Clinical use of manometry for the diagnosis of intestinal motor abnormalities

CLINICAL REVIEW

DIGEST LIYER OIS 2000;32:532-42

Clinical use of manometry for the diagnosis of intestinal motor abnormalities V. R. L. R. G. 6. R.

Stanghellini Cogliandro Cogliandro De Giorgio Barbara Salvioli Corinaldesi

Digestive symptoms suggestive of intestinal motor disorders, such as abdominal pain and distension, fullness, vomiting, constipation and diarrhoea, are very common and non-specific, and may be clinical manifestations of both organic and functional diseases. Both radiology and endoscopy are important in the diagnosis of structural gastrointestinal lesions that can affect motility and offer indirect signs of impaired gastrointestinal functions, but the diagnosis of gut motility disorders currently relies on the manometric assessment of contractile activities. Small bowel manometry helps to identify normal motility features and consequently to identify abnormal motor patterns. Small bowel manometry can help to differentiate mechanical obstruction from pseudo-obstruction and neurogenie from myogenic motor disorders. Manometry is an invasive technique which is not well accepted by patients and requires specific skills from investigators. Also, manometric assessment is limited to referral centres with a specific interest in the field of digestive functions, in general, and motiliv, in particular Only patients who remain undiagnosed after extensive traditional work-up and fail repeated courses with medical therapy should be referred for the manometric test. Understanding the underlying pathophysiologic mechanisms of abnormal motility and developing new therapies are the goals of the current research in this fascinating field of medicine.

Digest Liver Dis 2000;32:532-42 Key words: manometry; myopathy; neuropathy; small bowel motility

Physiological small bowel motor functions In normal subjects, interdigestive gastrointestinal motility comprises a sequence of three distinct phases that constitute the so-called migrating motor complex (MMC). These phases are respectively characterized by: a) motor quiescence (phase I); b) irregular contractions of progressively increasing frequency (phase II); and c) a burst of propagated contractions which occurs at the maximal frequency allowed by the underlying basal electrical rhythm for a given segment of the alimentary tract (phase III or activity front) and propels gastrointestinal contents in an aboral direction. The absence of activity fronts results in gastric bezoares and small bowel bacterial overgrowth. Postprandially, cyclical motor activity abruptly disappears and regular antral contractions associated with apparently uncoordinated phasic contractions of variable amplitude in the small bowel occur aimed at optimising intraluminal digestion and absorption. Gastrointestinal motility results from the integration of several control mechanisms ranging from the

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smooth muscle cell to the central nervous system. Myogenic control is determined by the electrophysiologic characteristics and contractile responsiveness of smooth muscle cells which exhibit spontaneous slow depolarizations of their membranes referred to as slow waves or basal electrical rhythm. These myoelectric events originate from interstitial cells of Cajal which are specialised non-neuronal cells distributed through the muscularis externa of the alimentary tract. Slow wave propagation occurs distally and circumferentially through intercellular gap junctions and is associated with muscular contractions only when superimposed by action potentials, under the influence of neuroendocrine stimuli. Both the extrinsic innervation (vagal and sympathetic nerve pathways) and the intramural neural network, known as the enteric nervous system (ENS) which comprises the myoenteric and submucous ganglia determine neurogenic control. Phase I and III of MMCs require a normal function of ENS, conversely the duration of phase II depends on extrinsic stimuli and decreases when extrinsic stimuli decreases when extrinsic stimuli decline (i.e., during sleep). Normal postprandial motility requires an intact vagal innervation. Neural reflexes and endocrine/paracrine mechanisms concur to the regulation of motor and secretory processes during both interdigestive and postprandial periods. In addition, postprandial motor patterns are regulated by the physicochemical properties of intraluminal contents ‘-5.

