Autonomic dysfunction causes motor neuron disease

Gastrointestinal dysfunction

In recent years, similar pathological mechanisms for gastrointestinal autonomic disorders affecting both the central and peripheral gastrointestinal nervous systems have been identified in most neurodegenerative diseases.

Most metabolic, hereditary, autoimmune, paraneoplastic, and toxic neuropathies can result in gastrointestinal autonomic dysfunction.

In addition to dietary measures, medicinal products can be used for the symptomatic treatment of gastrointestinal dysfunction, e.g. B. antidopaminergic substances, cholinesterase inhibitors, drugs that improve gastrointestinal motility, such as erythromycin, or serotonergic substances and also antiemetics and laxatives are used.

The gastrointestinal nervous system: anatomy and physiology

The gastrointestinal tract is innervated by both the intrinsic and extrinsic nervous systems. The intrinsic or enteric nervous system (ENS) is located directly in the intestinal wall. Although it regulates gastrointestinal function independently, it is modulated by the extrinsic nervous system made up of the sympathetic and parasympathetic autonomic nervous systems (ANS).
The ENS is formed by two plexuses: on the one hand by the plexus myentericus (Auerbach plexus), which is located between the circular and longitudinal muscle layers of the tunica muscularis, and on the other hand by the plexus submucosus (Schabadasch and Meissner plexus), which is located below the Muscle layer located in the tela submucosa. The two plexuses modulate gastrointestinal motility through the interstitial Cajal cells ("interstitial cells of Cajal", ICC). These mesenchymal cells, which are in contact with each other or with cells of the smooth muscles, serve as "pacemakers" by generating "slow waves" in the smooth muscles of the intestinal wall and thus maintaining a spontaneous basic rhythm of the peristaltic movement1. ICC are also the target of both excitatory impulses, induced by acetylcholine and substance P (SP), as well as inhibitory signals, mediated by the vasoactive intestinal polypeptide (VIP) and nitric oxide (NO)2 (Tab. 1).



The ENS controls gastrointestinal motility, predominantly in the small intestine, during the fasting period in the form of propulsive, peristaltic antegrade movements known as the migrating motor complex (MMC). The MMC is important to keep the upper gastrointestinal tract free of food particles and to regulate the intestinal flora. The ENS also partially controls both the basic tonic contractions of the upper and lower esophageal sphincter, pylorus and anal sphincter as well as the transient relaxation of the lower esophageal sphincter during food intake.
Through the supply of food, both mechanical stimuli through distension and chemical immunomodulatory signals stimulate the ENS and, independently of the central and peripheral autonomic innervation, reflexively generate an inhibitory or excitatory modulation of the basic gastrointestinal activity3.
The ENS not only controls gastrointestinal motor activity, but also regulates mucosal blood flow and targets neuroendocrine and immunological gastrointestinal cells. The vessels of the mucosal microcirculation play an essential role in the absorption of nutrients and, together with neuroendocrine and immunological gastrointestinal cells, regulate the modulation of the endocrine, immunological and inflammatory activity of the gastrointestinal tract.
Cholinergic, serotonergic, substance P and VIP producing myenteric neurons may be involved in inflammatory and immunological activity. NO-producing neurons can both inhibit and generate an inflammatory response4.

