Keywords
neurogastroenterology, Wilson disease, malabsorption, gluten sensitivity, Crohn disease, bariatric surgery
In recent years, the presence of gastrointestinal (GI) dysfunction in the setting of neurologic disease has received increasing attention, particularly in disorders such as Parkinson disease. Much less attention has been devoted to the occurrence of neurologic dysfunction in primary GI disease processes. The enteric nervous system (ENS), which lines virtually the entire GI tract, contains approximately the same number of neurons as the spinal cord and is capable of generating and controlling many functions entirely independently of the central nervous system (CNS). It should therefore not be surprising, then, that processes that affect the GI system, including the enteric nervous system, also may affect the CNS or systems controlled by the CNS.
Gastrointestinal Disorders
Bariatric Surgery
The growing girth of the American populace has led to immense growth in bariatric surgery for the treatment of obesity, which is typically performed after dietary and medical management has failed. Gastric restriction procedures (e.g., gastric stapling, laparoscopic banding) and gastric bypass procedures (e.g., Roux-en-Y gastric bypass) have been performed most frequently, but sleeve gastrectomy, in which approximately 75 to 85 percent of the stomach is removed along the greater curvature, is growing in popularity. Neurologic complications may occur following all of these procedures.
Neurologic complications were noted in one study in only 4.6 percent of 500 patients nearly 2 years after surgery, but other studies have suggested higher rates. Peripheral neuropathy was reported in 16 percent of 435 patients after bariatric surgery, compared with only 3 percent of 126 patients undergoing cholecystectomy. In a subsequent cohort drawn from a single tertiary referral center, the same group of investigators noted peripheral neuropathy in only 7 percent and did not report on the frequency of other types of neurologic complications. Although peripheral nervous system disorders appear to be the most frequent neurologic complications, encephalopathy, myelopathy, and optic neuropathy all have been reported.
Polyneuropathy, mononeuropathy, and radicular or plexus involvement have been described following bariatric surgery. Peripheral neuropathy typically is chronic, although acute inflammatory demyelinating polyneuropathy also has been reported. Carpal tunnel syndrome is the most frequent mononeuropathy, accounting for 79 percent of cases in one study. Lateral femoral cutaneous neuropathy (meralgia paresthetica) develops in only 0.5 to 1.4 percent of individuals despite recent weight loss being a well-known risk factor for its development.
Nutritional deficiencies (see Chapter 15 ) due to malabsorption are responsible for the development of neuropathy in many, though not all, instances. Deficiencies of thiamine, riboflavin, pyridoxine, vitamin B 12 , and vitamin E have all been described. Thiamine deficiency, with neuropathic beriberi as one consequence, may be particularly important. Immunologic mechanisms also have been proposed as causing neuropathy in these patients. Compression either during or following surgery is likely responsible for most of the mononeuropathies.
Muscle weakness has been described in 7 percent of patients. Postoperative rhabdomyolysis may occur and is especially frequent in patients undergoing Roux-en-Y gastric bypass; small series suggest up to three-quarters of patients may experience this complication, which presents with muscle pain, typically in the gluteal region, accompanied by an increase in serum creatine kinase levels. The development of surface and deep tissue pressure during surgery may be responsible. The risk of rhabdomyolysis is greatest when the BMI of the patient is greater than 56 kg/m 2 . Osteomalacia and associated osteomalacic myopathy may develop postoperatively. An acquired myotonic syndrome also has been reported.
Spinal cord dysfunction is another potential complication of bariatric surgery. Symptoms may not occur until 5 to 10 years later. Many of these patients are found to have low serum vitamin B 12 or copper levels.
Cortical dysfunction, bearing the characteristics of Wernicke encephalopathy, was found to complicate bariatric surgery in around one-quarter of patients in one study but was noted much less frequently in a larger prospective investigation.
