Clin Rheumatol (2012) 31:733–738 DOI 10.1007/s10067-011-1923-y CASE BASED REVIEW Association of amyotrophic lateral sclerosis and Behcet’s disease: is there a relationship? A multi-national case series Hela Mrabet & Afshin Borhani-Haghighi & Emel Koseoglu & Melike Mutlu & Recep Baydemir & Shahriar Nafissi & Slim Eschebbi & Emel Delibas & Shahdokht Samangooie & Fatih Yetkin & Amel Mrabet & Yesim Parman & Seyed Taghi Heydari & Gulsen Akman-Demir Received: 7 November 2011 / Accepted: 16 December 2011 / Published online: 11 January 2012 # Clinical Rheumatology 2012 Abstract Neurological involvement may be seen in 5–30% of the patients with Behcet’s disease (BD). Occasionally, parenchymal neurological involvement in BD can present as a spinal cord syndrome. However, motor neuron disease-like presentation is extremely uncommon. Here we are reporting five patients (all male; median age, 38) fulfilling both International Study Group criteria for BD and El Escorial criteria for amyotrophic lateral sclerosis (ALS). These patients were identified by a questionnaire sent to the members of the Neuro-Behcet Study Group of the International Study Group for BD. Three out of five patients had only motor presentations. In two patients, sensory and urinary manifestations were present as well. Spinal cord MRIs were normal in all, and brain MRIs were normal in four patients; one patient had nonspecific white matter changes. Two patients passed away H. Mrabet : S. Eschebbi : A. Mrabet Department of Neurology, Charles Nicolle Hospital, Tunis, Tunisia A. Borhani-Haghighi Transgenic Technology Research Center and Department of Neurology, Shiraz University of Medical Sciences, Shiraz, Iran E. Koseoglu : R. Baydemir : E. Delibas : F. Yetkin Department of Neurology, Faculty of Medicine, Erciyes University, Kayseri, Turkey M. Mutlu : Y. Parman Department of Neurology, Istanbul University, Istanbul, Turkey S. Nafissi Department of Neurology, Tehran University of Medical Sciences, Tehran, Iran 1–3 years after diagnosis of ALS, and two patients were lost to follow-up 3 and 11 years after admission; one patient is still alive 3 years after onset. The patients that are presented here might represent a rare form of neurological involvement in BD as well as sole coincidence. Larger prospective series are needed to further answer this issue. Keywords Amyotrophic lateral sclerosis . Behcet’s disease . Motor neuron disorders . Neuro-Behcet’s disease Introduction Behcet’s disease (BD) is complicated by neurological manifestations in 5–30% of patients with BD. Neuro-Behcet’s S. Samangooie Arad Hospital, Tehran, Iran S. T. Heydari Health Policy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran G. Akman-Demir Department of Neurology, Istanbul Bilim University, Istanbul, Turkey A. Borhani-Haghighi (*) Department of Neurology, Shiraz University of Medical Sciences, Motaharri clinic, Namazi Square, Shiraz, Iran e-mail: borhanihaghighi@yahoo.com 734 disease (NBD) usually presents as central nervous system (CNS) involvement [1, 2]. Parenchymal CNS involvement in BD more commonly takes the form of a brainstemcognitive syndrome due to a brainstem-diencephalic meningoencephalitis or, much less commonly, a spinal cord syndrome; another form of CNS involvement is dural sinus thrombosis [2]. On the other hand, peripheral nervous system involvement has rarely been reported in BD, and the causal relationship with the disease is unclear. There have been single case reports on neuropathic [3], neuromuscular [4], or myopathic presentation in BD [5]. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with a constellation of upper motor neuron (UMN) and lower motor neuron (LMN) signs [6]. The age at onset is usually in late adult life, and the disease runs a progressive course of variable duration. To our knowledge, there is only one case report with BD and ALS [7]. In this study, we evaluated patients with BD and ALS. Clin Rheumatol (2012) 31:733–738 ankle clonus, atrophy of extremity muscles, and fasciculation of the tongue. The patient had normal results from ocular motor, sensory, and cerebellar examinations. He was positive for HLA A9/A28/B51. Cerebral and spinal MRIs were normal. Electrophysiological studies revealed normal nerve conduction accompanied by fibrillation