EntericEnteric NeuropathyNeuropathy and and DiverticularDiverticular DiseaseDisease
ClassicClassic pathogeneticpathogenetic conceptsconcepts
Diet
Ageing
Smooth muscle disorder
Connective tissue disorder
low fiber intake
myochosis
elastosis
predominant in the elderly
Enteric neuropathy ?
EntericEnteric NeuropathyNeuropathy and and DiverticularDiverticular DiseaseDisease
WhyWhy shouldshould entericenteric nervesnerves bebe involvedinvolved ??
increased intraluminal pressure
final common pathway for mucosal herniation
segmental hypercontractility („bladder colon“ / „concertina colon“)
increased motor activity
high amplitude propagated contractions
increased motility indices (manometric + myoelectric studies)
most evident after postprandial + pharmacological stimulation
increased painfull sensations
abdominal bloating
intestinal spasms
EntericEnteric NeuropathyNeuropathy and and DiverticularDiverticular DiseaseDisease
WhyWhy shouldshould entericenteric nervesnerves bebe involvedinvolved ??
intraluminal pressure motor activity painfull sensations
... ... mediatedmediated byby thetheentericenteric nervousnervous systemsystem (ENS)(ENS)
EntericEnteric NeuropathyNeuropathy and and DiverticularDiverticular DiseaseDisease
StructuralStructural alterationsalterations of of thethe ENSENS
MacBeth, J MacBeth, J ClinClin PatholPathol, 1965, 1965
• increase of nerve tissue
• glial cell proliferation
• ectopic ganglia
control diverticular disease First evidence in the literature
„Neuromuscularderangement“
EntericEnteric NeuropathyNeuropathy and and DiverticularDiverticular DiseaseDisease
StructuralStructural alterationsalterations of of thethe ENSENS
Stoss & Stoss & MeierMeier--RugeRuge, , SurgSurg EndoscEndosc, 1991, 1991
• submucous giant ganglia
• submucous nerve fiber hypertrophy
Intestinal neuronal dysplasia
diverticular disease
EntericEnteric NeuropathyNeuropathy and and DiverticularDiverticular DiseaseDisease
StructuralStructural alterationsalterations of of thethe ENSENS
Wedel et al., Wedel et al., ViszeralchirViszeralchir, 1999, 1999
• decreased ganglionic size• decreased nerve cell content• increased glial cell content
myenteric hypoganglionosis (25% of cases)
control diverticular disease
EntericEnteric NeuropathyNeuropathy and and DiverticularDiverticular DiseaseDisease
StructuralStructural alterationsalterations of of thethe ENSENS
Wedel et al., Wedel et al., ViszeralchirViszeralchir, 1999, 1999• submucous giant ganglia• submucous nerve fiber hypertrophy
Intestinal neuronal dysplasia (20% of cases)
control diverticular disease
EntericEnteric NeuropathyNeuropathy and and DiverticularDiverticular DiseaseDisease
StructuralStructural alterationsalterations of of thethe ENSENS
Simpson et al., Simpson et al., GastroenterolGastroenterol, 2002, 2002
• increased intramuscularnerve fibers
• increased mucosalnerve fibers
proliferative nerve remodelling
regenerative hyperinnervation
control chronic diverticular disease
EntericEnteric NeuropathyNeuropathy and and DiverticularDiverticular DiseaseDisease
FunctionalFunctional alterationsalterations of of thethe ENSENS
Neurotransmitters
• increased VIP-positive neuronsMilnerMilner et al., et al., GastroenterologyGastroenterology, 1990, 1990
• upregulation of tachykinins (substance P, neuropeptide K)• upregulation of galanin• in patients with painfull diverticular disease
Simpson, Simpson, SchofieldSchofield & & SpillerSpiller, , BritBrit J J SurgSurg, 2003, 2003
„„ ......visceralvisceral hypersensitivityhypersensitivity originatesoriginates locallylocally, , possiblypossibly as a as a resultresult of nerve of nerve damagedamage followingfollowing acuteacute diverticulitisdiverticulitis..““
EntericEnteric NeuropathyNeuropathy and and DiverticularDiverticular DiseaseDisease
FunctionalFunctional alterationsalterations of of thethe ENSENS
Neuroreceptors GolderGolder et al., et al., LancetLancet, 2003, 2003
• decreased cholinergic innervation• increased muscarinergic receptors
control diverticular disease
„... cholinergic hypersensitivity due to upregulation of muscarinergic receptors.“
EntericEnteric NeuropathyNeuropathy and and DiverticularDiverticular DiseaseDisease
FunctionalFunctional alterationsalterations of of thethe ENSENS
in-vitro contractility
GolderGolder et al., et al., LancetLancet, 2003, 2003
• increased contractionsafter exogenous acetylcholine
HuizingaHuizinga et al., et al., ScandScand J J GastroenterolGastroenterol, 1999, 1999
• uncoordinated contractionsafter exogenous acetylcholine
EntericEnteric NeuropathyNeuropathy and and DiverticularDiverticular DiseaseDisease
FunctionalFunctional alterationsalterations of of thethe ENSENS
in-vitro contractility
• decreased ability to relaxafter electrical field stimulation
• decreased ability to relaxin response to VIP / NO
Tomita et al., Tomita et al., RegulRegul PeptPept, 1993, 1993
EntericEnteric NeuropathyNeuropathy and and DiverticularDiverticular DiseaseDisease
SummarySummary of ENS of ENS alterationsalterations
Structural alterations
Functional alterations
• myenteric hypoganglionosis• submucosal hyperganglionosis• mucosal nerve fiber hypertrophy
• upregulation of neurotransmitters• upregulation of muscarinergic receptors• hypercontractility• insufficient relaxation
Enteric neuropathy ?
EntericEnteric NeuropathyNeuropathy and and DiverticularDiverticular DiseaseDisease
SummarySummary of ENS of ENS alterationsalterations
Structural alterations
Functional alterations
• myenteric hypoganglionosis• submucosal hyperganglionosis• mucosal nerve fiber hypertrophy
• upregulation of neurotransmitters• upregulation of muscarinergic receptors• hypercontractility• insufficient relaxation
Enteric neuropathy !
EntericEnteric NeuropathyNeuropathy and and DiverticularDiverticular DiseaseDisease
SummarySummary of ENS of ENS alterationsalterations
Enteric neuropathy !
intraluminal pressure
motor activity
painfull sensations
development of diverticula
generation of symptoms
EntericEnteric NeuropathyNeuropathy and and DiverticularDiverticular DiseaseDisease
TheThe openopen questionquestion::Primary lesion ?
Secondary lesion ?
• enteric neuropathy causes colonicmotor disturbances
• enteric neuropathy predisposes to diverticular disease
• enteric neuropathy = causative event
• enteric neuropathy results frominflammatory injury
• enteric neuropathy generates symptoms
• enteric neuropathy = concomittant event
EntericEnteric NeuropathyNeuropathy and and DiverticularDiverticular DiseaseDisease
ConclusionsConclusions
Enteric neuropathy...
• is associated with diverticular disease
• is characterized by both structuraland functional alterations
• could account for the disturbed motilityand symptom generation in diverticulardisease
• should be considered in a targetedtherapeutic approach (e.g. spasmolytics,muscarinergic antagonists, antinociceptiva)
EntericEnteric NeuropathyNeuropathy and and DiverticularDiverticular DiseaseDisease
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