Neurologic Disorders Associated with Gastrointestinal Diseases and Nutritional Deficiencies

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Chapter 103 Neurologic Disorders Associated with Gastrointestinal Diseases and Nutritional Deficiencies


The gastrointestinal tract and nervous system are interrelated. Gastrointestinal and liver abnormalities are associated with central nervous system (CNS) disease, and conversely, CNS abnormalities can cause gastrointestinal dysfunction. In addition, the CNS depends on the gastrointestinal system for glucose, absorption and metabolism of a variety of other nutrients and vitamins required for normal brain function, and the removal of toxic metabolic wastes. Gastrointestinal impairment may interfere with these functions. For example, patients with celiac disease can have cerebellar ataxia, as well as cerebral, brainstem, and peripheral nerve abnormalities. However, antigliadin antibodies can be found in subjects with neurological dysfunction of unknown cause, particularly in sporadic cerebellar ataxia (“gluten ataxia”). Liver disease can cause hepatic encephalopathy, hepatitis C virus infection can cause neurological abnormalities related to vasculitis, and inflammatory bowel disease is associated with thromboembolic CNS complications, inflammatory muscle disease, and inflammatory polyneuropathy. Whipple’s disease can involve the CNS and present with mental and psychiatric changes, supranuclear gaze palsy, motor abnormalities, hypothalamic dysfunction, cranial nerves abnormalities, seizures and ataxia.

Some neurologic complications of gastrointestinal diseases are nutritional, related to malabsorption, including those of vitamin B1, nicotinamide, vitamin B12, vitamin D, and vitamin E [Ghezzi and Zaffaroni, 2001]. Other complications are related to the toxic effects of waste products (e.g., ammonia).

Neurologic abnormalities affecting the central, peripheral, or enteric nervous system may give rise to gastrointestinal abnormalities. Achalasia and Hirschsprung’s disease are the result of defects of innervation of the esophagus and distal large bowel, respectively, the consequence being a disorder of motility affecting the relevant part of the gastrointestinal tract. Many neurogenic and primary muscle disorders are associated with abnormalities of gut motility. In many neurologic disorders, dysphagia is only one part of the clinical picture but in some – for example, the Chiari malformation – dysphagia may be the sole or major feature. Disturbances of bowel motility, when seen in neurogenic disorders, are associated with autonomic neuropathy, which is particularly common in diabetes mellitus. Primary muscle disorders can lead to dysphagia (for example, with polymyositis or oculopharyngeal dystrophy) or defects of large bowel motility (e.g., Duchenne’s muscular dystrophy). Many neurodevelopmental abnormalities can result in esophageal reflux. Stroke may result in dysphagia in a number of patients [Ghezzi and Zaffaroni, 2001].

This chapter reviews neurologic complications of the most common gastrointestinal and liver diseases, as well as disorders associated with malnutrition, and vitamin deficiencies. Gastrointestinal manifestations of neurologic abnormalities involving the enteric nervous system are discussed for some of the common motility disorders. These manifestations are reviewed more comprehensively, as are the anatomy and physiology of the enteric nervous system, in a chapter dedicated to the autonomic nervous system. In addition, several excellent reviews related to neurologic and gastrointestinal disorders have been published previously [Di Nardo et al., 2008; Wood, 2007b; Kellow et al., 2006; Schemann, 2005; De Giorgio et al., 2004; Chelimsky and Chelimsky, 2003; Camilleri 2003].

Neurologic Complications of Common Gastrointestinal and Liver Diseases

Disorders Associated with Gastrointestinal Disease

The Enteric Nervous System

The enteric nervous system (ENS) is an elaborate network of neurons and neural connections in the gastrointestinal tract. It modulates motility, microcirculation, sphincter tone and activity, hormone secretion, and immune and inflammatory responses of the gastrointestinal tract.

The ENS is closely connected to the CNS and there is bidirectional communication between them. The ENS relays information collected in the periphery (bowel) to the CNS through motor and sensory sympathetic and parasympathetic connections [Burns and Pachnis, 2009]. There are many different classes of enteric neurons that differ in their neurotransmitters’electrophysiological properties, morphology, inputs, channel and receptor expression, targets (muscle, other neurons, etc.), and the direction in which their axons project. Neural circuits underlying motility reflexes consist of inhibitory motor neurons, excitatory (cholinergic) motor neurons, interneurons, and intrinsic sensory neurons [Young, 2008]. Excitatory and inhibitory molecules include acetylcholine, biogenic amines, and the opioid system. Intermediate cells include neuroendocrine cells, interstitial cells of Cajal, and cells of the immune system [Altaf and Sood, 2008]. The parasympathetic innervation via the vagus nerves influences both the motor and secretomotor function of the upper gastrointestinal tract, while the sympathetic adrenergic fibers from the prevertebral ganglia innervate only the secretomotor neurons.

The brain–gut axis plays a prominent role in the modulation of gut functions. Signals from different sources (sound, sight, smell, somatic and visceral sensations, pain) reach the brain. These inputs are modified by memory, cognition, and affective mechanisms, and are integrated within the neural circuits of the CNS, spinal cord, autonomic nervous system, and ENS. These inputs can have physiologic effects, such as changes in motility, secretion, immune function, and blood flow to the gastrointestinal tract. One of the most important neurotransmitters is serotonin, which plays a key role in the pathogenesis of the most common chronic functional gastrointestinal disorder, irritable bowel syndrome.

Similarly, stimuli affecting receptors in the gut mucosa or the oral cavity can be transmitted to the CNS. For example, functional magnetic resonance imaging (fMRI) has revealed activation of several forebrain regions in response to intragastric infusion of solutions that activate the sensation of taste [Kondoh et al., 2009]. Glucose activates the nucleus accumbens; monosodium glutamate (MSG) activates the medial preoptic area, dorsomedial nucleus of the hypothalamus, and habenular nucleus. Both glucose and MSG activate the amygdala. Glucose-induced brain activation develops slowly and persists for a long time, whereas activation by MSG develops rapidly during infusion and is reduced rapidly after ending the infusion. Vagal afferents may be playing an important role in this process.

The ENS arises from progenitors, neural crest cells, which migrate from the caudal hindbrain, enter the foregut, and then move caudally through the gut mesenchyme to colonize the entire gastrointestinal tract. Contact between enteric nerves and effectors are developed at 26 weeks’ gestational age. Motility patterns mature with age. Neurotrophin-3 is required for the differentiation, maintenance, and proper physiological function of late-developing enteric neurons that are important for the control of gut peristalsis [Chalazonitis, 2004].

Studies in humans with Hirschsprung’s disease (distal aganglionosis), and of animal models of Hirschsprung’s disease, have led to the identification of many of the genetic, molecular, and cellular mechanisms responsible for the colonization of the gut by enteric neuron precursors [Young, 2008]. Genetic defects, including those related to the neurogenic receptor with tyrosine kinase activity (RET), can interfere with migration and development of enteric ganglia.

In the mature ENS, there is complex synaptic circuitry within myenteric ganglia that underlies motility reflexes. Developmental disorders involving the enteric nervous system in children include abnormalities such as dysphagia, feeding intolerance, gastroesophageal reflux, abdominal pain, and constipation. Alteration in bowel motility has been described in most of these disorders and can result from a defect in the enteric neurons of the gut or their central modulation.


Swallowing is a complex dynamic process that requires the recruitment and coordination of the muscles of the lips, tongue, palate, pharynx, larynx, and esophagus. Swallowing occurs in three main anatomic regions: oral, pharyngeal, and esophageal. Therefore, swallowing disorders may be due to impairment of any or all of these regions. Difficulty swallowing, or dysphagia, can be present in children. Certain groups of infants with specific developmental or medical conditions are at higher risk for developing dysphagia, including those with neurologic conditions or structural deficits (e.g., cleft lip or palate). Left untreated, these problems can lead to failure to thrive, aspiration pneumonias, gastroesophageal reflux, or the inability to establish and maintain proper nutrition and hydration. Individuals with dysphasia also are more likely to develop aspiration pneumonia, and pneumonia has the highest mortality rate of all the different types of nosocomial infections [Prasse and Kikano, 2008].