potentials and fasciculations at rest, and high-amplitude polyphasic motor unit potentials in maximal effort in various muscles of the lower and upper limbs and the tongue. The patient was treated with colchicine (1 mg per day), 1 g IV methylprednisolone (MP, repeated monthly for 6 months), riluzole tablets (100 mg per day), anti-spastic medications, and physical therapy. Progressively, the patient developed pseudobulbar palsy and exacerbation of weakness, and he became bedridden with dysphagia and difficulty of breathing. Three years after the onset of neurological symptoms, he passed away due to respiratory failure. Patient 2 Patients and methods In order to define cases with both BD and ALS, we conducted a survey among the members of the International NBD study group including 46 physicians from 24 countries. Only five cases were identified that fulfilled both the International Study Group’s criteria for BD [8] and the El Escorial criteria for ALS [9]. Among these, one each was from Tunis, Tunisia (among 55 NBD patients); Shiraz, Iran (among 58 NBD patients); and Kayseri, Turkey (among 100 NBD patients); and two were from Istanbul, Turkey (among 354 NBD patients). Here, we report retrospective data of these five patients with BD and ALS. The frequency of ALS in BD patients was compared with the frequency of ALS in the normal population where data were available. Case presentations Patient 1 A 38-year-old Tunisian man was admitted to the Neurological Department of Charles Nicolle Hospital, Tunis, Tunisia, for neurological investigation. He had been diagnosed as BD with recurrent oral ulcers (ROU) and genital ulcers (GU), folliculitis, uveitis, and positive pathergy reaction since the age of 25. He was on corticosteroids but not immunosuppressive drugs. He developed progressive weakness of the upper and lower limbs and had repeated falls in the last 6 months prior to admission. Neurological examination showed generalized spasticity, particularly in the legs, associated with generalized hyperreflexia, bilateral Hoffman and Babinski signs, A 46-year-old man referred to the NBD clinic of Istanbul University, Istanbul, Turkey, in 1997, with the complaint of slowly progressive left leg weakness which started 1 year prior to admission. He was diagnosed with BD 15 years ago with attacks of ROU, GU, folliculitis, and positive pathergy test. According to his medical history, he had been treated for pulmonary tuberculosis 20 years ago. He had a temporary bout of urinary hesitancy 4 years ago and needed urinary catheterization at that time. He had received shortterm courses of cyclosporine and oral MP 9 years and 1 year ago, respectively. His family history revealed a brother with BD, a sister with walking difficulty due to neurosyphilis, and a cousin with ALS. Neurological examination showed normal muscle strength, but bilateral leg spasticity, exaggerated deeptendon reflexes, ankle clonus, and Babinski signs. Superficial sensation was normal, but vibration sense was slightly impaired. Cerebellar functions were normal. His cranial, cervical, and dorsal MRIs were normal. His CSF examination result was also normal regarding cells, biochemistry, IgG index, and oligoclonal bands. During his follow-up, his leg spasticity became more prominent in the following 2 years. A course of IV MP was tried with the diagnosis of probable NBD. He had little benefit; afterwards, azathioprine was started in addition to symptomatic anti-spastic medication. However, his neurological condition continued to deteriorate slowly. Four years later, he started to use a unilateral cane for walking. His gait spasticity became evident, and leg weakness was added. He had been treated with another course of IV MP that time. Little benefit was observed. His gait difficulty increased slowly, and he started using bilateral assistance for walking Clin Rheumatol (2012) 31:733–738 6 years after admission. In 2004, he started complaining of weakness of his hands and difficulty in swallowing. However, at that time, EMG was normal other than upper motor neuron involvement. In 2005, hand weakness increased with additional thenar and hypothenar atrophy. This time, EMG revealed widespread lower motor neuron involvement. There were high-amplitude long-duration polyphasic motor