Scandinavian Journal of Gastroenterology. 2014; 49: 173–176
ORIGINAL ARTICLE
Crohn’s disease: Is there a place for neurological screening?
JAN STOVICEK1, PETRA LISKOVA2, JIRI LISY3, STEPAN HLAVA1 & RADAN KEIL1 Scand J Gastroenterol Downloaded from informahealthcare.com by University of Otago on 04/23/15 For personal use only.
1
Gastroenterology, Clinic of Internal Medicine, 2nd Medical Faculty of Charles University, Prague, Czech Republic, Clinic of Neurology, 2nd Medical Faculty of Charles University, Prague, Czech Republic, and 3Clinic of Radiology, 2nd Medical Faculty of Charles University, Prague, Czech Republic
2
Abstract Objective. Neurological complications of inflammatory bowel diseases (IBDs) are not rare but are under-diagnosed; some are probably immune-mediated. Several previous studies have suggested a higher incidence of demyelinating diseases such as multiple sclerosis in IBD patients. In this single-center, prospective, observational study, the authors focus on T2 focal white-matter lesions of the central nervous system on magnetic resonance imaging (MRI) in IBD patients that may be due to demyelination. Material and methods. A total of 70 patients with Crohn’s disease were examined before beginning antiTNF-a therapy. These patients were treated with azathioprine, mesalazine or both. Patients were examined by a neurologist to detect possible signs of demyelinating disease, and patients underwent brain MRI (native T1, T2, and FLAIR sequences). Results. Thirty-seven patients (53%) exhibited abnormalities on neurological examination, and 26 patients (37%) displayed abnormalities on MRI. In seven cases, these MRI abnormalities (periventricular lesions) were suspected to be due to demyelination. Cerebral spinal fluid investigation (including polyclonal bands) was completely negative in five cases and was borderline in one case, and multiple sclerosis was confirmed in one case. Pathological MRI findings in 19 other patients were clinically nonsignificant; most were nonspecific sporadic lesions in white matter or mild atrophy. Conclusions. The results support previous data that the frequency of neurological findings in IBD patients is generally underestimated. With the extension of biological anti-TNF-a treatment for IBD, the possibility of a higher risk of developing multiple sclerosis should be considered.
Key Words: Crohn’s disease, demyelinating diseases, inflammatory bowel diseases, multiple sclerosis
Introduction Extraintestinal manifestations of inflammatory bowel disease (IBD) can involve practically any organ system, although the joints, skin, eyes, liver, and biliary system are most commonly involved. Neurological complications are not rare but are often underdiagnosed. The pathogenesis of neurological involvement is variable, encompassing micronutrient deficiency, prothrombotic events, and immune-mediated processes. Demyelinating diseases such as multiple sclerosis (MS) and optic neuritis occur more often among IBD patients compared to non-IBD patients. Previous studies have documented a higher prevalence of demyelinating diseases in patient with Crohn’s
disease (CD) and ulcerative colitis, mostly based on retrospective cohort studies [1,2]. Additionally, imaging trials have confirmed a higher occurrence of T2 focal white-matter lesions of the central nervous system on magnetic resonance imaging (MRI) in IBD patients. However, the precise relationship between IBD and these neurological diseases has not been established. Neurological diseases in IBD patients have become more important in light of new biological treatment modalities. In particular, anti-TNF-a therapy is an important addition to the treatment of several autoimmune diseases, including rheumatoid arthritis, Bechterew’s disease, psoriasis, CD, and ulcerative colitis. TNF-a is also considered to act in the
Correspondence: Jan Stovicek, MD, Gastroenterology, Clinic of Internal Medicine, 2nd Medical Faculty of Charles University, Prague, Czech Republic. E-mail: [email protected]
(Received 14 August 2013; revised 13 November 2013; accepted 13 November 2013) ISSN 0036-5521 print/ISSN 1502-7708 online 2014 Informa Healthcare DOI: 10.3109/00365521.2013.867358
Scand J Gastroenterol Downloaded from informahealthcare.com by University of Otago on 04/23/15 For personal use only.