Inhibition of gastric emptying and stimulation of colonic transit is the most consistent pattern in the motility response of the gastrointestinal tract to acute short-term stress. Endogenous corticotropin-releasing factor (CRF) plays a significant role in CNS mediation of stress-induced inhibition of upper gastrointestinal motor function and stimulation of lower gastrointestinal motor function. CRF is involved in the central mechanisms by which stress inhibits gastric emptying while stimulating colonic motor function. Systemic or central administration of interleukin-1β has the same functional response through activation of CRF release. The paraventricular nucleus of the hypothalamus and the dorsal vagal complex are sites of action for CRF that inhibit gastric function, while the paraventricular nucleus and the locus ceruleus complex are sites of action for CRF to stimulate colonic motor function. The central actions of CRF are conveyed by autonomic pathways and are different than pathways that stimulate pituitary hormone secretion. CRF also acts on the locus ceruleus to induce selective stimulation of colonic transit without influencing gastric emptying. These findings help our understanding of the pathophysiology of the irritable bowel syndrome (IBS) [Tache et al., 1993, 1999] and provide evidence that stress affects visceral sensitivity in humans [Monnikes et al., 2001].

Episodic Gastrointestinal Disease

Episodic gastrointestinal disease due to alterations in ENS function include IBS, functional dyspepsia, chronic abdominal pain, and motility disorders such as gastroparesis, constipation, gastroesophageal reflux disease, and cyclic vomiting syndrome. Periodic vomiting or abdominal pain is an example of periodic gastrointestinal diseases, which, along with benign paroxysmal torticollis and benign paroxysmal vertigo, may be precursors to migraine [Cuvellier and Lepine, 2010]. Neuromodulatory interventions mostly are carried out using pharmacological agents, although interventions involving electrical stimulation have been suggested [Gaman and Kuo, 2008]. Psychologic stress factors also may play a role [Ammoury et al., 2009].

Cyclic Vomiting Syndrome and Recurrent Abdominal Pain

Cyclic vomiting syndrome (CVS), described first by Gee [1882], is manifested by repeated bouts of vomiting lasting for hours or days, which can cause dehydration, hypochloremic alkalosis, and ketosis in an otherwise healthy child [Abu-Arafeh and Russell, 1995]. Abdominal pain and fever may be present, and the patient may become pale, drowsy, and lethargic [Li and Balint, 2000]. The time of onset and duration of the episodes tend to be stereotypic for the individual patient. CVS usually occurs in infancy but can start later childhood and usually resolves during adolescence. In some children, recurrent abdominal pain may last for hours, with or without headaches, nausea, and vomiting. Pallor, weakness, fever, skin blotching, and other autonomic findings are common.

A 2005 epidemiologic study done in Ireland found that the annual incidence of CVS was 3.15 per 100,000 children per year [Fitzpatrick et al., 2008]. The median age at onset of CVS was 4 years (range 0.5–14 years), with 46 percent of the children having an onset at or before the age of 3 years, and the median age of diagnosis was 7.42 years (range 1.8–15 years). The median duration of an episode was 24 hours, but the range was up to 5 days. Of school-age children, 85 percent had missed a substantial amount of school in the year prior to the study due to CVS. Another study of school-age children with CVS in Turkey found that the mean-onset age was 7 ± 3.4 years. Episodes were accompanied by pallor and anorexia in all children, and by headache and abdominal pain in the majority of individuals [Ertekin et al., 2006].

The pathophysiology of CVS is not understood clearly. A brain “generator” for vomiting is present in the brainstem’s nucleus tractus solitarius. It receives efferent innervation from chemoreceptors in the area postrema in the floor of the fourth ventricle, which are sensitive to different stimuli from vagal gastrointestinal fibers, the oculovestibular system, and the cortex. Vomiting, therefore, can be a result of gastrointestinal, autonomic, or cerebral dysfunction secondary to tumors, hydrocephalus, toxins, hormonal changes, familial dysautonomia, or migraine [Johns, 1995].

CVS and migraine share comorbid dysautonomias, including orthostatic intolerance and syncope [Chelimsky et al., 2009]. Autonomic abnormalities, primarily sympathetic autonomic dysfunction, affecting the vasomotor and sudomotor systems were reported in 6 children with CVS [Chelimsky and Chelimsky, 2007]. Both CVS and recurrent abdominal pain are associated with migraine, although, in at least half of all patients, headaches are not present. Recurrent abdominal pain has been referred to as abdominal migraine [Bentley et al., 1995]. A history of migraine headache in first-degree relatives is common [Symon and Russell, 1995].

Mitochondrial dysfunction is a hypothesized component in the multifactorial pathogenesis of common migraine and CVS. A mitochondrial component in migraine is supported by the finding that subjects with migraine have lactic acidosis accumulation in skeletal muscle mitochondria and decreased respiratory chain complex. Mitochondrial DNA sequence variations are suspected of being a risk factor in the pathogenesis of CVS. Mitochondrial DNA polymorphisms have been associated with CVS and migraine [Zaki et al., 2009]. In one study, the 16519C polymorphism was detected in 21 of 30 CVS subjects (70 percent) and 58 of 112 migraineurs (52 percent), compared to 1 of 63 (1.6 percent) controls. These patients had, in addition to CVS, multiple neuromuscular abnormalities meeting diagnostic criteria for Kearns–Sayre syndrome, and severe symmetrical growth retardation [Boles et al., 2007]. Other suggested causes of CVS include metabolic abnormalities, ion channelopathies, excessive hypothalamic-pituitary-adrenal axis activation, or heightened autonomic activity [Li and Balint, 2000; Li and Misiewicz, 2003]. Epileptiform abnormalities also have been observed, suggesting that the mechanism of CVS involves spontaneous spreading depression, similar to that seen in migraine patients. The differential diagnosis of CVS includes gastrointestinal obstruction, metabolic disorders, renal disease, and neurologic space-occupying lesions [Forbes, 1995]. It is important to evaluate individuals with CVS symptoms thoroughly, even if they are asymptomatic and well between vomiting episodes, as this does not assure the absence of another disease [Catto-Smith and Ranuh, 2003].

Treatment of cyclic vomiting is by fluid and electrolyte replacement and treatment of esophagitis, which may be caused by the continued vomiting. Antimigraine, antiemetic, and antiepileptic agents have been used [Li and Misiewicz, 2003]. Lorazepam has antiemetic and anxiolytic properties. Phenothiazines, butyrophenones, metoclopramide (Reglan), or trimethobenzamide (Tigan) may be effective as antiemetics, but may cause extrapyramidal side effects. Ondansetron, a newer antiemetic, also may be considered. Prophylactic therapy with propranolol [Forbes and Withers, 1995] and a beneficial effect of oral or nasal sumatriptan have been described [Benson et al., 1995; Kowalczyk et al., 2010; Kakisaka et al., 2009]. Antiepileptic drugs, such as phenobarbital or valproic acid, have been suggested as ameliorating symptoms [Hikita et al., 2009]. Prophylactic therapy with valproate at a dose of 10–40 mg/day had a beneficial effect on some children with CVS [Hikita et al., 2009]. A beneficial effect of amitriptyline also has been described [Ghosh et al., 2009]. Flunarizine also was found to be effective as a prophylactic agent in a study of a small number of children with CVS and abdominal migraine [Kothare, 2005].

Anatomic Gastrointestinal Disorders

Gastroesophageal Reflux

Gastroesophageal reflux (GER) is present when reflux of gastric contents causes troublesome symptoms or complications [Sherman et al., 2009]. While infant regurgitation was found in 12 percent of Italian children followed for 2 years, 88 percent of these infants improved by age 12 months, and only 1 of 210 had gastroesophageal reflux disease (GERD) [Campanozzi et al., 2009]. GER occurs in about one-third of all children with severe psychomotor retardation, as well as in other neurologic conditions, including myopathies and cerebral palsy. It occurs in children with sequelae of birth asphyxia and lower esophageal sphincter tone abnormalities [Pensabene et al., 2008].

