Clinical manifestations

Presentation and course

Clinical features are primarily gastrointestinal and consist of abdominal pain and non-bloody diarrhea. In addition, weight loss is common. Scarring and stricture formation can lead to partial intestinal obstruction, and fistula formation is also frequent. The clinical course of Crohn disease often entails exacerbations and remissions. Although Crohn disease may involve virtually all levels of the gastrointestinal tract, it demonstrates a distinct predilection for the distal small intestine and proximal colon. In contrast to ulcerative colitis, involvement in Crohn disease is patchy or segmental and extends deeply, often transmurally. Non-caseating granulomas may form, but are not invariably present.

Extraintestinal manifestations of Crohn disease are surprisingly common, with reported frequencies ranging from approximately 25% to over 50% of individuals (44; 80; 116; 17; 89). Some of the extraintestinal manifestations, such as involvement of joints, skin, mouth, and eyes, seem to correlate with the presence of active colonic inflammation. Karmody and colleagues reviewed sensorineural hearing loss as an extraintestinal association of inflammatory bowel disease (56). As inflammatory bowel disease is considered to be a local or systemic immunopathy, the associated sensorineural hearing loss might also be an expression of systemic immune dysfunction. Other clinical processes, such as gallstones and renal calculi, correlate more directly with small intestinal involvement (44).

Neurologic manifestations in inflammatory bowel disease patients are more common than previously estimated and may follow a different pattern of involvement in Crohn disease and ulcerative colitis (119). Even though the prevalence is not clear, the neurologic dysfunction in Crohn disease has multifactorial etiology with both peripheral as well as central nervous system involvement (78). In comparison with many of the systemic manifestations of inflammatory bowel disease, neurologic involvement occurs less frequently in Crohn disease. Lossos and colleagues reported the presence of neurologic involvement in 3% of 638 persons they studied with either Crohn disease or ulcerative colitis (67). In their comprehensive review, they described 4 categories of neurologic involvement: peripheral neuropathy, myopathy or myoneural junction dysfunction, cerebrovascular disease, and myelopathy. Other groups of investigators have also documented demyelinating processes, seizures, and encephalopathy in patients with inflammatory bowel disease. Although neurologic impairment often becomes evident during periods of disease activity, it can also emerge when the disease process is in the dormant phase.

Peripheral nervous system involvement. The peripheral nervous system is the dominant site of neurologic dysfunction in ulcerative colitis and Crohn disease, accounting for 31.5% of neurologically affected patients (67). A rather extensive array of peripheral neuropathic processes has received recognition. Acute inflammatory demyelinating neuropathy (Guillain-Barré syndrome), axonal sensorimotor neuropathy, mononeuropathy, brachial plexopathy, mononeuritis multiplex, multiple compressive neuropathies, and cranial neuropathies have all been described in the setting of inflammatory bowel disease (67; 24; 77; 19).

Nerve and nerve root disease. Gondim and colleagues performed a retrospective study of 18 patients with Crohn disease and 15 with ulcerative colitis who had developed peripheral neuropathy with no other identifiable etiology (41). The neuropathy was demyelinating in nature in 5 of the 18 (28%) individuals with Crohn disease. In 2 of the 5 (11%), it demonstrated characteristics of multifocal motor neuropathy, whereas in the other 3 (17%) it met criteria for chronic inflammatory demyelinating neuropathy. Eleven patients (61%) had large-fiber axonal neuropathy (4 sensory, 7 sensorimotor), and 2 (11%) were diagnosed with small-fiber neuropathy. Small- and large-fiber axonal sensory neuropathies were more frequently present in younger individuals, whereas patients with large fiber sensorimotor axonal neuropathy tended to be older. Although both axonal and demyelinating neuropathies often responded to immunotherapy, the response was more consistent and robust in patients with demyelinating neuropathy. Among individuals with demyelinating neuropathy who underwent immunomodulatory therapy, 80% experienced moderate (20%) or major (60%) improvement, whereas 60% in the non-demyelinating group derived moderate benefit. Its phenotype is diverse (most commonly small to predominantly axonal sensory large-fiber neuropathy), but usually more severe in Crohn disease (42).