174
Stovicek J. et al.
pathogenesis of MS and its animal model (experimental autoimmune encephalomyelitis). As an antagonist of the pro-inflammatory action of TNF-a, anti-TNF-a antibodies were initially considered as a possible treatment for demyelinating diseases. However, several trials indicated that anti-TNF-a therapy worsened the clinical course of MS. These reports suggest the possibility of developing MS or optic neuritis in patients with autoimmune diseases such as rheumatoid arthritis and CD on anti-TNF-a treatment. This relationship has not been well established, and there is no general agreement on the causality of the relationship between anti-TNF-a therapy and MS onset in IBD patients. Given these previous observations, anti-TNF-a treatment is hypothesized to lead to the exacerbation of preexisting latent demyelination in some cases. Based on this hypothesis, we sought to evaluate the neurological status of CD patients before beginning anti-TNF-a therapy in order to avoid possible complication in patients with latent demyelinating diseases.
Methods The aim of this observational, single-center study was to document the neurological status of CD patients, particularly the signs of demyelinating disease, such as T2 focal white-matter lesions of the central nervous system on MRI. A total of 70 CD patients who had not yet undergone anti-TNF-a therapy were included in this study. The inclusion criteria were: . .
The protocol of the study was approved by the local ethics committee. Results A total of 70 CD patients (27 women, 43 men, average age 36 years, range 18–66 years) were examined before beginning anti-TNF-a therapy. The overall frequency of pathological findings (either on neurological examination or on MRI) was 67%. Thirty-seven patients (53%) displayed some abnormalities on neurological examination. The most common findings were areflexia of the abdominal wall or legs, impairment of vibration sensation, and mild hemiparesis. Abnormalities on MRI were detected in 26 patients (37%). Most of these pathologies were nonspecific sporadic lesions in white matter or mild atrophy Figure 1. In one case, we found acoustic neurinoma as an incidental finding. In seven cases, these MRI abnormalities (periventricular lesions) generated a suspicion of demyelination Figures 2 and 3. These patients were asymptomatic. Five of these patients exhibited abnormalities on neurological examination. All seven of the patients with abnormal MRI results underwent a cerebrospinal fluid investigation that
History of CD for >1 year. Patients with moderate or severe CD indicated for anti-TNF-a therapy because of failure or intolerance of previous treatment with azathioprine, corticosteroids or both. The exclusion criteria were:
. .
Previous treatment with anti-TNF-a agents in patient’s history. Serious neurological disease in patient’s history.
Patients were examined by a single neurologist to detect possible signs of demyelinating disease. They underwent MRI of the brain (native T1, T2, and FLAIR sequences). The MRI investigation was analyzed by an independent investigator. Both neurologist and radiologist were blinded for the results of the other. The results were compared with expected incidences in the general population using the Poisson distribution.
Figure 1. FLAIR image of a 46-year-old man with small gliotic foci in subcortical white matter of both frontal lobes, which correspond with nonspecific sporadic involvement not related to MS.
Scand J Gastroenterol Downloaded from informahealthcare.com by University of Otago on 04/23/15 For personal use only.
Neurological screening & Crohn’s disease
175
Figure 2. FLAIR image of a 35-year-old man showing multiple foci of demyelination which involve periventricular white matter. The finding corresponds with the diagnosis of MS.
Figure 3. Gadolinium-enhanced T1/SE image of the same patient shown in Figure 1 proves absence of enhancement corresponding with inactive foci of demyelination in MS.
included examination of oligoclonal bands. Results were completely negative in five cases and the finding was evaluated as borderline in one case, and MS was confirmed in one case. The pathological MRI findings from the other 19 patients were determined to be clinically nonsignificant. In this group of CD patients, 3% were associated with a suspicion of demyelinating disease (99% confidence interval: 0.149–8.727). Given an expected MS incidence of 6/100,000/year, the risk of developing a demyelinating disease was significantly higher in CD patients than in the general population (99% confidence interval: 0.002–0.125, p = 0.01).