There may be incompetent lower esophageal sphincter tone, which allows entry of gastric contents and acid into the esophagus, with possible aspiration and esophagitis [Hillemeier, 1996]. Some patients also may have a hiatal hernia [Mittal and Balaban, 1997]. Factors related to the frequent occurrence of GER with neurologic conditions include esophageal muscle weakness, hypotonia, incoordination of the swallowing mechanism, scoliosis, and immobility. Cases of “dysphagia-GER complex” have been reported in patients who suffered from perinatal asphyxia, cerebellar hemorrhage, or congenital dysphagia of unknown origin and had lower brainstem dysfunction, with different combinations of facial nerve palsy, inspiratory stridor, central sleep apnea, and dysphagia [Saito et al., 2006].

Symptoms of GER include pain, discomfort, irritability, and vomiting. Anemia and recurrent aspiration pneumonia also may occur. Respiratory symptoms resulting from reflux, aspiration, and laryngospasm that cause apnea, cyanosis, and stiffening may be confused with seizures. A relation between hiatal hernia, GER, and dystonic neck posture, described by Sandifer, was reported by Kinsbourne in 1964. The dystonic posture consists of extension and rotation of the neck. Others have suggested that the dystonic posture allows for better peristalsis and clearance of acid from the distal esophagus. It has been suggested that, in children with severe neurologic impairment, self-injurious behaviors or considerable agitation may be a marker for GER [Goessler et al., 2007b].

Esophageal pH monitoring demonstrates intermittent periods of reduced pH that indicate reflux of acid gastric contents into the distal esophagus [Hillemeier, 1996]. Esophageal manometry may show decreased sphincter pressure and reduced peristaltic activity. A barium swallow of the upper intestinal tract also should be performed to determine the presence of other anatomic or functional abnormalities that may mimic reflux. As reflux can be acidic (pH <4) or nonacidic (pH >4), the use of combined pH measurements and multiple intraluminal impedance monitors is recommended [Del Buono et al., 2006]. In children in whom the etiology of GER is not established, evaluation for a neurologic cause should be considered. The diagnosis of GER in children with neurologic impairment is more difficult because symptoms frequently are less specific.

Medications that enhance gastrointestinal motility (e.g., metoclopramide, cisapride, ranitidine, sucralfate) usually are beneficial in children with GERD [Cucchiaraa, 1996; Hillemeier, 1996; Horvarth et al., 2008]. The effects of therapy in decreasing respiratory symptoms such as apnea are less likely in children with underlying neurologic disorders [Bagwell, 1995]. Children with GERD who do not respond to medical therapy may benefit from gastrostomy and Nissen fundoplication, which can be done laparoscopically [Iwanaka et al., 2010]. The procedure may improve quality of life, have a positive effect on growth, and reduce proton pump inhibitory use and frequency of respiratory symptoms [Engelmann et al., 2009]. Surgical treatment is usually more effective for the resolution of digestive than of respiratory symptoms [Tannuri et al., 2008]. Major postoperative complications or recurrent GERD occur more frequently in neurologically impaired children [Bagwell, 1995; Mathei et al., 2008; Goessler et al., 2006; Goessler et al., 2007b].

Intestinal Pseudo-Obstruction

Chronic intestinal pseudo-obstruction is one of a number of esophageal and gastrointestinal motility disorders, which include esophageal achalasia, pre- and post-fundoplication motility disorders, gastroparesis, motility disorders occurring after repair of congenital atresias, motility disorders associated with gastroschisis, motility after intestinal transplantation, motility disorders after colonic resection for Hirschsprung’s disease, chronic functional constipation, and motility disorders associated with imperforate anus [Gariepy and Mousa, 2009].

Intestinal pseudo-obstruction is manifested by intestinal obstruction in the absence of mechanical blockage [Scott, 1996]. Box 103-1 lists some of the more common causes of intestinal pseudo-obstruction in children. Acute pseudo-obstruction (paralytic ileus) usually occurs postoperatively or secondary to the use of medications, including anticholinergic agents, phenothiazines, tricyclic antidepressants, narcotics, and certain anticonvulsants, particularly benzodiazepines and barbiturates. Infant botulism can present as colonic ileus, mimicking Hirschsprung megacolon. Infant botulism should be considered in infants with constipation and neurologic abnormalities. Cases of vincristine-related pseudo-obstruction have been described. Most have been attributed to a drug interaction with itraconazole, accidental vincristine overdose, or liver failure [Diezi et al., 2010]. Abnormal motor function may also contribute to the overall intestinal dysfunction of children who have other underlying gastrointestinal diseases, such as Hirschsprung’s disease or gastroschisis.

Chronic pseudointestinal obstruction (CIPO) may be due to a variety of abnormalities involving the intestinal musculature (chronic myopathic intestinal pseudo-obstruction) or intestinal innervation (chronic neuropathic intestinal pseudo-obstruction). Pathologies associated with CIPO may be due to abnormalities of neural innervation or to intestinal smooth muscle structure. CIPO also can occur in association with systemic neurologic, endocrine, and connective tissue diseases or malignancy. When no recognizable etiology is found, CIPO is referred to as idiopathic (CIIPO) [Millar et al., 2009; De Giorgio et al., 2010]. Chronic pseudo-obstruction not related to a clearly identified cause probably involves degenerative and inflammatory abnormalities, which compromise the ENS and lead to impairment in gastrointestinal transit [Di Nardo et al., 2008].

Clinical manifestations typically include recurrent episodes of bowel obstruction without a mechanical obstructive cause. Symptoms include poor feeding, vomiting, abdominal distention, megacolon, and constipation.

The ability to study gastrointestinal motility has improved greatly in the past few years, with the development of less invasive diagnostic testing methods. Evaluation for pseudo-obstruction requires exclusion of structural, mechanical, and pharmacologic etiologies, followed by additional studies to evaluate motor activity and motility, including breath hydrogen determination, scintigraphy, and manometric studies [Scott, 1996]. A mitochondrial neurointestinal encephalopathy may cause chronic pseudo-obstruction in addition to cranial nerve abnormalities, ataxia, ophthalmoplegia, facial and limb muscle weakness, and pigmentary retinopathy. Brain MRI demonstrates diffuse leukoencephalopathy. Muscle biopsy reveals neuropathic and myopathic changes, scattered ragged red fibers, and focal cytochrome oxidase deficiency [Zimmer et al., 2009].

Medical and surgical therapies often are unsatisfactory and long-term outcome frequently is poor [Stanghellini et al., 2007]. Optimal treatment of children with intestinal motility disorders relies on a multidisciplinary approach, which focuses on optimizing nutrition, improving gastrointestinal motility, and reducing psychosocial disability [Di Lorenzo and Youssef, 2010]. Intestinal transplantation has become an accepted treatment for intestinal failure and its complications. Disorders of bowel motility may represent up to 25 percent of patients on waiting lists for intestinal transplantation.

Hirschsprung’s disease

Hirschsprung’s disease, or aganglionic megacolon, is a congenital disorder that is characterized by the absence of intestinal ganglion cells in the submucosal and myenteric plexuses, which causes proximal bowel distention. It is the consequence of defective migration of neural crest cells to the colonic submucosa and is one of a spectrum of neurocristopathies, a group of diverse disorders resulting from defective growth, differentiation, and migration of neural crest cells, with a wide spectrum of neurologic abnormalities. These include Hirschsprung’s disease associated with congenital hypoventilation syndrome (i.e., Haddad syndrome), a rare disorder characterized by failure of automatic respiratory control, which, in the neonate, requires continuous mechanical ventilation [Dejhalla et al., 2006]. Approximately 1.5 percent of Hirschsprung’s disease patients and 10 percent of those with total colonic aganglionosis (TCA) have congenital central hypoventilation syndrome (CCHS) [Croaker et al., 1998]. Some of the patients with CCHS/Hirschsprung’s disease also will have neuroblastoma or ganglioneuroma. Other autonomic nervous system dysfunctions also may occur. Although TCA is considered to be the same condition as Hirschsprung’s disease by some investigators, patients with TCA (i.e., 2–14 percent congenital aganglionosis) display clinical, histopathologic, and genetic differences that may account for altered clinical presentation [Moore and Zaahl, 2009]. Mutations in the PHOX2B gene have been described in some individuals with Hirschsprung’s disease [Bajaj et al., 2006].

