Handbook of Clinical Neurology, Vol. 120 (3rd series) Neurologic Aspects of Systemic Disease Part II Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 40

Neurologic manifestations of inflammatory bowel diseases JOSE´ M. FERRO1*, SOFIA N. OLIVEIRA2, AND LUIS CORREIA3 Neurology Service, Department of Neurosciences, Hospital de Santa Maria, University of Lisbon, Lisbon, Portugal

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Department of Neurology, Hospital da Luz, Lisbon, Portugal

Department of Gastroenterology and Hepatology, Hospital de Santa Maria, University of Lisbon, Lisbon, Portugal

INTRODUCTION Inflammatory bowel diseases (IBD) are chronic, relapsing and remitting inflammatory conditions affecting the digestive system, idiopathic in their etiology, comprising two main distinctive diseases, ulcerative colitis (UC) and Crohn’s disease (CD). In UC the inflammation is restricted to the mucosa of the colon, with an almost invariable involvement of the rectum and a variable continuous proximal extension. CD is a condition that involves transmurally any segment of the digestive tract, from mouth to anus, with spared segments and skip lesions. In CD aphthoid ulcers become transmural fissures and, after a variable time interval, inflammation evolves to cause destruction and disability settles in, with fistula or fibrotic stenosis formation, as well as the potential for abscess formation or secondary occlusion (Cosnes et al., 2002). About onethird of CD patients develop perianal disease (Schwartz et al., 2002), from anal fissures to simple or complex perianal fistulae or secondary abscesses. Both diseases can be phenotypically classified according to age, location, extension, behavior, and activity, by several clinical and endoscopic classifications. The most important of them is the Montreal classification, which allows for prognostic validation (Silverberg et al., 2005). Between 10% and 15% of colitis patients resist classification after applying strict clinical, endoscopic, radiologic, and histologic criteria, defining an intermediate condition known as unclassified colitis, or, as named by the pathologist in possession of a colectomy specimen, indeterminate colitis (Lennard-Jones, 1989). The incidence of IBD varies between different areas of the globe, though with a north–south gradient, well documented in Europe and North America. In general,

it is recognized that there is a stable incidence of UC and a rising incidence of CD, with the former maintaining a higher incidence. In a systematic review (Molodecky et al., 2012), the highest reported incidence of UC was 24 and 19.2 per 100 000 person-years and 12.7 and 20.2 per 100 000 patient-years in CD, in Europe and the US, respectively. The pathogenesis of IBD remains unclear. It is generally accepted that the disease appears in non-Mendelian genetically susceptible persons (Satsangi et al., 1997). The genetic predisposition can be demonstrated by an elevated concordance in twins (Orholm et al., 2000) and firstdegree relatives (Lahari et al., 2001), mutations in the NOD2/CARD15 gene (Kugathasan et al., 2004), or association with certain characteristic major histocompatibility complex elements (Bouma et al., 1997). Exposure to environmental risk factors such as infections (acute gastroenteritis, dysbiosis) (Porter et al., 2008), antibiotics, food antigens (breastfeeding, sugar or fat excess, fiber deficits, milk proteins, etc.) or nonsteroidal anti-inflammatory drugs, particularly in infancy, produces pathologic changes in the innate and adaptive immune system; these include changes in the mucosal barrier function, against luminal bacteria or antigens, eliciting an inappropriate immune response against microorganisms that generally would not generate that kind of response. Besides the classic gastrointestinal manifestations, namely bloody diarrhea in UC or abdominal pain, fever, bowel habit change, or perianal disease in CD, a variable number of IBD patients present with complaints located outside the gastrointestinal tract, such as joints, mouth, eyes, skin, and liver, with some more rare manifestations. These are called the IBD extraintestinal manifestations (EIM) (Peyrin-Biroulet et al., 2011).