Celiac Disease
Celiac disease (CD) is characterized by a constellation of diarrhea, malabsorption, weight loss, and gaseous distension that develops as a consequence of damage to the mucosa of the small intestine, triggered by an immune-mediated response to gluten. The prevalence of CD in American and European populations has been estimated to be approximately 1 percent, but because the number of undiagnosed patients may be considerable, its prevalence is probably much higher. Genetic factors play a role, and 90 to 95 percent of individuals with CD carry HLA-DQ2.5 or -DQ8 heterodimers.
Individuals with classic CD are found to have serum antigliadin antibodies along with additional gliadin-related antibodies (e.g., anti-endomysial, antitransglutaminase). The pathology of CD extends beyond the GI tract, leading to proposals that the term gluten sensitivity be used for individuals displaying more widespread involvement, with the label CD reserved for those with evidence of enteropathy on small bowel biopsy.
Neurologic dysfunction has been reported in around 6 to 12 percent of patients with CD. It is often ascribed to nutritional deficiency secondary to malabsorption, although immunologic mechanisms may be an alternative explanation in some instances.
Ataxia
Gluten ataxia has no uniquely distinguishing clinical characteristics and remains a controversial entity. Gait ataxia is present in all individuals by definition; limb ataxia, dysarthria, and ocular signs are present in most. The combination of ataxia and action myoclonus has been described in some patients. The mean age of onset of symptoms is 53 years. Cerebellar atrophy and white matter abnormalities may be evident on magnetic resonance imaging (MRI). The classic GI symptoms of CD are present in only a minority of individuals with gluten ataxia (less than 10%). Evidence of classic CD is found on duodenal biopsy in 25 to 33 percent.
In the initial reports, antigliadin antibodies (IgG, IgA, or both) were found in 41 percent of patients with sporadic idiopathic ataxia, compared with only 15 percent of those with clinically probable multiple system atrophy (MSA), 14 percent with familial ataxia, and 12 percent of normal controls. More recently, 148 out of 635 (23%) patients with sporadic ataxia evaluated at the same clinic were noted to have evidence of gluten sensitivity. Individuals with gluten ataxia, independent of intestinal involvement, demonstrate antitransglutaminase 6 IgG and IgA antibodies, whereas antitransglutaminase 2 IgA antibodies are present in persons with gastrointestinal disease. The cerebellar damage has been attributed to a chronic, immune-mediated inflammatory process. Autopsy examination in several affected individuals has demonstrated Purkinje cell loss and lymphocytic infiltration within the cerebellum as well as the posterior columns of the spinal cord. Cerebellar IgA deposits containing transglutaminase 6 have also been found.
Gluten ataxia sometimes responds to a gluten-free diet. Intravenous immunoglobulin therapy reportedly ameliorates the ataxia in some patients. Screening has been suggested for all individuals who present with adult-onset ataxia without any other obvious cause, but this recommendation remains controversial.
Peripheral Neuropathy
In one retrospective chart review, peripheral neuropathy accounted for 17 percent of the neurologic abnormalities in patients with CD. In another study, chronic axonal sensorimotor neuropathy was identified in 23 percent. Sural nerve biopsy demonstrates axonal injury in these patients. The etiology of the neuropathy is uncertain; both nutritional and autoimmune mechanisms have been proposed.
As with sporadic ataxia, some studies suggest that the prevalence of CD or of antigliadin antibodies is higher in individuals with peripheral neuropathy than in the general population. This has led to the use of the term gluten neuropathy for individuals with idiopathic neuropathy and serologic evidence of gluten sensitivity. Improvement with a gluten-free diet has been reported by some, but other studies have failed to show improvement.
Myopathy
CD is more prevalent in patients with inflammatory myopathies, particularly inclusion-body myositis. Immunologic mechanisms probably are responsible in most instances, but in one patient with CD and a myopathy resembling inclusion-body myopathy, reversal of both clinical and pathologic abnormalities was documented upon treatment with vitamin E and institution of a gluten-free diet.
