enteric autoantibodies and gut motility disorders

Gastroenterol Clin N Am 37 (2008) 397–410

GASTROENTEROLOGY CLINICSOF NORTH AMERICA

Enteric Autoantibodies and GutMotility Disorders

Purna Kashyap, MBBSa,b,d, Gianrico Farrugia, MDa,b,c,d,*aEnteric NeuroScience Program, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USAbDivision of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW,Rochester, MN 55905, USAcDepartment of Physiology and Biomedical Engineering, Mayo Clinic, 200 First Street SW,Rochester, MN 55905, USAdMiles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic, 200 First Street SW,Rochester, MN 55905, USA

Asmall proportion of patients with occult or established neoplasms

develop a gastrointestinal motility disorder, referred to as paraneoplas-tic dysmotility. The diagnosis of paraneoplastic dysmotility requires the

onset of gastrointestinal dysmotility associated with the presence of a tumorand specific serum antibodies. In these patients, a humoral immune responseinvolving circulating anti-neuronal antibodies is commonly seen. The exactmechanism by which these antibodies are generated is unclear. They areknown to target onconeural antigens shared by enteric neurons and tumorcells, suggesting that the antibody is generated against the tumor antigen withthe enteric neuron as the ‘‘innocent’’ bystander [1]. The antigens for theseantibodies may be localized to the nucleus, plasma membrane, or cytoplasm.

ANTIBODIES ASSOCIATED WITH PARANEOPLASTICAND IDIOPATHIC DYSMOTILITY
ANNA-1 (Anti-Hu) The most common neuronal autoantibody associated with paraneoplastic dys-motility is the type 1 anti-neuronal nuclear antibody (ANNA-1) [1,2]. ANNA-1recognizes the nuclear protein Hu, which belongs to a family of conservedRNA binding proteins that includes HuC, HuD, HuR, and Hel-N1. Theseproteins are expressed in the neurons of the central, peripheral, and enteric ner-vous system, with the exception of HuR, which is ubiquitously expressed in
This work was supported by grants DK57061, DK52766, and P01 DK 68055 from the National Institutesof Health.

*Corresponding author. Division of Gastroenterology and Hepatology, Mayo Clinic,200 First Street SW, Rochester, MN 55905. E-mail address: [email protected](G. Farrugia).

0889-8553/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.doi:10.1016/j.gtc.2008.02.005 gastro.theclinics.com

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398 KASHYAP & FARRUGIA

proliferating cells [3]. The tumor that most commonly expresses ANNA-1 issmall cell lung cancer [4]. Other tumors that may express ANNA-1 includebreast, prostate, ovarian carcinomas, and lymphomas [5]. Antibodies toANNA-1 are consequently most commonly found in patients with small celllung cancer with associated paraneoplastic gastrointestinal dysmotility. Al-though there is a strong association between the presence of ANNA-1 in thesetting of a gastrointestinal motility disorder and the presence of an occult ormanifest tumor, the exact mechanism by which ANNA-1 antibodies causeenteric neuronal dysfunction remains unclear, because the proteins to whichthe antibody is directed are not expressed on the cell membrane. Nevertheless,there is some evidence that the antibodies may directly influence motility.A preliminary study in guinea pig ileum has suggested that anti-Hu antibodiesimpair the ascending excitatory reflex and therefore peristalsis. Enteric neuro-nal degeneration has also been reported in patients with paraneoplastic dysmo-tility as a possible pathogenetic mechanism [6]. Anti-HuD–positive sera frompatients with a paraneoplastic gut dysmotility disorder as well as commercialanti-HuD antibodies have been shown to induce apoptosis in a human neuro-blastoma cell line (SH-Sy5Y) as well as guinea pig cultured myenteric neurons.It was further demonstrated that the apoptosis was dependent on mitochon-dria, as evidenced by the specific activation of effector caspase-3 and the cyto-chrome c–dependent proapoptotic messenger apaf-1 [7]. Mitochondrialdysfunction leading to subsequent neuronal injury is well described and hasalso been implicated in dorsal root ganglion apoptosis in streptozocin-induceddiabetes in rats [8]. Pardi and colleagues [9] described a patient with suddenonset of gastroparesis and small bowel dysfunction and the presence of highcirculating levels of ANNA-1. This patient was subsequently found to havedecreased and disorganized interstitial cells of Cajal networks and a smallcell lung cancer expressing c-Kit, also expressed on interstitial cells of Cajal.