The actual pathologic process inciting the peripheral neuropathy in individuals with Crohn disease is uncertain. In some instances, nutritional factors (folate or vitamin B12 deficiency) have been responsible (22; 66), whereas in others the peripheral neuropathy has been attributed to medications used in treatment, such as metronidazole (28; 106). In other cases, the explanation is not so clear (79). Response to immunosuppressive therapy or plasmapheresis has suggested an autoimmune basis, at least in some instances, and vasculitis with circulating immune complexes has been identified by some investigators (54). However, not all cases have been immunoresponsive. Infection with Campylobacter jejuni has been linked to both acute inflammatory demyelinating neuropathy and exacerbations of inflammatory bowel disease, but the organism has not been identified in any individual experiencing the combination of the 2 processes. As for nerve root involvement, this is rare and has been described in context with lumbar spinal infection secondary to colonic diverticular disease in 1 of the case reports (52). In addition, Smith and Kavar reported a patient with Crohn disease who developed an extensive spinal epidural abscess communicating with an intra-abdominal collection (105).

A distinctive and unusual type of cranial nerve involvement may also become evident in individuals with Crohn disease. Melkersson-Rosenthal syndrome is characterized by the clinical constellation of recurrent facial nerve palsy, intermittent orofacial swelling, and fissuring of the tongue (lingua plicata). Not only has this syndrome been noted in the presence of Crohn disease, its pathologic hallmark, noncaseating granuloma formation, also is seen in Crohn disease. This has led some to suggest that Crohn disease and Melkersson-Rosenthal syndrome are actually part of the same pathologic spectrum (64). Laryngeal involvement in Crohn disease is very rare, and almost 10 cases have been reported with difficulty in breathing due to edema and ulceration from the larynx to the hypopharynx. Hasegawa and colleagues described the first case in which limited ulceration occurred on the vocal fold without airway involvement (47). Caramoy and colleagues made the diagnosis of chronic recurrent retinopathy centralis serosa due to many years of corticosteroid intake for bronchial asthma and Crohn disease (14). Photodynamic therapy was carried out on the right eye and the corticosteroids were discontinued.

Muscle and myoneural junction disease. Muscle involvement may develop in the setting of both ulcerative colitis and Crohn disease, but occurs more frequently in the latter. It accounted for 16% of the cases of neurologic dysfunction in the series compiled by Lossos and colleagues (67). A variety of myopathic processes has been noted in the presence of Crohn disease. Shimoyama and colleagues revealed that myositis in Crohn disease is immune-mediated based on similar CD68-positive macrophages from the resected colon as well as the muscle (101).

Rhabdomyolysis may develop in individuals with Crohn disease (16). Although rhabdomyolysis may be secondary to electrolyte depletion, it may also occur without obvious provocation. The rhabdomyolysis may be subclinical, producing no noticeable symptoms of muscle involvement.

Inflammatory myopathic processes are another potential extraintestinal manifestation of Crohn disease. Dermatomyositis, polymyositis, rimmed vacuole myopathy, and granulomatous myositis have all been noted in this setting. Approximately 50% of the time the appearance of myositic symptoms correlates with disease activity in the bowel. However, the symptoms of myositis may even precede the appearance of gastrointestinal dysfunction in some patients (03). Myositis may also be completely asymptomatic, with only elevation of serum creatine phosphokinase as a clue (48). As with peripheral nerve involvement, an autoimmune basis generally is presumed to be present. Vasculitis involving muscle has also been described in the setting of Crohn disease (39). Focal myositis may also occur. In fact, myositis involving the gastrocnemius muscle has been christened the “gastrocnemius myalgia syndrome” (18). Orbital myositis, sometimes recurrent, has also been reported in Crohn disease (29).

Dysfunction at the myoneural junction may on rare occasions occur in the context of Crohn disease. Myasthenia gravis has been reported (73; 32), although descriptions of this association are sparse. It is of interest that in at least 1 individual with Crohn disease and myasthenia, improvement in gastrointestinal problems (perineal and perianal abscesses and fistulas) occurred following thymectomy (32).

