Clinical manifestations

Presentation and course

Gastroesophageal reflux disorder may be associated with sleep disorders without symptoms of reflux. A subset of individuals with complaints of disturbed sleep have significant gastroesophageal reflux without heartburn.

Neurologic manifestations of gastroenterological disorders are listed in Table 1.

Table 1. Neurologic Manifestations of Gastroenterological Disorders

Gastrointestinal disorders and migraine. Migraine may be associated with gastroparesis, colic, irritable bowel syndrome, inflammatory bowel syndrome, and celiac disease (64). Gastroparesis may occur during migraine attacks, and children with colic are likely to suffer from migraine. Migraine is more frequent in the rest of the conditions mentioned earlier, and its frequency may diminish with treatment of the primary gastrointestinal disorder.

Gut microbiota and neuroinflammation. Microbes living in the gut may remotely influence the activity of cells in the brain that are involved in controlling inflammation and neurodegeneration. Interferon signaling in astrocytes reduces inflammation and experimental autoimmune encephalomyelitis via the ligand-activated transcription factor aryl hydrocarbon receptor (AHR). In multiple sclerosis, the circulating levels of AHR agonists are decreased. Dietary tryptophan is metabolized by the gut microbiota into AHR agonists that act on astrocytes to limit CNS inflammation (53).

Neurologic manifestations of celiac disease. Celiac disease or gluten-sensitive enteropathy is a gluten-related systemic autoimmune disease characterized by abnormal immunological response to ingested gluten in genetically susceptible individuals. Laboratory investigations should include intestinal biopsy and immunological tests. Extraintestinal neurologic manifestations in order of frequency are headache/migraine, attention-deficit hyperactivity disorder, epileptic seizures, mental retardation, cerebellar ataxia, and behavior disorders (10). Celiac crisis has been reported to present with status epilepticus and encephalopathy in the absence of profound gastrointestinal symptoms (20). Among all those reported, confirmed neuropsychiatric manifestations of celiac disease are loss of short-term memory, anxiety and depression, psychosis, ataxia, seizures, irritability, and chronic headache (29). A case report shows that psychosis may also be a manifestation of nonceliac gluten sensitivity and should be considered in the differential diagnosis (30).

Certain dietary nutrients, such as choline, which is contained in meat and eggs, are processed specifically by the gut microbiota to produce trimethylamine (TMA), which is absorbed in the gut and converted in the liver to TMA-N-oxide by hepatic flavin-containing monooxygenases. Increased levels of TMA oxide have been associated with an increased risk of stroke by increasing the accumulation of macrophage-specific cholesterol and the formation of foam cells and reducing net reverse cholesterol transport (62).

Gastrointestinal beriberi and Wernicke encephalopathy. There is a case report of a patient with gastrointestinal disturbances such as anorexia, nausea, and vomiting resulting in thiamine deficiency who presented with neurologic symptoms fulfilling the criteria of Wernicke encephalopathy (48). This patient responded only to intravenous thiamine.

Enteric neuropathies. The complexity of the enteric nervous system renders it susceptible to develop enteric neuropathies with poorly characterized pathophysiology and outcomes (46).

Prognosis and complications

Not relevant as the article is an overview of a subspecialty and not a single disease entity.

Biological basis

Etiology and pathogenesis

The enteric nervous system. Establishing the relationship of the enteric nervous system (ENS) to the central and autonomic nervous systems is helpful in understanding the pathophysiology of various neurogastroenterological disorders.

The ENS of humans contains approximately 500 million neurons and is the largest nervous system outside the brain. Its neurons are distributed in thousands of small ganglia, most of which are found in two plexuses, the myenteric and submucosal plexuses. Previously, three types of sensory neurons were recognized in the gastrointestinal tract: dorsal root ganglia, nodose or jugular ganglia, and intrinsic primary afferent neurons. Current research indicates that there are at least 8, and at most 20, different types of neurons in the ENS. There is bidirectional flow of information between the ENS and CNS and between the ENS and sympathetic prevertebral ganglia, but the relative roles of the ENS and CNS differ considerably along the digestive tract. For example, CNS plays a major role in controlling contractile activity as well as acid secretion of the stomach whereas ENS in the small intestine and colon controls muscle activity, local blood flow, and several other functions (16). A high-resolution neuronal imaging method with electrophysiology has revealed a novel pattern of rhythmic coordinated neuronal firing in the ENS that generates rhythmic neurogenic depolarizations in smooth muscle that underlie contraction of the gastrointestinal tract (59). Monoamines play a role in the physiology of the gastrointestinal tract, and examples include the following (42):

Neuroimmune regulation. Sensory neurons communicate with the immune system to modulate tissue inflammation. This neuroimmune regulation is carried out via ion channels and sensory neuropeptides, such as substance P, calcitonin gene-related peptide, and vasoactive intestinal peptide (28). Sensory neurons also play a role in regulating host defense against enteric bacterial pathogens.