Patients with Waardenburg’s syndrome, which consists of dysmorphic facial features, partial or total heterochromia irides, piebaldism of the skin or hair, and congenital deafness affecting one or both ears, also may have Hirschsprung’s disease [Toki et al., 2003]. Aganglionosis in Waardenburg’s syndrome is similar in gender ratio and extent of aganglionosis to that in Haddad syndrome.

The combination of unusual facial features (hypertelorism, cleft palate, and maxillary deficiency) and Hirschsprung’s disease constitutes the Goldberg–Shprintzen syndrome [Goldberg and Shprintzen, 1981]. Other abnormalities in this syndrome include mental retardation and epilepsy [Tanaka et al., 1993]. Computed tomography (CT) demonstrates diffuse cerebral atrophy. This syndrome may be a manifestation of abnormal neuronal migration because the parasympathetic ganglia involved in Hirschsprung’s disease and the connective tissues of the affected face and oropharyngeal structures all are derived from the neural crest. Patients presenting with the phenotypic features of the Goldberg–Shprintzen syndrome and short-segment Hirschsprung’s disease associated with CCHS require permanent mechanical ventilation. In these individuals, seizures and developmental delay are common [Shahar and Shinawi, 2003]. Hirschsprung’s disease also can occur in patients with Down syndrome, Smith–Lemli–Opitz syndrome, agenesis of the corpus callosum, familial piebaldness, and a variety of other syndromes.

In a study of 17 patients with Hirschsprung’s disease, 10 (58.8 percent) were isolated and 7 (41.1 percent) were associated with other structural abnormalities and psychomotor retardation [Carracosa-Romero et al., 2007]. Neuroimaging in all of individuals identified cerebral dysgenesis that was compatible with neuronal migrational disorders.

It has been suggested that the pathophysiology of Hirschsprung’s disease also involves a more generalized immaturity of ENS neurons. Neuronal maturation in normoganglionic colon also was assessed in human specimens from patients with Hirschsprung’s disease and compared with specimens from patients with anorectal malformation, idiopathic constipation, and normal controls [Miyahara et al., 2009]. Polysialylated neural cell adhesion molecule immunohistology was positive, indicating immaturity in all specimens at a young age; these findings decreased with age but remained strongly positive in Hirschsprung’s disease, suggesting persistent immaturity. A study of the central and peripheral nervous systems, using brain MRI, nerve conduction velocity studies, and histopathology of the ENS, in a SOX10 (22q13) mutation-associated Hirschsprung’s patient who presented with persistent gut functional disorders, even after definitive surgery, revealed brain hypomyelination, peripheral dysmyelinating neuropathy, and enteric neuroglia deficiency, which implied systemic glial maldevelopment [Shimotake et al., 2007]. This may explain persistent gut dysmotility and absorption insufficiency after pull-through surgery, especially in children with allelic SOX10 truncating mutations. Investigation of the enteric nerve tissue responses to acetylcholine and noradrenaline in colonic tissues obtained from patients with Hirschsprung’s disease and related conditions (intestinal neural dysplasia and hypoganglionosis) demonstrated reduced cholinergic and adrenergic nerves [Tomita and Howard, 2007]. These studies suggest that dysmotility in Hirschsprung’s disease may be related to reduced cholinergic and adrenergic functional activity, resulting in the persistent dysmotility that is seen.

Hirschsprung’s disease also represents a complex disorder of signaling molecules resulting from the effects of at least nine known susceptibility genes. Affected families carry a 200 times higher risk, but genetic counseling via pedigree analysis is difficult and the significance of genetic variations remains unclear [Moore and Zaahl, 2008]. Studies have suggested an autosomal-dominant or multifactorial mode of inheritance in individuals with Hirschsprung’s disease. Recently, dominant mutations in the RET gene and a recessive mutation in the endothelin receptor type B gene have been identified [Chakravarti, 1996; Heanua and Pachnis, 2007]. A role has been suggested for possible alterations in homeobox (HOX) genes, alone or in combination with RET gene abnormalities [Garcia-Barcelo et al., 2007].

Other pseudo-obstruction syndromes

Children with muscular or myotonic dystrophies may have intestinal pseudo-obstruction. In addition, X-linked recessive neuropathic forms of intestinal pseudo-obstruction have been described [Auricchio et al., 1996].

Several syndromes have been associated with pseudo-obstruction. POLIP (polyneuropathy, ophthalmoplegia, leukoencephalopathy, and intestinal pseudo-obstruction) syndrome is a familial, possibly autosomal-recessive, chronic neuropathic intestinal pseudo-obstruction that accompanies a progressive severe neuronal disease manifested by external ophthalmoplegia, ptosis, severe sensorimotor neuropathy, and neuronal hearing loss, without significant cognitive involvement. Autopsy examination in three cases revealed degenerative neuronal changes with eosinophilic intranuclear inclusion bodies and demyelination in the myenteric plexus and the peripheral nervous system, possibly secondary to axonal atrophy. Cranial nerves and spinal roots were less severely involved and spinal cord and brainstem neurons were intact [Simon et al., 1990].

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a rare autosomal-recessive disorder with heterogeneous multisystem involvement that has been associated with multiple mitochondrial DNA deletions. It is characterized by peripheral neuropathy, ophthalmoplegia, deafness, leukoencephalopathy, and gastrointestinal symptoms due to visceral neuropathy. Clinical manifestations include progressive gastrointestinal dysmotility and cachexia, accompanied by ptosis/ophthalmoplegia, hearing loss, and a demyelinating neuropathy. Although symptoms start between the first and fifth decades, they usually begin before age 20 years in 60 percent of individuals.

The diagnosis of MNGIE can be established if certain confirmatory laboratory studies are present, including an elevated plasma lactate level and elevated plasma thymidine and deoxyuridine concentrations, as well as reduced leukocyte thymidine phosphorylase enzyme activity. Electron microscopy of rectal biopsy tissue may suggest a mitochondrial disorder [Walia et al., 2006]. ECGF1, the gene encoding thymidine phosphorylase, is associated with this disease.

Malabsorption Syndromes

A variety of well-known gastrointestinal disorders associated with malabsorption can cause selected nutritional, biochemical, and vitamin deficiencies, including vitamin E and vitamin B12 deficiency. Neurologic involvement is present in some children with these disorders. Neurologic abnormalities associated with specific vitamin deficiencies are reviewed later in this chapter.

Celiac Disease

Celiac disease is an immune-mediated malabsorption disorder characterized by permanent gluten intolerance. Exposure to gluten perpetuates an enteropathy leading to malabsorption with chronic diarrhea, weight loss, and abdominal distention. The small intestine mucosa is abnormal, and jejunal biopsy demonstrates villous atrophy, absence of surface mucosa, and crypt hyperplasia. The disease can present with mild symptoms, such as irritable bowel syndrome, anemia, slight weight loss, and fatigue. In many individuals, it may be clinically silent, despite manifest small-bowel mucosal lesions, accounting for underdiagnosis of the disease [Feigbery, 1999; Maki and Collins, 1997; Catassi et al., 1996; Kolho et al., 1998; Holmes, 1996].

Celiac disease affects nearly 1 percent of most populations but remains largely unrecognized. Using combined determination of serum immunoglobulin G (IgG) and IgA antigliadin antibody testing [Catassi et al., 1996], the prevalence of the disease in young Italians aged 6–15 years was 1 in 184. Using IgA antiendomysium antibody determination among healthy Finnish adults, the prevalence was as high as 1 in 130 individuals [Kolho et al., 1998]. A prevalence rate of 4 percent was reported by Not et al. [1998].