Psoas abscess formation is an important, well-recognized complication of Crohn disease (12; 62; 102; 117) that carries with it the potential for significant morbidity and even mortality (114; 07). Abscess formation is a consequence of a fistulous extension into the psoas muscle, and is characterized clinically by flank, pelvic, or abdominal pain, fever, leukocytosis, flexion contracture of the hip, and gait impairment. Psoas abscess may be the presenting clinical feature of Crohn disease (88). Diagnosis is confirmed by ultrasound or abdominal CT. Abscesses in other muscles, such as the obturator and hamstring, may also develop in the setting of Crohn disease (25; 59). Crohn disease and ulcerative colitis patients are more prone to neuromuscular diseases than patients with gastritis and dyspepsia (43).

Central nervous system involvement. A variety of causes may attribute to central nervous system involvement, including demyelination, cerebrovascular disease, seizures, sleep disturbance, encephalopathy, and spinal cord dysfunction.

Demyelinating disease. An association between inflammatory bowel disease and multiple sclerosis has been suggested (58; 45; 108). Although the association may be stronger for ulcerative colitis than it is for Crohn disease (87; 82), cases of concomitant Crohn disease and multiple sclerosis have also surfaced (86; 11). In several instances, a temporal correlation between the onset of the demyelinating process and the institution of anti-tumor necrosis alpha factor therapy with infliximab was evident (113; 33). Barabino and colleagues described the first report of optic neuritis in a pediatric patient with Crohn disease (06). This could be part of an autoimmune disorder such as a recurrent isolated optic neuritis, the first manifestation of multiple sclerosis, or perhaps another developing demyelinating disease. A study done by Kunchok and colleagues revealed that exposure to TNF inhibitors in patients with autoimmune diseases appeared to be associated with increased risk for inflammatory CNS events; however, this needs to be further researched (60).

Spinal cord dysfunction. Chronic, slowly progressive myelopathy is yet another neurologic manifestation of inflammatory bowel disease, accounting for 26% of the patients with neurologic involvement in the series of Lossos and colleagues (67). Most, though not all, of these individuals were suffering from Crohn disease rather than ulcerative colitis. An inflammatory basis was suspected and oligoclonal banding was noted in 1 patient. Subacute combined degeneration of the spinal cord, secondary to vitamin B12 deficiency following resection of the terminal ileum, may also be responsible for the development of myelopathy in persons with Crohn disease (10; 04). Epidural or subdural spinal empyema, secondary to fistulous extension from the rectum, is a rare complication of Crohn disease, and may present with back and leg pain and progressive leg weakness (92; 51; 49; 37).

Cerebrovascular disease. Vascular complications are well documented though relatively infrequent extraintestinal manifestations of inflammatory bowel disease. In a massive undertaking, Talbot and colleagues reviewed the records of 7199 patients with either Crohn disease or ulcerative colitis and noted the presence of vascular complications in 1.3% (112). Deep venous thrombosis and pulmonary embolus were the most common sites of involvement, whereas individuals with cerebrovascular events accounted for only 9.8% of the total vascular complications (9 of 92 patients). For reasons that are uncertain, vascular complications occur more frequently in ulcerative colitis than in Crohn disease (26). Cerebrovascular events in inflammatory bowel disease may appear both during active exacerbations and during periods of disease quiescence.

Cerebrovascular complications in Crohn disease may emerge in a variety of forms. Large artery disease, such as carotid artery stenosis, with consequent cerebral infarction has been reported in individuals with Crohn disease (118). Multiple strokes may occur and may precede the appearance of bowel symptoms (72). Spinal cord ischemia has also been described (104). Venous sinus thrombosis, especially involving the superior sagittal sinus, is another potential cerebrovascular complication of Crohn disease (103; 35; 76; 69; 94) and may also be the presenting feature (94). Cerebral vasculitis, with multiple lesions in the brain and involvement of multiple vessels on neuroimaging, is yet another potential cerebrovascular manifestation of Crohn disease (40; 96; 36).