Epilepsy
An association between CD and epilepsy is controversial. The reported prevalence of epilepsy in CD has ranged from 0.8 to 7.2 percent and that of CD in individuals with epilepsy from 0.8 to 8.1 percent. In one large study, the presence of CD-associated antibodies did not differ between 968 patients with epilepsy and a group of 584 individuals without epilepsy. A specific syndrome of epilepsy, bilateral occipital lobe calcifications, and CD has been described, largely in Italians. The mechanism for such an association is obscure. Even in CD patients without calcifications, seizures originate most frequently in the occipital lobe. A gluten-free diet may improve seizure control, especially when started early.
Other Manifestations
A number of other neurologic manifestations of CD have been reported but less extensively evaluated, including migraine, learning disabilities, autonomic neuropathy, and neuromyelitis optica. The significance of these associations is uncertain.
Inflammatory Bowel Disease
Two similar but distinct disease entities, ulcerative colitis and Crohn disease, are part of a group of conditions collectively labeled as inflammatory bowel disease (IBD). These two conditions share many clinical and even pathologic features, but also display important differences ( Table 13-1 ). An autoimmune etiology in genetically susceptible individuals, characterized by a dysregulated mucosal immune response to antigens normally present within the intestinal lumen, is suspected in both.
| Feature | Crohn Disease | Ulcerative Colitis |
|---|---|---|
| Diarrhea | Common, nonbloody, less urgent | Common, bloody, urgent |
| Rectal Bleeding | Occasional | Very common |
| Weight Loss | Common | Uncommon |
| Abdominal Pain | Prominent | Not prominent |
| Stricture Formation | Common | Rare |
| Fistula Formation | Common | Very rare |
In Europe and North America, the incidence of ulcerative colitis is in the range of 3 to 15 per 100,000 persons. Incidence rates of 6 to 10 per 100,000 have been reported for Crohn disease in the same regions, but in other parts of the world, such as Asia, a previously low incidence appears to be increasing.
Involvement outside the GI tract is well described in IBD. Neurologic dysfunction is probably relatively infrequent, with wide-ranging estimates from 0.2 to 47.5 percent of patients. Neurologic dysfunction may precede the appearance of GI symptoms, and both peripheral and central nervous system involvement occurs ( Table 13-2 ). Autoimmune mechanisms are primarily responsible for the development of neurologic involvement in IBD; however, nutritional deficiency, infection, and other processes may also secondarily involve the nervous system. Treatment for both Crohn disease and ulcerative colitis involves potent medications, including antitumor necrosis factor α (anti-TNF-α) agents, that can have neurologic complications.
| Peripheral |
|
| Myopathic |
|
| Central |
|
| Seizures |
|
Peripheral Neuropathy
Peripheral neuropathy is the most frequent neurologic complication of both Crohn disease and ulcerative colitis, and has been reported in 1.9 to 13.4 percent of IBD patients. The etiology of peripheral nerve involvement in IBD appears to be multifactorial, including nutritional deficiency, medication side effects, and an autoimmune mechanism as part of the primary disease. Involvement may take the form of focal (e.g., mononeuropathy, cranial neuropathy, brachial plexopathy), multifocal (e.g., mononeuritis multiplex, multifocal motor neuropathy), and generalized (acute or chronic inflammatory demyelinating polyneuropathy, small- or large-fiber axonal sensorimotor neuropathy) neuropathic processes. Carpal tunnel syndrome appears to be the most frequently occurring isolated mononeuropathy. Axonal neuropathy occurs more frequently than demyelinating neuropathy.
Two specific patterns of cranial nerve involvement have been described in IBD. Acute sensorineural hearing loss or chronic subclinical hearing impairment has been described in ulcerative colitis. In contrast, Melkersson–Rosenthal syndrome, characterized by recurrent facial nerve palsy along with intermittent orofacial swelling and fissuring of the tongue, has been reported in patients with Crohn disease.
