Gastric Dysfunction in Parkinson’s Disease

Ayal Rozenberg , Tanya Gurevich , Nir Giladi,

and Amos D. Korczyn

Introduction

Parkinson’s disease (PD) is a common degenerative illness affecting the central, autonomic, and the enteric nervous systems (ENS) [ 1 ] . Common gastrointestinal (GI) manifestations include sia- lorrhea, probably re fl ecting swallowing dysfunction, and more severe deglutition problems, resulting in dysphagia, aspiration and possibly weight loss [ 2– 5 ] . Constipation is very common among PD patients, often antedating the motor manifestations of the disease [ 6 ] . Relatively little attention has been paid to dysfunction of the prox- imal part of the GI system, the esophagus, and the stomach. This dysfunction may be important not only due to its unpleasant clinical symptoms but also because it may affect drug absorption and, therefore, motor manifestations of PD. In one study, impairment of gastric motility (gastroparesis) was found in 70% of PD patients, especially in those with response fl uctuations [ 7 ] . Conversely, among 146 consecutive patients with gastroparesis seen in a gastroenterology clinic, the condition was related to PD in only 7.5% [ 8 ] . Although con- siderable progress has been made in delineating many aspects of GI dysfunction in PD, therapeutic approaches to these symptoms are lagging behind. A growing body of evidence indicates that GI symptoms mostly re fl ect direct involvement of the GI tract by the neurodegenerative process, although the effects of PD on skeletal muscle function in the oropharynx, anorectum, and pelvic fl oor also contribute to the problems [ 9 ] .

The fi nding of Lewy bodies in the ENS has prompted the “dual-hit” hypothesis, which pro- poses the possible entry of a pathogen, probably viral, into the central nervous system (CNS) through the gastric system as a consequence of saliva swallowing with subsequent spread via the vagus nerves to the medulla and eventually the basal ganglia [ 10 ] .

James Parkinson, in his famous monograph [ 11 ] , recognized the serious GI features that PD patients manifest. This issue failed to claim proper attention until 1965 when Eadie and Tyrer focused attention on GI dysfunction in PD

patients [ 12 ] . Since then, a growing number of studies have investigated the anatomical and pathophysiological bases and the clinical manifestations of gastric dysmotility, as well as drug in fl uences on gastric motility, in PD patients.

The regulation of GI motor function by the autonomic nervous system (ANS) is under the extrinsic control of the parasympathetic and sympathetic nervous systems and by the intrinsic enteric plexuses [ 13 ] . The ENS plays a key role in the generation and coordination of antral contractions and peristalsis and in the regulation of gastric emptying. Interstitial cells of Cajal, which are located in the greater curvature of the stomach, act as a slow gastric pacemaker. Intrinsic innervation of the ENS consists of a network of neurons within the gut wall that are arranged in two principal plexuses, the myenteric plexus of Auerbach and the submucosal plexus of Meissner.

This intrinsic system is activated by vagal fi bers and inhibited by the sympathetic system, origi- nating in the intermediolateral column of the spi- nal cord between the fi fth and the ninth thoracic segments. Extrinsic nerves control the striated muscle portions of the esophagus and the exter- nal anal sphincter.

Clinical Manifestations

Gastric motor dysfunction is a disorder of the upper gut and typically is characterized by delayed gastric emptying (GE) that may be associated with early satiety, anorexia, upper abdominal fullness, bloating and sometimes pain, nausea, and vomiting [ 14, 15 ] . Nausea in patients with PD is most often caused by dopaminergic medications [ 16, 17 ] , and the results of double blind studies with dopaminergic agonists con fi rmed that these drugs are, indeed, associated with nausea [ 18, 19 ] . The frequency of nausea in one group of patients with PD who were on these medications and another group of patients who were untreated was reported to be similar, however, suggesting that although dopaminergic medications are associated with nausea and vomiting, they cannot fully explain those symptoms in PD [ 20 ] .

Ancillary Investigations

The gastric symptoms of PD are nonspeci fi c and it was only the introduction of ancillary investigations that allowed their origin to be con fi rmed. Untreated PD patients have signi fi cantly slower GE time compared with controls [ 21 ] , but the same slowness of GE also is observed in individuals with multiple-system atrophy (MSA) [ 22 ] . Abnormalities in gastric myoelectric activity have been documented in PD, and electrogastrography (EGG) reveals frequent dysrhythmias. Gastric motility is especially impaired in patients with advanced disease [ 23 ] . PD patients have a signi fi cantly slower GE time for solids, regardless of age or gender, and a positive correlation has been reported between rigidity and action tremor with slow GE [ 24 ] . However, another group of investigators noted no differences in the myo- electrical activity between PD patients with or without upper GI complaints [ 25 ] . There is some similarity between the abnormal EGG patterns of PD patients and patients after the acute phase of a vagotomy procedure; however, there is improvement with time in vagotomized patients but slow deterioration in PD patients, presumably re fl ecting progressive ENS involvement [ 26 ] .

The dysrhythmia of GE, which is in fl uenced by food, was examined in a study on subjects in different stages of PD. A signi fi cant association between preprandial dysrhythmia of gastric motility and duration of disease, duration of levodopa treatment and, especially, with motor fl uctuations was demonstrated. Preprandial dysrhythmia of GE was detected in almost all patients with motor fl uctuations, compared with PD subjects without motor fl uctuations [ 27 ] . This study employed a new method measuring gastric emptying using the C ¹³ -sodium octano- ate breath test, which entails fewer technical dif fi culties for advanced PD patients and patients with motor fl uctuations than did the older method of obtaining radioisotope images of the GI tract [ 27 ] .

Pathology and Pathophysiology

Neuropathological changes have been described in PD in all parts of the nervous system responsible for gastric motility, explaining the gastric motility problems in this disease. GI involvement in PD is a good example of the interaction between the CNS and the ANS. The recent dem- onstration of neuropathologic abnormalities in the ENS, analogous to those regarded as being pathognomonic for the parkinsonian process in the brain, suggests that the ENS, called “the little brain in the digestive system” [ 28 ] , and the CNS (“large brain”) may exemplify parallel pathologic changes [ 9 ] .

Lewy bodies, a pathological hallmark of PD, were found to be widely distributed in Auerbach’s and Meissner’s plexuses in the GI tract [ 29, 30 ] . Additional supportive proof of a degenerative process taking place in the ENS has been demonstrated by an immunocytochemistry stain for a -synuclein in the submucosal Meissner’s plexus, with extension into the gastric mucosa and in proximity to the fundic glands [ 31 ] .

Neurons immunoreactive for tyrosine hydrox- ylase (TH) were also shown to exist in these plexuses of normal humans, and a possible relationship between presumably pathological processes involving these catecholaminergic neurons and the occurrence of Lewy bodies in the ENS in PD has been suggested [ 32 ] . However, a -synuclein deposits in the brain in PD are not con fi ned to dopaminergic neurons.

Loss of neurons has been reported in the dor- sal motor nucleus of the vagus nerve (DMNX) in PD patients with autonomic failure [ 33 ] . This nucleus consistently showed early Lewy bodies in PD before similar changes occur in pigmented nuclei of the brainstem [ 33, 34 ] . Moderate neuronal loss and the presence of Lewy bodies have been noted in the intermediolateral columns of the thoracic cord in PD patients with autonomic failure, in addition to neuronal loss in the sacral segments [ 35, 36 ] . Lewy bodies were present also in sympathetic ganglia, with or without obvious neuronal loss [ 37 ] . Comparison of the

pathological fi ndings involving the nervous system that controls gastric motility revealed involvement of the CNS in both MSA and PD patients, but the latter also had involvement of the ENS [ 22 ] . The changes involving both the ANS and ENS are considered by some investigators to be the primary cause of GI dysfunction in PD [ 26 ] .

Recently, Schulz et al. proposed an interesting theory of a possible mechanism that linked PD and Helicobacter pylori ( H. pylori ) infection.

Cholesterol glucosides constitute part of the lipid pro fi le of H. pylori and have some resemblance to cycad-derived sterol glucosides, a substance that induces loss of striatal dopaminergic termi- nals. This similarity in the sterol glucosides struc- ture might explain how the cholesterol glucosides arising from an H. pylori infection may act as neurotoxins, promoting the degeneration of the dopaminergic neurons in parkinsonism [ 38 ] .

The Effect of Medications on Gastric Motility

The frailty of GI function in old age, and particularly in patients with PD, underlies the very frequent complaints of nausea, gastric fullness, or constipation following drug exposure [ 39 ] . The effect of dopaminergic drugs is well known [ 40 ] , with important in fl uences on gastric motility and gastric symptoms.

Levodopa slowed gastric emptying to a similar extent in both elderly and young normal volunteers [ 41 ] . Dhasmana et al. [ 42 ] provided evidence that the reduced GI motility elicited by dopamine and dopamine agonists is primarily through activation of dopamine receptors involved in intestinal contractions. Levodopa treatment initially slows down gastric emptying by its peripheral action on the gastric wall. This action results in an indirect effect on the movement of the pyloric sphincter [ 43 ] . The peripheral GI effect of levodopa occurs despite cotreatment with a decarboxylase inhibitor, since some peripheral conversion to dopamine occurs in the stomach [ 44, 45 ] . In contrast to healthy subjects, PD patients are in fl uenced differently by dop-

amine derivatives, Apomorphine facilitates swallowing in PD patients [ 46 ] . This fi nding has also been demonstrated in a short-term study with PD patients at mild and moderate stages of the disease [ 21 ] . PD patients with a fl uctuating type of response had a signi fi cantly delayed GE compared with those with a smooth response [ 7 ] . Chronic exposure to levodopa also may modify the activity of the DMNX in the medulla oblongata. Several groups have shown that dopaminergic cells are present in the DMNX [ 47– 49 ] . Following the development of response fl uctuations, PD patients had a dramatic shortening of GE time—almost to the rate recorded in healthy volunteers—when measured during the

“on” state induced by levodopa. Accelerated GE in PD patients with motor fl uctuations (all with long-term exposure to levodopa) also was described by Murata et al. [ 50, 51 ] , who demonstrated accelerated absorption of levodopa after prolonged exposure to levodopa in intact rats and in PD patients. The ability of chronic levodopa treatment to accelerate its own absorption from the gut was also reported by Abrahms et al. [ 52 ] and Muenter and Tyce [ 53 ] shortly after levodopa was introduced for the treatment of PD. Such an effect is supported by the clinical observation that taking medications during the “off” state can frequently result in a “delayed on” or a “no on”

state. Furthermore, a “delayed on” state, which is often associated with prolonged GE [ 54 ] , is most frequent after the fi rst morning dose, usually taken after 6–10 h of fasting (and no medications) while the patients is still “off”. Yeh et al. [ 55 ] showed that the second daily dose of levodopa had a signi fi cantly shorter absorption time. These results should encourage patients to take their medications while still in the “on” state in order to accelerate levodopa absorption and improve the absorption of subsequent doses of levodopa.

Dopaminergic agents (e.g., apomorphine and bromocriptine) signi fi cantly slow GI transit in rats; this effect is blocked by dopamine antago- nists [ 42 ] . Although the effect of other antiparkinsonian medications on GI motility may be largely overestimated [ 56 ] , it is nevertheless wor- thy of consideration. Gastric relaxation invari- ably precedes nausea and emesis produced, for

example, by the classical emetic agent, apomorphine [ 57 ] . Other dopamine agonists, and possibly selegiline, may produce nausea and vomiting as adverse effects, not only by stimulating cate- cholamine receptors in the medulla oblongata involved in the emetic response but also due to the direct dopaminergic effects in the GI tract [ 45 ] . A comparison study of the in fl uence of entacapone in combination with levodopa/decarboxylase inhibitor to levodopa/decarboxylase inhibitor alone demonstrated increased absorption, especially for salt and acid that could be explained by the basic environment induced by entacapone in the gut [ 58 ] . No difference in GE was observed after a one-time administration of entacapone with and without levodopa/decarboxylase inhibitor [ 58, 59 ] .

Anticholinergic agents, such as trihexyphenidyl and benztropine, also may impair gastric emptying. Trihexyphenidyl decreased levodopa absorption in rats [ 60 ] , but increased the amount of levodopa absorbed by young healthy volunteers [ 61 ] . Thus, the concomitant administration of trihexyphenidyl to patients receiving levodopa may decrease the therapeutic ef fi cacy of levodopa by slowing its absorption [ 62 ] . Benzhexol did not change the amount of levodopa absorption in healthy young controls, but it did increase the second peak of absorption at the cost of the initial peak [ 63 ] . By their anticholinergic effect, tricy- clic antidepressants, and atropine may cause gastroparesis. Vagotomy worsens the “delayed on”

and “dose failure” phenomena [ 60 ] .

Medications with antidopaminergic effects in fl uence gastric motility as well. Metoclopramide is a dopamine antagonist that can reverse the delayed GE caused by a dopaminergic agent [ 43 ] . This classical prokinetic drug is, however, not a useful treatment in PD because of its ability to cross the blood–brain barrier, thereby exacerbat- ing parkinsonism. Domperidone, an antidopaminergic derivative with similar prokinetic action [ 64 ] , does not cross the blood–brain barrier and is in common use in PD patients.

Cisapride, a prokinetic drug with indirect cholinergic activity by means of stimulation of serotonin receptors, also enhances gastric motility, resulting in GI smooth muscle contraction,

possibly contributing to its antiemetic effect [ 65 ] . Cisapride improves the “delayed on” and

“dose failure” phenomena [ 66 ] , but the use of cisapride has been restricted due to serious safety problems.

Motor Fluctuations and the Gut

The mechanisms responsible for motor fl uctuations in PD are not fully understood [ 54 ] . Some factors associated with unstable drug effects are pharmacokinetic, including a short half-life, peripheral O-methylation and transport across the blood–brain barrier. Erratic gastric motility also may contribute to the complex pharmacokinetics of levodopa [ 55 ] . Djaldetti et al.

[ 60 ] described a PD patient who experienced

“delayed on” and “dose failure” phenomena after a vagotomy and pyloroplasty procedure, which may imply a connection between levodopa absorption and delayed GE.

Erratic gastric motility in PD patients results in periods of effective contractions that induce ef fi cient transit of food into the duodenum caus- ing rapid uptake of levodopa, which may contribute to the motor fl uctuations. Although the

“wearing off” phenomenon may be due to changes in central pharmacokinetics caused by diminished presynaptic dopamine storage capac- ity, peripheral levodopa pharmacokinetics, and especially erratic intestinal absorption of oral levodopa due to delayed GE, may account for the

“delayed on” and “dose failure” phenomena [ 54,

67 ] . The main support for this hypothesis is that these events can often be prevented or amelio- rated by taking levodopa before meals on an empty stomach

Kurlan et al. [ 68 ] assessed motility and plasma levodopa concentrations in PD patients exposed to levodopa administration in order to clarify the in fl uence of GE on levodopa-related motor fl uctuations and demonstrated that it is possible to produce steady plasma levodopa concentrations with a corresponding reduction in motor fl uctuations by continuous intraduodenal administration of the drug [ 69 ] . Other enteral routes, such as gastric ones, have produced more variable

plasma levodopa concentrations and an accept- able clinical response [ 68 ] .

It seems that the success of levodopa treatment depends, in part, on normal gastric motility, and that stagnation of levodopa within the stomach due to reduced gastric motility and prolonged transit time may affect the bioavailability of the drug. In a recent study, however, there was no difference in GE time between PD patients under long-term levodopa/decarboxylase inhibitor therapy with and without motor fl uctuation [ 70 ] .

Taking a levodopa dose before or after ingest- ing a meal is an important determinant of drug absorption. Time to peak plasma levodopa con- centration increased threefold (from 45 ± 23 to 134 ± 76 min, p < 0.001) when levodopa was administered after meals in a study by Baruzzi et al . [ 46, 71 ] . Fatty food can slow GE, at least in non-PD persons [ 71 ] .

Bypassing the stomach and administering levodopa via nasoduodenal or gastrojejunostomy tubes [ 60, 68 ] may be an optimal decision for patients with severe motor fl uctuations.

Intraduodenal administration of levodopa is thought to be an ideal model for the development of continuous-release preparations of levodopa [ 68, 69 ] . The success of modern intraduodenal levodopa/decarboxylase inhibitor intestinal gel infusion makes this the procedure of choice in fl uctuating patients.

Therapy for Gastric Motility Disturbances in PD

Nonpharmacological treatment of gastroparesis in PD includes a diet that consists of small, frequent low-fat and low-protein meals. Special consideration must be given to protein intake due to the potential correlation between decreased absorption of levodopa and a protein-rich diet.

Astarloa et al. [ 72 ] established a positive effect of a diet rich in insoluble fi bers on plasma levodopa concentrations (particularly 30–60 min after dosing) and motor function of PD patients following a levodopa dose. Avoidance of anticholinergic medications may also help in the management of gastroparesis. The muscarinic cholinergic agent,

bethanechol, enhances gastric contractions but not in a coordinated way to stimulate gastric emptying and, therefore, is limited in terms of acting as a prokinetic agent [ 73 ] . The most commonly used prokinetic medication in PD is the peripheral dopamine receptor antagonist, domperidone, fi rst proposed by Agid et al. [ 74 ] and by Quinn et al. [ 75 ] . Domperidone in a daily dose of 80 mg signi fi cantly reduced upper GI symptoms (nausea, vomiting, anorexia, abdominal bloating, heartburn, and regurgitation) and accelerated GE of a solid meal but did not interfere with response to antiparkinsonian treatment [ 64 ] . In addition, domperidone has an antiemetic effect by acting on the chemoreceptor trigger zone. Domperidone is not available in the USA but is commonly used in other countries for the management of GI symptoms. It is typically dosed orally at 10–20 mg, three or four times daily. A supposi- tory form is available as well.

Cisapride has no direct antidopaminergic effect and is effective and well tolerated in fl uctuating PD patients, in whom it produces a signi fi cant shortening of the time from latency to

“on” and reduction of the number of dose fail- ures. This effect is related to improved pharmacokinetic parameters of levodopa [ 66, 76 ] , although exacerbation of tremor also has been reported [ 77 ] . The usual dose of cisapride is 10–20 mg four times daily, usually given 30 min before meals. Because of potential cardiac arrhythmias precipitated by numerous drug inter- actions and medical conditions, cisapride was withdrawn from the open market in the USA and the UK in 2000 but is still in use in a few countries worldwide.

Mosapride is a gastroprokinetic agent that acts as a selective 5HT4 agonist. It was tested in an open label study involving fi ve PD patients with fl uctuations; the investigators reported signi fi cantly shortened GE time, reduced fl uctuations, and improved motor function in all patients, and no adverse reactions were noted [ 78 ] .

The motilin receptor agonist, erythromycin, may be effective in patients with gastroparesis, especially in relieving acute gastric stasis when given at a dose of 1–3 mg/kg intravenously every 8 h. Oral dosing of 50–250 mg four times

Dalam dokumen Parkinson's Disease and Nonmotor Dysfunction (Halaman 156-166)