Role of the vagus nerve in gut to brain communication. The vagus nerve is the main channel of communication between the gastrointestinal tract and the brain. In experimental studies, sensory signals from the gut facilitate the hippocampal-dependent learning and memory function in rats, which is severely impaired following disconnection of this pathway (60). These findings have clinical implications (eg, bariatric surgery such as vertical sleeve gastrectomy for obesity or vBloc that involve disruptive manipulation of the vagus nerve) and may have memory impairment as a side effect. On the other hand, transcutaneous stimulation of the vagus nerve has led to memory improvement in patients with Alzheimer disease (22).

Etiology. Neurologic causes of various gastroenterological disorders are listed in Table 2; gastroenterological manifestations of neurologic disorders are shown in Table 3.

Table 2. Causes of Neurogastroenterological Disorders

Table 3. Significant Gastroenterological Manifestations of Neurologic Disorders

Pathogenesis

Disturbances of the myenteric nervous system. Gastrointestinal motor dysfunction can result from disturbances at all levels of extrinsic neural control. The enteric nervous system, consisting of intrinsic afferent neurons, interneurons (interstitial cells), and motor neurons, may be affected primarily or as a part of other disorders. Interstitial cells of Cajal are the pacemakers in gastrointestinal muscles, and these cells also mediate or transduce inputs from the enteric nervous system and generate as well as propagate slow waves in gastrointestinal muscles. Alterations of these cells occur in various disorders of gastrointestinal motility, such as Hirschsprung disease.

Two major neural plexuses that comprise the enteric nervous system are the myenteric Auerbach plexus and the submucous Meissner plexus, which have the capability to maintain basic intestinal function even in the absence of control by the external autonomic nervous system. Injury or alterations in the myenteric plexus can lead to severe disturbances of the motility of the intestine. In Chagas disease, the parasite Trypanosoma cruzi destroys enteric neurons, which leads to achalasia of the lower esophageal sphincter (achalasia cardia). In longstanding diabetes, degeneration and reduction in the number of myenteric neurons can lead to gastroparesis. Myenteric plexus is subject to damage by drugs such as vincristine because it is not protected by a blood-nerve barrier. In congenital megacolon (Hirschsprung disease), portions of the colon are aganglionic, and sustained contraction of a variable length of the preceding colon produces enlargement of the colon.

The term "enteric neuropathies" is used for various conditions affecting motor function of the human gastrointestinal tract. The pathology of motility disorders such as achalasia, gastroparesis, intestinal pseudo-obstruction, colonic inertia, and megacolon cannot be easily correlated with clinical features. Combined clinical and histopathological studies may facilitate the application of basic sciences to the clinical management of patients with enteric neuropathies.

There is a neurogenesis program in the adult gut outside of the CNS, indicating the vulnerability of the enteric nervous system to exogenous influences. Neurogenesis can occur in the adult due to the presence of enteric neural precursor cells (ENPC); acquired diseases of the enteric nervous system, such as achalasia, may result from a loss of ENPCs like congenital disorders such as Hirschsprung disease (27). The ability to identify the adult ENPCs will enable an understanding of the pathogenesis of enteric neuromuscular diseases as well as the development of novel regenerative therapies.

The enteroendocrine system. This is the primary sensor of ingested nutrients and is involved in secretion of gut hormones, which modulates multiple physiological responses including gastrointestinal motility and secretion, glucose homeostasis, and appetite (49). A study of the molecular mechanisms underlying enteroendocrine system contributes to our current understanding of the regulation of gut hormone secretion, including the interaction between the enteroendocrine system and the enteric nervous system. Further insight into how these systems collectively regulate postprandial physiology will further facilitate the development of novel therapeutic strategies for disorders of enteroendocrine system.

Microbiome of the gut and effect on the brain. Commensal microorganisms that inhabit the gut are called the “gut microbiome.” They are beneficial for human health. Bacteria in the gut can produce neurotransmitters such as GABA, serotonin, and norepinephrine, which can directly and indirectly regulate activity in the enteric nervous system and vagus nerve. A study in healthy women has shown that consumption of a fermented milk product with probiotic affects activity of brain regions that control central processing of emotion and sensation (63). However, gut microbes can make proteins or stretches of peptides with sequences like those of humans. This molecular mimicry is usually harmless, except when it causes immune cells to react against native human proteins, which can lead to several autoimmune disorders.