Inflammatory bowel disease carries an increased risk of venous and arterial thrombosis. The pathogenic mechanisms of this predisposition are unclear; however, a possible role of inherited risk factors for thrombosis in determining this predisposition has been suggested. Hyperhomocysteinemia may impart an increased risk for thromboembolic events in individuals with Crohn disease (71; 81), and strokes related to either vitamin B12 (84) or vitamin B6 (118) deficiency have been reported. Hypercoagulability due to a variety of factors, including elevations of factors V, VIII, platelets, and fibrinogen, along with decreased antithrombin III, has also been described in the context of Crohn disease (97; 13; 09). Ischemic stroke in Crohn disease has been reported in the setting of antiphospholipid syndrome, with the presence of both anticardiolipin and lupus anticoagulant antibodies (75). However, other investigators have documented that anticardiolipin antibodies, although elevated in patients with Crohn disease, do not correlate with the presence of thromboembolic disease (02).

In fact, no single or specific abnormality has been identified as the sole hypercoagulable culprit in persons with Crohn disease and no consistent abnormality of any of the routinely recognized coagulopathy susceptibility factors has been discovered (55). Furthermore, responses to both immunosuppressive therapy and anticoagulation have been reported in patients who have suffered vascular events, suggesting that a single explanation is improbable and that both hypercoagulable and autoimmune processes may be playing roles in different individuals (40; 96).

Seizures are an infrequently reported neurologic complication of inflammatory bowel disease (31). They may occur as a complication of the surgical management of these diseases, presumably precipitated by factors such as fluid overload, electrolyte imbalance, hypoxia, and steroid administration or withdrawal (99). Seizures have also been reported as a complication of cyclosporine treatment in individuals with Crohn disease (05; 90). Preliminary human studies have shown that patients with inflammatory bowel disease are at increased risk for altered sleep patterns (109). Changing circadian rhythm significantly worsens the development of colitis in animal models. Further research is recommended to clarify the role of disturbances in inflammatory bowel disease (83).

Diffuse encephalopathy with altered consciousness may also develop in individuals with Crohn disease. Both Wernicke encephalopathy and possible selenium-induced encephalopathy have been described in individuals receiving total parenteral nutrition (57; 46). Wernicke encephalopathy has also been reported in an individual with clinically inactive Crohn disease (30). Acute encephalopathy may also be precipitated by agents used to treat Crohn disease, such as sulfasalazine (98). Derrey and colleagues described a first case of an intracerebral inflammatory pseudotumor in the literature associated with an inflammatory bowel disease (27). No clear association has been found, but the intracranial lesion could be the result of the immunosuppressive therapy for Crohn disease, or part of a systemic disimmune process.

As far as sleep disorders are concerned, in a study done by Takahara and colleagues in a Japanese population, they revealed that restless legs syndrome should be considered as one of the causes of sleep disturbance; however, it does not impact the quality of life in patients with Crohn disease (111).

Prognosis and complications

The prognosis of any neurologic event occurring in the setting of Crohn disease depends on the specific clinical situation and etiology of the process in question.

Clinical vignette

A 31-year-old man presented with intractable pelvic pain and intermittent diarrhea. His past medical history was unremarkable except for off-and-on diarrhea and abdominal pain for at least the previous 10 years. The patient had been diagnosed with irritable bowel syndrome, but his symptoms persisted despite symptomatic treatment. He continued to have progressive weight loss of almost 50 pounds and had recently developed pain in the pelvis and anterior and posterior right thigh, leading him to visit the emergency department. The patient was found to have a high-grade fever and leucocytosis. He underwent testing, including colonoscopy, and was diagnosed with Crohn disease. An abdominal CT revealed psoas abscess as a consequence of a fistulous extension into the psoas muscle. A combination of low-dose prednisone, azathioprine, and intermittent infliximab was prescribed for the management of this patient.

