatory disease commonly characterized by oral and genital ulcerations, with skin and eye involvement. Its cause is still unknown, but vasculitis is the major pathologic feature. BD is a rare condition, seen more commonly in Turkey, as well as in Middle Eastern, Mediterranean and Far Eastern countries. Neurological involvement is reported to manifest as brainstem or corticospinal tract syndromes, increased intracranial pressure mostly related to venous sinus thrombosis or aseptic meningitis, isolated behavioral symptoms or isolated headache. This report presents a 34-year-old BD patient with secondary cerebral infarction due to head trauma. The clinical and central nervous system findings of BD are discussed.     

The role of functional neuroimaging in the differential diagnosis of idiopathic Parkinson’s disease and multiple system atrophy

Abstract. Parkinsonism is a symptom of a number of neurodegenerative disorders in the elderly. Even though clinical criteria for various parkinsonian disorders have been developed recently, the differential diagnosis of parkinsonian disorders based on clinical symptoms remains unsatisfactory, particularly in early disease stages. Early differential diagnosis on the other hand is important as prognosis and treatment options differ substantially. Multiple system atrophy (MSA) is one of the major differential diagnoses of idiopathic Parkinsons disease (PD). Radiotracer-based imaging methods such as positron emission tomography (PET) remain the established method for differential diagnosis of parkinsonian disorders. The following paper provides a review of different PET imaging methods for the differential diagnosis of PD and MSA patients.     

Central nervous system involvement in Beh?et's disease]

Central nervous system involvement in Beh?et's disease, usually called neuro-Beh?et's syndrome (NB), includes acute type and chronic progressive type. Acute NB is characterized by acute meningoencephalitis with focal lesions, presenting high intensity areas in T2-weightened images or FLAIR images on MRI scans. Cyclosporin A frequently causes acute NB. Acute NB responds to steroid therapy, and is usually self-limiting. By contrast, chronic progressive NB is characterized by intractable slowly progressive dementia, ataxia and dysarthria with persistent elevation of cerebrospinal fluid IL-6 activity (more than 20 pg/ml). In our series, most patients (approximately 90%) with chronic progressive NB were HLA-B51 positive, and had history of attacks of acute NB prior to the development of progressive neurological symptoms. Chronic progressive NB is resistant to conventional treatment with steroid, cyclophosphamide, or azathioprine. However, recent studies suggest the efficacy of low dose methotrexate in chronic progressive NB.     

Behçet’s Syndrome and Nervous System Involvement

Purpose of Review

Although Behçet’s syndrome (BS) is classified as a rare disease in European countries and the USA, its neurologic involvement “neuro-Behçet’s syndrome (NBS)” is commonly included in the differential diagnosis of many inflammatory and vascular central nervous system (CNS) disorders. Clinical and neuroimaging findings support two major forms of NBS: parenchymal NBS (p-NBS) and an extra-parenchymal form that presents with cerebral venous sinus thrombosis (CVST). The present review summarizes recent findings on the etiopathogenesis and clinico-radiological features of this disorder as well as its treatment options.

Recent Findings

Recent laboratory and clinical findings include the discovery of antibodies to human and mouse neuro-fibrils showing cross-reactivity with Streptococcus spp. and Mycobacterium tuberculosis heat shock proteins (HSP) in NBS. Diagnostically, two distinct magnetic resonance imaging (MRI) patterns of spinal cord involvement have been observed: (a) “Bagel sign” and (b) “motor neuron” patterns. Therapeutic studies have shown that infliximab effectively prevents further relapses and stabilizes the symptoms of patients experiencing ongoing clinical relapses while being treated with single or multiple immunosuppressant drugs.

Summary

Primary neurological involvement referred to as NBS. The majority of patients with NBS present with parenchymal involvement that commonly affects the brain stem-diencephalic region. Headache, dysarthria, ataxia, and hemiparesis are the main clinical features of NBS.

     

Increased complexin-1 and decreased miR-185 expression levels in Behçet’s disease with and without neurological involvement

Although complexin 1 (CPLX1) is not known as an inflammation factor, recent identification of a complexin 1 (CPLX1) polymorphism in Behçet’s disease (BD) has sparked an interest in the role of this molecule in autoinflammation. DNA samples were isolated from peripheral blood mononuclear cells (PBMC) of BD and neuro-Behçet’s disease (NBD) patients and expression levels of CPLX1 and miR-185, a predicted target miRNA for CPLX1 and an inflammation-related miRNA, were investigated by real time PCR assays. PBMC expression levels of CPLX1 were significantly increased in BD and NBD patients. By contrast, levels of miR-185 were reduced in both patient groups. A moderate inverse correlation was found between levels of CPLX1 and miR-185. No correlation could be found between expression levels and clinical features of patients. Significant expression alterations of CPLX1 in BD and NBD patients suggest that this molecule has a proinflammatory action. The putative role of CPLX1 in BD pathogenesis remains to be further studied.     