The microbiota communicates with the brain through the microbiota-gut-brain axis in a bidirectional way that involves the autonomic nervous system. The vagus nerve can sense the microbiota metabolites through its afferents and transfers the gut information to the central nervous system where it is integrated in the central autonomic network, where it generates either an adapted or an inappropriate response (03). A cholinergic antiinflammatory pathway in vagal nerve fibers can dampen peripheral inflammation and decreases intestinal permeability, thus, very probably modulating microbiota composition. A low vagal tone has been described in patients with inflammatory bowel disease indicating peripheral inflammation, and vagal nerve stimulation has the potential to restore homeostasis in the microbiota-gut-brain axis.

Gut microbiota changes have an impact on several neurologic disorders, including neurodevelopmental disorders such as autism spectrum disorder, psychiatric disorders (eg, major depressive disorder, anxiety, and schizophrenia), and neurodegenerative disorders (41). An imbalance in the microbiome may cause other disorders as well. Patients with Alzheimer disease have a proinflammatory state in the blood and proinflammatory bacteria in their gut. Toxic proteins that have been identified in familial Alzheimer disease and other familial dementias (amyloid, tau, alpha-synuclein, and others) are the culprits, but it is not known why they deposit in the sporadic cases. Types of bacteria living in the gut could influence the development of Alzheimer disease symptoms in mice. An experimental study has shown that by altering the gut microbiome, long-term antibiotic treatment reduces inflammation and slows the growth of amyloid plaques in the brains of male mice, but the same treatment was found to have no effect on female animals (11). Mucus is integral to gut health and its properties may be affected in neurologic disease. Factors that influence the nervous system may also affect the volume, viscosity, porosity of mucus composition, and subsequently, gastrointestinal microbial populations. Reduced gut mucus protection may make patients with neurologic diseases more susceptible to gastrointestinal problems (19).

Microbial molecule, capsular polysaccharide A from Bacteroides fragilis, promotes a protective, antiinflammatory response during viral infection and a mouse study has shown that Bacteroides fragilis polysaccharide A can temper the immune system so that infection does not result in an uncontrolled, potentially fatal inflammatory response in the brain (50). The investigators found that mice pretreated with the candidate probiotic Bacteroides fragilis or polysaccharide A survived a lethal herpes simplex virus infection whereas mice pretreated with a placebo did not survive despite the fact that both groups were given acyclovir, an antiviral that is the standard of care for herpes simplex virus encephalitis.

Experimental data indicate that the chemotherapeutic paclitaxel concurrently affects the gut microbiome, colonic tissue integrity, microglia activation, and fatigue in female mice, thus, identifying a novel relationship between colonic tissue integrity and behavioral responses that is not often assessed in studies of the brain-gut-microbiota axis (33). If similar findings can be confirmed clinically, dietary strategies such as probiotics or prebiotics or possibly fecal transplantation may be used to promote gut bacterial populations and conditions that protect the brain from inflammation and reduce chemobrain symptoms.

A small open-label clinical trial has evaluated the impact of microbiota transfer therapy (MTT) on gut microbiota composition and symptoms in children diagnosed with autism spectrum disorder. In addition to relief of gastrointestinal symptoms at the end of treatment, behavioral symptoms of autism spectrum disorder improved significantly, and the improvement was maintained at 8 weeks after cessation of treatment (23). The investigators urged caution against overinterpretation of results and families attempting to replicate the treatment on their own. Results of a systematic review of literature were inadequate to confirm a global microbiome change in children with autism spectrum disorder and causality could not be inferred to explain the etiology of the behaviors associated with autism spectrum disorder (21). Mechanistic studies of pathomechanism are needed to elucidate the specific role of the gut microbiome in the pathogenesis of autism spectrum disorder.

The first demonstration of a sensitive and specific diagnostic microbiome in a human cerebrovascular disease is that combinations of microbiome signatures and plasma inflammatory biomarkers show associations with disease severity and hemorrhage of cavernous hemangiomas (47).

Depressive disorders often run in families, which, in addition to the genetic component, may point to the microbiome as a causative agent. An experimental study has found reduced lactobacillus and increased circulating kynurenine levels as the most prominent changes in chronically stressed mice (38). Ongoing studies are investigating the activity of kynurenine, a major biomarker for depression, in the human brain and potential of lactobacillus probiotic as a dietary supplement to help patients with depression.

