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Keywords:

  • inflammatory bowel disease;
  • extraintestinal manifestations;
  • central nervous system;
  • white matter lesions;
  • MRI

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Background: Neurological manifestations in patients with inflammatory bowel disease supposedly are rare, although the exact frequency is not known. Most previous reports involve cerebral venous thrombosis, central nervous system vasculitis, or peripheral nerve inflammation.

Methods: Two cases of patients diagnosed with inflammatory bowel disease developing neurological symptoms with corresponding lesions in the white matter of the central nervous system led us to search a neurological database with clinical and radiological data for similar cases.

Results: We identified five patients who presented with acute neurological deficits preceding or following a diagnosis of inflammatory bowel disease with evidence of lesions in the central nervous system white matter on magnetic resonance imaging. Ancillary investigations did not provide evidence of systemic infetcion, coagulation disorders, or vasculitis.

Conclusions: These cases, together with previous reports, suggest that white matter lesions may be another extraintestinal manifestation of inflammatory bowel disease.

(Inflamm Bowel Dis 2009)

Crohn's disease (CD) and ulcerative colitis (UC) are chronic relapsing inflammatory bowel disorders of unknown etiology.1, 2 Disturbed immunological processes are thought to play a major role in the pathogenesis. Inflammatory bowel diseases (IBDs) are usually considered systemic illnesses, as many organs outside the gastrointestinal tract may be involved. Extraintestinal manifestations include ocular (uveitis, iritis), hepatic (primary sclerosing cholangitis), pancreatic (pancreatitis), joint (arthritis), and skin (erythema nodosum, pyoderma gangrenosum) manifestations and occur in up to 25% of patients.1 Neurological symptoms in patients with IBD have been documented as well, including peripheral neuropathies, myopathies, or cerebrovascular events, the latter resulting from coagulation disorders or central nervous system (CNS) vasculitis.3–5 Several reports suggest that the CNS white matter might also sporadically be affected in IBD patients.6, 7 We describe 5 patients who developed acute neurological symptoms before or after a diagnosis of IBD was made, all of whom had magnetic resonance imaging (MRI) demonstrating lesions of the CNS white matter.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Two recent cases of acute neurological symptoms with corresponding MRI lesions in patients diagnosed with IBD prompted us to search a neurological database for similar cases. This database contains clinical and radiological data of all patients with (nonvascular) CNS white matter lesions who were seen by an multiple sclerosis (MS) specialist (R.Q.H.) at the Department of Neurology of the Erasmus Medical Center Rotterdam in the period 1999–2007. Co-occurring inflammatory diseases are systematically recorded for all patients suspected to have demyelinating disease. From this database we identified 5 patients with a diagnosis of IBD (CD or UC), either prior to or after the onset of neurological symptoms. The medical records and MRI images of these patients were reviewed to obtain information on medical history, medication use, family history, clinical symptoms, MRI findings, disease course, and treatment.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patient A was a 57-year-old Caucasian woman who was admitted because of a numb feeling and paresthesias in both legs and difficulty walking that had developed within 24 hours. Her medical history revealed hyperthyroidism, which had responded well to therapy, and a diagnosis of UC 20 years earlier. Family history was negative for neurological disease. At the time of presentation the bowel inflammation was in remission and she did not use any medication. Neurological examination revealed a slightly increased muscle tone in both legs, weakness of the proximal muscles of the left leg, hypesthesia of both legs, and bilateral increased tendon reflexes with extensor plantar response on the left. MRI of the spinal cord demonstrated 3 intramedullary lesions with contrast enhancement: in the medulla oblongata, at the level of C4, and at the level of Th6 (see Fig. 1). Cerebrospinal fluid (CSF) examination was normal and an extensive laboratory workup did not reveal any abnormalities, except for a positive antinuclear antibody (ANA) test. In the next 3 months neurological signs improved without intervention. A follow-up MRI no longer showed contrast enhancement of the lesions. On a third MRI, performed 5 months after symptom onset, the lesions had become considerably smaller. A diagnosis of autoimmune myelitis, probably associated with UC, was made. At the last visit the neurological examination was normal except for mild dysesthesias in both legs.

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Figure 1. Patient A; MRI of the spinal cord demonstrating a lesion in the medulla oblongata and an intramedullary lesion with mass effect at the level of C3-C5.

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Patient B, a Caucasian female without a family history of neurological diseases, presented with complaints of double vision at the age of 19. Her only past medical history of note was psoriasis; she was not taking any medication at the time of presentation. Neurological examination was normal. MRI of the brain demonstrated multiple periventricular white matter lesions in both the right and left hemisphere, without contrast enhancement. Several oligoclonal bands were found in the CSF; the CSF was otherwise normal. The results of routine laboratory testing were unremarkable. A diagnosis of possible MS was made and the patient was treated with intravenous methylprednisolone for 5 days, after which her symptoms disappeared. One year later she was diagnosed with CD, for which prednisone was started. After 3 years she developed arthralgias of the smaller joints, which were considered to be associated with either the psoriasis or CD. Four years later she was also diagnosed with Sjogren's disease after a diagnostic lip biopsy. Serological tests for autoimmune antibodies remained negative throughout the years. After 5 years, new episodes of neurological deficits have not yet occurred, suggesting monophasic disease.