although only a subset of these cases was immunemediated [4]. Two population-based cohort studies reported a higher risk of developing autoimmune demyelinating diseases such as MS or optic neuritis in IBD patients (54% higher risk than controls, according to the General Practice Research Database study) [1,2]. In a retrospective evaluation of MRI in 54 CD patients, Chen et al. found abnormal cerebral white-matter lesions (hyperintensities) in 72% of subjects, compared with 34% of non-CD control subjects. They concluded that these hyperintensities could be an extraintestinal manifestation of CD, but the clinical importance of these hyperintensities remains unclear [5]. Reports of a negative influence of anti-TNF-a therapy on MS motivated our assessment of the neurological status of CD patients before beginning anti-TNF-a therapy. An increased risk of exacerbating MS was previously described in a large, double-blind, randomized study with the anti-TNF-a agent lenercept (TNFR I fusion protein), which had to be prematurely interrupted [6]. Central and peripheral demyelinating disorders were rarely described in patients treated with infliximab, adalimumab, and etanercept [7–9]. TNF-a is suspected to play a direct role in the pathogenesis of demyelinating diseases. TNF-a
Discussion The frequency of neurological findings in IBD patients has been reported to be up to 47% [3]. In our group of CD patients, the percentage of pathological neurological findings was >50%. IBD patients are at higher risk of developing other autoimmune diseases, including central and peripheral demyelinating diseases. Peripheral neuropathy was previously described in 37% of IBD patients,
Scand J Gastroenterol Downloaded from informahealthcare.com by University of Otago on 04/23/15 For personal use only.
176
Stovicek J. et al.
interacts with two types of receptors (TNFR1 and TNFR2) that act through different pathways. As a result, TNF-a activity is thought to affect both demyelination and remyelination during the development of MS. This hypothesis is supported by several observations. TNF-a levels are elevated in sera and in the cerebrospinal fluid of patients with progressive MS [6,10,11], and anti-TNF-a drugs were previously effective in animal models [7]. On the other hand, MS patients have been reported to worsen during anti-TNF-a therapy, as described above. The causality of the relationship between the onset of demyelinating diseases and anti-TNF-a treatment remains unclear. Anti-TNF-a therapy may provoke MS onset in genetically predisposed patients or in preexisting latent MS cases and may not be the cause of the disease. This hypothesis is based on observations of a higher incidence of demyelinating diseases in an IBD population and in some case series documenting the presence of symptoms before starting anti-TNF-a treatment [12]. Our observations are consistent with this hypothesis; the frequency of pathological neurological findings in our patient population was high (>50%), as was the number of suspicious MRI findings confirmed by our cerebrospinal fluid investigations. In our investigation, there were two positive oligoclonal band findings (one borderline and one sufficient to diagnose MS). Despite the limits of this observational study, these results suggest the importance of neurological screening of IBD patients. To date, there are no recommendations for neurological screening before starting anti-TNF-a treatment. Tuberculosis screening in these patients is standard; we highlight the fact that the incidences of these two complications are similar in the general population (4–6/100,000/year) [13,14]. Conclusion Our results are consistent with previous reports that the frequency of neurological findings in IBD patients is generally underestimated. With the expansion of biological therapies, especially anti-TNF-a treatment for IBD, the possibility of a higher risk of these patients developing MS should be considered. An increased awareness for neurological symptoms is important. In indicated patients, we recommend a neurological examination, followed by MRI, if necessary.
Declaration of interest: The study was supported by Ministry of Health, Czech Republic – conceptual development of research organization, University Hospital Motol, Prague, Czech Republic 00064203.