Gut microbiota represents a feasible target for modulating kynurenine pathway metabolism, and further development of this approach will improve our understanding of how the gut microbiota shapes brain and behavior (24). It will facilitate successful translation of microbiota-gut-brain axis research from bench to bedside.

A genome-wide association study has traced the connections between genetics, the gut microbiome, and memory in a mouse model bred to resemble the diversity of human population (36). The authors identified single-nucleotide polymorphisms that were significantly associated with short-term memory and learning. Further work is needed to show if Lactobacillus can improve memory in humans. In the future, it may be possible to use probiotics to improve memory in targeted populations, such as those with learning disabilities and neurodegenerative disorders.

Because foods containing nitrates are alleged to trigger migraines, the relation between food and microbiomes has been studied in those suffering from migraines. Oral samples collected by the American Gut Project were subjected to 16S rRNA sequencing, which confirmed that those with migraines had much higher levels of nitrate-reducing bacteria in their mouths (18).

Autoimmune gastrointestinal dysmotility. This is a manifestation of autoimmune dysautonomia and can occur as an idiopathic phenomenon, eg, idiopathic gastrointestinal dysmotility. It may or may not be accompanied by autoimmune neurologic disorder. Gastrointestinal dysmotility may be due to underlying cancer. This has been reported to be associated with paraneoplastic type 1 antineuronal nuclear antibodies and neuronal acetylcholine receptor antibodies in a case of small cell lung cancer (31).

Mouse models of experimental autoimmune encephalomyelitis show features of gastrointestinal dysmotility that persist in the absence of extrinsic innervation, suggesting direct involvement of ENS. The absence of gastrointestinal dysmotility together with experimental autoimmune encephalomyelitis and serum immunoreactivity in multiple sclerosis against ENS targets suggest that multiple sclerosis could be classified among other diseases known to induce autoimmune gastrointestinal dysmotility (58).

Role of aging. Some of the changes in the function of gastrointestinal system with aging are due to age-related neurodegenerative changes in the enteric nervous system. There is loss of enteric neurones in both submucosal and myenteric plexuses with selective preservation of nitrergic, but not cholinergic, neurones. These findings may lead to the discovery of therapeutic approaches that may help ameliorate deterioration of bowel function in advanced age. Animal experimental evidence indicates that reactive oxygen species are elevated in aging enteric neurons, which may be reduced by neurotrophic factors. Further data suggest that glial cell-line derived neurotrophic factor may play a protective role in the gut throughout life, and that dysregulation of neurotrophic factor support could contribute to neuronal ageing in the gut (26).

Gastrointestinal disorders associated with diabetes mellitus. Diabetes is associated with several disturbances of gastrointestinal motility through changes in intestinal smooth muscle or alterations in extrinsic neuronal control. The multifactorial pathogenesis includes disturbances of the enteric nervous system. Diabetic enteric neuropathy can cause changes in gastric emptying, diarrhea, or constipation (09). Gastric mucosal biopsy is a safe, practical method for histologic diagnosis of gastric autonomic neuropathy gastroparesis as a complication of type 1 diabetes (55).

Role of the CNS in gastrointestinal disorders. Many peptides and neurotransmitters are involved in CNS regulation of gastrointestinal motility and are found in the enteric nervous system. Peptides, including calcitonin gene-related peptide, cholecystokinin, neuropeptide Y, neurotensin, oxytocin, somatostatin, opioid peptides, and corticotrophic-releasing hormone, affect gastrointestinal motility when injected into the CNS of experimental animals.

Physical stress as well as psychological stress is known to contribute to gastrointestinal disorders. Most of the stressors are known to be associated with the release of corticotrophic-releasing hormone. The action of corticotrophic-releasing hormone on gastrointestinal motor function is mediated by the CNS through the autonomic nervous system independent of the pituitary-adrenal axis. Intestinal motor inhibition induced by surgery involves the release of corticotrophic-releasing hormone from the brain. Neuropeptide Y as well as corticotrophic-releasing hormone in the paraventricular nucleus of the hypothalamus is involved in the CNS regulation of gastrointestinal function.

Several CNS nuclei and neurotransmitters control gastric acid secretion and gastrointestinal motility. Central structures include the hypothalamus, the nucleus ambiguus, the dorsal motor nucleus of the vagus, the cingulate gyrus, the hippocampus, and the amygdala. Neurotransmitters that mediate this CNS control of the enteric nervous system include acetylcholine, norepinephrine, serotonin, and gamma amino butyric acid. The effects are multiple and include control of mucosal function such as secretion and absorption. The role of neurotransmitters in the pathogenesis of intestinal disorders is illustrated by the following example.