Small bowel manometry Small bowel manometry provides the assessment of frequency, amplitude and coordination of the phasic pressure waves caused by occlusive contractions of the gut wall. Technical aspects Pressure sensitive systems typically comprise a series of sensors built on a catheter, an amplifier, and a recorder. Small bowel recording performed for clinical purposes requires a minimum of three sensors, spaced lo- 15 cm apart, to allow assessment of migration of the activity fronts. These sensors are generally represented by simple side holes of a perfused catheter in stationary manometry, and by miniaturized transducers mounted on a catheter in ambulatory manometry. Patients are studied after an overnight fast and after at least 48 hours off any medications that may affect motility. Patients must be studied both during fasting and after eating. Ambulatory manometry is generally carried out for 12-24 hours. For stationary manometry, fasting recording must be carried out until an activity front and/or clear-cut abnormalities are recorded. It is

generally advisable to carry out fasting recording for at least 6 hours and after feeding recording for at least one hour. The test meal should be balanced, containing solid components and at least 500 Kcal, in order to assure a consistent postprandial motor response. Meal size and content, however, may need to be adjusted based on the peculiar clinical problems of individual patients. If antral motility is recorded, mixed solid-liquid meals should be adopted 6-‘3. Analysis of manometric recordings Manometric patterns are assessed quantitatively and qualitatively. “Ad hoc” software programmes can assess both aspects, but the visual interpretation by an experienced investigator remains the gold standard of qualitative analysis. Physiological and pathological manometric patterns are summarised in Table I. Physiological fasting motility During fasting, MMC features must be carefully analysed. Since the periodicity and duration are highly variable both between and within individuals, normal values are hard to define. Specifically, since the lower end of the normal range of MMC frequency per 24 hours is one, only the complete absence of MMCs in a 24-hour recording can be classified as abnormal 14. Normal activity fronts (Fig. 1) consist of regular rhythmic contractions at high frequency, generally lasting from 2 to 15 minutes. Migration in an aborad direction is a basic requisite for a normal phase III. The propagation velocity of phase III and the maximal frequency of contractile activity decrease progressively from the proximal duodenum to the distal jejunum, while its duration progressively increases 15.Notably, significant variations of phase III characteristics exist both be-

Fim.1. Normal activity front recorded with a, gastrointestinal manometric probe [proximai ports 1 cm apart; d&tat ports IO cm apart]; note the aboral propagation of regular rhythmic contractions at the maximal frequency from the antrum to the jejunum.

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Clinical use of manometry for diagnosis of intestinal motor abnormalities

lb&

I. Physiological and pathological manometric patterns,

Fasting motility Phase I

Period of motor quiescence following a phase 111and defined as less then three pressure waves every 10 min.

Phase II

Period of apparently uncoordinated contractions that can be quantitatively defined by amplitude, duration, propagation di& tance and velocity of single contractions, and by a cumulative motility index

Phase Ill

Regular rhythmic contractions at high frequency, lesting from 2-I 5 min and migrating in an abored direotion Propagation velocity end maximal frequency of phase ill decrease progressively from the duodenum to the jejunum; duration of phase ill progressively increeses in the aboral direction

Postprandial motility Disappearance of cyclicel activity

Fasting motility Phase I

Absence of phase I

Phase II

Absence of phase II EWsta, sustained contractions Disoreta clustered contractions Giant contractions

Extrinsic neumpathy Intrinsic neumpathy IGS, mechanical sub-occlusion Mechenical sub-occlusion, IE6, diarmoea

Phase IB

Absence of phase Ill fin 24 hours.1 Abnormal conformation and/or propagation of phase Ill

Intrinsic neuropathy intrinsic neumpathy

Inability of an adequate meal to abolish MMC for at least 1GO min Bursts, sustained contractions Discrete clustered contractions Giant contractions

Extrinsic neumpethy, delayad gaetric emptying Intrinsic neuropethy Mechanical sub-occlusion, I133 Mechanical sub-occlusion