References [1] Bernstein CN, Wajda A, Blanchard JF. The clustering of other chronic inflammatory diseases in inflammatory bowel disease: a population-based study. Gastroenterology 2005; 129:827–36. [2] Gupta G, Gelfand JM, Lewis JD. Increased risk of demyelinating diseases in patients with inflammatory bowel disease. Gastroenterology 2005;129:819–26. [3] Singh S, Kumar N, Loftus EV, Kane SV. Neurologic complications in patients with inflammatory bowel disease: increasing relevance in the era of biologics. Inflamm Bowel Dis 2013;19:864–72. [4] Oliveira GR, Teles BC, Brasil EF, et al. Peripheral neuropathy and neurological disorders in an unselected Brazilian population-based cohort of IBD patients. Inflamm Bowel Dis 2008;14:389–95. [5] Chen M, Lee G, Kong LN, Lamont S, Chaves C. Cerberal white matter lesions in patients with Crohns disease. J Neuroimaging 2012;22:38–41. [6] The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. TNF neutralization in MS: Results of a randomized, placebocontrolled multicenter study. Neurology 1999;53:457. [7] Kollias D, Douni E, Kassiotis G, Kontoyiannis D. On the role of tumor necrosis factor and receptors in models of multiorgan failure, rheumatoid arthritis,multiple sclerosis and inflammatory bowel disease. Immunol Rev 1999;169: 175–94. [8] Nozaki K, Silver RM, Stickler DE, Abou-Fayssal NG, Giglio P, Kamen DL, et al. Neurological deficits during treatment with tumor necrosis factor-alpha antagonists. Am J Med Sci 2011;342:352–5. [9] Tristano AG. Neurological adverse events associated with anti-tumor necrosis factor alpha treatment. J Neurol 2010; 257:1421–31. [10] Lin J, Zitiny D, Desai S, et al. TNFalfa blockade in human diseases: an overview of efficacy and safety. Clin Immunol 2008;126:13–30. [11] Robinson WH, Genovese MC, Moreland LW. Demyelinating and neurologic events reported in association with tumor necrosis factor alpha antagonism: by what mechanisms could tumor necrosis factor alpha antagonists improve rheumatoid arthritis but exacerbate multiple sclerosis? Arthritis Rheum 2001;44:1977–83. [12] Andreadou E, Kemanetzoglou E, Brokalaki Ch, Evangelopoulos ME, Kilidireas C, Rombos A, et al. Demyelinating disease following Anti-TNFa Treatment: a causal or coincidental association? Report of four cases and review of the literature. Case Rep Neurol Med 2013;2013:671935. [13] Pugliatti M, Rosami G, Karton H, Riise T, Drulovic J, Vecsei L, et al. The epidemiology of muliple sclerosis in Europe. Eur J Neurol 2006;13:700–22. [14] The World Bank Database. Available from data worldbank.org.
ORIGINAL ARTICLE
Crohn’s disease: Is there a place for neurological screening?
JAN STOVICEK1, PETRA LISKOVA2, JIRI LISY3, STEPAN HLAVA1 & RADAN KEIL1 Scand J Gastroenterol Downloaded from informahealthcare.com by University of Otago on 04/23/15 For personal use only.
1
Gastroenterology, Clinic of Internal Medicine, 2nd Medical Faculty of Charles University, Prague, Czech Republic, Clinic of Neurology, 2nd Medical Faculty of Charles University, Prague, Czech Republic, and 3Clinic of Radiology, 2nd Medical Faculty of Charles University, Prague, Czech Republic
2
Abstract Objective. Neurological complications of inflammatory bowel diseases (IBDs) are not rare but are under-diagnosed; some are probably immune-mediated. Several previous studies have suggested a higher incidence of demyelinating diseases such as multiple sclerosis in IBD patients. In this single-center, prospective, observational study, the authors focus on T2 focal white-matter lesions of the central nervous system on magnetic resonance imaging (MRI) in IBD patients that may be due to demyelination. Material and methods. A total of 70 patients with Crohn’s disease were examined before beginning antiTNF-a therapy. These patients were treated with azathioprine, mesalazine or both. Patients were examined by a neurologist to detect possible signs of demyelinating disease, and patients underwent brain MRI (native T1, T2, and FLAIR sequences). Results. Thirty-seven patients (53%) exhibited abnormalities on neurological examination, and 26 patients (37%) displayed abnormalities on MRI. In seven cases, these MRI abnormalities (periventricular lesions) were suspected to be due to demyelination. Cerebral spinal fluid investigation (including polyclonal bands) was completely negative in five cases and was borderline in one case, and multiple sclerosis was confirmed in one case. Pathological MRI findings in 19 other patients were clinically nonsignificant; most were nonspecific sporadic lesions in white matter or mild atrophy. Conclusions. The results support previous data that the frequency of neurological findings in IBD patients is generally underestimated. With the extension of biological anti-TNF-a treatment for IBD, the possibility of a higher risk of developing multiple sclerosis should be considered.