Biological basis

Etiology and pathogenesis

An autoimmune etiology, characterized by a dysregulated mucosal immune response to antigens normally present within the intestinal lumen, is suspected by most investigators to underlie the development of Crohn disease (01; 63). However, persistent speculation has also focused on the theory that the organism, Mycobacterium avium subspecies paratuberculosis, which incites a very similar granulomatous bowel disease in cattle (Johne disease), might be the actual cause of Crohn disease and that the immune response is, therefore, an appropriate or exaggerated response to the foreign stimulus (50; 100; 15). Genetic factors also appear to play a role in the generation of the immune response in Crohn disease in that the NOD2/CARD15 gene, which is involved in the immune detection of bacterial products, has been identified as a susceptibility gene for Crohn disease (74; 85). Huff and colleagues have shown that association results and expression data support IRF1 as a strong candidate for Crohn disease causation (53). These data indicate that the 503F variant has hitchhiked to relatively high frequency, thus, forming the IBD5 risk haplotype.

The etiology of the various neurologic complications of Crohn disease is diverse and is discussed in the paragraphs describing the specific neurologic complications in the Clinical Manifestations section.

The gastrointestinal pathological changes in Crohn disease consist of areas of focal intestinal inflammation that may begin with surface ulcers but can ultimately extend transmurally with potential formation of sinus tracts and fistulas. Fibrosis, with thickening of the bowel wall, may also develop and lead to stricture formation. Steiner and colleagues evaluated whole body protein metabolism during corticosteroid therapy in children with newly diagnosed Crohn disease (107). Previous studies demonstrated decreased protein breakdown following either corticosteroid or anti-TNF-α therapy. There were no significant differences in protein breakdown or loss between Crohn disease patients at diagnosis and controls. Whole body protein breakdown and loss increased significantly following 2 weeks of corticosteroid therapy in children with newly diagnosed Crohn disease, which may have profound effects on body composition.

Neurovascular complications of both venous and arterial kinds can be seen in patients with inflammatory bowel disease. The pathogenic mechanisms are complex and postulated to have low serum folate, pyridoxine, and cyanocobalamin levels in association with elevated homocysteine levels as well as increased activation of platelets and microvascular endothelial dysfunction (21). The pathogenesis of peripheral nervous system damage in inflammatory bowel disease also remains unclear. However, multiple mechanisms have been proposed, including immune, iatrogenic related to several drugs, and micronutrient deficiencies secondary to malabsorption-related disorders (34).

Epidemiology

It remains very challenging at this time to pinpoint an exact incidence. However, this population of patients with inflammatory bowel disease has a low frequency of severe neurologic disorders (08). Reported annual incidence rates for Crohn disease vary widely in different parts of the world. It appears to be very rare in Africa and South America, infrequent in Japan, and more common in Europe and North America (95). Reported incidence rates in the United States range from 3.6 to 8.8 per 100,000 (61; 95). During the latter half of the 20th century, a significant rise in the incidence of Crohn disease, but not ulcerative colitis, was noted, especially in North America and northern Europe (65). The explanation for this increased incidence, which has appeared to stabilize since about 1980, is uncertain but suspicion has fallen on a variety of environmental factors. In one of the studies looking into a cohort of patients with cerebral venous thrombosis, 2.3% of cases were found to have inflammatory bowel disease (20). Cerebral venous thrombosis should be considered in patients with inflammatory bowel disease presenting with unusual headache or focal neurologic symptoms.

Formal incidence and prevalence studies of the neurologic complications of Crohn disease have not been performed.

Prevention

There are no known means of preventing Crohn disease.

Differential diagnosis

The differential diagnosis for any individual neurologic symptom in an individual with Crohn disease is the same as when it presents in isolation. A discussion of the differential diagnosis of each of the neurologic complications of Crohn disease is beyond the scope of this article.

Diagnostic workup

The diagnostic workup of any neurologic complication of Crohn disease depends on the type of neurologic process present and must be tailored to fit the specific situation.

In each instance, the goal is to confirm the presence of the specific problem and to exclude other processes that might be occurring simultaneously with, but independently from, the Crohn disease itself. Some general guidelines for evaluation follow.