unit potentials, fasciculation and fibrillation potentials, and positive spikes in bilateral hand, arm, and leg muscles, as well as abdominal muscles, whereas nerve conduction velocities were normal. Azathioprine was stopped, and riluzole was discussed with the patient; but he refused to take it. His condition continued to deteriorate slowly in the next years. He was lost to follow-up after 2008. Patient 3 A 37-year-old man was admitted to the NBD clinic of Istanbul University, Istanbul, with the complaints of bilateral leg weakness and stiffness, and urinary hesitancy. He had ROU for 17 years and GU 5 years ago and received a diagnosis of BD after positive pathergy test 5 years ago. He was not using any regular medication, other than colchicine. Leg weakness had started 1 year prior to admission and progressed within weeks. Right leg stiffness and dragging were added gradually. After a few weeks, he noticed urinary hesitancy. The first neurologic examination revealed spastic paraparesis with mild muscle weakness, exaggerated tendon reflexes, and extensor plantar responses. His deep and superficial sensations were normal. His cranial, cervical, and dorsal spinal cord MRI scans were normal. Cerebrospinal fluid was normal, regarding cells, biochemistry, IgG index, and oligoclonal bands. Results of nerve conduction and needle EMG examinations were normal. Median somatosensory-evoked potentials (SEP) were normal, but tibial SEPs revealed that bilateral dorsal columns were affected rostral to the lumbar region. He was given a course of IV MP with the diagnosis of probable neuro-BD. He had very little benefit. He was started on azathioprine treatment. During regular outpatient visits, his neurological condition deteriorated slowly. Ten months later, he had bilateral finger extension and finger abduction weakness in the upper extremities on neurologic examination. Walking distance was getting shorter, and he needed a cane for walking about 100 m. Bilateral leg spasticity was more prominent. He did not come to his regular visits in the following year. Twenty months after his first admission, he was admitted with the complaint of bilateral arm weakness and dysphagia, and he described fasciculations in his arms which he first noted 3 months ago. He had both upper and lower extremity weakness. Muscle atrophy on hands and feet was noted. 735 There was bilateral extensor plantar response. EMG was consistent with widespread lower motor neuron disease. Azathioprine was stopped, and riluzole was started. However, his progression continued. Within about 3 years after admission, he was quadriplegic, with bulbar involvement as well. He was lost to follow-up 3 years after admission. Patient 4 A 38-year-old man referred to the neurology clinics of Erciyes University, Kayseri, Turkey, with complaints of fasciculations in his legs after an episode of thrombophlebitis in his left leg. He had been followed with the diagnosis of BD for 8 years, with attacks of ROU, GU, papulopustular skin lesions, and positive patergy test. He had been taking colchicine 1 mg daily. In his neurological examination, he had only fasciculations in both his legs and unresponsive plantar reflex at the left. His muscle strength was normal. He did not have any sensory or urinary symptoms and signs. In his EMG, widespread neurogenic involvement with spontaneous activity in all extremities and paraspinal muscles were detected. Nerve conduction studies and late responses showed no pathology. In cranial MRI, right frontoparietal subcortical lesions were detected which were hyperintense in T2 and fluid-attenuated inversion recovery images and ambiguously hypointense in T1 images. The larger one was about 8 by 21 mm in size, cresentic in shape, and spreading from the frontal subcortical region to the deep white matter. The smaller one was round with a diameter of about 7 mm in the right parietal subcortical region. There was no contrast enhancement. Cervical, thoracic, and lumbosacral MRI showed no abnormality. Biochemical and microscopic examination of CSF showed normal results. Anti-GM1 antibody was negative. He was followed up with regular examinations with 3-month intervals with the addition of azathioprine 100 mg/day in his treatment regimen. Almost 1 year after admission, bilateral