Postprandial motility

tween and within subjects. Phase I is characterized by motor quiescence that, in the proximal small bowel, is defined as less than three pressure waves every 10 minutes, following a phase III. Phase II is the predominant phase of MMC during the awake state in the duodenum and jejunum. Phase II motor activity is characterised by apparently uncoordinated contractions that can be quantitatively defined by duration, amplitude, propagation distance and velocity of single contractions, and by a cumulative motility index. The percent of individual propagated contractions and, in general, the frequency of contractions, in phase II, are higher during daytime than during rest at night. Significant inter- and intra-individual variations exist with respect to motility index, while the percentage of cycle length occupied by phase II remains relatively constant Is. Distinct motility patterns of phase II have been identified both in physiologic and pathologic conditions. Propagated contractions occur rather infrequently in the small bowel of healthy subjects, since small bowel motility is mainly aimed at delaying transit and pro534

mote mixing and absorption. Propagated clustered contractions are composed of 3-10 contractions, each having a significantly higher amplitude and duration compared to isolated individual contractions, which occur at the slow wave frequency, with regular intervals of quiescence lasting at least one minute, and propagated aborally. These patterns are distinguished from phase III by their periodicity, duration, velocity and extent of propagation. The frequency of propagated clustered contractions is significantly higher in the duodenum than in the jejunum; conversely, the number of contractions of each cluster and the duration of single contractions are higher in the jejunum 16. They are only occasionally seen in young healthy adults, but they are relatively frequent in elderly individuals in whom they are probably due to a reduced flexibility of the small bowel wall 17-19.Bursts ofcontractions are periods of intense contractions propagated or isolated, that do not correspond to the definition for activity fronts nor for propagated clustered contractions and may be distinguished from the background of contrac-

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tile activity during phase II due to their higher frequency and amplitude. Short bursts of contractions, at the slow wave frequency, have been described in healthy subjects *O. Conversely, non-propagated bursts of prolonged duration (>2 minutes) are considered an abnormal pattern (see below). Ultra-rapid contructions, that are contractions propagated aborally over long distances and at high velocity, can also be recorded during phase II of the MMC. Physiological postprandial motility Cyclical activity is interrupted by meals and its contractile pattern is characterized by the loss of cyclical activity (Fig. 2). Typical postprandial contractions propagate over shorter distances than those of phase III, and are devoted to mix thyme and digestive secretions. In addition, distinct propagated contractions of higher amplitude and longer duration propel thyme aborally. Their occurrence is unpredictable, but they are generally more frequent during the postprandial period than during phase II, both in the duodenum and jejunum. Propagated clustered contractions can occur in the postprandial period of healthy subjects and their characteristics are similar to those described for phase II 2’. Analysis of postprandial tracings should take into consideration at least two aspects: a) the disappearance of MMC, which indicates the ability of a caloric meal to induce a feed response: failure of an adequate meal to abolish MMC for at least 120 minutes and to generate a feed motor response should be regarded as abnormal and may suggest vagal dysfunction, but can also depend on markedly delayed gastric emptying 22; b) amplitude and frequency of contractions which are commonly summarised in one parameter known as “motility index”.

Abnormal motor patterns The presence of qualitative motor abnormalities should be carefully evaluated in manometric analyses ’ **. Qualitative abnormalities of activity fronts include: a) “abnormal propagation”, defined as presence of simultaneous, retropulsive or incompletely propagated activity fronts (Fig. 3), and b) “abnormal configuration”, defined as presence of a tonic component, lasting for at least 3 minutes and reaching an amplitude of at least 30 mmHg. “Bursts” and “sustained uncoordinated contractions” are well-defined motor abnormalities characterized by groups of contractions lasting, respectively, at least 2 and 30 minutes that are uncoordinated and possibly associated with tonic elevation of the baseline pressure. Sustained contractions are typically recorded in a single site of the intestine (Figs. 4, 5).

Fi2.3. Abnormal activity front remrded with an intestinal msnometric pmbe (ports 10 cm apart); note abnormal propagation in pmximal tract of smell bowel.

Fi2.4. Bursts recordad with an intestinal manomett+c prube; note uncoordinated and intense periods of phasic and tonic contractions at different levels of intestine.

62. 2. Normal gastrointestinal motility in post-prandial period, acorded with a gastmintastinal manometric probe [proximal parts 1 :m apart: distal ports 10 cm apart]; note loss of cyclical activity and Jrasence of irregular but persistant contractions in antrum and small bowel.