*Correspondence to: Jose´ M. Ferro, Department of Neurosciences, Hospital de Santa Maria, Av. Prof. Egas Moniz, 1649-035 Lisbo, Portugal. Tel: þ351-21-795-7474, Fax: þ351-21-795-7474, E-mail: [email protected]

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EIM can have multiple mechanisms, such as metabolic complications of the disease (e.g., osteoporosis, nephrolithiasis in ileal CD), adverse effects of the medications (e.g., corticosteroid myopathy or anti-TNF demyelination), but mainly immune-mediated mechanisms. This group, classic EIM, has a phenotypic preference for colonic disease (UC and colonic CD) and can be divided in two subgroups: EIM related to intestinal activity (aphthous ulcers, peripheral arthritis or erythema nodosum) or EIM independent of the activity of the intestinal disease (axial arthritis, pyoderma gangrenosum, primary sclerosing cholangitis). Finally, it is necessary to recognize that there is an IBD-independent group of immune-mediated diseases that can coexist with greater prevalence in IBD, such as celiac or thyroid disease, vitiligo, diabetes, or, more rarely, lupus. In general, as represented by a cohort of 950 prospectively studied Swiss patients (Vavricka et al., 2011), EIM occur more frequently in CD, both globally (43%, versus 31% in UC) and specific to the different manifestations (arthritis 33% versus 21%; aphthous stomatitis 10% versus 4%; uveitis 6% versus 4%; erythema nodosum 6% versus 3%; ankylosing spondyloarthropathy 6% versus 2%) with the exception of primary sclerosing cholangitis (CD 1% versus UC 4%).

NEUROLOGIC MANIFESTATIONS IN INFLAMMATORY BOWEL DISEASE (Tables 40.1 and 40.2)

Table 40.1 Peripheral nervous system manifestations of inflammatory bowel disease Peripheral neuropathy Axonal, large fibers Axonal, small fibers Demyelinating, acute Demyelinating, chronic Mononeuropathy Multifocal motor Myopathy Dermatomyositis Polymyositis Rimmed vascular myopathy Granulomatosis myositis Myasthenia Cranial neuropathy Melkersson Rosenthal syndrome Optic neuritis Hearing loss Sixth nerve palsy

Table 40.2 Central nervous system manifestations of inflammatory bowel diseases Cerebrovascular Ischemic arterial stroke Large artery disease Small vessel disease Cardioembolism, patent foramen ovale Cardioembolism, endocarditis Vasculitis Associated with anti-TNF-a therapy Cerebral venous thrombosis Demyelinating Multiple sclerosis Asymptomatic white matter lesions Related to anti-TNF-a therapy Spinal cord Myelopathy Spinal empyema Other Seizures Headache Encephalopathy

Prevalence Neurologic and psychiatric involvement in inflammatory bowel disease (IBD) is rare though probably underreported. The true incidence is unknown, with values varying from 0.25% to 47.5% (Lossos et al., 1995; Elsehety and Bertorini, 1997; Oliveira et al., 2008; Sassi et al., 2009). In a series of 638 patients with IBD, Lossos et al. (1995) reported 19 patients (3%) with neurolgic involvement that preceded the onset of intestinal symptoms by up to 10 years in 26% and started up to 12 years after IBD presentation in the remaining patients. In 10% it was associated with IBD exacerbation and most patients (53%) exhibited other extraintestinal manifestations and complications. Elsehety and Bertorini (1997) reported a 33.2% incidence of neurologic and neuropsychiatric complications in 253 patients with pathologically confirmed Crohn’s disease, a much higher prevalence than that reported in other series. Two prospective cohort studies (Oliveira et al., 2008; Sassi et al., 2009) looked at the prevalence of peripheral neuropathy and found 13.4% and 8.8% respectively. Asymptomatic focal brain white matter lesions have also been found in MRI studies of patients with IBD as compared to healthy age-matched controls (43.1% versus 16.0%; RR 2.6, 95% CI 1.3–5.3) but their clinical significance is unclear (Geissler et al., 1995).

Pathophysiology Both the central and peripheral nervous systems can be affected in IBD. Several mechanisms are possibly

NEUROLOGIC MANIFESTATIONS OF INFLAMMATORY BOWEL DISEASES involved: malabsorption and nutritional deficiencies, metabolic agents, infections induced by immunosuppresion, side-effects of medication and iatrogenic complications of surgery, thromboembolism, immunologic abnormalities, and disturbances of the so-called “brain–gut axis,” referring to the neuronal influence on enteric disease and vice versa (Derbyshire, 2003; Konturek et al., 2004) via neuroendocrine pathways such as the hypothalamic– pituitary–adrenal axis, release of corticotropin and adrenal corticoid secretion, the autonomic nervous system and its effects on immune functions (Zois et al., 2010). It is important to separate immune- and nonimmunemediated mechanisms directly related to the disease itself from other causes, such as side-effects of medication and nutritional deficiencies.