Irritable bowel syndrome is a chronic condition characterized by dysregulation of intestinal motor, sensory, and central nervous system functions. Manifestations are abdominal pain, bloating, and symptoms associated with irregular bowel function, such as constipation, diarrhea, or an alternating pattern between the 2. It is likely that serotonin (5-HT) acts as a key sensitizing agent in the etiology of irritable bowel syndrome. Acting mostly at 5-HT3 receptors, it enhances the sensitivity of visceral neurons projecting between the gut and the central nervous system. Its action at 5-HT4 receptors promotes the sensitivity of enteric neurons that react to luminal stimuli. 5-HT4 and 5-HT3 receptors also mediate, respectively, sensitizing and physiological actions of 5-HT (serotonin) on gastrointestinal motor and secretory functions.

GABAergic transmission to dorsal motor nucleus of the vagus and vagal efferent output to the gastrointestinal tract are regulated by variations in the levels of neurotransmitters that act as second messengers on the brainstem neurons that form vagovagal reflex circuits. Disturbances of the brainstem vagal circuits may underlie the pathophysiological changes observed in gastroparesis (05).

Loss of appetite observed during sickness is attributed to the proinflammatory cytokine IL-18, which has been shown in experimental studies in the mouse to decrease food intake by acting on neurons of the bed nucleus of the stria terminalis, a component of extended amygdala, to influence feeding via its projections to the lateral hypothalamus (14). The circuit affected by IL-18 may be a potential drug target for treating loss of appetite.

Pathogenesis of gastrointestinal disturbances in neurologic disorders.

Neurodegenerative disorders. Neurodegenerative disorders not only affect the CNS but also cause gut dysfunctions, suggesting they have an impact on both CNS and gut-innervating neurons. CNS and gut biology, aided by the gut-brain connecting neurons, modulate each other's functions and cause progressive CNS disorder and persistent gut dysfunction (56).

Parkinson disease. The pathogenesis of various gastrointestinal disturbances in Parkinson disease is uncertain. Some of these problems, such as dysphagia and constipation, may be secondary to abnormalities in skeletal muscle function or side effects of antiparkinsonian medications. The pathological process in Parkinson disease may involve the enteric nervous system as well. Lewy bodies, like those in the CNS, have been demonstrated in the enteric nervous system as well as the autonomic ganglia. A depletion of dopaminergic neurons takes place in the colon of patients with Parkinson disease who suffer from constipation and megacolon. Constipation is a minor symptom in most patients with Parkinson disease; severe constipation, however, is associated with time since diagnosis and severity of disease.

Autonomic nervous system dysfunction is also common in patients with Parkinson disease and includes sexual dysfunction, swallowing and gastrointestinal disorders, bowel and bladder abnormalities, sleep disturbances, and derangements of cardiovascular regulation. These disorders may be caused by an underlying degenerative process that affects the autonomic ganglia, brainstem nuclei, and hypothalamic nuclei. In addition to loss of mesencephalic dopamine-containing neurons, the dorsal motor nucleus of the vagus nerve and central noradrenergic nuclei are also affected in Parkinson disease. Patients with Parkinson disease experienced higher frequency of dysphagia and constipation, which is associated with slow colonic transit, decreased phasic rectal contraction, and paradoxical sphincter contraction on defecation. The hypothesis that alpha-synuclein pathology could spread from the gut to brain via the vagus nerve was tested by assessing alpha-synucleinopathy in the brain in a novel gut-to-brain alpha-synuclein transmission mouse model, and the findings were as follows (25):

Analysis of data on vagotomized patients for various indications from nationwide Swedish registers with follow-up for 5 years, has revealed suggestive evidence for a potential protective effect of truncal, but not selective, vagotomy against development of Parkinson disease (32). The results, along with gastrointestinal symptoms, which can manifest years before the diagnosis of Parkinson disease, provide preliminary evidence that the disease may start in the gut.

Wilson disease. Dysphagia is a common symptom of patients with Wilson disease, and they may die of aspiration pneumonia. Wilson disease may present with objective swallowing dysfunction, even in the absence of neurologic manifestations. Genotyping studies have revealed several mutations in Wilson disease, eg, an association between 3402delC and dysphagia.

Down syndrome. Gastroesophageal reflux and dysphagia occur in subjects with Down syndrome, but the precise pathomechanism is not established.

Shy Drager syndrome. In this form of primary autonomic failure, gastrointestinal abnormalities manifest at an early stage of the disease. These are attributed to atrophy, and loss is seen in various brain stem nuclei including those of the vagus and the intermediolateral cell mass in the thoracic and lumbar spinal cord. No pathological changes have been reported in the enteric nervous system. Constipation and dysphagia are common. Postprandial hypotension in these patients is due to combined disturbances of the gastrointestinal, cardiovascular, and autonomic nervous systems.

Autonomic neuropathy. Gastrointestinal manifestations of autonomic neuropathies are varied and complex because of numerous associated disorders. Diabetic neuropathy is the best-known example, but the pathogenesis is poorly understood. The neuropathy itself induces motility disorders, which produce further complications such as gastroparesis.

Cerebrovascular disease. Dysphagia is the most frequent gastrointestinal complication of stroke and is due to involvement of lower cranial nerve nuclei in brain stem syndromes. Stress ulcers have been considered as a complication of stroke where an interaction between the CNS, gastric circulation, gastric mucosa, and intraluminal contents plays a role. Cerebrovascular disorders are often accompanied by gastrointestinal mucosal damages. The pathophysiologic investigation of stress-related gastroduodenal mucosal damages has suggested that increased activity of the autonomic nervous system plays an important role in the development of these lesions.

Multiple sclerosis. The pathophysiology of gastrointestinal dysfunctions in multiple sclerosis is not as well explained as bladder dysfunction in patients with spinal cord involvement. Constipation may be due to slow colonic transit and abnormal rectal function. Fecal incontinence may be due to impaired sense of filling of the rectum and poor voluntary contraction of the anal sphincter.

Spinal cord injury. Autonomic function of the gastrointestinal system is impaired significantly following spinal cord injury. The term "neurogenic bowel" is usually applied to impairment of bowel function resulting from spinal cord injury but may also result from involvement of spinal cord in multiple sclerosis. Two patterns of neurogenic bowel exist: (1) the upper motor neuron bowel is due to spinal cord lesions above the sacral level, and (2) the lower motor neuron bowel results from lesions of the sacral spinal cord, nerve roots, or peripheral nerve innervation of the colon.

Upper gastrointestinal transit is prolonged in patients with spinal cord injury not only in those with cervical lesions but also in those with cauda equina lesions, which is secondary to colonic dysfunction and constipation (17).

Epidemiology

No proper epidemiological studies of the incidence of gastroenterological complications of neurologic diseases have been conducted. Some of the available information is as follows:

Parkinson disease. True prevalence of esophageal motility disorders in Parkinson disease is not known. Dysphagia is reported in about 52% to 82% of patients with Parkinson disease.

Diabetic neuropathy. About 70% of diabetic patients have gastrointestinal symptoms, but their relation to neuropathy is unclear. Constipation is found more frequently in patients with autonomic neuropathy than those without it. Gastroparesis may occur due to autonomic dysfunction.

Cerebrovascular disease. The reported incidence of dysphagia following stroke varies according to the testing method: 37% to 45% using cursory screening techniques, 51% to 55% using clinical testing, and 64% to 78% using instrumental testing (39).

Multiple sclerosis. Multiple sclerosis can induce autoimmune gastrointestinal dysmotility. Frequent gastrointestinal disorders in patients with multiple sclerosis are constipation and fecal incontinence.

Spinal cord injury. Almost all patients with spinal injury experience constipation. In one survey, Mean Fecal Incontinence Score was higher for spinal cord injury patients than controls and for complete compared with incomplete injury (35). Fecal incontinence affected quality of life for 62% of spinal cord injury patients, compared with 8% of controls.

Prevention

Prevention of neurogastric complications of systemic as well as neurologic disorders depends on preventive measures wherever feasible for the primary disease. For example, control of diabetes may reduce the development of autonomic peripheral neuropathy and gastrointestinal manifestations.

Differential diagnosis

A patient may present with neurologic symptoms that are due to an underlying gastroenterological disorder. In a reverse case scenario, the presenting gastrointestinal symptoms may be due to an underlying neurologic disorder. These have been discussed in previous sections.

Confusing conditions

The differential diagnosis of a patient presenting with gastroenterological symptoms and suspected neurologic disease involves determining if the disease is primarily in the gastrointestinal system or secondary to a neurologic disorder. Measurement of gastrointestinal motility and transit help in confirming the motor function of the gut and distinguishing between neuropathic and myopathic disorders.

Diagnostic workup

Basic laboratory tests include blood counts, blood chemistry, and stool examination. Blood glucose analysis is ordered in the case of suspected diabetic neuropathy.