Risk factors and differential diagnosis of Alzheimer’s disease

Due to demographic changes the frequency of dementia is increasing dramatically. About 50–60% of patients with dementia are clinically associated with AD, which is a multifactorial and long-term disease both in clinical and preclinical aspects. Various genetic and non-genetic risk factors play a role in influencing age of onset and disease progression.     

Transcranial Doppler detection of microembolic signals in patients with Behçet’s disease

We evaluated the prevalence of microembolic signals (MES) in patients with Behçet’s disease (BD). We also attempted to determine the frequency of MES in BD patients with or without neurological involvement. This study enrolled 55 patients fulfilling the diagnostic criteria of International Study Group for BD. Bilateral transcranial Doppler ultrasound of the middle cerebral arteries was performed. MES were identified based on the criteria of International Consensus group on Microembolus Detection. Patients with BD were divided into two groups in respect of the presence of neurological involvement (n = 10) or not (n = 45), and counts of MES in the two were compared with each other and with normal subjects. We found MES in 16 patients (29%) with BD. The frequency was higher in patients with neurological involvement than in those without (80% vs. 17%, P < 0.001). In patients with neurological involvement there was a positive correlation in regression analysis between the prevalence of MES and disease duration (P = 0.025). There was a significantly higher prevalence of MES in BD patients than in control subjects. The frequency of MES was higher in patients with neurological involvement than in those without. TCD detection of MES may allow the recognition of subset of patients at high risk for the appearance of neurological involvement.     

P300 and neuropsychological evaluation in Behçet’s disease with and without neurological manifestations

Abstract. We evaluated cognitive dysfunction in Behçets disease (BD) with and without neurological manifestations by P300 and neuropsychological tests. Thirtyfour BD patients without neurological manifestations, eighteen BD patients with neurological manifestations and 15 controls were studied. P300 potentials and neuropsychological tests were performed. P300 latency values and neuropsychological tests were not significantly different from the normal controls in BD patients without neurological manifestations. In neurologically symptomatic patients attention and memory deficits and delayed P300 potentials were found.     

The involvement of astrocytes and kynurenine pathway in Alzheimer’s disease

The kynurenine pathway (KP) and several of its neuroactive products, especially quinolinic acid (QUIN), are considered to be involved in the neuropathogenesis of Alzheimer's disease (AD). There is growing evidence suggesting that astrocytes play a critical role in the regulation of the excitotoxicity and inflammatory processes that occur during the evolution of AD. This review focuses on the role of astrocytes through their relation with the KP to the different features associated with AD including cytokine, chemokine and adhesion molecule production, cytoskeletal changes, astrogliosis, excitotoxicity, apoptosis and neurodegeneration.     

Neurological manifestations of Behçet’s disease in Japan: a study of 54 patients

The type and frequency of neurological manifestations of Behçet’s disease (BD) vary with ethnicity. We analyzed the neurological manifestations of BD in Japanese patients. All patients undergoing treatment at one of the two Yokohama City University hospitals from July 1991 to December 2007 and who fulfilled the Japanese criteria for BD revised in 1987 were studied retrospectively by chart review. Patients had been neurologically assessed by neurologists. We recorded neurological signs and symptoms, magnetic resonance imaging or computed tomography findings, and results of cerebrospinal fluid examinations from the records of each patient. We studied 412 patients with BD, of whom 54 (13%) had neurological involvement (neuro-Behçet’s disease: NB). NB patients included a significantly higher proportion of males (61%) than non-NB patients (42%, P = 0.009). The majority of patients (n = 38, 70%) had acute parenchymal NB, 15 (28%) had chronic progressive parenchymal NB, and 1 (2%) had the non-parenchymal type. Headache and fever were more frequently reported by patients with acute parenchymal NB. Personality changes, sphincter disturbances, involuntary movements, and ataxia occurred predominantly in patients with chronic progressive parenchymal NB. Lesions were distributed throughout the CNS, but mainly in the brainstem, white matter, and basal ganglia. Analysis of end-point clinical outcomes revealed a poor prognosis for patients with chronic progressive NB. In Japan, most NB patients have the parenchymal type, and male gender is a predisposing factor. Because of the unfavorable prognosis associated with chronic progressive NB, development of effective therapies are urgently needed.     

Aseptic meningitis as the sole manifestation of Behçet’s disease

We report a 33-year-old woman who had aseptic meningitis alone, without any other systemic manifestations, due to Behçet’s disease. Behçet’s disease should be listed as a differential diagnosis of acute aseptic meningitis because, in acute aseptic meningitis caused by Behçet’s disease, early treatment with corticosteroids could ameliorate this disorder.