The extrinsic nervous system: sympathetic and parasympathetic autonomous nervous system (ANS): Endocrine cells located in the intestinal mucosa can modulate gastrointestinal function by releasing intestinal hormones (e.g. gastrin, motilin) ​​in situ. However, the main control of enteric function is incumbent on the extrinsic nervous system.
The extrinsic nervous system is formed by networks of the sympathetic and parasympathetic nervous systems, which regulate gastrointestinal function and connect the ENS to the central nervous system (CNS).
The CNS receives viscerosensory afferents, processed by chemo and mechanoreceptors of sensory nerves, and initiates regulatory reflexes (cranial or spinal) through autonomic sympathetic and parasympathetic pathways.
The cranial parasympathetic autonomous supply of the stomach and the upper part of the intestine takes place via the vagus nerve (cranial nerve X), which carries around 80–90% sensory fibers and whose cell bodies are located in the ganglion nodosum (inferior ganglion of the vagus nerve). The afferent fibers end in the nucleus solitarius (core of the tractus solitarius) in the medulla, which has projections to other brain regions such as the hypothalamus and the amygdala. The dorsal nucleus of the vagus nerve, located in the medulla, sends efferent projections to the local ganglia of the gastrointestinal tract. The right vagus nerve descends to the esophagus, forms part of the esophageal plexus and enters the abdominal cavity through the diaphragm as the posterior vagal trunk. After releasing fibers to the esophageal plexus, the left vagus nerve descends into the abdomen as the anterior vagus trunk. The vagus nerve is in direct connection with the myenteric plexus of the stomach and thus controls both gastric motility and emptying.
The spinal autonomic system is formed by splanchnic (sympathetic) and pelvic (parasympathetic) nerves. The cell bodies of the afferent fibers of these nerves are located in the dorsal root ganglia. The efferent fiber cords of the splanchnic nerves (thoracic, lumbar, sacral) originate from the border cord (T1 – L2), the cell bodies of which are located in sympathetic neurons in the intermediolateral nucleus. After switching in the celiac ganglion, superior mesenteric ganglion and inferius ganglion, these enter the solar plexus, intermesenteric plexus and hypogastricus. The pelvic nerves arise from the lateral gray matter of the sacral spinal cord (S2 – S4) and form the sacral plexus (inferior hypogastric plexus).
The sympathetic gastrointestinal innervation promotes the redistribution of the regional blood flow during stress, sporting activity, temperature fluctuations and changes in position and thus controls the vasomotor tone. The parasympathetic gastrointestinal autonomic system, on the other hand, controls reflexes that are important for gastrointestinal motility, sphincter control and secretion.
Preganglionic autonomic nerves, sympathetic and parasympathetic, are usually composed of small, thin myelinated or unmyelinated fibers and use acetylcholine as a neurotransmitter4a.
The sympathetic postganglionic autonomic nerves of the gastrointestinal tract are adrenergic, use adrenaline / noradrenaline as a neurotransmitter and consist of long axons of unmyelinated, small fibers (type C). The postganglionic parasympathetic autonomic nervous system, on the other hand, uses acetylcholine as a neurotransmitter and is characterized by short, unmyelinated axons.

The central nervous system (CNS) and the control of gastrointestinal autonomic function: Various central structures are involved in the control of gastrointestinal autonomic innervation. Regions of the prosencephalon including the amygdala, hypothalamus, insular and anterior cingular cortex modulate the autonomic function and are responsible for processing emotions, stress, stimuli, endocrine responses and visceral sensations.
Some pontomesencephalic brainstem regions such as the periaqueductal gray and parabrachial nuclei are just as important to regulate the autonomic function in response to pain and stress stimuli through the connection of deep brainstem areas and spinal autonomic centers with regions of the prosencephalon5.
Various neurotransmitters are involved in the CNS modulation of the cranial and spinal autonomic systems. Monoamines such as adrenaline, noradrenaline (NE), serotonin, neuropeptides such as substance P and neuropeptide Y, hormones including thyrotropin-releasing hormone, met-enkephalin, vasopressin, oxytocin and amino acids such as GABA, glutamate, glycine
are released at the preganglionic neuronal level. While hormones such as ghrelin and motilin accelerate gastric emptying and are released during the fasting period, cholecystokinin (CCK), gastrin, glucagon-like peptide 1 (GLP1) are secreted after ingestion and slow gastric emptying6.