Special diagnostic procedures vary according to whether the upper or lower gastrointestinal system is involved. Barium swallow and gastric emptying test are done in the case of dysphagia and stomach disorders, respectively. Abdominal radiographs and barium follow-through examinations are done in cases of chronic intestinal pseudo-obstruction. Endoscopic studies include gastroscopy and colonoscopy, depending on the part of the gastrointestinal system involved. Special neurogastroenterological tests are done according to the suspected disease:

Management

Gastrointestinal manifestations of neurologic disease. Some general approaches to treatment of various gastrointestinal manifestations of neurologic disease are outlined here.

Irritable bowel syndrome. Transverse tripolar dorsal column stimulation has been used for irritable bowel syndrome associated with abdominal pain resistant to conservative treatments (51).

Gastroparesis. Prokinetic agents, such as metoclopramide and cisapride, enhance gastric emptying and improve the symptoms of gastroparesis. A severely distended stomach may require decompression through a gastric tube. Rarely, a feeding gastrostomy may be required. Symptomatic treatment for nausea may be adequate if gastric emptying is normal.

Gastric mucosal disturbances. These may occur in acute stroke. The suppression of gastric acid secretion by using H2-receptor antagonists or proton-pump inhibitors is useful for the prevention and management of stroke-induced gastric mucosal damages.

Constipation. In neurologic disorders, such as Parkinson disease, constipation is usually treated with stool softeners, addition of fiber to the diet, prokinetic agents (ie, cisapride), and enemas. Cisapride relieves nausea and facilitates delivery of dopaminergic agents. Cisapride was taken off the market in the United States because of adverse effect of cardiac rhythm disturbances but is available on special request. Linaclotide, which activates chloride secretion through chloride-2 channels and cystic fibrosis transmembrane regulator, is approved for treatment of chronic idiopathic constipation. Various drugs in clinical trials or those used off-label for chronic idiopathic constipation and opioid-induced constipation are described elsewhere (07). Prucalopride, a benzofuran 5-HT4 agonist, accelerated bowel movement in chronic constipation without cardiovascular side effects. It has successfully completed clinical trials and is approved by the European Medicines Agency.

Methylnaltrexone is approved by the U.S. Food and Drug Administration (FDA) for the treatment of opioid-induced constipation in patients receiving palliative care when response to laxative therapy has not been sufficient; however, it is not yet approved for adults with chronic, noncancer visceral pain. Lubiprostone, a bicyclic fatty acid, was approved by the FDA for treatment of opioid-induced constipation in patients with noncancer pain, based on results of clinical trials. Linaclotide inhibits colonic nociceptors and relieves abdominal pain via guanylate cyclase-C and extracellular cyclic guanosine 3',5'-monophosphate.

Dyssynergic defecation may be treated by using neuromuscular conditioning and biofeedback therapy. A review of published studies showed that test sacral nerve stimulation was successful in 42% to 100% of patients with chronic constipation, and of those who proceeded to implantation of a permanent sacral nerve stimulator, up to 87% showed an improvement in symptoms at a median follow-up of 28 months (61).

Fecal incontinence. Care of the patients with denervation-induced fecal incontinence requires protection of the perianal skin and use of incontinence pads. Biofeedback training may be helpful for patients who have some residual innervation.

Sacral nerve stimulation reduces symptoms in up to 80% of patients with fecal incontinence and because its effects are not limited to the distal colon and the pelvic floor, neuromodulation at spinal or supraspinal levels have been suggested as part of the mode of action.

Management of loss of normal bowel function in neurologic disorders. Loss of normal bowel function caused by injuries to the nervous system, neurologic disease or congenital defects of the nervous system is termed “neurogenic bowel dysfunction” and includes combinations of fecal incontinence, constipation, abdominal pain, and bloating. If medical treatment of gastrointestinal disorders fails, surgical procedures may be needed. Neurostimulation procedures that have been investigated include sacral nerve stimulation, peripheral nerve stimulation, and magnetic stimulation. However, there is not yet consensus about efficacy of neurostimulation for clinical use.

Bowel dysfunction in spinal cord injury. The general principles of management of neurogastroenterological disorders are applicable in spinal cord injury. Patients with lower motor neuron bowel tend to suffer more difficulties in management of their neurogenic bowel than those with upper motor neuron bowel. Therefore, more intensive and aggressive bowel care programs should be provided for patients with spinal cord injury and lower motor neuron bowel.