Key Words: Crohn’s disease, demyelinating diseases, inflammatory bowel diseases, multiple sclerosis
Introduction Extraintestinal manifestations of inflammatory bowel disease (IBD) can involve practically any organ system, although the joints, skin, eyes, liver, and biliary system are most commonly involved. Neurological complications are not rare but are often underdiagnosed. The pathogenesis of neurological involvement is variable, encompassing micronutrient deficiency, prothrombotic events, and immune-mediated processes. Demyelinating diseases such as multiple sclerosis (MS) and optic neuritis occur more often among IBD patients compared to non-IBD patients. Previous studies have documented a higher prevalence of demyelinating diseases in patient with Crohn’s
disease (CD) and ulcerative colitis, mostly based on retrospective cohort studies [1,2]. Additionally, imaging trials have confirmed a higher occurrence of T2 focal white-matter lesions of the central nervous system on magnetic resonance imaging (MRI) in IBD patients. However, the precise relationship between IBD and these neurological diseases has not been established. Neurological diseases in IBD patients have become more important in light of new biological treatment modalities. In particular, anti-TNF-a therapy is an important addition to the treatment of several autoimmune diseases, including rheumatoid arthritis, Bechterew’s disease, psoriasis, CD, and ulcerative colitis. TNF-a is also considered to act in the
Correspondence: Jan Stovicek, MD, Gastroenterology, Clinic of Internal Medicine, 2nd Medical Faculty of Charles University, Prague, Czech Republic. E-mail: [email protected]
(Received 14 August 2013; revised 13 November 2013; accepted 13 November 2013) ISSN 0036-5521 print/ISSN 1502-7708 online 2014 Informa Healthcare DOI: 10.3109/00365521.2013.867358
Scand J Gastroenterol Downloaded from informahealthcare.com by University of Otago on 04/23/15 For personal use only.
174
Stovicek J. et al.
pathogenesis of MS and its animal model (experimental autoimmune encephalomyelitis). As an antagonist of the pro-inflammatory action of TNF-a, anti-TNF-a antibodies were initially considered as a possible treatment for demyelinating diseases. However, several trials indicated that anti-TNF-a therapy worsened the clinical course of MS. These reports suggest the possibility of developing MS or optic neuritis in patients with autoimmune diseases such as rheumatoid arthritis and CD on anti-TNF-a treatment. This relationship has not been well established, and there is no general agreement on the causality of the relationship between anti-TNF-a therapy and MS onset in IBD patients. Given these previous observations, anti-TNF-a treatment is hypothesized to lead to the exacerbation of preexisting latent demyelination in some cases. Based on this hypothesis, we sought to evaluate the neurological status of CD patients before beginning anti-TNF-a therapy in order to avoid possible complication in patients with latent demyelinating diseases.
Methods The aim of this observational, single-center study was to document the neurological status of CD patients, particularly the signs of demyelinating disease, such as T2 focal white-matter lesions of the central nervous system on MRI. A total of 70 CD patients who had not yet undergone anti-TNF-a therapy were included in this study. The inclusion criteria were: . .
The protocol of the study was approved by the local ethics committee. Results A total of 70 CD patients (27 women, 43 men, average age 36 years, range 18–66 years) were examined before beginning anti-TNF-a therapy. The overall frequency of pathological findings (either on neurological examination or on MRI) was 67%. Thirty-seven patients (53%) displayed some abnormalities on neurological examination. The most common findings were areflexia of the abdominal wall or legs, impairment of vibration sensation, and mild hemiparesis. Abnormalities on MRI were detected in 26 patients (37%). Most of these pathologies were nonspecific sporadic lesions in white matter or mild atrophy Figure 1. In one case, we found acoustic neurinoma as an incidental finding. In seven cases, these MRI abnormalities (periventricular lesions) generated a suspicion of demyelination Figures 2 and 3. These patients were asymptomatic. Five of these patients exhibited abnormalities on neurological examination. All seven of the patients with abnormal MRI results underwent a cerebrospinal fluid investigation that
History of CD for >1 year. Patients with moderate or severe CD indicated for anti-TNF-a therapy because of failure or intolerance of previous treatment with azathioprine, corticosteroids or both. The exclusion criteria were:
. .