Another nuclear autoantigen associated with disease is Ri, expressed in neu-rons of the central nervous system, small cell lung cancer, and some breastcancer cells [10]. Formation of type 2 anti-neuronal nuclear antibodies(ANNA-2 or anti-Ri) is far less common than the formation of anti-Hu andis usually associated with neurologic symptoms from midbrain, brain stem, cer-ebellar, or spinal cord dysfunction [11]. ANNA-2 has not been associated withgastrointestinal dysmotility.

Calcium Channel Antibodies
The second most commonly reported antibodies in patients with paraneoplas-tic dysmotility target voltage-activated calcium channels. Calcium channelswere originally classified based on pharmacology as L, N, P/Q, R, and T chan-nels, a classification still used today. This classification corresponds to thecurrent accepted nomenclature that classifies voltage-gated Ca2þ channelsinto Cav1.1-Cav1.4 (L-type Ca2þ channels), Cav2.1 (P/Q), Cav2.2 (N),Cav2.3 (R), and Cav3.1-Cav3.3 (T) based on the amino acid sequence of thealpha 1 subunit (the pore-forming subunit) of the channel. P- or Q-type calcium

399ENTERIC AUTOANTIBODIES AND GUT MOTILITY DISORDERS

ion channels regulate acetylcholine release at the neuromuscular junction aswell as central neurotransmission. N-type calcium channels are particularly in-volved in cerebrocortical, cerebellar, spinal, and autonomic neurotransmission.Both channel types are expressed in small cell lung cancer and are common tar-gets of autoantibodies in such patients. These antibodies are predominantlyseen in patients with Lambert-Eaton myasthenic syndrome in associationwith small cell lung cancer [12]. Antibodies to P/Q- and N-type calcium chan-nels are found in some patients with paraneoplastic dysmotility, and their pres-ence should trigger a targeted search for an occult malignancy; however, theseantibodies are less frequently found when compared with ANNA-1 antibodies,and their association with the eventual finding of a malignancy in the setting ofa gastrointestinal motility disorder is not as strong as for ANNA-1. These an-tibodies may coexist with ANNA-1.

Nicotinic Acetylcholine Receptors
Another class of autoantibodies associated with gastrointestinal dysmotility isdirected against neuronal nicotinic acetylcholine receptors. Antibodies directedtoward the extracellular segment of acetylcholine receptor protein in the postsyn-aptic membrane of skeletal muscle are found in patients with myasthenia gravisassociated with thymic epithelial tumors [13]. Neuronal nicotinic acetylcholine re-ceptors are also present on neurons in the sympathetic and parasympathetic ner-vous systems as well as the enteric nervous system. Antibodies targeting thisprotein can disrupt cholinergic synaptic transmission leading to autonomic fail-ure. These antibodies are seen in both idiopathic and paraneoplastic forms ofautonomic neuropathy resulting in autoimmune autonomic neuropathy [14]. Pa-tients with ganglionic receptor blocking antibodies often manifest with symptomsof gastrointestinal dysmotility, abnormal pupillary response, and subacute onsetof autonomic neuropathy [15]. This antibody is of use to differentiate autoim-mune autonomic neuropathy from degenerative autonomic neuropathy, whichis often more insidious and not usually associated with gastrointestinal manifes-tations. It is important to make this distinction because the diagnosis affects theprognosis and therapy. Degenerative autonomic neuropathy is a slowly progres-sive disorder, whereas autoimmune autonomic neuropathy can be life threaten-ing and often responds to therapy such as immunomodulators [15]. Neuronalnicotinic acetylcholine receptor antibodies are most likely directly pathogenicbecause their levels correspond to the severity of autonomic dysfunction, and be-cause a decrease in their level is accompanied by clinical improvement [15].Symptoms of autonomic failure can also be induced experimentally by passivetransfer of antibodies. Mice injected with rabbit IgG containing ganglionic acetyl-choline receptor antibodies develop gastrointestinal dysmotility and autonomicdysfunction. Similar results are obtained by injecting mice with sera from patientswith ganglionic acetylcholine receptor antibody [16].
Purkinje Cell Cytoplasmic Autoantibody, Type 1
Purkinje cell cytoplasmic autoantibody, type 1 (PCA-1) (sometimes called‘‘anti-Yo’’) targets a neuronal signal transduction protein Cdr. The antibody


was originally defined as a marker of paraneoplastic cerebellar degenerationrelated to ovarian or breast carcinoma with remarkably limited metastasis[17,18]. In vitro, its Cdr antigen, a prominent cytoplasmic component of largeneurons in the central and autonomic/enteric nervous systems [19], has beenshown to promote neuronal apoptosis and degeneration by inhibiting c-myctranscriptional activity [20]. Paraneoplastic gastrointestinal dysmotility hasbeen documented in a minority of PCA-1–seropositive patients (with and with-out cerebellar ataxia) in association with gynecologic or breast carcinoma [21].

Other Autoantibodies
Antibodies have also been detected against other cytoplasmic antigens such asamphiphysin, present on the cytoplasmic side of the synaptic vesicle membrane[22]. Anti-striational autoantibody targets the skeletal muscle proteins actinin,alpha actin, myosin, titin, and ryanodine receptor [23,24]. They may be seenin patients with myasthenia gravis associated with thymoma [25] and paraneo-plastic neurologic disorders with primary lung cancer but are usually not asso-ciated with gastrointestinal dysmotility [13]. Voltage-gated potassium channelautoantibodies have been reported in rare patients with slow transit constipa-tion [26] and in a patient with diarrhea-predominant irritable bowel syndrome[27]. Their significance is currently unknown. Likewise, glutamic acid decar-boxylase-65 (GAD) antibodies have been reported in a significant percentageof patients with achalasia, but, again, this finding is currently of uncertain path-ogenetic significance [28].
CLINICAL PRESENTATION OF A PARANEOPLASTICDYSMOTILITY SYNDROMEParaneoplastic dysmotility of the gastrointestinal tract is often manifested asesophageal dysmotility (pseudoachalasia), gastroparesis, intestinal pseudo-obstruction, or constipation. Patients frequently present with a dominantsymptom but often have pan-gut involvement. In patients who have hada full thickness biopsy, all had an inflammatory lymphocytic and plasma cellinfiltrate of the myenteric plexus and loss of ganglion cells. The smooth musclelayers are often spared [29–31].

Pseudoachalasia
Pseudoachalasia accounts for about 2% to 4% of all cases that have the mano-metric criteria of incomplete or absent relaxation of the lower esophagealsphincter seen in true achalasia. Most patients with pseudoachalasia have a pri-mary tumor at the gastroesophageal junction [32,33]. This form of pseudoacha-lasia is not a form of paraneoplastic dysmotility, because it is usually due toobstruction of the lower esophageal sphincter by the tumor or direct involve-ment of myenteric plexus with the neoplastic cells. Nevertheless, depletion ofganglion cells in the dorsal nucleus of the vagus nerve as a consequence of neu-ronal degeneration distant to primary tumor can occur [34]. In a small propor-tion of patients, there is no evidence of neoplastic involvement of thegastroesophageal junction, but they demonstrate anti-neuronal antibodies,


most often ANNA-1 [35,36]. Liu and colleagues [36] described a case series of13 patients with pseudoachalasia in which eight patients had direct infiltrationof the esophageal wall and involvement of the myenteric plexus. The totalnumber of ganglion cells was normal, and it is unclear how the neoplastic cellsaltered ganglion cell function. In the same series, they described a patient withsmall cell lung cancer and lymph node metastasis with achalasia-like symptomsbut no radiographic or histologic involvement of the esophagogastric junction.The patient had ANNA-1 antibodies, suggesting a paraneoplastic dysmotility.Histologically, there was complete absence of myenteric ganglion cells andboth perineural and intraneural lymphocytic infiltration. Lee and colleagues[21] published a series of 12 cases in which esophageal dysmotility was seenin four patients with small cell lung cancer. Two patients had pseudoachalasia,one had a nonspecific esophageal motility disorder, and one had abnormal ma-nometry but no esophageal symptoms.

Paraneoplastic Gastroparesis
Gastroparesis is characterized by reduced emptying of gastric content, oftenassociated with decreased gastric motility. The presentation of gastroparesis of-ten includes nausea, vomiting of food consumed several hours earlier, bloating,epigastric fullness, and the finding of retained gastric contents on endoscopy.Gastroparesis was reported to be the most common paraneoplastic syndromeassociated with ANNA-1 antibodies by Lucchinetti and colleagues [5]. As istrue for other paraneoplastic gastrointestinal dysmotilities, paraneoplastic gas-troparesis is commonly associated with small cell lung cancer [37]; however,it has also been reported in association with other tumors, including pancreaticcancer with no other identifiable cause [38,39]. It has been described in a patientwith untreated breast cancer in whom improvement occurred with cisaprideand chemotherapy and resulting tumor remission [40]. It is not possible to con-clude whether the patient’s symptoms improved with the prokinetic therapy ortreatment of the underlying tumor, but it is more than likely that a paraneoplas-tic dysmotility responds to treatment of the underlying tumor. Gastroparesishas also been reported in a patient with retroperitoneal leiomyosarcoma withno evidence of local invasion or metastasis and resolved completely after resec-tion of the tumor [41]. As described previously, Pardi and colleagues [9]reported a patient with small cell lung cancer with both ANNA-1 and P/Q-type calcium channel antibody with gastroparesis and a disrupted interstitialcell of Cajal network, suggesting that enteric neurons are not the only entericneural target of the paraneoplastic autoimmunity. Gastroparesis has also beenassociated with other autoantibodies, including ganglionic acetylcholine recep-tor antibodies. This finding was observed by Vernino and colleagues [15] ina patient with bladder cancer and also in patients with idiopathic gastroparesiswith no known antecedent risk factors and no underlying cancer. These obser-vations strongly suggest that the histologic nature of the underlying malignancydoes not always dictate a certain autoantibody formation or specific dysmotilitysyndrome.


Paraneoplastic Chronic Intestinal Pseudo-Obstruction
Chronic intestinal pseudo-obstruction is defined as recurrent episodes or persis-tent symptoms of bowel obstruction in the absence of mechanical obstruction.Most cases of chronic intestinal pseudo-obstruction are due to primary defectsin the contractile apparatus (nerves, interstitial cells of Cajal, smooth musclecells) of the gut or are secondary to an infiltrating disease such as amyloidosisor scleroderma [42–44]. Paraneoplastic intestinal pseudo-obstruction is mostoften reported in cases with small cell lung cancer and thymoma and is usuallyassociated with the presence of circulating ANNA-1 antibodies [45–49]. Therehave also been several case reports of patients with pseudo-obstruction withother primary cancers. Chronic intestinal pseudo-obstruction along with acha-lasia, gastroparesis, and constipation was reported in a patient with metastasiz-ing bronchial carcinoid [50]. Intestinal pseudo-obstruction associated withlymphoplasmacytic infiltration of the myenteric plexus and the presence ofANNA-1 antibodies was found in a patient about 1.5 years after removalof a paravertebral ganglioneuroblastoma [51]. Viallard and colleagues [52] re-ported a case of colonic dysmotility associated with antibodies against volt-age-gated potassium channels in a patient with invasive thymoma andacquired neuromyotonia, which improved after plasmapheresis.
As discussed previously, Lee and colleagues [21] published a case series of12 patients in which chronic intestinal dysmotility and acute colonic pseudo-obstruction were observed in patients with cancer and ANNA-1, PCA-1, oranti–N-type calcium channel antibodies. All of the patients with small celllung cancer had ANNA-1 antibodies, a patient with ovarian cancer was positivefor PCA-1 antibody, and a patient with lymphoma had N-type calcium channelantibody. Histologically, the ANNA-1 antibodies in these patients were reactivewith both nucleus and cytoplasm, as opposed to the findings in cases of idio-pathic colonic pseudo-obstruction, in which a predominant cytoplasmic stain-ing has been observed. Interestingly, in this study, the investigators observedthat the gastrointestinal dysmotility preceded the small cell lung cancer bya mean period of 8.7 months, whereas in the patients who had other malignan-cies, antibodies were found after the tumor diagnosis. These data suggest thatthe diagnosis of new onset gut dysmotility accompanied by the presence ofANNA-1 antibodies should prompt a search for occult small cell lung cancer.Even if the initial screen is negative, vigilance should be maintained in the sub-sequent years. It was also observed that the patients with colonic pseudo-obstruction and small cell lung cancer often had additional disease, includingperipheral, sensorimotor, or autonomic neuropathies, cerebellar degeneration,or encephalopathy.