I##. 3. Sustained contractions recorded with an intestinal menometric probe; note uncoordinated and intense pePinds of phasic end tonic contractions lasting >30 min recorded at level of distal duodenum.

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Clinical use of manometry for diagnosis of intestinal motor abnormalities

These patterns have been described in extrinsic and intrinsic neuropathies (see below). Regular or irregular, often propagated, “clustered contractions”, rarely separated by more or less complete quiescence have been described both in healthy subjects and in irritable bowel syndrome (IBS) patients; in the latter group, they have been reported to be associated with abdominal pain. Simultaneous, postprandial clustered contractions, lasting at least 20 minutes, are associated with mechanical obstruction (Fig. 6) 17.“Giant contractions” are prolonged contractions lasting at least 10 set and can be either propagated or non-propagated. “Propagated giant contractions” lasting at least 10 set have been described in secretory diarrhoea; “non propagated giant contractions” lasting at least 20 set are specific of mechanical obstruction (Fig. 7) 23.

Other abnormal motor patterns that can occur during both the interdigestive and postprandial state are: a) “hypomotility”, that is characterized by a flat baseline interrupted by low-amplitude tonic or phasic contractions; recording of antral hypomotility has been advocated for directing a more careful search of an underlying neuropathic or myopathic disorder 24. In our hands, antral hypomotility appears to be a very specific finding and, for this reason of limited clinical value 25; b) “hypermotility”, that is characterised by powerful phasic contractions occurring at, or close to, the maximal frequency. Usually, these patterns continue essentially unchanged during the feed pattern and should be compared to normal values obtained in each laboratory. Pathological ders

,

4

L

I

-I

FQ. &. Clustered contractions recorded in post-prendiel period with a gastrok$estinel manometric probe (proximal ports 1 cm apart: distal ports IO cm apart]; note regular clusters of contractions which occur simukanaously at different levels of intestine, at approximately I- to Z-minute intervals snd last about 1 minute each.

IQ. 7. Giant contractions recorded in interdigestive end post-prandial periods with an intestine1 manometric probe (proximal ports 1 cm apart; distal ports IO cm apertl; note, during fasting, presence of repetitive broad-based contractions which occur simulteneously at different levefs of intestine, and their persistence in post-prandisl period.

536

conditions

associated with motility disor-

Several digestive and extra-digestive diseases are associated with motor disorders of the small bowel. Derangement of the myogenic and/or neurogenic activity are responsible for the abnormalities of small bowel motility (Table II). Manometry can distinguish between neuropathic disorders, where intraluminal pressures are uncoordinated and have normal or even increased amplitude, and myopathic disorders that are characterized by normally coordinated, low amplitude pressure activities in mild forms and by a complete absence of contractions in advanced forms ‘. It is worth pointing out that manometry only records occlusive contractions and that the lack of pressure waves is a typical finding in all patients with markedly distended intestinal loops, regardless of the underlying pathophysiological mechanisms. Post surgical syndromes Small bowel motor abnormalities are frequent findings in patients who remain symptomatic after gastric surgery. The Roux-en-Y stasis syndrome is characterized by nausea, vomiting and stasis in the gastric remnant after gastrectomy and Roux-en-Y reconstruction. It can be caused not only by derangement of the tonic contractile activity of the gastric remnant, but also by motor abnormalities of the Roux limb. Delayed gastric and/or Roux limb transit are present in 77% of patients with Roux-en-Y syndrome; manometric abnormalities are present in 88% of patients with a Roux-en-Y reconstruction and are significantly more frequent in symptomatic than in asymptomatic individuals 2s. Whether these motor abnormalities actually follow the surgical procedure or were already present before, causing the syndrome that required a Roux-en-Y reconstruction, remains to be established. Chronic intestinal pseudo-obstruction Chronic intestinal pseudo-obstruction (CIP) is characterized by symptoms of mechanical obstruction in the absence of any