PERIPHERAL NERVOUS SYSTEM The peripheral nervous system (PNS) is frequently affected in IBD and peripheral neuropathy is one of the most common complications (Lossos et al., 1995; Elsehety and Bertorini, 1997; Oliveira et al., 2008), reported in up to 31.5% of patients. However, wellknown causes of peripheral neuropathy such as vitamin deficiencies and secondary effects of medication should be differentiated from a primary involvement of the PNS in IBD, and prospective data are notably absent. Oliveira et al. (2008) identified peripheral neuropathy as the most common neurolgic complication in their cohort of IBD patients (36.6%), probably immune-mediated and therefore directly disease-related in 13.4%, the remainder being related to vitamin deficiency or metronidazole toxicity. Peripheral neuropathy appeared to be more frequent in UC (Lossos et al., 1995; Gondim et al., 2005) but recent studies have shown comparable incidence in UC and CD patients (Gondim et al., 2005; Oliveira et al., 2008). Several different phenotypes have been described including sensory, motor, autonomic, and mixed, both axonal and demyelinating, acute and chronic (Gondim et al., 2005). In the largest retrospective series (Gondim et al., 2005), demyelinating chronic inflammatory polyneuropathy, small and large-fiber axonal neuropathies were found in UC patients. An acute inflammatory demyelinating polyradiculopathy has also been described in UC (Lossos et al., 1995). Axonal polyneuropathy presents with sensory loss and dysestesias in glove and stocking distribution with decreased or absent ankle jerks. Small fiber sensory neuropathy presents with subjective numbness in the absence of objective abnormalities on electromyography and nerve conduction studies. Patients with IBD have also been found to have mononeuropathies or multifocal motor neuropathies (Gondim et al., 2005).

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Patients with demyelinating neuropathies (particularly chronic inflammatory demyelinating polyneuropathy) respond better to immunomodulatory therapy that those with axonal neuropathy (Lossos et al., 1995; Gondim et al., 2005). Peripheral neuropathies are not related to disease activity and do not respond to treatment of the underlying IBD. An inflammatory myopathy has also been found in association with IBD (Gendelman et al., 1982; Bhigjee et al., 1987; Sowa, 1991). It is probably more frequent in CD than in UC, and in the series by Lossos et al. (1995) was responsible for 16% of cases of neurolgic dysfunction. Dermatomyositis, polymyositis, rimmed vacuole myopathy, and granulomatous myositis have all been described and may also be completely asymptomatic (Hayashi et al., 1991). Myositis in CD is probably an immune-mediated disease (Shimoyama et al., 2009) as the same CD68 þ macrophages that are found in the diseased colon are also present in the muscle. Involvement of the neuromuscular junction has only rarely been described in the context of IBD (Martin and Shah, 1991; Finnie et al., 1994). It is important to report that at least one patient with CD and myasthenia had significant improvement of gastrointestinal symptoms following thymectomy (Finnie et al., 1994).

CRANIAL NEUROPATHIES Melkersson–Rosenthal syndrome (recurrent facial nerve palsy with facial edema, tongue fissuring, and granulomas) has been described by several authors in IBD (Lloyd et al., 1994; Lossos et al., 1995). Other cranial neuropathies, such as optic neuritis (Sedwick et al., 1984; Lossos et al., 1995), can also be found in single case reports. Sensorineural hearing loss has also been described (Kumar et al., 2000; Akbayir et al., 2005), and is probably an under-recognized, immunologic manifestation of IBD. Of relevance also is the possibility of recovery with early treatment with steroids and immunosuppressive agents (Bachmeyer et al., 1998).

CEREBROVASCULAR COMPLICATIONS Patients with inflammatory bowel disease (IBD) have a remarkable thromboembolic tendency and are at increased risk of both venous and arterial thrombotic complications. In hospital series of IBD, the prevalence of arterial and venous thrombosis is around 4%, while in autopsy studies, this percentage may be more than 30%. The incidence of thrombotic complications ranges from 0.5% to 6.7% per year (Bernstein et al., 2001; Papa et al., 2003). IBD is also a risk factor for recurrent venous thromboembolism (Novacek et al., 2010).

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In a cohort of 49 799 Danish patients with IBD compared with 477 504 members of the general population, patients with IBD had twice the incidence of deep venous thrombosis and pulmonary embolism. Relative risks were higher at young ages (hazard ratio 6.0 below age 20), though actual incidence increased with age (Kappelman et al., 2011). In a retrospective case control study including 17 487 IBD patients and 69 948 controls had an increased risk of arterial thrombotic events. In particular, women under the age of 40 exhibited a twofold higher risk for stroke (Ha et al., 2009). Thromboembolism is more frequent in IBD than in other chronic inflammatory or chronic bowel diseases (Miehsler et al., 2004). Strokes in patients with IBD were already reported in the 1930s. In 1986, Talbot and colleagues (1986) described a 1.3% prevalence of thromboembolic complications among 7199 patients with IBD observed during a 10 year period in a single institution. Among the 92 patients with thromboembolic complications, 61 had deep vein thrombosis or pulmonary embolism. Nine patients had cerebrovascular thrombotic events. There were no subarachnoid or intracerebral hemorrhages. Several other case series (Lossos et al., 1995; Elsehety and Bertorini, 1997; Barclay et al., 2010; Benavente and Morı´s, 2011; Cognat et al., 2011) and case reports of arterial ischemic or cerebral venous thrombosis have been published since then, with a frequency ranging from 0.6% to 4.7%. Cerebrovascular complications are somewhat more frequent in Crohn’s disease than in ulcerative colitis. They are not related to the duration or the severity of IBD, but cerebrovascular events are more frequent during bouts of inflammation. Rarely, they can antedate other manifestations of IBD.

complications. Vitamin deficiencies due to malabsorption, namely B12 and folate, cause hyperhomocysteinemia, in particular when combined with a MTHFR deficit. Cytokines, such as interleukin 1 and 6 and TNF-a can activate the coagulation cascade during periods of active inflammation. Other immune mechanisms include the coexistence of prothrombotic antibodies such as lupus anticoagulant, anticardiolipin antibodies, and atypical (non-MPO, non-PR3) ANCA antibodies, the latter in ulcerative colitis.

Arterial ischemic stroke Ischemic events can be both cerebral and ocular. Ischemic stroke occurs through several mechanisms: (1) large artery disease, including even a case of common carotid occlusion; (2) small vessel disease, e.g., corona radiata (Ogawa et al., 2011) or pontine lacunar infarcts; (3) cardioembolism, related to (a) paradoxical embolism though a patent foramen ovale in patients with lower limb, pelvic, or mesenteric venous thrombosis, either symptomatic or not, (b) endocarditis (Kreuzpaintner et al., 1992); (4) vasculitis.

Stroke and anti-TNF-a therapy A few cases of arterial ischemic complications have been reported as a complication of anti-TNF-a therapy (Vannucchi et al., 2011; Cohen et al., 2012). One of the authors (JMF) has observed two cases of deep intracerebral hemorrhage in young, nonhypertensive males with IBD treated with anti-TNF drugs. No underlying arteriovenous malformation, venous thrombosis, or other lesion was identified (Fig. 40.1).

Vasculitis Pathophysiology The prothrombotic state in IBD has multiple contributors, namely blood coagulation, platelets, endothelium, prothrombotic mutations, vitamin deficiencies, inflammation, and other immune mechanisms (Santos et al., 2001; Bermejo and Burgos, 2008. The hypercoagulation state is related to raised levels of factor V and VIII, fibrinogen, fibrinopeptide A and PAI-1, and decreased levels of protein S and antithrombin. Thrombocytosis is common in IDB, secondary both to anemia and inflammation. Platelet function is disturbed and Von Willebrand factor, a potent mediator of platelet adhesion and aggregation, is increased. In some patients endothelial dysfunction was reported. Prothrombotic mutations such as factor V Leiden and methylenetetrahydrofolate reductase (MTHFR) were identified in some IBD patients with cerebrovascular

Systemic and organ-specific vasculitis, namely cerebral, has been reported in association with IBD, especially with ulcerative colitis (Scheid and Teich, 2007). However, cerebral vasculitis is very rare and only a handful of cases, small case series, and a few nonsystematic reviews have been published (Martı´n de Carpi et al., 2007; Scheid and Teich, 2007). Vasculitis in IBD is immune-mediated, via genetic susceptibility and HLA status, T lymphocyte-mediated cytoxicity, or immune complex deposition (Scheid and Teich, 2007). In other cases IBD is associated with primary vasculitides (giant cell arteritis, Wegener, pANCA vasculitis) (Jacob et al., 1990; Ronchetto and Pistono, 1993; Gobron et al., 2010) or with other immune diseases (Cogan syndrome, thrombotic thrombocytopenic purpura, and lupus) (Chebli et al., 2000; Baron et al., 2002; Hisada et al., 2006; Ullrich et al., 2009).

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Fig. 40.1. MRI showing frontoparietal hemorrhagic stroke in a patient with inflammatory bowel disease, treated with anti-TNF-a agents.

The clinical manifestations of cerebral vasculities in IBD are protean and include headache (Holzer et al., 2009), cranial nerve palsies, focal deficits such as hemiparesis, sensory disturbances, aphasia and visual defects, multifocal signs and vigilance or cognitive troubles, isolated or in combination (Scheid and Teich, 2007). The onset can be acute or subacute. Presentation as a single stroke syndrome is infrequent. Levels of nonspecific inflammatory markers such as ESR or CRP may be elevated. Cerebrospinal fluid examination may reveal increased proteins or a mild pleiocytosis. Magnetic resonance imaging of the brain rarely shows large territorial infarcts. Acute lesions may be detected on diffusionweighted imaging (DWI). The most common findings are deep white matter or periventricular white matter lesions, detectable in FLAIR or T2 sequences (Scheid and Teich, 2007). These lesions are not specific and per se do not allow a definite diagnosis of vasculitis, which relies on the demonstration of inflammation on a vessel wall. In several cases reported in the literature no imaging or biopsy of the vessels was obtained and therefore the diagnosis of vasculitis is only probable. Intraarterial, MR (Schluter et al., 2004), or CT angiography can reveal multiple arterial stenoses or other aspects suggestive of vasculitis, but many of them can also be seen in noninflammatory vasculopathies and in the reversible cerebral vasoconstriction syndrome, in which the arterial stenoses usually regress in a follow-up angiography performed 6–8 weeks later. Moreover, angiography can be normal in vasculitis affecting only small arteries. In large artery vasculitis (Takayasu and giant cell arteritis), the temporal superficial, the carotid, and the axillary arteries are accessible to ultrasound which may demonstrate

inflammatory “halos.” Recently, appropriate MR sequences were reported to depict wall inflammation in medium-size intracerebral vessels, such as the proximal segments of the middle cerebral artery (Mandell et al., 2012). In a few cases of vasculitis associated with IBD, namely UC, necropsy of brain biopsy was obtained. In three cases necrotizing vasculitis was found (Glotzer et al., 1964; Nelson et al., 1986; Carmona et al., 2000), although in one of them hemorrhagic acute disseminated encephalomyelitis could not be ruled out (Glotzer et al., 1964). In other cases only a lymphocyte infiltrate was found (Kraus et al., 1996). Although the outcome is general favorable, a few cases were rapidly fatal. The majority improved with steroids, but in some patients symptoms developed while they were already on steroids. In these patients ciclosporin, plasma exchange, and more recently biologic anti-TNF agents (Ullrich et al., 2009) were used with variable success.

CEREBRALVENOUS THROMBOSIS Thrombosis of the dural sinus and cerebral veins is at least as frequent as arterial stroke in IBD. Thrombosis appears to be more common in ulcerative colitis than in Crohn’s disease, but in some series the opposite was found (Cognat et al., 2011). Cognat and coworkers (2011) recently published eight cases from two centers in Paris and reviewed 49 other cases of cerebral venous thrombosis associated with IBD confirmed by MR. Other cases not included in this review have been published (Milandre et al., 1992; Lossos et al., 1995;

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Papi et al., 1995; Barclay et al., 2010; Nudelman et al., 2010; Casella et al., 2011; Kothur et al., 2012). The publications of Milandre et al. (1992), Nudelman et al. (2010), and Casella et al. (2011) also provide a review of previous reports. When compared to patients with cerebral venous thrombosis with other causes, patients with IBD-related cerebral venous thrombosis are younger and more often male. A more recent review of 65 cases published in English was performed by Katsanos and coworkers (2013). The clinical presentation, consisting of headaches, focal signs, seizures, or encephalopathy, and the sites of the venous occlusions are similar to the usual cerebral venous thromboses. They can occur from 2 months to 17 years after the first attack of IBD. Occasionally, the diagnosis of IBD is established only when cerebral venous thrombosis occurs (Cognat et al., 2011; Katsanos et al., 2013). Although IBD may be asymptomatic when the venous thrombosis occurs, almost all patients had biologic markers of inflammation such as elevated leukocyte count, CRP, or ESR. When concomitant causes of cerebral venous thrombosis are systematically searched for, the majority had other risk factors, such as oral contraceptives, severe iron deficiency anemia, anti-TNF-a treatment, thrombocytosis, hyperhomocystenemia, folate and B12 deficiencies, infection, lupus anticoagulant, and inherited thrombophilia (Milandre et al., 1992; Papi et al., 1995; Nudelman et al., 2010; Casella et al., 2011; Cognat et al., 2011). Despite the potential risk of intestinal bleeding, treatment of acute cerebral venous thrombosis with full dose intravenous heparin or low molecular weight heparin is effective and safe (Tsujikawa et al., 2000; Cognat et al., 2011; Katsanos et al., 2013). Endovascular thrombolysis was tried in a few cases, with favorable and safe outcomes (Philips et al., 1999; Kothur et al., 2012). This limited evidence supports the use of approved guidelines for cerebral venous thrombosis management (Einha¨upl et al., 2006; Saposnik et al., 2011) also when associated with IBD. The prognosis is usually good, but a few cases were fatal (Cognat et al., 2011; Katsanos et al., 2013).

DEMYELINATING DISEASE Multiple sclerosis (MS) has been frequently associated with IBD, particularly with UC (Rang et al., 1982; Sadovnick et al., 1989; Purrmann et al., 1992; Buccino et al., 1994; Kimura et al., 2000; Pandian et al., 2004; Bernstein et al., 2005; Gupta et al., 2005), although evolving diagnostic criteria for MS could mean that some patients actually have an MS-like disease instead of true MS. Both patients with IBD who later developed MS and patients with MS who developed IBD have been described. Kimura et al. (2000) found a 1% prevalence of

clinically definite MS among 400 patients with IBD. Gupta et al. (2005) estimated a relative risk for MS and optic neuritis in CD of 1.54 and of 1.74 in UC when compared with the general population. Between 40% and 50% of IBD presented asymptomatic white matter lesions in a study by Perkin and Murray-Lyon (1998). MS and IBD share similar epidemiology, age of presentation, clinical course, and geographic distribution. However, despite all evidence, the physiopathology of this relationship between diseases is still unknown, although some animal studies may shed some light on the issue. Extensive perivenular demyelination and astrocytosis has been found in monkeys suffering from IBD and cerebral venous thrombosis, possibly due to perivenular edema (Sheffield et al., 1981). Also, IBD may be viewed as a chronic variant of a predemyelinating state that can trigger demyelinating episodes. IBD has also been associated with other chronic inflammatory diseases suggesting a common immunologic etiology (Bernstein et al., 2005). Antitumor necrosis factor-a therapy is contraindicated in the treatment of patients with IBS and multiple sclerosis and there is evidence of onset of a demyelinating process with institution of this therapy (Thomas et al., 2004; Freeman and Flak, 2005).

OTHER CENTRAL NERVOUS SYSTEM COMPLICATIONS A slowly progressive spastic paraparesis due to myelopathy has been reported in association with IBD (Gibb et al., 1987; Ray et al., 1993; Suzuki et al., 1994; Lossos et al., 1995) and in the series by Lossos et al. was present in 26% of patients. An immune-mediated inflammatory origin has been suggested but vitamin B12 deficiency with resulting subacute combined degeneration of the spinal cord may also be responsible in patients with CD following terminal ileum resection. Epidural and subdural spinal empyemas secondary to fistulous extension from the rectum are rare complications of CD and can result in pain and progressive leg weakness (Sacher et al., 1989; Hershkowitz et al., 1990; Heidemann et al., 2003; Gelfenbeyn et al., 2006). In CD patients, Elsehety and Bertorini (1997) reported seizures (5.9%), headaches (4.3%), major depression (4.3%), anxiety disorder (2%), and other less frequent complications (less than 1%) such as Parkinson-like syndrome, cerebellar syndrome, ischemic optic neuritis, orbital pseudotumor, sixth nerve palsy, organic brain syndrome, and chronic fatigue syndrome. A single case of inflammatory pseudotumor of the cerebellum in a patient with CD was reported by Derrey et al. (2012). An association of epilepsy and IBD appears to be preferentially with CD (Elsehety and Bertorini, 1997) but

NEUROLOGIC MANIFESTATIONS OF INFLAMMATORY BOWEL DISEASES secondary seizures related to metabolic and structural causes have been described in UC (Schneidermann et al., 1979; Johns, 1991; Lossos et al., 1995). Diffuse encephalopathy may also develop in patients with CD, possibly related to vitamin deficiency including Wernicke encephalopathy, selenium toxicity due to parenteral nutrition, or precipitated by treatment with sulfasalazine (Schoonjans et al., 1993; Kawakubo et al., 1994; Hahn et al., 1998; Eggsp€ uhler et al., 2003).

PSYCHIATRIC SYNDROMES The most frequent psychiatric syndromes associated with IBD are depression and anxiety. In two Canadian national surveys with 3076 and 1438 respondents with IBD, 16.3% and 14.7%, respectively, reported depressive symptoms (Fuller-Thomson and Sulman, 2006). Depression was more frequent in women and younger respondents and in patients with pain or functional limitations.

MEDICATION-INDUCED NEUROLGIC COMPLICATIONS Steroids In the 1950s, Bunim et al. (1955) described glucocorticoidrelated myopathy, a well known side-effect of this therapy due to direct catabolic effects on the skeletal muscle. It can occur with any of the glucocorticoid preparations, in both initiation of treatment and chronic use. Patients typically present with painless proximal muscle wasting and weakness, normal muscle enzymes (Askari et al., 1976), and improve after decrease in drug dosage.

Metronidazole Metronidazole is an antimicrobial agent with bactericidal effects against anaerobic agents used in the treatment of IBD. Patients treated with metronidazole, particularly with high doses, have presented seizures, dizziness and vertigo, ataxia, confusion, irritability, insomnia, headache, tremors and peripheral neuropathy (Frytak et al., 1978; Kusumi et al., 1980; Halloran, 1982). Peripheral neuropathy is usually pure sensory or autonomic with occasional ataxia; it is mostly transient and resolves completely with discontinuation.

Ciclosporin Mild tremor, but also headache, visual abnormalities, and seizures in the context of a syndrome resembling posterior leukoencephalopathy have been described in patients treated with ciclosporin (Schwartz et al., 1995; Wijdicks et al., 1995; Hinchey et al., 1996).

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Anti-TNF-a agents (infliximab, adalimumab, certolizumab) A possible link between TNF-a and demyelinating disease has been suggested although a causal relationship has not been established. In 2001, Mohan et al. described 19 patients with brain and spinal cord demyelination on magnetic resonance imaging, presenting with confusion, ataxia, dysesthesia, and paresthesia, who improved after discontinuation of therapy (Mohan et al., 2001). In postmarketing reports both optic neuritis and demyelinating polyneuropathy have also been reported with infliximab and adalimumab (Shin et al., 2006; Simsek et al., 2007; Eguren et al., 2009). Progressive multifocal leukoencephalopathy (PML), a severe demyelinating disease of the central nervous system caused by reactivation of the polyomavirus JC (JC virus) has been reported in patients treated with infliximab (Kumar et al., 2010) and glucocorticoids (Newton et al., 1986), alone or in combination with immune suppressive agents. The risk of PML is associated with duration of treatment, prior use of immune suppressant medication, and JC virus antibody status, being minimal in JC virus antibody-negative patients (Biogen Idec). PML typically presents with cognitive impairment and behavioral changes and can progress to cause motor weakness, visual and language disturbances, and seizures. Diagnosis can be confirmed by quantitative detection of JC virus DNA in the cerebrospinal fluid (Aksamit, 2008).

Anti-a4 integrin (natalizumab) Natalizumab is a humanized monoclonal antibody to a4 integrin recently approved for treatment of CD (Sandborn et al., 2005) outside Europe. PML has been described in association with natalizumab in CD patients (Van Assche et al., 2005).

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