Chronic Constipation
Chronic constipation without accompanying pseudo-obstruction is not a com-mon presentation of a paraneoplastic syndrome. Vernino and colleagues [15]reported constipation in two patients with ganglionic acetylcholine receptorantibody associated with thymoma and small cell lung cancer.


MANAGEMENT ALGORITHM FOR PARANEOPLASTICDYSMOTILITYCurrently, there is insufficient evidence to recommend a paraneoplastic anti-body profile for every patient with new onset of a gut motility disorder; how-ever, the presence of significant weight loss, a rapid onset of the disease, anda past or present smoking history should prompt the physician to considertesting for the presence of autoantibodies associated with paraneoplastic dys-motility. Several laboratories offer a paraneoplastic autoantibody profile. Inpatients testing positive for ANNA-1, together with the appropriate gastroin-testinal motility work-up, including tests to exclude obstruction, investiga-tions should be initiated to look for small cell lung cancer, becauseparaneoplastic dysmotility may precede the diagnosis of the primary malig-nancy in patients testing positive for ANNA-1 [21]. A reasonable strategyis to start with a CT of the chest. If it is negative, follow-up with a PETscan and directed biopsies of any suspicious lymph nodes or masses are in-dicated. In a subset of patients with a high suspicion of malignancy, if thework-up is negative, one may consider bronchoscopy followed by mediasti-noscopy to increase the diagnostic yield. An alternative strategy is to repeatCT of the chest at 6-month intervals for at least 1 year. Importantly, findingan alternate primary malignancy should not stop the search for possiblesmall cell lung cancer, because in nearly 13% patients, an unrelated primarymalignancy coexists with small cell lung cancer, the most common being re-nal cell cancer [5].

The presence of other autoantibodies without concomitant ANNA-1 positiv-ity is less likely to predict the presence of a malignancy. It is unclear what strat-egy to use in this situation. The authors’ current management algorithm, notevidence based, is to obtain a CT of the chest and, if negative, repeat thescan once in 6 months.

Treatment of Paraneoplastic Dysmotility
The diagnosis of a paraneoplastic dysmotility is unfortunately associated witha bad outcome. Death often occurs within 6 months of the diagnosis, usuallyfrom the underlying malignancy but accelerated by difficulties in maintainingnutrition. There are no effective treatments available for paraneoplastic dysmo-tility. Several treatments have been investigated, including immunosuppressivetherapy with steroids and cyclophosphamide, plasmapheresis, and intravenousimmunoglobulin, but none have been convincingly shown to alter outcome[5,53]. The mainstay of treatment is to address the underlying primarymalignancy. It is important to provide supportive care including nutritionalsupport either enterally or parenterally, adequate hydration, and the use ofprokinetics to promote motility and the treatment of complications such as bac-terial overgrowth. One additional management strategy is to use high-doseintravenous steroids for 3 days. If there is a clinical response, a switch ismade to 6-mercatopurine or azathioprine; however, this approach often needsto be aborted due to the need for chemotherapy.