Y. Stanghellini et al.

I

Tsbh8II. Causes of disonlars of smalt intestinal motility,

Myopathies

Famitiel holFuw visceral myopathy Sporadic hollow visceral myopathy

Clystmphis myotonios Progressive muscular dystrophy

Neuromyopathiaa

Sporadic visceralnewmyopathy ~o~neum-gas~mjn~s~~net~fl~phsla~~y

systimic SCla#SiS

Intrinsic neuropathies

Familial visoaral neuropathy Sporadii visceral neumpathy

Extrinsic neumpathies

demonstrable lesion occluding the gut lumen. It can be secondary to many organic, systemic and metabolic diseases, but, in most instances, it is “idiopathic” 27. Small bowel manometry provides evidence of gut dysmotility in all CIP patients 28.The correlation of manometric abnormalities and clinical course of this severe condition has received some attention. Patients with severe late radiation enteropathy presenting with fasting and postprandial hypomotility generally have a severe course of the disease with malnutrition as opposed to those with normal small bowel motility whose nutritional state remains stable 28. Small intestine manometry has also proven to be capable of distinguishing neuropathic from myopathic forms, thus predicting the clinical outcome in children with CIP. Indeed, children with myopathic CIP, characterized manometrically by low amplitude activity fronts or no detectable motor activity during the study period, seem to have a poor clinical outcome (i.e., death or parenteral nutrition dependence) after 1- 10 years follow-up, compared to children with uncoordinated contractility and a higher motility index, suggesting a neuropathic form 29. Manometric studies can help to identify subgroups of CIP children who are responsive to pharmacological therapy: children with duodenal hypomotility have excellent response to cisapride, while the absence of MMC is associated with a need for greater intensity of nutritional support and decreased response rate to cisapride 303’.

Dermatomyositis Am.,Grtnrir Pw I ~yT”w”~Kl Jejunal diverticula Chronic intastind pseudo- obstruction Hirschsprung’s disease Chagas disease Von Recktinghau sen’s #disease Viral Infections Diabatic autonamic neuropathy !3mrtic autonomic naumpathy ?Spifd cord injwy &sin diseases Pandysautonomia Shy-Dregar syndrome

The absence of abdominal vagal dysfunction is associated with a better response to cisapride in adults 32. An increased frequency of activity fronts (2 5 AFs/4 hrs) after octreotide administration is a predictive factor of good clinical response 33. Small bowel manometry can also help to select CIP patients in whom jejunal tube feeding can be successfully used as an alternative to parenteral nutrition. Specifically, the presence of activity fronts is generally associated with a successful adaptation to jejunal feeding and symptomatic improvement, while patients without activity fronts have more severe symptoms and prognosis 31. Recent studies in adult CIP patients confirmed that small bowel manometry is invariably abnormal and, in keeping with the poor prognosis of children with small bowel hypomotility, an intense although uncoordinated small bowel motor activity characterized by high frequency bursts, seems to be associated with a favourable longterm clinical outcome 34. Nevertheless, the clinical usefulness of small bowel manometry in patients with “obvious” chronic intestinal pseudo-obstruction (i.e., repeated documented subocclusive episodes that do not respond to surgery) is limited since the management of patients is not substantially modified. The main advantage of this technique is to provide the evidence that “something is wrong” in the patient’s gut and, possibly, to suggest that either the intrinsic nerves or the smooth muscle cells are affected (see below). This is psycho-