Previous treatment with anti-TNF-a agents in patient’s history. Serious neurological disease in patient’s history.
Patients were examined by a single neurologist to detect possible signs of demyelinating disease. They underwent MRI of the brain (native T1, T2, and FLAIR sequences). The MRI investigation was analyzed by an independent investigator. Both neurologist and radiologist were blinded for the results of the other. The results were compared with expected incidences in the general population using the Poisson distribution.
Figure 1. FLAIR image of a 46-year-old man with small gliotic foci in subcortical white matter of both frontal lobes, which correspond with nonspecific sporadic involvement not related to MS.
Scand J Gastroenterol Downloaded from informahealthcare.com by University of Otago on 04/23/15 For personal use only.
Neurological screening & Crohn’s disease
175
Figure 2. FLAIR image of a 35-year-old man showing multiple foci of demyelination which involve periventricular white matter. The finding corresponds with the diagnosis of MS.
Figure 3. Gadolinium-enhanced T1/SE image of the same patient shown in Figure 1 proves absence of enhancement corresponding with inactive foci of demyelination in MS.
included examination of oligoclonal bands. Results were completely negative in five cases and the finding was evaluated as borderline in one case, and MS was confirmed in one case. The pathological MRI findings from the other 19 patients were determined to be clinically nonsignificant. In this group of CD patients, 3% were associated with a suspicion of demyelinating disease (99% confidence interval: 0.149–8.727). Given an expected MS incidence of 6/100,000/year, the risk of developing a demyelinating disease was significantly higher in CD patients than in the general population (99% confidence interval: 0.002–0.125, p = 0.01).
although only a subset of these cases was immunemediated [4]. Two population-based cohort studies reported a higher risk of developing autoimmune demyelinating diseases such as MS or optic neuritis in IBD patients (54% higher risk than controls, according to the General Practice Research Database study) [1,2]. In a retrospective evaluation of MRI in 54 CD patients, Chen et al. found abnormal cerebral white-matter lesions (hyperintensities) in 72% of subjects, compared with 34% of non-CD control subjects. They concluded that these hyperintensities could be an extraintestinal manifestation of CD, but the clinical importance of these hyperintensities remains unclear [5]. Reports of a negative influence of anti-TNF-a therapy on MS motivated our assessment of the neurological status of CD patients before beginning anti-TNF-a therapy. An increased risk of exacerbating MS was previously described in a large, double-blind, randomized study with the anti-TNF-a agent lenercept (TNFR I fusion protein), which had to be prematurely interrupted [6]. Central and peripheral demyelinating disorders were rarely described in patients treated with infliximab, adalimumab, and etanercept [7–9]. TNF-a is suspected to play a direct role in the pathogenesis of demyelinating diseases. TNF-a
Discussion The frequency of neurological findings in IBD patients has been reported to be up to 47% [3]. In our group of CD patients, the percentage of pathological neurological findings was >50%. IBD patients are at higher risk of developing other autoimmune diseases, including central and peripheral demyelinating diseases. Peripheral neuropathy was previously described in 37% of IBD patients,
Scand J Gastroenterol Downloaded from informahealthcare.com by University of Otago on 04/23/15 For personal use only.
176
Stovicek J. et al.