Demyelinating Disease
An association between IBD, especially ulcerative colitis, and multiple sclerosis has been reported. In one study examining two large populations, the odds ratio for multiple sclerosis in patients with IBD was around 1.5. White matter lesions may be present on MRI in patients with IBD; whether these represent multiple sclerosis or another ischemic or demyelinating process is unclear. The development of demyelination within the CNS as a side effect of anti-TNF-α agents has been reported.
Cerebrovascular Disease
Vascular complications are rare, but well-documented, extraintestinal manifestations of IBD. A large, population-based case-control study involving over 8,000 patients with Crohn disease demonstrated an increased risk of ischemic stroke only in younger individuals (age<50 years) with the disorder. Responses to both immunosuppressive therapy (e.g., corticosteroids and azathioprine) and anticoagulation have been reported, suggesting that both hypercoagulable and autoimmune processes may play a role.
A variety of cerebrovascular events has been reported in ulcerative colitis and Crohn disease, including both large artery and lacunar infarcts. Cerebral venous sinus thrombosis in IBD occurs more frequently in ulcerative colitis than Crohn disease; individuals with active disease are at greater risk. The lateral and superior sagittal sinuses are involved most frequently. Severe iron-deficiency anemia may be a significant risk factor for thrombosis.
Myopathy
Myopathy is relatively rare in IBD, occurring in 0.5 percent of patients. Symptoms may precede the appearance of GI dysfunction, but this is unusual.
Generalized inflammatory muscle disease has been described as well as focal involvement of muscle, primarily in Crohn disease. Abscess formation in the psoas or other muscles is an important potential complication; psoas muscle abscess is characterized by flank, pelvic or abdominal pain, usually associated with fever and leukocytosis, and diagnosis is confirmed by ultrasound or computerized tomography (CT). Focal myositis involving the gastrocnemius and other muscles has been reported.
Myelopathy
Slowly progressive myelopathy may develop in the setting of IBD and accounts for around 25 percent of patients with neurologic involvement in one study. It is more likely to occur in patients with Crohn disease, who may develop vitamin B 12 deficiency as a consequence of surgical resection of the terminal ileum. Patients with Crohn disease also may develop a more acute myelopathy or cauda equina syndrome due to empyema from extension of a fistula to the epidural or subdural space.
Other Manifestations
Seizures may occur as a complication of the surgical management of IBD, precipitated by fluid overload, electrolyte imbalance, hypoxia, and corticosteroid administration or withdrawal. They may occur also as a complication of cyclosporine treatment. Diffuse encephalopathy and acute disseminated encephalomyelitis have also been reported. Both Wernicke encephalopathy and possible selenium-induced encephalopathy have been described in individuals with Crohn disease receiving total parenteral nutrition. Autonomic neuropathy has been reported rarely in both Crohn disease and ulcerative colitis.
Whipple Disease
Although originally described as a GI disease, with symptoms of diarrhea, weight loss, and abdominal pain, Whipple disease is a multisystem disorder that also may be characterized by joint, dermatologic, lymphatic, cardiac, pulmonary, ocular, and neurologic dysfunction. The average age of symptom onset is approximately 50 years, and males are affected much more frequently than females. Farmers are at increased risk of developing Whipple disease; one possible explanation is that the organism responsible, Tropheryma whipplei , is a member of the actinomycete family found in the soil.
Neurologic dysfunction is the presenting feature in approximately 5 percent of persons with Whipple disease. Symptoms of CNS involvement eventually develop in 10 to 43 percent of patients, and postmortem examinations demonstrate CNS lesions in over 90 percent of individuals ( Table 13-3 ). Cognitive changes are the most frequently observed neurologic manifestation, occurring in 71 percent of patients, often accompanied by psychiatric symptoms such as depression and personality or behavioral changes. Cerebellar dysfunction with gait and balance impairment occurs in approximately 20 percent of persons; pyramidal tract abnormalities also may occur. Symptoms indicative of hypothalamic involvement, such as insomnia, hypersomnia, hyperphagia, polyuria, and polydipsia, are uncommon. Peripheral neuropathy also has been reported.
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