Gastrointestinal autonomic disorders in neurodegenerative diseases

In recent years, increasingly similar pathological mechanisms affecting both the central and peripheral gastrointestinal nervous systems have been identified in most neurodegenerative diseases (Tab. 2).
Due to the lack of degradation mechanisms and structural alterations induced by genetic mutations, environmental toxins or viral pathogens, proteins that are normally expressed in neurons can accumulate and form misfolded cellular and extracellular aggregates. These inclusion bodies represent the pathological characteristic of the various neurodegenerative diseases.
The corresponding protein aggregates, which differ in terms of pattern and density of distribution in the individual neurodegenerative diseases, are present in numerous CNS structures, sympathetic and spinal ganglia and also in the gastrointestinal plexus. Aggregated α-synuclein (in Parkinson's disease - PD, multiple system atrophy - MSA, Lewy body dementia), dew protein (in progressive supranuclear palsy and corticobasal degeneration), β-amyloid (in Alzheimer's disease), SOD-1 and TDP43 (in motor neuron diseases and frontotemporal degeneration) can affect neighboring cells through exocytic mechanisms including inflammation and oxidative stress, which lead to cell death and neurodegeneration. In prion-like diseases, these protein aggregates can spread from the periphery (from the myenteric and submucosal plexus through autonomous innervation) into the spinal cord, into the brain stem and into other CNS structures or vice versa7. Some authors consider the gastrointestinal tract to be the origin of neurodegeneration (e.g. in Parkinson's disease or MSA), since gastrointestinal dysfunction is a common premotor symptom in these diseases8–11.




Parkinson's disease, Lewy body dementia: α-Synuclein aggregates, which form Lewy bodies and Lewy neurites, are the hallmark of Parkinson's disease and Lewy body dementia and are already in the early phase of the disease (corresponding to the Braak PD pathology stages)12 Present in the dorsal vagus nucleus, olfactory bulb, midbrain and neostriate. Furthermore, Lewy bodies can also be found to a large extent in the spinal cord, in sympathetic ganglia, in the parasympathetic and enteric nervous systems and lead to gastrointestinal premotor symptoms such as dyspepsia, oesophageal achalasia and constipation, which are caused by slowed gastrointestinal motility10, 13. The presence of Lewy bodies in the submandibular salivary glands and the corresponding sympathetic and parasympathetic structures may explain the reduced saliva secretion in the early phase of Parkinson's disease.

Constipation is also more common in PD patients than in healthy people14, and recent studies have shown that constipated patients have a 3.3–4.2-fold increased risk of developing Parkinson's disease15. Almost 90% of PD patients suffer from constipation, which often worsens with increasing progression16. Disturbed gastric emptying, which causes symptoms of the upper gastrointestinal tract, is also present and interferes with the optimal absorption of levodopa and the effectiveness of the therapy, which can subsequently be accompanied by a worsening of the levodopa-induced long-term side effects such as fluctuations17. In addition, receptors for hormones that affect gastric emptying, such as ghrelin, CCK, and GLP-1, are expressed in the basal ganglia and may have an impact on motor and non-motor symptoms of Parkinson's disease6, 17.
While dopaminergic medication can also induce gastrointestinal side effects, there have been reports of subthalamic deep brain stimulation (SNT-DBS), which can improve gastrointestinal Parkinson's symptoms, such as delayed gastric emptying17.

MSA, PAF: In the context of MSA, filamentous glial cytoplasmatic inclusions ("glial cytoplasmatic inclusions", GCI) consisting of α-synuclein are spread over a large area within the CNS structures and become with the neuronal cell death in the striatonigral pathways (in the Parkinson's variant, MSA -P) and also in the olivopontocerebellar networks (in the cerebellar variant, MSA-C). GCI are also found in the anterior horn and in sympathetic ganglia. In patients with pure autonomic failure (PAF), Lewy bodies and neuronal cell loss are predominantly present in postganglionic sympathetic neurons, but also in the brain stem and myenteric plexus11. Massive autonomic dysfunction such as dysphagia and anal incontinence also characterize these neurodegenerative diseases.