CLINICAL PRESENTATION OF A NON-PARANEOPLASTICDYSMOTILITY SYNDROME ASSOCIATEDWITH CIRCULATING ANTIBODIESAchalasiaIdiopathic achalasia is a relatively common esophageal motility disorder(1:100,000) characterized by ineffective peristalsis and an abnormal relaxationof the lower esophageal sphincter [54]. A consistent finding in idiopathic acha-lasia is the loss of nitrergic neurons with a relative preservation of cholinergicneurons [55–57]. As the disease progresses, the enteric neuronal loss becomesmore generalized. Most studies that have reported on biopsy specimens takenfrom patients with relatively early disease have shown the presence of aninflammatory infiltrate in the myenteric plexus. This infiltrate is predominantlydue to CD3-positive T cells, suggesting an underlying immune-mediated pro-cess [58–60]. The serum from patients with achalasia often contains anti-neuronal antibodies; however, studies on their role in causation of diseasehave been inconclusive because similar antibodies are present in patientswith gastroesophageal reflux disease. Moses and colleagues [61] collectedsera from 45 patients with achalasia and 16 with gastroesophageal refluxdisease as well as from healthy controls and demonstrated that the sera frompatients who had achalasia and that from patients with gastroesophageal refluxdisease labeled myenteric neurons in the esophagus as well as the ileum andsubmucosal plexus neurons in guinea pig and mice with rare labeling of thespinal neurons. Based on these findings, they felt that the presence of anti-neuronal autoantibodies was likely secondary to tissue damage and not in-volved in the pathogenesis of achalasia. A recent study, at present reportedonly in abstract form, suggests that 60% of patients with primary idiopathicachalasia have circulating anti–GAD-65 antibodies. Like ANNA-1, GAD-65is not a membrane protein; therefore, it is unclear what role the antibodieshave in the pathophysiology of the disease [28].

Chronic Intestinal Pseudo-Obstruction
Chronic intestinal pseudo-obstruction can be divided into primary chronicintestinal pseudo-obstruction and secondary chronic intestinal pseudo-obstruc-tion, the latter a consequence of an underlying condition such as amyloidosis,scleroderma, and a variety of other systemic disorders. Primary chronic intes-tinal pseudo-obstruction may be due to genetic defects affecting the contractileapparatus but often is idiopathic with no identifiable cause detected. Anti-neuronal antibodies are detected in some patients with idiopathic chronic intes-tinal pseudo-obstruction, suggesting a possible cause. Antibodies such asANNA-1 usually indicate occult malignancy such as small cell carcinoma,but some patients with autoantibodies do not have underlying malignancy.Intestinal dysmotility has been observed in patients with antibodies such asthose for ganglionic acetylcholine receptor with no evidence of malignancyeven on long-term follow-up [15]. They likely represent the idiopathic formof autoimmune autonomic neuropathy. Ganglionic acetylcholine receptor


antibody has been associated with variable degrees of autonomic failure and isone of the more common antibodies detected in patients with intestinal dysmo-tility. As described previously in a series of 25 patients with ganglionic receptorantibodies published by Vernino and colleagues [15], at least four patients hadconstipation with no antecedent risk factors or malignancy. These antibodiesare likely pathogenic because they cause disease when injected in animalmodels [16], and there was a positive correlation between antibody levelsand the degree of autonomic failure [15].

Smith and colleagues [31] described two patients with intestinal pseudo-obstruction characterized histologically with acquired aganglionosis anda T-cell infiltrate affecting the myenteric neurons. Their sera contained anti-neuronal IgG antibodies similar to anti-Hu but demonstrated strong cytoplas-mic staining rather than nuclear staining. Neurogenic inflammatory chronicintestinal pseudo-obstruction is being increasingly recognized in a small but dis-tinct subset of patients with chronic intestinal pseudo-obstruction who undergoa full-thickness biopsy. The typical finding is a dense plasma cell and lympho-cytic infiltrate in and around the ganglia. The identity of the lymphocytic infil-trate (CD3-positive and both CD4- and CD8-positive cells) suggests a T-cellmediated injury to the ganglionic cells, although B cells have also been reported[42,43]. Myenteric ganglia are invariably involved; however, submucosal gan-glia may also be involved.