Clinical use of mannmetry for diagnosis af intestinal motor abnormalities

logically very important for the patients, their relatives and the doctors that will deal with these difficult cases. Small bowel manometry, unfortunately, does not help to differentiate CIP from other severe forms of diffuse gut dysmotility. Preliminary data show that malnourished patients complaining of severe digestive symptoms with or without subocclusive episodes present similar abnormal motor patterns, although CIP patients have a higher frequency of abnormal activity fronts and bursts 35. Small bowel motility disorders in functional gastrointestinal disorders Functional dyspepsia In functional dyspepsia, small bowel motor abnormalities have been reported usually only in patients with secondary dyspepsia or in patients with associated IBS 36. In a recent study carried out in 14 patients with severe dyspepsia, prolonged ambulatory recordings of antro-jejunal manometry showed a high prevalence of both antral and jejunal dysmotility during both the interdigestive (71%) and postprandial period (78%), but no correlation was found between symptoms and motility scores and the concomitant presence of IBS was not carefully ruled out 3’. Irritable bowel syndrome The causes of IBS have long been attributed to abnormal motility of the large bowel. More recently, increasing attention is being paid to the role that bowel motility may play in this syndrome. Several studies performed by ambulatory or stationary manometry show alterations of periodicity of MMCs and significantly more frequent bursts, clustered contractions, and prolonged propagated contractions in IBS patients compared to healthy controls 38-4o.Patients with IBS show an abnormally intense motor response to provocative stimuli, such as mental stress 4’-43, CCK 4’, fatty meals 41,and ileal distension 4144. Quantitative differences of postprandial jejunal contractility have been found between patients with IBS and healthy subjects: contraction frequency has been reported to be greater both in diarrhoea and constipation predominant subgroups, whereas contraction amplitude is decreased only in constipation predominant patients 39. Furthermore, the MMC cycle length is shorter and the small bowel transit is faster in patients with diarrhoea compared to constipation or to IBS with predominant pain/distension 38-45. Motor patterns such as bursts, clustered contractions and prolonged propagated contractions are often associated with abdominal pain. Typically, motor abnormalities often disappear in IBS patients during sleep, while they can be elicited by stressful situations 4647, thus suggesting an inductive role of the central nervous system. Chronic constipation In chronic idiopathic constipation small bowel manometry frequently reveals motor 538

abnormalities suggesting derangement of the neurogenie control mechanisms. Manometric studies performed on patients with chronic idiopathic constipation showed abnormal motor patterns in up to 70% of the cases: discrete clustered contractions in the fasting period and bursts of uncoordinated contractions both during fasting and after feeding are the most frequent abnormalities 48 49. Evidence of motor abnormalities present in the small bowel should discourage total colectomy in these patients 50.

Clinical value of small bowel manometry in motility disorders Small bowel manometry is a relatively cumbersome technique to perform, that is not always easy to interpret, and turns out to be useful in the clinical management of only a minority of patients. For these reasons, it should be restricted to a limited number of referral centres with a specific interest in the field. Small bowel manometry is an invasive test, but it is generally well tolerated by patients with otherwise undiagnosed gut motility disorders who do not respond to conventional therapies and whose quality of life is substantially impaired both by the severity of the symptoms and the uncertainties of the diagnosis. There are only a few specific indications for the test. In patients with intractable constipation, small bowel manometry should be performed if surgery is considered, since patients with small bowel dysmotility generally have a poor response to colectomy. Manometry is also indicated in the investigation of patients with unexplained nausea, vomiting, abdominal pain, and distension and in those with abnormal gastric emptying who fail to respond to regular treatment with prokinetics. An important application of small bowel manometry is represented by patients with recurrent subocclusive episodes, to differentiate a pseudo-obstruction syndrome from true mechanical obstruction, which is sometimes overlooked by traditional radiological tests, even if performed by experienced radiologists. If mechanical obstruction is suspected, small bowel manometry becomes important, particularly when the patient has an underlying condition that may produce intestinal subocclusions (i.e., postsurgical adhesions). Identification of motor patterns suggesting mechanical obstruction should prompt surgery, even when this is equivocal on barium small bowel radiography. Another common indication for manometry is to confirm the presence and extent of the intestinal involvement in patients with a known underlying disease, which may affect gastrointestinal motility at various levels (i.e., diabetes mellitus, progressive systemic sclerosis). As previously mentioned, the main limitation of this test is represented by

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the fact that, with the exclusion of the above conditions, its results do not substantially modify the management of patients, since several dysmotility syndromes share common underlying pathophysiological mechanisms and have s similar response to the limited therapeutic options currently available. Finally, it is important to point out that a completely normal tracing is also an important finding of manometric tests, since it allows us to rule out an abnormal motor activity in patients with severe digestive complaints and suggests we should consider the possibility of psychogenic disorders 42.In this respect, gastric emptying tests can also be used for screening motor disorders.