PSP, CBD, Alzheimer's: In patients with progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and Alzheimer's disease (AD), phosphorylated dew protein accumulates in neurons and glial cells of the brain and spinal cord. Neurofibrillary tangels (NFT), the hallmark of Alzheimer's disease, can also represent a non-specific pathology in the paravertebral sympathetic ganglia in Alzheimer's disease as well as in PSP and elderly patients. To date, no NFTs have been found in the myenteric plexus.
Since Alzheimer's disease is often associated with a Lewy body pathology, gastrointestinal dysfunctions similar to those in PD can also occur in AD patients. The corresponding symptoms include, in particular, impaired gastrointestinal motility, restricted gastric emptying and constipation.

Gastrointestinal autonomic disorders in the context of peripheral autonomic neuropathies

The sympathetic and parasympathetic autonomic nervous systems (ANS) are formed by small myelinated and unmyelinated fibers, the latter being predominant (approximately 80%). Most metabolic, hereditary, autoimmune, paraneoplastic, and toxic neuropathies involve the autonomic nervous system and can result in gastrointestinal autonomic dysfunction.
However, a clinical-neurological examination and an electrophysiological test are often not effective in diagnosing autonomic neuropathy. Autonomous function tests including heart rate variability during deep inspiration / expiration or Valsava maneuvers, blood pressure and heart rate changes during the tilt table examination or sudomotor stimulus response can be more informative in this regard.

Diabetic neuropathy: Among the metabolic neuropathies, diabetic neuropathy is the most common. The resulting hyperglycemia increases apoptosis-activating ATP-sensitive K+-Channels that lead to the destruction of enteric neurons within the myenteric and submucosal plexus, sympathetic ganglia, the vagus nerve and also the interstitial Cajal cells (ICC). Other pathogenetic mechanisms of neuronal cell death in diabetes mellitus (DM) involve decreased neuronal growth factor, increased circulating free fatty acids, altered TGF-β (transforming growth factor beta) and decreased antioxidants such as glutathione18. Furthermore, reduced blood flow and autoimmune / inflammatory processes may also play a role in terms of neuronal damage.
Denervation mainly affects sympathetic nerve endings, which have the function of reducing intestinal motility. Parasympathetic excitatory nerves are not damaged, at least at the onset of the disease. Loss of ICC is associated with impaired relaxation of the gastric fundus and the absence of slow, phasic peristaltic movements. Delayed gastric emptying and increased distal retention lead to gastroesophageal reflux, early onset of bloating, stomach pain, and vomiting18–20. Symptomatic gastroparesis is a rare complication of diabetic neuropathy that can occur in 4.8% of type 1 and 1% of type 2 DM patients. The decreased release of NO from vagal efferent fibers and its enzyme, nNOS, which is responsible for its generation, seems to play an important role in the pathogenesis of delayed gastric emptying21.
The reduced bowel movement consequently favors bacterial multiplication and diarrhea, which together with faecal incontinence is the most common symptom of diabetic neuropathy.Another mechanism that has emerged from some animal models and that may promote diarrhea involves the presence of accelerated intestinal transit18.

Hereditary sensory and autonomic neuropathies (HSAN) represent a group of rare diseases that are characterized by the degeneration of peripheral sensory and autonomic neurons and can lead to variable sensory and autonomic symptoms. It is classified into five types depending on heredity, neuropathology and symptoms. HSAN type III is the subtype that has the most autonomic symptoms. HSAN III, known as Riley-Day Syndrome or Familial Dysautonomy, is a rare autosomal recessive disease that primarily affects Ashkenazi Jews. The genetic basis is a mutation on chromosome 9q, which leads to a depletion of the IKAP / EPL1 protein and consequently affects cell motility22.
This genetic change results in a noticeable decrease in small C-fibers in the sensory and autonomic nervous system, which can be detected in the skin and peripheral blood vessels. Children develop early and severe symptoms such as loss of sensitivity (with frequent trauma and self-harm), lack of tear production, difficulty swallowing, pneumonia, orthostatic hypotension, autonomic crises with vomiting, and gastrointestinal dysmotility. Furthermore, early onset oropharyngeal problems in children with HSAN III are associated, which are manifested by a reduced sucking reflex, swallowing problems and consecutive salivation. Daily vomiting as a result of physical and emotional stressful situations can be another symptom23.

Fabry disease: Further hereditary sensory and autonomic neuropathies include the X-linked inherited disease Fabry's disease, also known as angiokeratoma corporis diffusum, which is caused by an α-galactosidase deficiency24 and porphyry neuropathy is characterized. The latter manifests itself as an attack-like, acute, hepatic porphyria, which can be induced by taking medication. Initially, this is characterized by abdominal pain, possibly resulting from the autonomic dysfunction, which leads to constipation, pseudo-obstruction and gastrointestinal dysmotility. The neuropathy progresses and can cause severe paralysis by affecting sensorimotor nerves25.

MNGIE: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disease caused by a mutation in the coding gene for thymidine phosphorylase. The predominant symptoms include external ophthalmoplegia, gastrointestinal motility disorders, peripheral neuropathy, and leukoencephalopathy. These patients are also mostly cachectic and suffer from neuropathic pain26.

Idiopathic, post-infectious, or paraneoplastic autoimmune neuropathies can lead to acute or subacute autonomic failure in the form of severe gastrointestinal dysmotility or pseudo-obstruction. Symptoms such as vomiting, abdominal pain, and constipation can resemble mechanical obstruction. Esophageal dysmotility (with achalasia) and gastrointestinal hypermotility can also occur in the context of autoimmune dysautonomy. The term autoimmune gastrointestinal dysmotility (AGID) is generally accepted in this regard to denote a gastrointestinal manifestation as a result of an autoimmune autonomic neuropathy.
Tumors, viral infections or vaccinations, but also idiopathic autonomic diseases can cause an abnormal immunological response and the formation of antibodies that attack autonomic nerves and / or ganglia. An increased protein content can often be detected in the CSF, which also occasionally also has positive antineuronal antibodies such as anti-Hu (often associated with a small cell lung carcinoma, or less often with a thymoma), anti-Ri, cytoplasmic antigens (amphiphysin, anti- Yo), antibodies against voltage-gated neuronal potassium channel complexes (VGKC), calcium channels, glutamate decarboxylase 65 (GAD65) or perinephrine IgG.
In some cases a specific autoantibody against the ganglionic nicotinic acetylcholine receptor (AChR) can be isolated27. The tumors most commonly associated with autoimmune diseases include small cell lung cancer, ovarian and breast cancer, and lymphoma28, 29. In paraneoplastic diseases, dysautonomy can occur both in isolation and in combination with other neurological symptoms such as sensorimotor polyneuropathy, cerebellar symptoms or limbic encephalitis.
Autoimmune autonomic ganglionopathy is a purely autonomic dysfunction that is characterized by acute or subacute sympathetic and parasympathetic failure as well as by a monophasic course and spontaneous remission or healing. Similar to Guillain-Barré syndrome, acute autonomic ganglionopathy can also develop into a chronic form and be associated with a viral infection that has taken weeks before the onset of symptoms (in about 60%). Specific antibodies against ganglionic AChR are isolated in approximately 50% of cases. Decreased plasma catecholamine levels are also a common feature of this condition30.

Gastrointestinal autonomic dysfunction associated with infections: Chagas disease

Autonomic dysfunction of the gastrointestinal tract can occur as part of a parasitic infection known as American trypanosomiasis or Chagas disease and caused by the protozoan parasite (flagellates) Trypanosoma cruzi31. The most common routes of infection include bug bite, transfusions, and congenital or oral transmissions. The latter refers to the ingestion of food or liquids that are contaminated with faeces containing pathogens. Chagas disease affects 8-10 million people worldwide and is common in Latin American countries. Due to the increasing migration of people from endemic countries to North America and Europe, this disease also represents a global health problem32.
After an incubation period of 3–100 days, an asymptomatic / oligosymptomatic (self-limiting febrile illness) or a symptomatic phase of 4–8 weeks occurs. The latter is characterized by fever, hepato- / splenomegaly, lymphadenopathy and localized or generalized edema. Mortality is low (5–10%) and fatal outcomes have been described mainly in children. In the acute phase, a high level of parasitemia occurs, which allows direct parasitological diagnosis. The chronic form can take variable courses, with 60% of those infected remaining asymptomatic. Cardiomyopathy or gastrointestinal dysautonomy occurs in 20–40% of patients. The gastrointestinal symptoms (dysphagia, regurgitation, chest and abdominal pain, chronic constipation and obstruction), which occur in 30% of patients with Chagas disease, result from its dilation of the esophagus and the colon. Inflammatory infiltration and cell death are responsible for ganglionic neuronal cell death, which subsequently leads to reduced intestinal transit, muscular hypertrophy and occasionally dilation of the esophagus / colon. In this phase serological or molecular biological methods can be helpful for the diagnosis33.

Therapy of gastrointestinal autonomic dysfunction

The non-pharmacological treatment of gastrointestinal dysfunction includes dietary measures. Patients should avoid overeating and instead eat smaller, more frequent meals. Furthermore, care should be taken to chew the food sufficiently and to avoid fiber-rich and fatty foods. Targeted use of drugs that affect gastrointestinal motility, such as anticholinergics and opiates, is also recommended.
Basically, the symptomatic treatment of gastrointestinal dysfunction includes antidopaminergic substances, cholinesterase inhibitors, drugs that improve gastrointestinal motility such as erythromycin or serotonergic substances (i.e., selective 5-HT4 receptor agonists such as prucalopride or mosapride), and also antiemetics. Analgesics can also be helpful in the treatment of abdominal pain (Tab 3).



Antidopaminergic substances: The dopamine receptor antagonist metoclopramide is indicated in the case of gastroparesis34. This has both a peripheral (in the upper gastrointestinal tract) and a central effect. Due to the inhibition of the enzyme CYP2D6-45, the simultaneous use of antidepressants such as tricyclics, selective serotonin reuptake inhibitors and antidepressants with both serotonergic and noradrenergic reuptake inhibition (venlafaxine or duloxetine) is contraindicated due to the increased risk of metoclopramide-induced extrapyramide-induced side effects. The most common symptoms of fatigue and exhaustion while taking metoclopramide. Due to the possible risk of extrapyramidal effects, long-term use should be avoided in patients with extrapyramidal diseases, younger patients and children35.
Itopride is a peripherally acting, antidopaminergic substance that additionally increases the acetylcholine level by inhibiting acetylcholinesterase and is used as a prokinetic. It is metabolized by the monoamine oxidase system and can therefore also be prescribed in combination with other drugs such as antidepressants. Due to its exclusively peripheral antidopaminergic effect, itopride can also be used in patients with extrapyramidal disorders (i.e. PD)35.
Domperidone, a dopamine D2 receptor antagonist that does not cross the blood-brain barrier, is helpful in accelerating gastric emptying and is the drug of choice for delayed gastric emptying, nausea and vomiting in PD or MSA patients35a.

Macrolide antibiotics: Their use can also be considered to improve gastrointestinal dysmotility. Similar to motilin agonists, these accelerate the MMC (migrating motor complex), although chronic use is limited due to the temporary antimicrobial effect17, 36.

Further prokinetics: The selective 5-HT4 receptor agonists, prucalopride and mosapride, as well as lubiprostone, which activates type 2 chloride channels, and linaclotide, which stimulates guanylate cyclase-C, are newer prokinetics35, 37.

Some prokinetics such as the gastric hormone ghrelin, ghrelin agonists and motilin, represent a promising treatment option for reduced gastric motility in patients with diabetic neuropathy and PD. However, some of these substances are currently only available for study purposes and controlled studies to further evaluate safety and effectiveness are needed in this regard38, 39.
Linaclotide is a prokinetic drug that modulates chloride secretion from intestinal epithelial cells by activating guanylate cyclase-C. This prokinetic improves defecation by stimulating GI secretion and motility, increasing stool frequency and weight. The main undesirable side effect of linaclotide is diarrhea40. The use of linaclotide is justified in both chronic constipation and opioid-induced bowel dysfunction (OIBD)35, 37.

Antiemetics: Phenothiazines such as B. Prochlorperazine are often used in the therapy of nausea and vomiting. The antiemetic effect results from the central effect on dopaminergic and cholinergic receptors. Nonetheless, their use is limited by the potential risk of extrapyramidal side effects. Other antiemetics include 5-HT3 antagonists such as ondansetron and granisetron, cannabinoids, opioid agonists, benzodiazepines, and H1 receptor agonists such as diphenhydramine.

Laxatives can be used in patients with chronic constipation, although side effects such as dehydration and intestinal occlusion should be considered41, 42. The most commonly used groups of laxatives are osmotic laxatives, such as lactulose, sorbitol, macrogol, polyethylene glycol 3350, magnesium and sodium salts or substances that increase GI secretion and reduce surface tension, such as docusate, and stimulants such as sennosides and bisacodyl, which are the Promote gastrointestinal motility35.

Analgesics: For chronic abdominal pain, antineuralgic therapy with gabapentin and pregabalin, also in combination with tricyclic and tetracyclic antidepressants, can be helpful. Due to the range of gastrointestinal side effects such as opiate-induced bowel dysfunction (OIBD) as well as the risk of physical dependence and the potential for addiction, other analgesics, including weak opiates such as naloxone and oxycodone, should be used sparingly and only in therapy-resistant cases35.

Other interventions: In severe cases of pseudo-obstruction or ileus, surgical intervention may be necessary. Electrical gastric stimulation is also an effective therapy option for severe gastroparesis and therapy-resistant vomiting43.
In some open studies, intrapyloric botulinum toxin injection has been assessed as effective in a small cohort of patients with pylorospasm. However, consecutively conducted controlled studies could not confirm the positive effect44, 45.
AGID (autoimmune gastrointestinal dysmotility) induced by post-infectious dysautonomy is usually self-limiting and only requires symptomatic intervention in the acute phase. Other forms of AGID (i.e., paraneoplastic or as a manifestation of idiopathic autoimmune disease) may require immunotherapy with intravenous immunoglobulin (IVIg) or methylprednisolone (IVMP), although the data on therapeutic efficacy are controversial. If there is an appropriate response to therapy, long-term maintenance therapy can be considered28.

Chagas disease: With regard to the treatment of Chagas disease, only two nitroheterocyclic substances (benznidazole and nifurtimox) are currently available and thus represent the only treatment options.
Since these therapies have a wide range of side effects such as intolerance, allergic reactions and fever, it is difficult to treat patients adequately. Accordingly, more active substances are needed and some drug studies are currently being conducted in this regard32.

PD, MSA: Due to the possible risk of developing tardive dyskinesia, the use of metoclopramide to treat gastroparesis is limited in patients with synucleinopathy (PD, MSA). Domperidone and selective 5-HT4 receptor agonists (e.g. prucalopride, mosapride) are adequate options for treating gastrointestinal motility, especially gastroparesis that occurs in the context of L-dopa fluctuations46, 47.
Improved gastric emptying increases L-dopa absorption and thus improves motor symptoms at the same time. Interesting data in this regard showed an improvement in gastrointestinal motility after subthalamic deep brain stimulation (STN-DBS), which is an effective treatment option in selected PD patients. An STN-DBS can improve the autonomic gastrointestinal dysmotility on the one hand directly through the connection of the nucleus subthalamicus with autonomic centers or on the other hand indirectly through the postoperative reduction of dopaminergic drugs48.


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