Constipation is the most common problem. The use of cisapride for constipation in these patients is empirical and does not fulfill the criteria for evidence-based medicine. In clinical trials, cisapride does not seem to have clinically useful effects in people with spinal cord injuries. The antegrade continence enema procedure is a safe and effective means of treating intractable constipation and fecal incontinence in the adult spinal cord injury patient. This approach should be considered for those persons in whom medical management of bowel care has been unsuccessful.

There is often a fine dividing line between the constipation and fecal incontinence in patients with spinal cord injury; with any management intended to ameliorate, one risks precipitating the other. Functional magnetic stimulation is a noninvasive method for managing neurogenic bowel in individuals with spinal cord injury. Sacral nerve stimulation via subcutaneously implanted electrodes has been shown to symptomatically improve a minority of patients with resistant idiopathic slow transit constipation. Further studies are needed to identify patients who may benefit and to determine optimal stimulation parameters.

Implantable neuroprostheses are used for the simultaneous management of both bladder and fecal incontinence. In paraplegic patients where incontinence may alternate with constipation, attempts have been made by computerized stimulation of the sacral anterior roots to restore normal function to the anal sphincters. Long-term follow-up studies have shown that neural stimulation is a safe and effective method of bladder and bowel management after suprasacral spinal cord injury.

Gastrointestinal disorders with involvement of the enteric nervous system. Management of some of these disorders may require neurologic approaches.

Irritable bowel syndrome and inflammatory bowel disease. The difference between the two disorders is lack of inflammation in the former. Neuroimmune interactions have been implicated in irritable bowel syndrome. A pilot study of temporary sacral nerve stimulation for treatment of irritable bowel syndrome showed significant reduction of symptoms in patients with diarrhea as a predominant feature (34).

Chronic vagus nerve stimulation has antiinflammatory properties in a rat model of colitis and in a pilot study performed in patients with moderate Crohn disease, a form of inflammatory bowel disease (04). The basis for this is that the vagus nerve has dual antiinflammatory properties through its afferent, (ie, hypothalamic-pituitary-adrenal) axis and efferent (ie, the anti-tumor necrosis factor alfa) effect of the cholinergic antiinflammatory pathway fibers. This is a safer, nondrug therapy based on a physiological pathway, as compared with other treatments, such as drugs with anti-tumor necrosis factor alfa effects.

Fibromyalgia. There is considerable overlap between fibromyalgia and inflammatory bowel disease. Many patients experience both conditions together, and both involve pain and visceral hypersensitivity. A pilot trial (NCT00977197) showed that pregabalin, an antiepileptic used for the treatment of diabetic neuropathy and fibromyalgia, has shown some efficacy in irritable bowel syndrome for relief of abdominal pain and diarrhea (54).

SARS-CoV-2 infection and the enteric nervous system. COVID-19 is associated with gastrointestinal manifestation in a subset of patients. SARS-CoV-2 infects gastrointestinal epithelial cells expressing angiotensin-converting enzyme 2 receptors, which triggers a cascade of events and leads to mucosal inflammation with impact on the function of the enteric nervous system and activation of sensory fibers conveying information to the CNS; this may produce symptoms such as vomiting and diarrhea attributed to COVID-19 (37). Neurologic involvement can aggravate the course of the disease as coronaviruses can penetrate the cerebrospinal fluid and damage the structure and function of the nervous system. There are no specific drugs for the treatment of gastrointestinal symptoms in patients with COVID‐19, but systemic therapies may be used. The contribution of gut microbiota to severity and progression of the disease and the long‐term sequelae of the infection on digestive functions need further investigation.

Treatment of disorders of the ENS. Advances in neurogastroenterology have improved the prospects of improved management of enteric neuropathies. These include intestinal transplantation, novel drugs, neuromodulation, transfer of fecal microbiota, as well as stem cell and gene therapy (46). Among the experimental methods, transplantation of neural stem cells is a promising therapeutic approach for disorders of the enteric nervous system characterized by a loss of critical neuronal subpopulations. ENS progenitor or stem cells could be transplanted into the gut wall to replace the damaged or absent neurons and glia of the ENS (06). However, several obstacles need to be overcome to progress from successful preclinical studies in animal models to ENS stem cell therapies in the clinic.

To discover rational and more effective therapies for neurogastrointestinal disorders, important future challenges include a proper understanding of the molecular and cellular changes that underlie enteric neuropathies. For research in functional gastrointestinal disorders, a multidisciplinary approach that integrates neuroimaging studies with methods from other branches of neuroscience, particularly, cognitive and autonomic neuroscience, has been suggested to develop personalized approaches to problems with interindividual variations such as visceral pain (13).