tochondrial dysfunctions have been shown to cause gastrointestinal and oesophageal motor disorders due both to neurogenic and myogenic abnormalities. There are many reports of chronic intestinal pseudo-obstruction and opthalmoplegia in the literature; in these patients, skeletal muscle biopsy specimens show the “ragged” red fibres typical of mitochondrial myopathy 61. These studies open new perspectives in the understanding of the pathophysiology of intestinal motor disorders and need to be further developed and expanded. Further areas of interest to be covered in the near future include crucial biopathological events such as neuronal apoptosis, neurotrophic factor abnormalities, mitochondriopathies and visceral myopathies.

In search of causes underlying motility disorders

References

In the vast majority of intestinal motor disorders, underlying causes and mechanisms remain obscure. Nonetheless, recent efforts have been directed towards the identification of morphological or functional abnormalities in the two major control systems of intestinal motility, i.e., the enteric nervous system and intestinal musculature. Putative mechanisms of altered motility in IBS involve minimal inflammation, as suggested by studies reporting an increased number of inflammatory cells in the muscularis externa and mucosa5’ and the development of IBS symptoms and intestinal motor dysfunction following acute infectious gastroenteritis 5254.Inflammatory mechanisms have also been implicated in the pathophysiology of some cases of severe gut dysmotility. Indeed, we and others have described and characterized a dense inflammatory infiltrate confined to the myenteric plexus (i.e., myenteric ganglionitis) along with neural of enteric ganglia degeneration in a subset of patients of CIP 54-56.The causative role of the inflammatory infiltrate in the generation of dysmotility is strongly suggested by the clinical recovery following immunosuppression 5556. These patients develop circulating anti-neuronal autoantibodies the role of which in the pathogenesis of CIP is yet to be determined 57. On the other hand, degeneration and loss of the intrinsic neurones of the gut characterize other forms of severe dysmotility, in the absence of any identifiable inflammatory involvement. These degenerative neuropathies may be due to different mechanisms, such as altered calcium signalling and mitochondrial dysfunction 5s. Degenerative neuropathies include both familial and sporadic forms. Genetic studies in families affected by CIP have shown an autosomal recessive or dominant mode of inheritance 59. However, our preliminary data in a family with CIP have excluded the involvement of the genes related to the pathogenesis of Hirschsprung disease (the most common form of neurogenic CIP) 60.Mi-

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EUROPEAN ASSOCIATION FOR THE STUDY OF THE LIVER

(EASL)

36THANNUAL MEETING April l&22,2001 Prague, Czech Republic Abstract deadline: November 27,200O Wednesday,April 18, 2000 EASL will host a joint meeting with the European Society for Biomedical Research on Alcoholism and with the European Liver Transplantation Association. The 2001 Postgraduate Course will be on “Clinical Management of Portal Hypertension and its Complications” and the President’s Meeting will be on “Bile Formation and Gallstones - From Genes to Therapy”. The two single topics symposia will focus on “Clinical Autoimmune Hepatitis” and on “Clinical Virology for Hepatologists”. The two State of the Art Lectures will discuss “Neurophysiological Abnormalities in Liver Disease” and “Angiogenesis and Turnout-growth”. The President of the 2001 meeting is Professor Zdenek Marai;ek, Prague, Czech Republic. EASL will offer 120 Travel Bursaries to selected young investigators and 30 to Eastern Europeans, pending on submission of an abstract. In addition,$rst authors under 3.5years of age and in training who submit abstracts will have free registration. This is part of the policy of EASL to encourage young investigators to attend and present at its scienti$c meeting. For further information, please contact: EASL Liaison Bureau c/o Kenes International 17, Rue du Cendrier, P.O. Box 1726, CH-1211, Geneva 1, Switzerland Tel.: +41-22-9080488 - Fax: +41-22-7322850 - E-mail: [email protected] - www.easl.ch

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