Neurologic symptoms infrequently are the presenting manifestation of celiac disease [Luostarinen, 2001]. Also, in some patients, gluten sensitivity can be present with neurologic abnormalities without meeting the strictly defined criteria for celiac disease [Fasano and Catassi, 2001; Hadjivassiliou et al., 1998]. Neuropathy, manifested by paresthesias, numbness, reduced tendon reflexes, sensory ataxia, and weakness, occurs late in the disease and usually in adults with severe steatorrhea [Kaplan et al., 1988]. Nerve conduction velocity studies and nerve biopsies show evidence of distal axonopathy. The neuropathy is believed to result from vitamin deficiency. CT scans in celiac disease patients may demonstrate cerebral calcifications, as well as cerebral and cerebellar atrophy and white-matter lesions. If undetected or neglected, celiac disease may cause considerable late complications from malabsorption or secondary autoimmune diseases [Feigbery, 1999; Maki and Collins, 1997; Holmes, 1996]. Therapy consists of permanently excluding gluten from the diet, which allows healing of the mucosal intestinal lesions and improved absorption of nutrients.

Neurologic and psychiatric abnormalities are more common in adults and children with celiac disease compared with nonceliac disease subjects [Holmes, 1996; Hadjivassiliou et al., 1998; Volta et al., 2002; Zelnick et al., 2004; Bushara, 2005]. Approximately 25–50 percent of patients develop symptoms, including depression, seizures (some with cerebral calcifications), ataxia, migraine, dementia, and, rarely, peripheral neuropathy or myopathy [Collin and Maki, 1994; Holmes, 1996]. The most common neurologic problem is ataxia [Luostarinen et al., 2001; Kieslich et al., 2001]. Celiac disease is found in 9 percent of patients with idiopathic cerebellar ataxia, in comparison with 2 percent of the healthy Finnish population. Antigliadin antibodies are more prevalent in patients with ataxia than in the general population. In studies of patients with cerebellar ataxia of unknown cause, the reported percentage of biopsy-proven celiac disease has been variable (i.e., 1.9–16 percent) [Burk et al., 2001]. Seizures occur in 3.5–5.5 percent of patients with celiac disease [Holmes, 1996]. Bruzelius et al. [2001] found a significantly increased frequency of epilepsy and dementia in patients with celiac disease. Specific syndromes of occipital calcifications and epilepsy, and cerebellar degeneration with or without epilepsy, also have been described in children with celiac disease [Arroyo et al., 2002; Labate et al., 2001]. A significant percentage of patients with Down syndrome have celiac disease or are positive for antiendomysial antibodies [Zachor et al., 2000].

Psychiatric abnormalities seen in celiac disease include anxious behavior, depressive syndromes, and schizophrenia [Addolorato et al., 1996; Pynnonen et al., 2004; Ludviggson et al., 2007]. Common symptoms include apathy, anxiety, and irritability [Bushara, 2005; Carta et al., 2002]. Psychiatric symptoms do not always disappear after the start of a gluten-free diet [Ciacci et al., 1998; Fera et al., 2003; Cakir et al., 2007; Addolorato et al., 2008a; Carta et al., 2002, Corvaglia et al., 1999]. While state anxiety disappears after a gluten-free diet is started, depression persists in treated patients. Cases of psychosis or schizophrenia with celiac disease have been reported [De Santis et al., 1997]. There are reports of immunopathological changes in the intestinal mucosa of autistic children, but a direct association between autism and celiac disease has not been shown. Reports of behavioral improvement in autistic children on a gluten-free diet and casein-free diet have not been substantiated.

The mechanisms involved in the etiology and pathogenesis of psychiatric symptoms related to celiac disease remain unclear. Similarly, the role of a gluten-free diet in the improvement of symptoms is uncertain. It is possible that the antigliadin antibodies may be markers of autoimmune activity with an unidentified neurotoxic antibody [Hadjvassiliou, 1996]. Abnormalities of tryptophan availability and serotonin metabolism were suggested [Pynnonen et al., 2004]. Low tryptophan levels were found in 4 of 11 patients with celiac disease [Holmes, 1996] and were lowest in children with behavioral abnormalities. Mood and mental ability improved in some of the children after the start of a gluten-free diet.

Untreated patients with celiac disease can have signs of attention-deficit hyperactivity disorder (ADHD). Niederhofer and Pittschieler [2006] investigated a cohort of 78 patients with celiac disease. The patients had positive serum for endomysium antibodies and elevated tissue transglutaminase antibodies, as well as total or partial villous atrophy and the typical jejunal or duodenal mucosal inflammatory features associated with celiac disease. After at least 6 months of gluten-free diet, patients or their parents reported a significant improvement in their behavior and functioning compared to the period immediately before diagnosis and dietary treatment. The authors suggest that ADHD should be included in the list of neurobehavioral conditions associated with celiac disease, and that celiac disease should be included in the differential diagnosis of ADHD [Taddeucci et al., 2005].

The pathogenesis of central or peripheral nervous system dysfunction in gluten enteropathy remains unclear. It has been suggested that neurologic dysfunction in celiac disease is the result of malabsorption causing folic acid, vitamin B12, or vitamin E deficiencies. Hypocalcemia and hypokalemia also have been implicated [Ventura et al., 1991]. Although some patients have malabsorption, the majority of patients with neurologic symptoms do not, and there is no evidence to indicate that the neurologic complications are secondary to this problem.

Abnormalities of humoral and cell-mediated immunity suggest that celiac disease is an immunologic disorder [Walker-Smith, 1996]. It is caused by an inappropriate immune response to the gliadin component in dietary gluten [Dietrich et al., 1997]. There is a genetic susceptibility and 90 percent of patients have the human leukocyte antigen (HLA) DRG 3 DQ-2 haplotype. There is a close relation between the biochemical properties of tissue transglutaminase and the basic molecular mechanisms responsible for celiac disease [Gentile et al., 2002]. Antiendomysial, antigliadin, and antireticulin antibodies also are associated with the disease. Anti-tissue transglutaminase antibody assay has been used as a serologic screening test for celiac disease but clinical symptoms, histologic abnormalities, and presence of antiendomysial antibodies do not always coexist. New genetic loci and candidate genes that may contribute to the risk of celiac disease and its overlap with type 1 diabetes mellitus have been identified. Novel deamidated gliadin peptides antibodies have better diagnostic accuracy over native gliadin-based tests [Rubio-Tapia and Murray, 2009].

The exact relation between gluten sensitivity, as judged by high antigliadin antibodies, intestinal pathology, and the antibodies that correlate with mucosal damage (antiendomysium and anti-tissue transglutaminase antibodies) and neurologic disease, is hard to define. It is not clear whether gluten sensitivity can cause cerebellar degeneration or other neurologic symptoms. Antigliadin antibodies are not specific for neurologic symptoms associated with celiac disease and also have been described in a variety of CNS and autonomic nervous system diseases, including neuropathy, and cerebellar ataxia. Their presence in patients with neurologic disease (i.e., ataxia) may not necessarily prove the presence of gluten sensitivity [Hadjivassiliou et al., 2003; Wills and Unsworth, 2002].

CNS antineuronal antibodies are found more frequently in celiac disease patients with neurologic symptoms, suggesting their etiological importance. In a large series of adult patients (n = 160), CNS antineuronal antibodies were found in 8 of 13 (61 percent) patients with neurologic manifestations, compared to only 1 of 20 (5 percent) patients without neurologic disease and none of the controls [Volta et al., 2002]. A study by Pratesi et al. [1998] found serum antibodies reacting with human brain vessels in untreated celiac disease patients with neurologic involvement. This interaction decreased significantly after a gluten-free diet. These findings support the hypothesis that neurologic involvement in celiac disease is the consequence of an autoimmune mechanism mediated by antineuronal antibodies [Hadjivassiliou, 1996].

Neuropathologic findings in celiac disease patients, including cerebellar lymphocytic infiltration, Purkinje cell loss, and posterior column damage, support an autoimmune etiology for the neurologic abnormalities [Wills, 2000; Hadjivassiliou et al., 1998]. Neuropathology in an adult with a pancerebellar syndrome consisted of cerebellar and basal ganglia cell loss and fibrillary gliosis. Abnormalities also have been described in the cortex, spinal cord, and muscle [Steinberg and Frank, 1993]. In a study of patients with celiac disease and neuropathy, antiganglioside antibodies were found in 65 percent of 20 patients. These antibodies bind to the Schwann cell surface, nodes of Ranvier, and axons in the peripheral nerves [Chin et al., 2003]. This suggests that autoimmune mechanisms are likely responsible for the neuromuscular symptoms described in this condition.