interacts with two types of receptors (TNFR1 and TNFR2) that act through different pathways. As a result, TNF-a activity is thought to affect both demyelination and remyelination during the development of MS. This hypothesis is supported by several observations. TNF-a levels are elevated in sera and in the cerebrospinal fluid of patients with progressive MS [6,10,11], and anti-TNF-a drugs were previously effective in animal models [7]. On the other hand, MS patients have been reported to worsen during anti-TNF-a therapy, as described above. The causality of the relationship between the onset of demyelinating diseases and anti-TNF-a treatment remains unclear. Anti-TNF-a therapy may provoke MS onset in genetically predisposed patients or in preexisting latent MS cases and may not be the cause of the disease. This hypothesis is based on observations of a higher incidence of demyelinating diseases in an IBD population and in some case series documenting the presence of symptoms before starting anti-TNF-a treatment [12]. Our observations are consistent with this hypothesis; the frequency of pathological neurological findings in our patient population was high (>50%), as was the number of suspicious MRI findings confirmed by our cerebrospinal fluid investigations. In our investigation, there were two positive oligoclonal band findings (one borderline and one sufficient to diagnose MS). Despite the limits of this observational study, these results suggest the importance of neurological screening of IBD patients. To date, there are no recommendations for neurological screening before starting anti-TNF-a treatment. Tuberculosis screening in these patients is standard; we highlight the fact that the incidences of these two complications are similar in the general population (4–6/100,000/year) [13,14]. Conclusion Our results are consistent with previous reports that the frequency of neurological findings in IBD patients is generally underestimated. With the expansion of biological therapies, especially anti-TNF-a treatment for IBD, the possibility of a higher risk of these patients developing MS should be considered. An increased awareness for neurological symptoms is important. In indicated patients, we recommend a neurological examination, followed by MRI, if necessary.
Declaration of interest: The study was supported by Ministry of Health, Czech Republic – conceptual development of research organization, University Hospital Motol, Prague, Czech Republic 00064203.
References [1] Bernstein CN, Wajda A, Blanchard JF. The clustering of other chronic inflammatory diseases in inflammatory bowel disease: a population-based study. Gastroenterology 2005; 129:827–36. [2] Gupta G, Gelfand JM, Lewis JD. Increased risk of demyelinating diseases in patients with inflammatory bowel disease. Gastroenterology 2005;129:819–26. [3] Singh S, Kumar N, Loftus EV, Kane SV. Neurologic complications in patients with inflammatory bowel disease: increasing relevance in the era of biologics. Inflamm Bowel Dis 2013;19:864–72. [4] Oliveira GR, Teles BC, Brasil EF, et al. Peripheral neuropathy and neurological disorders in an unselected Brazilian population-based cohort of IBD patients. Inflamm Bowel Dis 2008;14:389–95. [5] Chen M, Lee G, Kong LN, Lamont S, Chaves C. Cerberal white matter lesions in patients with Crohns disease. J Neuroimaging 2012;22:38–41. [6] The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. TNF neutralization in MS: Results of a randomized, placebocontrolled multicenter study. Neurology 1999;53:457. [7] Kollias D, Douni E, Kassiotis G, Kontoyiannis D. On the role of tumor necrosis factor and receptors in models of multiorgan failure, rheumatoid arthritis,multiple sclerosis and inflammatory bowel disease. Immunol Rev 1999;169: 175–94. [8] Nozaki K, Silver RM, Stickler DE, Abou-Fayssal NG, Giglio P, Kamen DL, et al. Neurological deficits during treatment with tumor necrosis factor-alpha antagonists. Am J Med Sci 2011;342:352–5. [9] Tristano AG. Neurological adverse events associated with anti-tumor necrosis factor alpha treatment. J Neurol 2010; 257:1421–31. [10] Lin J, Zitiny D, Desai S, et al. TNFalfa blockade in human diseases: an overview of efficacy and safety. Clin Immunol 2008;126:13–30. [11] Robinson WH, Genovese MC, Moreland LW. Demyelinating and neurologic events reported in association with tumor necrosis factor alpha antagonism: by what mechanisms could tumor necrosis factor alpha antagonists improve rheumatoid arthritis but exacerbate multiple sclerosis? Arthritis Rheum 2001;44:1977–83. [12] Andreadou E, Kemanetzoglou E, Brokalaki Ch, Evangelopoulos ME, Kilidireas C, Rombos A, et al. Demyelinating disease following Anti-TNFa Treatment: a causal or coincidental association? Report of four cases and review of the literature. Case Rep Neurol Med 2013;2013:671935. [13] Pugliatti M, Rosami G, Karton H, Riise T, Drulovic J, Vecsei L, et al. The epidemiology of muliple sclerosis in Europe. Eur J Neurol 2006;13:700–22. [14] The World Bank Database. Available from data worldbank.org.