If peripheral nerve involvement is suspected, electromyography and nerve conduction velocity studies should be performed and additional laboratory studies obtained, as would be done for any routine peripheral neuropathy evaluation. It is particularly important to remember the potential for vitamin B12 deficiency in patients with Crohn disease as a consequence of terminal ileum involvement. Gemignani and colleagues described the utility of corneal confocal microscopy as a useful tool in patients with Crohn disease and non-length-dependent small-fiber neuropathy (38). Although vitamin D deficiency has been associated with neuromuscular dysfunction, there were no differences in serum vitamin D levels between the Crohn disease and healthy controls to explain the decreased muscle strength (93). Cerebrospinal fluid examination should be obtained if the clinical or electromyography and nerve conduction velocity features suggest a demyelinating process. In a study looking into the role of vitamin D and inflammatory bowel disease, the authors found no difference in mean serum 25(OH)D concentration between children and adolescents (115). In addition, patients with inflammatory bowel disease and increased erythrocyte sedimentation rate have significantly lower 25(OH)D than controls. The authors have recommended that inflammatory bowel disease patients with elevated erythrocyte sedimentation rate should be observed for vitamin D deficiency.

If the clinical presentation suggests muscle or myoneural junction involvement, electromyography and nerve conduction velocity should be obtained. Additional laboratory studies such as muscle enzymes and erythrocyte sedimentation rate are also useful. Muscle biopsy may be needed in some situations. If psoas abscess is suspected, ultrasound or CT of the abdomen and pelvis should be obtained. MRI may also be diagnostic.

MRI of the brain or spinal cord, as dictated by exam findings, is the primary means to identify potential demyelinating processes. CSF examination is also important. Evoked potentials, including visual, somatosensory, and brainstem, may also provide useful information.

The presence of myelopathy in an individual with Crohn disease should prompt neuroimaging of the spine with MRI. Once again, the possibility of vitamin B12 deficiency with consequent subacute combined degeneration should always be kept in mind and excluded with appropriate laboratory studies.

The diagnostic evaluation of an individual with Crohn disease who presents with symptoms or signs of cerebrovascular dysfunction should be undertaken expeditiously, as with any patient presenting with a cerebrovascular event. An emergent CT scan should be obtained to exclude intracranial bleeding. Subsequent studies may include MRI, MR angiography, MR venography, or conventional angiography, depending on the clinical situation. Cardiac evaluation with echocardiography may be considered and, in most instances, an extensive evaluation looking for evidence of a hypercoagulable state will be indicated.

In the patient presenting with a seizure or a diffuse encephalopathy, a structural lesion should be excluded with appropriate neuroimaging, typically with an MRI. An electroencephalogram should also be obtained. Metabolic and nutritional (particularly thiamine and vitamin B12 deficiency) derangements must be vigorously sought with appropriate laboratory studies. Of course, if the clinical picture suggests the possibility of meningitis, CSF examination becomes necessary. Biochemical concentrations of neurotransmitters or metabolites may change in corresponding brain regions in patients with Crohn disease, and Lv and colleagues have discussed the combined role of fMRI with magnetic resonance spectroscopy to detect these brain changes (68).

Management

The management of any neurologic event occurring in the setting of Crohn disease depends on the specific clinical situation and etiology of the process in question. Rubin and colleagues recommended that patients initiating adalimumab receive a loading dose of 160/80 mg subcutaneously at week 0/week 2, followed by up to 8 weeks of 40 mg every-other-week maintenance therapy prior to determining if there is non-response (91). Patients experiencing attenuation of response or inflammatory-mediated symptoms during maintenance therapy may benefit from dosage intensification to weekly adalimumab.

Another study looked at population-based estimates of leisure-time physical activity in Canadians diagnosed with Crohn disease or ulcerative colitis (70). Findings suggest that many living with complications associated with these conditions will not benefit from the protective role of physical activity. Although cannabinoids have been utilized off label for certain neurologic conditions, there are no clear safety and effectiveness data to support its use with Crohn disease (110).

Special considerations

Anesthesia

No specific information is available with regard to the neurologic complications of Crohn disease and anesthesia.