spasticity, extensor plantar responses, mild weakness, and atrophy in both legs and arms were observed. Upon these findings, rilusole (100 mg/day) and antispasticity treatment were started. Despite these treatments, his muscular weakness progressed in the next 2 years. In last follow-up visit, he had fasciculations in all his extremities and his tongue. He started to have difficulty in swallowing, speaking, and breathing. Along the 3-year follow-up period, his cranial MR findings did not show any change. Patient 5 A 32-year-old Iranian man with BD and ALS which have been previously reported [7] was also included in the study. In all patients, routine laboratory and thyroid studies were normal; antinuclear antibody, rheumatoid factor, vitamin Mx manifestation(s), EDx electrodiagnostic results, Rx treatments, Dx diagnosis, ROU recurrent oral ulcers, RGU recurrent genital ulcers, Cut cutaneous manifestations of BD, Uv uveitis, Arth arthritis, +Path positive pathergy reaction, UMNL upper motor neuron lesion, LMNL lower motor neuron lesion, Nl normal, NCS nerve conduction studies, EMG electromyography, Col colchicines, Cs corticosteroids, AZT azathioprine, CsA cyclosporine A 1 Progressive, dead − Nl Simultaneous UMNL+LMNL ROU, RGU, Cut, Uv, Arth, +Path 2 Iranian 32 5 M ROU, RGU, Cut, +Path 8 Turkish 38 4 M ROU, RGU, Arth, +Path 5 Turkish 37 3 M ROU, RGU, Cut, +Path 15 Turkish 56 2 M CSs, AZT, CsA (successively) AZT, Col Denervation from the beginning Nl Right frontoparietal subcortical lesions Nl CSs, AZT Nl then denervation in EMG Nl Nl Nl Nl CSs, AZT Col, CSs Nl NCS, denervation in EMG Signs of UMNL and then denervation in EMG Nl Nl Simultaneous UMNL+LMNL UMNL and then LMNL, seizure, previous urinary hesitancy, mild sensory signs UMNL and then LMNL, urinary hesitancy LMNL and then UMNL ROU, RGU, Cut, Uv 15 Tunisian M 38 1 EDx Spinal MRIs Brain MRI NBD Mx General BD Mx Duration of BD before ALS Nationality Sex Age Table 1 Demographic and clinical findings of patients with BD and ALS We are presenting five patients who fulfilled both International Study Group criteria for BD [8] and El Escorial criteria for ALS [9]. All of our patients were male. Both NBD and ALS occur more commonly in males [10, 11]. The age of our patients at the onset of neurological symptoms was between 32 and 46 years (median, 38). This range of age of onset is obviously lower than the mean age of onset for sporadic ALS which is usually around 60 years [6]. Three of the patients had a neurological presentation and course quite typical for ALS, while two had (case 2 and 3) presented with a progressive spastic paraparesis resembling primary lateral sclerosis and 1 to 8 years later developed LMN features. Three out of five patients had only motor presentations. In two atypical patients, sensory and urinary manifestations were present too. One third of patients with ALS report sensory symptoms [12]. We generally found slightly diminished vibration sensation in our ALS cases. It is already histopathologically proven that posterior columns can be involved in autopsy cases [13, 14]. Meanwhile, urinary symptoms are unusual in ALS; ALS was the cause of urinary symptoms in only 0.1–0.3% of lower urinary tract symptoms in a community-based cohort of men [15]. Brain and spinal MRIs were normal in four out of five patients and nonspecific in one. CSF analysis was done in three patients, and their results were completely normal. The median survival from the time of diagnosis in our patients was 1– 11 years (median, 3 years). This is reported to be 3 to 5 years in limb-onset ALS patients [6]. The most important question is whether these two disorders have an association or this is just coincidence. Current case series is from countries with relatively high prevalence of BD (420 per 100,000 population in Turkey; 80 per 100,000 population in Iran) [16–18]. On the other hand, ALS is relatively rare in these countries (1.57 per 100,000 population in Iran [19]). As the authors did not find published data about prevalence of ALS in Tunisia and Turkey, they limited their association analysis to the Iranian population. Considering the population of Fars Province as the target population of the BD clinic of the Shiraz University of Medical Sciences (4,336,878 based on the recently Rx Discussion Nl NCS, denervation in EMG 3 Progressive, alive + 2 Progressive, alive + 13 Progressive, alive − Progressive, dead + Riluzole Course of ALS in last follow-up B12, serum protein electrophoresis, tests for human immunodeficiency virus, human T lymphocyte virus-1, and syphilis were all negative. Lymphoma and other occult malignancies were ruled out. Tests for Lyme disease had not been done due to the rarity of this entity in our countries. Postpolio syndrome and multifocal neuropathy with conduction block were ruled out electrophysiologically. Demographic and clinical findings of patients are summarized in Table 1. 3 Clin Rheumatol (2012) 31:733–738 Survival (y) from Dx 736 Clin Rheumatol (2012) 31:733–738 released 2006 national census data), there must be 3,470 BD patients in Fars province. Fisher exact test shows the ratio of 1:3,470 patients is significantly higher than the prevalence of ALS in Iran (P00.004). Since large community-based studies have not been conducted, this rationale for association of BD and ALS cannot be referenced for sure. Considering ALS as a relevant (albeit rare) neurological syndrome of NBD has its own evidences. In the Hemminki et al. study, the standardized incidence ratio of BD in offspring of parents diagnosed with ALS was 2.96 (95% CI 1.27–5.86) in males, 2.09 (95% CI 0.20–7.70) in females, and 2.73 (95% CI 1.30–5.05) in both sexes [20]. Corticospinal signs due to brain or spinal cord involvement have been frequently reported with NBD [2, 21]; however, it is very unusual to present with normal MRIs. Although peripheral neuropathy is not a common syndrome in NBD [2, 11], subclinical electrophysiologically diagnosed neuropathy was detected in 14% of BD patients [3]. There is also at least one report of neurogenic muscular atrophy associated with BD [22]. Accordingly, simultaneous or successive presentation of UMN and LMN signs and ALS-like presentations can at least be a hypothetical manifestation of NBD. However, one would expect to see abnormal spinal MRI or CSF findings if that was the case. On the other hand, the role of inflammation in the pathogenesis of ALS has been widely studied. Release of proinflammatory cytokines (IL-6, IL-1β, TNF-α) may trigger apoptotic cascades [23]. CSF IL-6 may be elevated in both ALS and NBD [24–26]. However, whether this is a cause or an effect is unclear. Another possibility is probable neurotoxicity of previous immunosuppressive medication. However, three of the patients only used colchicine prior to the onset of neurological complaints, and one patient had received short-term (<1 year) cyclosporine treatment 9 years before the onset of symptoms. One other patient had received cyclosporine and azathioprine during the 2 years prior to the neurological onset. However, three of the patients had received azathioprine after the onset of neurological symptoms; one already had LMN findings at that time, while one each developed LMN signs 1 and 8 years later. Therefore, neurotoxicity due to immunosuppressive drugs does not seem to be a reasonable explanation. In none of our patients did we have MR tractography, hexosaminidase level, and superoxide dismutase type 1 gene studies. Anti-GM1 antibody was done in one patient which was negative. To our knowledge, the association of ALS with BD has only been described as a single case report which is also included in this study (patient 5) [7]. A possible association between these two disorders merit further investigation. Facing upcoming patients with this constellation, neurologists and rheumatologists needed to conduct tests like magnetization transfer ratio; MR spectroscopy; MR tractography; CSF IL-6, TNF-alpha, and other inflammatory markers; anti-GM1 antibody; hexosaminidase 737 level; and superoxide dismutase type 1 gene studies to shed light on the probable association of these two mysterious diseases. Knowing that both ALS [27] and progressive NBD [28] have no efficacious treatments re-necessitates the indication of these studies. Disclosures None. References 1. Borhani-Haghighi A, Samangooie S, Ashjazadeh N, Nikseresht A, Shariat A, Yousefipour G et al (2006) Neurological manifestations of Behcet’s disease. Saudi Med J 27(10):1542–1546 2. 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