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Expert Critique
FROM THE ASCO Reading Room
The most common manifestation of neurologic problems in IBD is peripheral neuropathy, but optic neuritis, demyelinating disease, and central nervous system manifestations have also been reported. No specific risk factor has been clearly associated with the development of neurologic complications in IBD. The most important factor for providers who care for IBD patients is to be aware of the association between neurologic complications and IBD as well as its treatment and to thoroughly investigate all new neurologic symptoms in a timely manner to prevent serious irreversible complications.
Neurologic involvement in inflammatory bowel disease (IBD) is uncommon but probably underreported, and gastroenterologists must be ready to recognize it. Acute or chronic manifestations encompass a broad range of peripheral and central neurological problems, with peripheral neuropathies the most frequent. Complications may arise spontaneously from the systemic inflammation of the primary disease, which is infrequent, as well as from secondary causes such as drugs and infections. Manifestations may present as multifocal motor neuropathies, Melkersson-Rosenthal syndrome, optic neuritis, sensorineural hearing loss, and cerebral vasculitis.
Prevalence
Few population-based studies have investigated these manifestations, and prevalence estimates in the literature have ranged widely from 0.25% to 47.5%, according to a 2010 overview by .
In a cohort of 638 IBD patients, in 1995 found neurologic involvement unrelated to iatrogenic causes in 3% of IBD patients -- 10 with Crohn's disease and nine with ulcerative colitis. More recent studies have found peripheral neuropathy prevalences in IBD patients of 8.8% and 13.4%. And an up to 50% higher prevalence of asymptomatic focal brain white matter lesions has been observed in MRI studies of IBD patients compared with healthy age-matched controls.
"The Olmstead County cohorts have shown a slightly increased incidence of neuropathies and demyelinating conditions in IBD patients than in the background population, but the increase is small," Ryan W. Stidham, MD, of the University of Michigan in Ann Arbor, told ľ¹ÏÖ±²¥. "While neuropathies and other complications are rare overall, they do happen and can have serious consequences, so it's important that healthcare providers be prepared to recognize them quickly."
The exact prevalence and incidence remain difficult to pin down: "It's hard, since there are so many different subcategories of neurologic manifestations, even without including psychological conditions like anxiety and depression," Joshua R. Korzenik, MD, of Brigham and Women's Hospital and Harvard ľ¹ÏÖ±²¥ School in Boston, told ľ¹ÏÖ±²¥. "These complications are not grouped together as a single entity, because they are related to such a diverse set of problems." These include nutritional deficiencies, medication side effects, infections, thromboembolism, and immunological abnormalities.
Underlying Mechanisms
According to Zois and colleagues, underlying disturbances in the mind-gut axis -- which mediate the reciprocal influence of the neuronal system of the brain and enteric disease via neuroendocrine pathways -- may also be at play. Abnormalities could potentially involve the hypothalamic-pituitary-adrenal axis, corticotropin and adrenal corticoid secretion, and the effects of the autonomic nervous system on immune function.
"There may be a connection here in a subtle way because of certain shared hormones and the products of the intestinal bacteria, but this is more theoretical than clearly identified and demonstrated causes," Korzenik said.
Manifestations
The acute or chronic manifestations encompass a broad range of peripheral and central neurological problems, with peripheral neuropathy being the most frequent. Complications include multifocal motor neuropathies, Melkersson-Rosenthal syndrome, optic neuritis, sensorineural hearing loss, and cerebral vasculitis.
"Straight neuromuscular complication as a direct consequence of IBD inflammation affects fewer than half of 1% of patients," Korzenik said. "The category we worry about most is an IBD-related hypercoagulable state where there's a question of an increased risk of clotting and stroke induced by the inflammatory response. Fortunately this is quite uncommon."
In an interview in , Jose Ferro, MD, PhD, of Lisbon University in Portugal, noted that IBD patients have an approximately threefold higher risk of developing venous cerebral thrombosis compared with the general population.
The risk is also increased for arterial thromboembolism, explained Stidham: "And that relative risk further increases from five-fold to upwards of nine-fold when you look at patients with active inflammation. The risk differential may be partly due to corticosteroid use, especially prednisone, which is associated with hypercoagulability."
IBD has been linked to demyelinating diseases such as multiple sclerosis. "There's been some suggestion that these diseases are potentially more threatening in Crohn's disease, but the numbers are so small that it's difficult to determine," he said.
Other central nervous system manifestations include epidural and subdural spinal empyema, vision problems, seizures, and encephalopathy. Some patients may be susceptible to headaches, chronic fatigue, and Parkinson-like syndrome.
Risk Factors
"There is really no way to identify in advance which patients are at risk," Korzenik said. "If there's a nutritional deficiency such as vitamin B12 or folic acid, we correct it. If the complication is due to medication, we don't add something to treat it; we usually discontinue the drug. It's a matter of being very aware of the potential complications of medications and discontinuing them if necessary after assessment early on."
Stidham noted that Crohn's disease patients who have short-gut syndrome or have had extensive surgeries are particularly at risk of peripheral neuropathies related to vitamin B12 deficiency -- typically distal paresthesias. Left untreated, these can move beyond discomfort to debilitating.
Although prolonged use of the antibiotic metronidazole has been implicated in neuropathies, it is modern biologic agents such as anti-tumor necrosis factor (TNF) that are an increasing concern, Korzenik said: "We worry about the effects of infections with anti-TNF therapy in particular."
One central neuropathy associated with anti-TNF is optic neuritis. "If a patient on anti-TNF describes paresthesia in the periphery or any visual changes, it's important for the provider to drill down to the details and have a pretty low threshold for having that investigated," Stidham said.
Possible links between anti-TNF and demyelinating disease have been observed. For example, a recent series described in found that most patients treated with various TNF inhibitors and followed for 1 to 4 years experienced a clinical neurologic event. In postmarketing reports, both optic neuritis and demyelinating polyneuropathy have been reported with infliximab (Remicade) and adalimumab (Humira).
In addition, the anti-cell adhesion antibody natalizumab (Tysabri), which blocks the leukocyte-binding cell receptor a4-integrin, has been associated with severe multifocal leukoencephalopathy since it can reactivate John Cunningham virus. "But since the approval of Entyvio [vedolizumab] a few years ago, we rarely use natalizumab now for Crohn's disease," Korzenik said. Progressive multifocal leukoencephalopathy has also been observed in people on infliximab.
But in situations where the patient's IBD is severe, it's not always a simple matter of discontinuing anti-TNF, since the disease may make life intolerable, said Stidham. "It's up to the gastroenterologist to be the first line of defense, to take a careful history of these symptoms, and if there's any question, to quickly refer the patient to a neurologist." If the neurologic manifestation is serious, such as a major peripheral neuropathy or a total loss of vision in one eye, and anti-TNF therapy is suspected, "then it's totally reasonable to hold the medication while the patient gets an urgent neurology evaluation."
And while serious neurologic manifestations are rare, he added, "you have to be able to recognize a zebra when you see it."