It also has been suggested that the neurologic abnormalities in celiac disease are due to vasculitis involving the vascular endothelium, possibly mediated by tissue transglutaminase, an enzyme considered important to the maintenance of vascular endothelial integrity [Kim et al., 2002]. This enzyme is present in the brain, being most abundant in the caudate, putamen, and substantia nigra, and antiendomysial antibody has been reported to immunofluoresce with cerebral vasculature [Pratesi et al., 1998]. The neurologic abnormalities therefore may be the result of vascular or inflammatory disease. A few cases of biopsy-proven CNS vasculitis have been described [Ozge et al., 2001], as well as cerebrospinal fluid (CSF) oligoclonal bands, myelin loss, and lymphocytic infiltration [Ghezzi and Zaffaroni, 2001].

Patients with celiac disease and villous atrophy improve after withdrawal of gluten from their diet. Neurologic abnormalities can be present before the appearance of celiac disease symptoms and may progress despite a gluten-free diet. In general, there is no evidence that a gluten-free diet or vitamin supplementation reverses the neurologic abnormalities, although, in an adult series by Volta et al. [2002], neurologic symptoms improved or disappeared in 7 of 13 individuals who started a gluten-free diet within 6 months of onset and in none of the 4 patients who started later. Similarly, in a follow-up study of children with the disease, there appeared to be a greater frequency of symptoms in the group following an unrestricted diet [Bardella et al., 1994]. Neurologic complications, specifically epilepsy with cerebral calcifications, occurred only in patients who were not treated. Improvement may follow gluten restriction in some patients with peripheral neuropathy or myopathy.

Inflammatory Bowel Disease

Inflammatory bowel diseases (IBD), including Crohn’s disease (regional enteritis) and ulcerative colitis, occur infrequently in children. Crohn’s disease is a chronic, inflammatory process that affects any region of the gastrointestinal tract, mostly the small bowel, in a discontinuous fashion [Hyams, 1996]. Inflammation involves all layers of the bowel. Patients complain of diarrhea, rectal bleeding, abdominal pain, vomiting, and weight loss. Therapy includes anti-inflammatory agents, corticosteroids, and supportive nutritional therapy [Justinich and Hyams, 1994]. Ulcerative colitis is a chronic relapsing inflammatory disease involving the mucosa of the colon and rectum in a continuous manner [Kirschner, 1996].

Both conditions often involve organs other than the gastrointestinal tract, producing extraintestinal symptoms in about 25–35 percent of patients. Neurologic manifestations are rare, occurring in about 3 percent of patients, and are dominated by CNS vascular complications, including arterial occlusion, vasculitis, and encephalopathy [Lossos et al., 1995; Mezoff et al., 1990], mononeuropathies, and abnormalities of the white matter. Incriminating mechanisms either are directly related to the disease (vitamin B12 or folate deficiency or an autoimmune vasculitis), or are secondary to long-term treatment with metronidazole [El Moutawakil et al., 2007]. The majority of patients experience the onset of neurologic symptoms within the first 5–6 years after the onset of IBD symptoms [Lossos et al., 1995]. Differentiating the true extraintestinal manifestations of IBD from secondary extraintestinal complications caused by malnutrition, chronic inflammation, or side effects of therapy can be difficult. The etiology of both diseases remains unknown, although they probably are of immune origin.

Radiologic findings include arterial occlusion, sagittal sinus thrombosis, and cerebral arteritis. A clinical syndrome mimicking migraine with recurrent neurologic deficits has been reported. In this report, MRI demonstrated multiple acute, subacute, and chronic ischemic lesions in different vascular territories, and MRI and CT angiography demonstrated evidence of vasculitis. Cases of patients diagnosed with IBD, who developed neurologic symptoms with corresponding lesions in the white matter of the CNS, also have been described [de Lau et al., 2009].

Myelopathy, myopathy, myasthenia gravis, and inflammatory demyelinating motor neuropathy also have been reported. Peripheral neuropathy and disturbed autonomic functions occur infrequently in patients with long-standing Crohn’s disease [Lindgren et al., 1991].

The pathophysiology of the neurologic manifestations is not known, but elevated factors V and VIII levels and decreased antithrombin 3 are characteristic of IBD. Myopathy in Crohn’s disease may be immunologically mediated and may lessen with improvement of the disease [Shimoyama et al., 2009].

Similarly to the situation in Crohn’s disease, three major pathogenic entities can be differentiated in ulcerative colitis:

There are similarities between ulcerative colitis-associated disorders of the white matter and acute disseminated encephalomyelitis (ADEM). Seizures, unspecified encephalopathies, and confusional states may be symptomatic and secondary to the underlying disease process [Scheid and Teich, 2007]. Epilepsy has been reported in patients with ulcerative colitis in the context of steroid taper, fasting, and abdominal surgery [Akhan et al., 2002].

Enteric Infections

Enteric viruses and bacteria that cause primary CNS infection are reviewed in Chapters 8082. A variety of systemic viral and bacterial infections may cause an encephalopathy resulting from the presence of endotoxins or electrolyte and fluid disturbances. Some of the more well-recognized entities are reviewed in this section.

Seizures and encephalopathy in infants with enteric infections and diarrhea can be caused by hyponatremia or hypernatremia. Hyponatremia may cause brain swelling because sodium and chloride ions cross the brain capillaries slower than water. Treatment consists of rehydration with adequate sodium salts and avoidance of more dilute fluids.

Hypokalemia can accompany diarrhea and cause neuromuscular manifestations, including hypotonia, diminished bowel sounds, weakness, lethargy, abdominal distention, and in severe cases, rhabdomyolysis and myoglobinuria. Neuromuscular manifestations become more prominent with serum potassium levels lower than 3 mEq/L. Severe hypokalemia occurs more frequently in children younger than 24 months and in infants receiving dextrose-containing intravenous fluids without electrolyte replacement, and is related to the type of rehydration therapy [Chhabra et al., 1995]. The exact mechanism by which hypokalemia causes muscle weakness still is unclear but it has been shown, in experimental models, to change the resting membrane potential, limit increases in blood flow in exercising muscles, and cause a reduction in muscle glycogen content.

Campylobacter jejuni

Campylobacter jejuni, a frequently identified bacterial cause of gastroenteritis, has been associated with Guillain-Barré syndrome and encephalopathy [Duret et al., 1991; Nasaralla et al., 1993]. There is some evidence that Guillain-Barré syndrome in these patients may be a more severe variant of the disease with predominantly axonal degeneration. Cross-reactivity between neural antigens and C. jejuni may be one of the mechanisms by which Guillain-Barré syndrome is triggered [Rees et al., 1993].

Nipah Virus

Nipah virus infection can produce a rapidly progressive, severe illness affecting the central nervous and respiratory systems [Hossain et al., 2008]. Neurologic sequelae are frequent following Nipah encephalitis. CNS disease frequently results in high case-fatality rates. Patients with encephalitis (32 percent overall) had persistent neurologic dysfunction, including static encephalopathy, oculomotor palsies, cervical dystonia, focal weakness, and facial paralysis. MRI abnormalities include multifocal hyperintensities, cerebral atrophy, and confluent cortical and subcortical signal changes. Behavioral abnormalities were reported by caregivers in over 50 percent of subjects under the age of 16 years. The onset of neurologic abnormalities can be delayed and new neurologic dysfunction may develop after the acute illness. Survivors of Nipah virus infection may experience substantial long-term neurologic and functional morbidity [Sejvar et al., 2007].

Infant Botulism

Infant botulism is a disease of young infants caused by the release of toxins (either type A, B, or E) produced by several anaerobic, Gram-positive bacteria, including Clostridium botulinum, Clostridium baratii, or Clostridium butyricum [Fox et al., 2005]. The botulinum toxins (BoNTs) are among the most poisonous biological substances. In a recent clinical report reviewing all cases of infant botulism poisoning over the past 30 years in a major U.S. city [Underwood et al., 2007], the two principal pathogenic serotypes identified were BoNT/A (40 percent of cases affecting mostly older infants) and BoNT/B (60 percent of cases affecting mostly younger infants). The neurotoxic effects of the disease are produced because of presynaptic blockage of the neuron’s neuroexocytosis of acetylcholine and disruption of acetylcholine transmission. The toxin blocks acetylcholine release by impairing calcium influx associated with membrane depolarization and causes an acute reversible motor unit disease. The toxin effect can last many weeks or months, depending on the BoNT’s serotype. At postsynaptic sites, BoNTs can also block transmission of action potentials by affecting the motor end-plate nicotinic receptors.

Infant BoNT infections typically occur between 2 weeks and 1 year of life (median 10 weeks). Initial symptoms can be severe, including constipation, cranial nerve deficits, pupillary involvement, generalized weakness and hypotonia, loss of deep tendon reflexes, and flaccid paralysis of striated skeletal muscles, including the diaphragm, which can lead to respiratory failure and death [Arnon, 1992; Cochran and Appleton, 1995; Hatheway, 1995]. Autonomic dysfunction also is common, and may cause constipation, dysphagia, reduced lacrimal and salivary secretions, impaired visual accommodation, and heart rate dysregulation [Patural et al., 2009].

Affected infants have a history of lethargy, irritability, poor feeding, constipation, and generalized weakness of 12 hours’ to 7 days’ duration. Examination reveals ophthalmoplegia with sluggish pupillary responses, as well as cranial nerve VII, IX, X, and XI abnormalities. Severe cases can present with areflexive flaccid coma or apnea, requiring prolonged ventilation. Botulinum neurotoxin can be detected in serum, and confirms the diagnosis. Progressive respiratory failure occurs in many patients, requiring prolonged periods of mechanically assisted ventilation, and is the cause of potential major morbidity. Other symptoms of autonomic dysfunction include delayed gastric emptying and a paralytic ileus. There usually are no major cardiovascular symptoms. However, there can be cardiac dysautonomia, manifested by a major decrease in all heart-rate variability indices, which may persist for weeks beyond observable physical recovery. The recovery of gastrointestinal motility is progressive and usually complete.

Repetitive nerve stimulation studies document an unusual incremental response, and electromyography demonstrates a distinctive pattern consisting of brief, small, motor unit potentials. Treatment is supportive, focusing primarily on the need to maintain adequate ventilation and nutrition in a critical care setting. Evaluation and treatment of botulism is further reviewed in Chapter 91.


Shigellosis is an acute bacterial enteritis caused by Shigella bacteria, and is characterized by intestinal and extraintestinal symptoms. Shigellosis has a worldwide distribution, but the majority of cases occur in developing countries. Sixty-nine percent of all episodes and 61 percent of all Shigella-related deaths involve children younger than 5 years of age. The mainstay of treatment is correction of fluid and electrolyte loss. Appropriate antibiotic therapy shortens the duration of clinical symptoms and fecal excretion of the pathogen. However, the increasing antimicrobial resistance of shigellae worldwide constitutes an international health problem [Ashkenazi, 2004].

Neurologic manifestations of dysentery caused by Shigella organisms are common and include convulsions, meningismus, headache, and, infrequently, an encephalopathy, with lethargy, confusion, hallucinations, delirium, or mutism [Selimoglu et al., 1995]. The Klüver–Bucy syndrome was described in a child suffering from Shigella encephalopathy [Guedalia et al., 1993]. Septic shock is a very unusual presentation of Shigella infection and can occur in young children, with symptoms including a severe encephalopathy [Beigelman et al., 2002]. Neurologic manifestations may appear before the onset of diarrhea and other gastrointestinal symptoms. Although seizures and encephalopathy usually are benign and rarely recur or have permanent sequelae [Ozturk et al., 1996], complications of shigellosis encephalopathy [van Dongen et al., 1993] and cases of severe fatal encephalopathy have been described. CT may demonstrate cerebral edema. Hemorrhage, demyelination, and brain necrosis have been reported in patients with Shigella-related fatal encephalopathy [Perles et al., 1995].

The mechanisms responsible for the neurologic complications of shigellosis have not been defined clearly. Some manifestations, especially seizures, may be related to fever. In the past, neurologic symptoms were attributed to the neurotoxicity of the shiga-toxin but it is thought that the role of this toxin is not essential and that other toxic products may be involved [Ashkenazi et al., 1990].

Seizures are the most common neurologic complication of shigellosis, occurring in 12–45 percent of hospitalized patients with culture-proven shigellosis; they are most common in children between 6 months and 4 years of age [Hiranrattana et al., 2005; Daoud et al., 1990]. The high incidence of seizures was found in studies that usually included children with severe shigellosis. By contrast, data collected from a well-defined pediatric population and over a prolonged period suggest that seizures are less common [Galanakis et al., 2002]. About 25 percent of children with seizures during shigellosis infection had a history of previous febrile seizures. A study of 55 children with Shigella organism-associated convulsions, who were followed for 6.9–14.1 years, found that none had subsequent nonfebrile seizures and only two had subsequent febrile seizures [Lahat et al., 1990]. Therefore, no chronic antiepileptic drug therapy is indicated [Ozturk et al., 1996]. It was suggested that corticotropin-releasing hormone plays a role in the increased susceptibility to seizures following exposure to Shigella dysenteriae [Yuhas et al., 2004]. Tumor necrosis factor-α, at high concentrations, may exert a suppressive effect on Shigella-mediated seizures [Yuhas et al., 2003].

Rotavirus Infection

Enteric rotavirus infection causing gastroenteritis with concomitant afebrile seizures has been described in infants [Lin et al., 1996; Tsai and Cho, 1996]. Transient electroencephalography (EEG) abnormalities also have been reported. Seizures did not recur, and no long-term anticonvulsant therapy was prescribed in these patients. Direct inoculation of three strains of rotavirus, including human rotavirus strain 2, into monkey brain caused a neurologic syndrome including transient paresis, with pathologic evidence of viral invasion of the CNS. The fact that rotavirus also causes exanthems in 4 percent of patients suggests that infection causes generalized viremia. It is possible that the virus invades the CNS hematogenously [Contino et al., 1994].

Other Gastrointestinal Diseases

Whipple’s Disease

Whipple’s disease is a chronic, multisystemic, bacterial, inflammatory systemic disorder. The disease is named after George H Whipple who, in 1907, was the first to describe an intestinal “lipodystrophy.” It is caused by a soil-borne, Gram-positive bacillus – Tropheryma whipplei [Panegyres, 2008]. It is a rare disease that is misdiagnosed frequently. It is described primarily in adults and is manifested clinically by intestinal features that include loss of weight, diarrhea, malabsorption, and abdominal pain, as well as polyarthritis, lymphadenopathy, cardiopathy, hyperpigmentation, hypotension, and cardiovascular, pulmonary, and neurologic dysfunction [Jovic and Jovic, 1996].

Jejunal biopsy reveals macrophages filled with glycoprotein granules that are positive with periodic acid–Schiff (PAS) staining. PAS-positive macrophages also have been identified in other body tissues, including the CNS. The presence of PAS-positive macrophages in biopsy specimens and demonstration of T. whippeli by electron microscopy are diagnostic signs of active Whipple’s disease.

Although Whipple’s disease generally is recognized as a multisystem chronic granulomatous disease, primarily involving the digestive system, up to one-third of patients demonstrate signs of neurologic involvement. On occasion, Whipple’s disease also can present as a primary neurologic disorder. Neurologic manifestations include progressive dementia, external ophthalmoplegia, myoclonus, seizures, ataxia, hypothalamic dysfunction (sleep disorders, hyperphagia, polydipsia), and meningitis [Alba et al., 1995; Jovic and Jovic, 1996; Perkin and Muray-Lyon, 1998]. Oculomasticatory myorhythmia, possibly caused by brainstem tegmental abnormalities, is a movement disorder nearly unique to patients with Whipple’s disease. It consists of rhythmic convergence of the eyes and synchronous contractions of the eyelids, jaw, face, and neck, with characteristics resembling spinal myoclonus. A review of 84 cases of CNS Whipple’s disease revealed that 80 percent of patients had systemic signs. Cognitive changes were frequent (71 percent), and 47 percent of the patients with cognitive changes also had psychiatric signs. Oculomasticatory myorhythmia and oculo-facial-skeletal myorhythmia, pathognomonic for CNS Whipple’s disease, were present in 20 percent of patients and were always accompanied by a supranuclear vertical gaze palsy. Tissue biopsy was a sensitive technique; 89 percent of those who had biopsies had positive biopsy results.

Brain CT and MRI may be normal, but may show cortical or subcortical atrophy, hydrocephalus, and focal or multiple nodular enhancing lesions, including low-density focal lesions in the pontine tegmentum and temporal lobe [Schnider et al., 1995].

Increased protein and lymphocytic pleocytosis are detected in the CSF of patients with the disease. PAS-positive cells have been found in brain biopsy material.

Diagnosis can be confirmed by the finding of a positive polymerase chain reaction (PCR) test for T. whipplei in blood or CSF [Panegyres et al., 2006]. The CSF can sometimes contain PAS-positive macrophages. The diagnosis and treatment of definite CNS Whipple’s disease should be based on the presence of pathognomonic signs (oculomasticatory myorhythmia or oculo-facial-skeletal myorhythmia) and a positive biopsy or PCR result [Louis et al., 1996]. In the presence of clinical suspicion of CNS Whipple’s disease, PCR should be performed on the CSF and blood, even if the brain MRI is normal. Sometimes, brain biopsy may be necessary if the diagnosis is still suspected and the PCR is negative.

The disorder responds to antibiotic therapy. Without extended antibiotic treatment, the course of Whipple’s disease can be fatal. Medications include cotrimoxazole (trimethoprim-sulfamethoxazole). Third-generation cephalosporins, as well as penicillin and streptomycin, can be effective in patients who do not respond to trimethoprim-sulfamethoxazole [Panegyres, 2008; Alba et al., 1995]. Appropriate therapy, instituted early in the course of the disease and for an adequate time period, is associated with a better neurologic outcome. CNS relapse may be resistant to treatment. In cases with high clinical suspicion, in which Whipple’s disease cannot be diagnosed with procedures such as jejunal biopsy, antibiotic therapy is recommended. Recovery of established neurologic deficit may occur rarely [Jovic and Jovic, 1996].


The porphyrias are a heterogenous group of metabolic disorders characterized by abnormal heme biosynthesis. The abnormalities involve porphyrin metabolism in the metabolic pathway that converts glycine and succinyl-CoA to heme [Tefferi et al., 1994]. Every porphyria subtype is caused by abnormal function of a separate enzymatic step, resulting in a specific accumulation of heme precursors. The critical enzyme is a mitochondrial enzyme, gamma-aminolevulinic acid synthetase. Accumulation of the heme precursor, delta-aminolevulinic acid, is associated with the neurologic manifestations, and accumulation of photoreactive byproducts, the porphyrins, causes cutaneous photosensitivity and dermatopathic manifestations [Bont et al., 1996; Ellefson and Ford, 1996; Lockwood, 1995]. The hepatic porphyrias are transmitted genetically as autosomal-dominant disorders with variable expression. Although all subtypes are rare, acute intermittent porphyria (AIP) is the most common form of the neuroporphyrias. It manifests with occasional neurovisceral crises due to overproduction of porphyrin precursors, such as aminolevulinic acid (ALA), which is released from the liver into the circulation. More than 60 mutations causing AIP have been found [Schreiber, 1995]. The degrees of expression range from mild to severe, and acute episodes of neuropathic porphyrias can progress to paralysis and life-threatening respiratory failure. Although porphyria patients carry genetic defects and mutations, the manifestation of neuropsychiatric symptoms in hepatic porphyria patients is triggered by precipitating factors, including various drugs, hormones, fasting, and other agents. All precipitating factors can increase the demand for hepatic heme and induce the production of δ-aminolevulinic acid synthase (ALAs), which is the rate-limiting enzyme in the heme biosynthetic pathway. Depletion of free heme and the accumulation of heme precursors, such as δ-ALA and porphobilinogen, are responsible for neuropsychiatric manifestations seen acutely [Anderson et al., 2005; Satoh et al., 2008].

Acute porphyrias present with acute attacks, typically consisting of severe abdominal pain, nausea, constipation, polyneuropathy mental symptoms, confusion, and seizures, and can be life-threatening. Porphyrias are rare and sometimes are misdiagnosed because various symptoms and signs mimic other diseases. Screening of porphyrin metabolites in neurologic patients with acute polyneuropathy or encephalopathy associated with pain or dysautonomia reveals the presence of urinary porphyrins and their precursors in 21 percent of cases. Cutaneous porphyrias present with either acute painful photosensitivity or skin fragility and blisters.

In general, presentation in childhood is uncommon [Parsons et al., 1994]. Rare recessive porphyrias usually manifest in early childhood with either severe cutaneous photosensitivity and chronic hemolysis, or chronic neurologic symptoms with or without photosensitivity.

Symptoms include features of autonomic neuropathy, including severe abdominal pain, vomiting, constipation, hypertension, tachycardia, and bladder dysfunction [Gupta and Dolwani, 1996]. Other symptoms are those of peripheral axonal neuropathy, including motor weakness and sensory involvement that correlate with peripheral axonal neuropathy, and neuropsychiatric symptoms. Acute porphyric neuropathy predominantly involves the motor system and can be manifested by symptoms, signs and CSF abnormalities resembling acute Guillain-Barré syndrome [Suarez et al., 1997; Barohn et al., 1994; Albers and Fink, 2004], causing confusion with this order.

The pathogenesis or porphyric neuropathy is complex, but overproduction of ALA via direct neurotoxicity, oxidative damage, and modification of glutamatergic release may initiate the neuronal damage.

Acute encephalopathy in patients with hepatic porphyria is manifested as a combination of neuropsychiatric symptoms, including confusion, anxiety, depression, and insomnia, with seizures, the syndrome of inappropriate antidiuretic hormone secretion (SIADH), and, rarely, focal CNS deficits, such as aphasia, hemiparesis, and visual field abnormalities [Crimlisk, 1997; Bylesjo et al., 1996], along with abdominal pain and peripheral neuropathy. In rare instances, patients have presented with acute cortical blindness [Wessels et al., 2005]. Psychotic symptoms during an AIP attack have been reported [Altintoprak et al., 2009]. Structural brain abnormalities, demonstrated on neuroimaging, are uncommon. MRI ischemic lesions also have been reported [Gurses et al., 2008]. Posterior reversible encephalopathy syndrome has been found in patients with severe encephalopathy on MRI acquired during an acute attack, and could explain the pathogenesis of encephalopathy and seizures in AIP.

In general, the underlying mechanisms causing symptoms have remained poorly understood, partly due to lack of a suitable animal model [Satoh et al., 2008]. Two hypotheses, the possible neurotoxicity of δ-ALA and heme deficiency in the nervous tissue, have been suggested. The present evidence suggests that multiple mechanisms interact in causing the varied symptoms, including ALA interaction with gamma-aminobutyric acid (GABA) receptors, altered tryptophan metabolism, and, possibly, heme depletion in nerve cells [Meyer et al., 1998]. Neurologic manifestations are nonspecific, and careful interpretation of abnormal excretion of porphyrin precursors should be done before symptoms can be related to the inherited acute porphyrias.

Currently, the prognosis of neuropathy and encephalopathy in AIP is good, even in severe attacks, but the variability of symptoms may interfere with the diagnosis of AIP. Physicians should be aware of a potentially fatal outcome of the disease or long-term permanent neurologic damage [Pischik and Kauppinen, 2009].

Diagnosis is essential to enable specific treatments to be started as soon as possible. Biochemical analyses detect porphyrins and their precursors from blood, urine, or feces.

Measurement of urinary porphobilinogen is the best biochemical test for AIP, although it is nonspecific and does not distinguish AIP from other acute porphyrias. Therefore, identification of acute porphyria also requires heightened clinical awareness, a good medical history, and a careful evaluation of signs and symptoms during an acute attack, along with access to urinary porphobilinogen measurement [Elder and Sandberg, 2008

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