MANAGEMENT OF DYSMOTILITY ASSOCIATED WITHANTIBODIES OF LIKELY PATHOGENIC IMPORTANCETreatment needs to be directed toward managing the disorder as well as at-tempting to intervene in the immune-mediated process. Intestinal dysmotilityis often associated with complications such as bacterial overgrowth and malab-sorption. These conditions need to be treated appropriately. Treatment of theprimary disorder is often difficult and requires the judicious use of availablemedications including prokinetics. Among patients with idiopathic myentericganglionitis with intestinal dysmotility, the greatest benefit has been shownwith the use of immunosuppressive therapy such as steroids either alone orin conjunction with azathioprine or cyclophosphamide. Steroids that havebeen used in varying doses and tapers include prednisolone, methylpredniso-lone, and beclomethasone. A female patient with chronic intestinal pseudo-obstruction with underlying lymphoid infiltrate in the myenteric plexusshowed a mild improvement in symptoms with prednisone and cyclophospha-mide [62]. A young male patient with idiopathic myenteric ganglionitis andintractable vomiting failed therapy with prokinetics, but he responded to a ste-roid taper starting at 60 mg/d of methylprednisolone, with a sustained responseat 1 year [29].

Smith and colleagues [31] published a series of two patients with chronicpseudo-obstruction and IgG autoantibodies directed against enteric neurons.One patient improved with a trial of prednisolone used in a dose of 10 mg/d andrelapsed on discontinuation of the steroid. The other patient was treated initially


with prednisolone, 2 mg/kg for 4 weeks and reduced to 0.5 mg/kg everyother day, allowing the introduction of enteral feeds. This patient did poorlyin the long term and required intestinal transplantation. De Giorgio andcolleagues [63] described a patient with intestinal subocclusion and the pres-ence of anti-Hu (ANNA-1) antibodies who responded well to pulse dosesteroids (100 mg of intravenous methylprednisolone for 3 days). Schappiand colleagues [64] described three patients with predominantly eosinophilicmyenteric ganglionitis who had a good response to oral beclomethasone,prednisolone at 60 mg/d with azathioprine, or high-dose intravenousprednisolone.

Treatment with steroids often has to be tailored to the individual. Oneapproach is to attempt a short course of pulse steroids such as intravenousmethylprednisolone or to start with oral steroids in a dose of 60 mg/d with a ta-per over the next 4 to 6 weeks. If symptoms relapse after discontinuation,steroids should be reinstituted and a slower taper attempted. At this time itwould also be reasonable to consider immunomodulator therapy such as aza-thioprine starting at a dose of 2 mg/kg. Plasmapheresis may be beneficial inpatients with ganglionic receptor antibodies, who often show improvementwith a decrease in titers of the antibodies. Acetylcholinesterase inhibitorssuch as neostigmine [65] and pyridostigmine have been used successfully totreat intestinal dysmotility. Pasha and colleagues [66] described a patientwith idiopathic gastroparesis associated with N-type calcium channel antibodyand ganglionic acetylcholine receptor antibody who responded to treatmentwith pyridostigmine despite a 15-year history of gastrointestinal symptoms.Gastrointestinal motility tests such as gastroduodenal manometry and colonicmotility testing combined with the administration of neostigmine may help inmaking the decision to pursue pyridostigmine therapy.

A significant problem in the diagnosis and treatment of dysmotility attrib-uted to an autoimmune cause is the lack of a well-defined way to assess thedegree of inflammatory infiltrate and the response to therapy. We are currentlylimited to surgery, be it open or laparoscopic, to obtain full-thickness gut wallbiopsies. This requirement significantly limits the ability to repeatedly obtaintissue and to make informed decisions on the need for immunosuppressionas well as the duration of immunosuppression or other therapeutic modalities.A significant advance in the field will be the introduction of endoscopic meth-odology to obtain full-thickness biopsies. This tool would allow not only a de-termination of the utility of current approaches but would also permit studies todetermine the potential role inflammation and autoimmunity may have in thepathophysiology of a wide variety of gastrointestinal disorders not currentlythought to be immune mediated.

SUMMARYIncreasing evidence suggests an immune-mediated role in the pathogenesis ofseveral gastrointestinal motility disorders. The role of autoantibodies in para-neoplastic dysmotility is now well established, and the role of autoantibodies


in a subset of patients with non-paraneoplastic gastrointestinal dysmotility isbeing recognized and the antibodies characterized. It is hoped that a betterunderstanding of the role of autoimmunity and the specific antibodies involved,coupled with the development of less invasive techniques to obtain tissue or thedevelopment of better biomarkers, will lead to earlier diagnosis and targetedtreatment with appropriate immunosuppressant therapy.

Acknowledgments
The authors thank Kristy Zodrow for secretarial assistance.
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