Patient C was a 45-year-old Caucasian woman with a medical history of deep venous thrombosis, kidney stones, and UC, treated with azathioprine and prednisone. Her family history was unremarkable. She was admitted to the hospital because of right-sided weakness that had developed within a few hours. Brain computed tomography (CT) showed 2 hypointense lesions in the left hemisphere of uncertain etiology. During admission, her paresis worsened to complete paralysis of the right arm and leg. MRI of the brain showed a tumor-like lesion in the white matter of the left hemisphere without contrast enhancement (Fig. 2). Initially, a diagnosis of glioblastoma multiforme was made, based on the radiological findings and a diagnostic brain biopsy. In the absence of treatment options the patient was discharged. However, in the following months the hemiparesis improved. A second MRI revealed only slight residual abnormalities in the left side of the pons. Because of this unexpected clinical and radiological improvement the pathologist was asked to revise the results of the brain biopsy. The second pathology report stated that there were no definitive arguments in favor of glioblastoma and that the findings were compatible with CNS inflammatory demyelination. At the last visit the patient only experienced slight weakness of the right arm and leg and was able to walk using a walking aid.

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Figure 2. Patient C; MRI of the brain showing an inhomogeneous subcortical lesion with contrast enhancement in the left hemisphere extending into the midbrain, with some mass effect. This lesion was initially diagnosed as glioblastoma multiforme, but the revised pathology report stated that the findings were compatible with CNS inflammatory demyelination.

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Patient D was a 28-year-old Caucasian male who was diagnosed with UC at the age of 13 and had experienced an autoimmune hepatitis at the age of 20 years, for which he had been treated with azathioprine. His family history was negative for neurological illnesses. On presentation, he complained of paresthesias in both arms, fingers, legs, and toes. He had not noted any weakness. The patient's medications at that time consisted of salazopyrine and prednisone. Neurological examination only showed discrete hypesthesia of the fingertips and hyperreflexia. Brain MRI revealed no abnormalities. On an MRI of the spinal cord several lesions with contrast enhancement were seen at different levels, the largest at the level of C3. Laboratory and CSF examination were completely normal except for a borderline increased monoclonal immunoglobulin level in the CSF. A diagnosis of autoimmune myelitis was made and the patient was treated with intravenous methylprednisolone. Because the symptoms did not improve, treatment was started with monthly doses of cyclophosphamide. Follow-up MRI showed reduction of some of the previously observed lesions, but also several new lesions, some of which showing contrast enhancement. Eventually, after 6 doses of cyclophosphamide the patient's neurological signs completely recovered.

Patient E was a 34-year-old previously healthy Caucasian female without a family history of neurological diseases who was examined elsewhere because of abdominal pain and diarrhea. She was diagnosed with CD and treated with prednisone and mesalazine, upon which the abdominal symptoms disappeared. Two weeks later she was admitted with severe headache attacks and progressive memory complaints. On neurological examination she was disoriented and bradyphrenic, and had increased tendon reflexes. After admission her condition worsened to a state of confusion, with loss of spontaneous speech, inability to walk, and urine incontinence. An MRI of the brain demonstrated multiple white matter hyperintensities. Conventional angiography did not show signs of vasculitis. Extensive laboratory workup was completely normal; CSF testing only revealed several oligoclonal bands. As a diagnosis of acute disseminating encephalomyelitis (ADEM) was considered most likely, therapy was initiated with intravenous methylprednisolone, followed by oral prednisone. In the following weeks the patient's symptoms gradually improved. One month after symptom onset she was able to speak and walk again and was transferred to a rehabilitation center.

The clinical and radiological characteristics of all patients are summarized in Table 1.

Table 1. Clinical Characteristics of Described Patients
PatientSexIBD TypeAge IBDaExtraintestinal manifestationsAge CNS SymptomsbIBD MedicationcNeurological Signs on PresentationNeurological DiagnosisMRI FindingsTreatmentOutcome
  • IBD, inflammatory bowel disease; CNS, central nervous system; MRI, magnetic resonance imaging; F, female; M, male; UC, ulcerative colitis; CD, Crohn's disease; MS, multiple sclerosis; ADEM, acute disseminating encephalomyelitis; GBM, glioblastoma multiforme.

  • ?

    Unknown.

  • a

    Age at onset of IBD.

  • b

    Age at onset of CNS symptoms.

  • c

    IBD medication used at time of onset of neurological symptoms.

AFUC37None57NoneBilateral pyramidal syndromeMyelitisThree intramedullary lesions, contrast enhancementNoneMild dysesthesias both legs
BFCD20Arthralgias19NoneDiplopiaProbable MSPeriventricular white matter lesionsMethylprednisoloneComplete recovery
CFUC?None45Imuran, PrednisoneRight-sided hemiparesisInitial diagnosis GBMMultifocal white matter lesions lef themisphereNoneSlight weakness right arm and leg
DMUC13Hepatitis28Salazopirine, PrednisoneParesthesias arms & legs, hyperreflexiaMyelitisSeveral lesions at different levelsSoluMedrol, CyclophosphamideComplete recovery
EFCD34None34Mesalazine, PrednisoneSevere encephalopathyADEMMultiple white matter hyperintensitiesMethylprednisolone, PrednisonePartial recovery

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

We describe 5 patients who presented with acute neurological deficits of varying severity preceding or following a diagnosis of IBD. In all patients, MRI of the brain or spinal cord demonstrated lesions in the CNS white matter, some of which with contrast enhancement. Ancillary investigations did not provide evidence of systemic infection, coagulation disorders, or vasculitis. All 5 patients eventually experienced partial or complete recovery of clinical as well as radiological signs, some of them after treatment with intravenous corticosteroids or immune-modifying therapy.

The number of patients with IBD treated at the Department of Gastroenterology of our hospital throughout the period 1999–2007 is estimated at about 900. However, not all IBD patients were systematically evaluated for neurological symptoms and MRI abnormalities. Our findings therefore do not allow firm conclusions about the occurrence rate of CNS lesions in patients with IBD. To obtain reliable frequency estimates a prospective study in a large patient cohort with routinely performed MRI in all subjects should be carried out.

Only very few systematic studies have investigated the frequency of neurological disorders in patients with IBD and the results have been inconsistent, due to differences in case finding methods and the outcomes that were evaluated.3, 4, 8 Previous studies were almost exclusively retrospective, just a few of them included a control group,6, 9, 10 and except for 1 study6 MR imaging was not part of the standard workup. In a large retrospective register-based study involving 638 patients with UC or CD, Lossos et al3 found neurological involvement in 3% of the cases. Neurological disorders associated with IBD mainly comprised cerebrovascular events such as arterial ischemic stroke or cerebral venous thrombosis due to vasculitis or coagulation abnormalities. Peripheral manifestations including inflammatory neuropathy and myositis have also been reported occasionally.3, 11 In a recent prospective study, 13.4% of 82 IBD patients were found to have an unexplained peripheral neuropathy.5 In addition, a number of studies have demonstrated an increased prevalence of demyelinating diseases, including MS, in patients with IBD.9, 10, 12–16 In a large retrospective study evaluating comorbidities in patients with CD, 0.5% of the patients had also been diagnosed with MS, while the estimated prevalence of MS in the general population is about 0.1%.14 Two other large register-based surveys also showed an elevated risk of MS in IBD patients as compared with a matched control group.9, 10 The nature of a possible link between IBD and MS has not been fully identified. Disturbances in functional T-cell subsets as well as in antigen presenting cells have been implicated. Especially aberrant proinflammatory activity, such as T-helper 17-mediated effects, have been suggested as a common pathway leading to destruction of the target tissue in both diseases.17

Monophasic lesions of the CNS white matter as occurred in our IBD cases have also been documented, although less frequently.6, 7, 11, 18 A few case reports describe focal lesions in the white matter in IBD patients who developed neurological symptoms.3, 7, 11 Geissler et al6 observed white-matter hyperintensities on brain MRI in almost half of the patients with IBD who were free of neurological symptoms, whereas lesions were only visible in 16% of the healthy age-matched controls. It is as yet unknown which pathogenetic mechanisms might underlie the occurrence of lesions in the CNS white matter in patients with IBD. Immune-mediated or inflammatory processes have been suggested to play a role, but direct evidence is lacking.3, 4, 11 Although the exact etiology remains to be elucidated and a causal relationship has not been definitively established, the 5 cases we present here suggest that CNS white matter lesions may occur as extraintestinal manifestations of IBD.

The lesions as well as the clinical signs appear to be at least partially reversible. Therefore, when patients with a history of UC or CD present with unexplained neurological symptoms, an association with IBD should be considered and referral to a neurologist for further diagnostic workup may be needed. The differential diagnosis of the MRI lesions may be difficult, especially when an IBD patient with sudden neurological symptoms has recently been treated with 1 of the new biologicals such as tumor necrosis factor (TNF)-alpha or very late antigen (VLA)-4 blocking agents. These agents have also been reported to trigger CNS white matter lesions as a rare side effect,19 and alternatively the concomitant immunosuppression may lead to opportunistic infections mimicking MS such as JC virus-mediated progressive multifocal leuko-encephalopathy (PML).20 None of the patients we describe was using anti-TNF-α medications at the time of onset of neurological symptoms. Previous reports of demyelinating lesions associated with IBD also mainly pertain to patients without TNF-α therapy. This has set off some dispute as to whether the supposed association between the use of biologicals and the development of white matter abnormalities is real or rather is explained by the underlying disease for which these medications were prescribed.9, 10 On the other hand, demyelinating lesions have also been documented in patients taking TNF-α blocking agents for other diseases like rheumatoid arthritis and the current thinking is that both the underlying disease as well as treatment may play a role.19

Some of the patients we describe seemed to improve after receiving corticosteroids or immunomodulating drugs, which are usually administered by neurologists in similar clinical situations. However, the lack of clinical evidence precludes making specific recommendations for the treatment of IBD-associated CNS lesions.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES