Diabetic Neuropathy Dr Michael Mulcahy Basildon University Hospital Diabetic Neuropathy • Classic glove and stocking sensori-motor neuropathy • Ischemic Mononeuropathy • Autonomic neuropathy • Entrapment neuropathies • Amyatrophy • Symmetric motor neuronopathy Diabetic Neuropathy – Common serious consequences • • • • • • • • Neuropathic Foot Ulceration Neuroischaemic Foot and amputations Increased risk of pressure ulceration Charcot’s Neuroarthropathic degeneration Erectile Dysfunction Diabetic Gastroparesis Reduced mobility Falls, fractures and injuries ‘Classic’ Diabetic neuropathy Peripheral glove and stocking sensori-motor polyneuropathy – Large fibre Axonopathy • • • • Painless parasthesia Reduced light touch, pressure, vibration, joint position. Loss of ankle reflex Sensory Ataxia – Small fibre axonopathy • Neuropathic pain • Reduced or altered pain and temperature response to stimuli • Autonomic neuropathy Diabetic Autonomic Neuropathy – Cardiovascular (arrhythmias, orthostatic hypotension and later hypertension, silent Myocardial Infarction) – GI tract (gastroparesis, diarrhoea, aspiration) – Urinary tract (retention, incontinence, erectile dysfunction) – Sweating (gustatory) – Metabolic (hypoglycaemic unawareness) – Reduced pupillary reflexes Asymmetrical proximal neuropathy (Diabetic Amyatrophy) • • • • • • • Pain (thigh, low back, often unilateral) Progressive weakness – wheelchair bound Loss of knee reflex Minor sensory component Weight loss Gradual recovery ?Immunologic +/- ischaemic Symmetrical Proximal motor neuropathy • Chronic Inflammatory Demyelinating Neuropathy (immunologic aetiology) – Exclude monoclonal gammopathy – Exclude vasculitis – Can affect upper limbs (Shoulder region) – Distal musculature also involved • Ischaemic lumbosacral radiculopathy Mononeuropathies • Entrapment neuropathies – Carpel tunnel – Ulnar neuropathy at elbow – Peroneal at fibular head – Lateral femoral cutaneous nerve (inguinal) • (Ischemic) mononuuropathies: most often – Oculomotor CNIII – CN IV – CN VII The Acute Diabetic Foot is a A Medical Emergency The ‘’Acute Diabetic Foot Attack’’ • • • • • Speed of treatment paramount Recognition of problem and its severity Proper examination Interpretation of imaging Rapid referral to Foot Treatment Team The Stairway to Amputation Infection Injury Vascular insufficiency Neuropathy Diabetes Wound Necrosis/ Amputation Gangrene Stage 6 Stage 5 Stage 4 Stage 3 Stage 2 Injury Vascular insufficiency Stage 1 Neuropathy Diabetes Wound Necrosis/Amputation Gangrene Infection The Stairway to Amputation YEARS DAYS Amputation Necrosis Infection Injury Vascular insufficiency Neuropathy Diabetes Wound Multiple level Intervention at each step to prevent amputation Major Limb Amputation •Sensible diet •No smoking •Well fitting shoes •Excellent metabolic control •Normotension •Statin Rx Plus Limited Plus Debridement amputation to effective/IV living tissue, further antibiotics revascularisation Plus VAC VAC Stage 6 MDT Cast Larvae protocol Larvae Plus • Regular wound podiatric Revascularisation Stage 5 care assessment Stage 4 • Total contact Amputation shoes Stage 3 Necrosis • Revascularisation Stage 2 Stage 1 Neuropathy Diabetes Injury Wound Infection Vascular insufficiency Speed of Rx is of the essence In hospital screening for the diabetic foot The Key: 1. Inspection of the foot. 2. Palpation of pulses or hand held Doppler 3. Test of sensation This test set is the in hospital ‘screening test’ for diabetic foot problems. Performed by the foot protection team – part of the duties of the in-reach acute diabetes assessment team. When an Ulcer is Present Answer the following questions? • What is the Depth ? superficial, full thickness of skin, down to muscle or bone • Is Infection Present ? Rubar Calor Dolar; Pus, systemicially unwell, blood markers • Is tissue Ischaemia present ? reduced or abscent pulses and/or Necrosis (may be localised) Also answer: • Is the patient systemically unwell ? • Is osteomyelitis present ? • Are gas forming organisms present ? • If Gangrene is present is it Wet or Dry ? The At Risk foot STAGE 2(a) Foot The High Risk Foot STAGE 2(b) Foot STAGE 3 Foot Presence of 1 risk Factor Neuropathy or Absent pulses or Foot deformity Neuropathy + absent Pulses +/deformity and /or previous ulceration episode, now healed. Relative Risk of ulceration here is 80 times the risk for those in Green box. Superficial Ulceration and skin fissures, no evidence of infection, or ?Charcot’s - hot swollen foot but no ulcer present The Infected Foot: Stage 4 STAGE 4 Foot STAGE 5 Foot when the Patient is Systemicially well and no necrotic or devitalised tissue is visible in the wound or foot If Charcots if archectural distortion already present The (Infected) stage 5 Foot -Patient systemicially unwell -Devitalised tissue -Necrosis -Visible/protruding bone -Gangrene Managed by GP and Podiatrist Managed by Podiatry and Orthotics intensively. Ring 01268 ………… Fax: Urgent Podiatry Referral. If Charcot’s suspected patient to minimise weight bearing on affected foot Ring: Fax referral: Same Day Urgent Podiatric referral or Diabetic Foot Clinic (DFC) Referral. Ring: Podiatry or K. Monk ward or Dr Mulcahy Fax : Refer to Hospital MDT Foot Team [AMU out of hours] DFC IP Care The patient with a foot ulcer Ranking the pathologies • Diabetic Neuropathy- neuropathy: Callus. Ulceration. Infection. – Lesions/ulcers are painless to touch • Peripheral vascular disease- proximal and or diffuse distal disease. • Many will also have renal/cardiovascular co morbidity. Angiogram. Beware contrast nephropathy. – Lesions are painful and often at friction sites rather than pressure sites • Many patients have both- the Neuro-ischaemic Foot – If the ulcer is painful then ischemia is usually the predominant pathology. • Charcot’s neuroarthropathic degeneration: severe distal neuropathy without peripheral vascular disease (bounding pulses). The shape of the foot is often distorted. Deep foot pain or discomfort on walking. Principles of care: Acute diabetic Foot ulcer 1. Rest the foot: Bed rest, Wheel Chair, Plaster Cast, Crutches, 2. Acquire deep tissue biopsy or bone samples for culture 3. Assess circulation, by palpation, Doppler +/- CT Angiogram. Restore viable circulation if required. 4. Debride most non viable tissue including bone as soon as possible. Several episodes of debridement may be required 5. Treat infection aggressively but responsibly. Decide on place of care - inpatient, OPD, community 6. Specialist dressings and Vacuum pump therapy for more involved wounds post debridement 7. Establish excellent metabolic/BP/lipid control 8. Plaster Casting for some wounds e.g. non healing wounds and all active Charcot’s 9. Orthotics referral and long term continuous use of Specialist foot wear 10. Long term podiatric and metabolic follow-up, community diabetes service. Diabetic Foot antibiotic formulary • Group 1: Patients who are systemically unwell or in septic shock. • Group 2: Serious/extensive soft tissue or bone infection requiring inpatient treatment. • Group 3: Osteomyelitis or other significant ulcer being managed on an out-patient basis from the diabetic foot clinic/theatre (DFC-T). • Group 4: Community based therapy. • Step-down therapy on discharge for group 1 and 2 patients • Pre-op antibiotics WHO-SSCL Group 1 (Sepsis syndrome) • 1st Line Treatment: Tazosin 4.5g iv tds + Gentamicin 5mg/Kg iv od. If MRSA add Teicoplanin 400mg iv bd for 3 days then 400mg od. • Penicillin allergic: Meropenem 1g iv tds + Gentamicin 5mg/Kg. If MRSA add Teicoplanin as above. • Anaphylaxis to penicillins: Teicoplanin 400mg iv bd x 3 doses then 400mg iv od + Gentamicin 5mg/Kg + Metronidazole 500mg tds iv. • NB Always review antibiotic Rx, with a view to narrowing spectrum, once results of culture available • All patients to be referred to the diabetes Foot Care Team immediately after discovery of a diabetic foot ulcer. • If response to antibiotics is poor at 48hrs further discuss with Microbiology. Group 2 (extensive/deep ulcer+/- osteomyelitis). • 1st line: Flucloxacillin 1g iv qds + Benzylpenicillin 1.2 million units iv qds. If MRSA +ve give iv Teicoplanin 400mg BD x3 doses, then OD + po Fusidic Acid 500mg tds • Penicillin allergic: Teicoplanin and Fucidic acid as per MRSA guideline above. • Review with culture results: • Remember that superficial swabs isolating gram negatives often reflect colonisation rather than the true infectious pathogen. Deep wound material or bone samples will normally be submitted by the DFC-T • If poor response to ABx at 48hrs please discuss with Microbiology. Groups 3 & 4 (Infected ulcer+/-osteomyelitis (community acquired), community care and out patient only care) • 1st line: Flucloxacillin 1g po qds + Fucidic acid 500mg po tds • Penicillin allergic: Clindamycin 450mg po qds • MRSA: Doxycycline 100mg po bd + Fusidic Acid 500mg po tds or Linezolid 600mg bd (microbiology approval and safety blood monitoring required) • NB Please check sensitivities of the MRSA prior to starting Rx and discuss with Microbiology if an alternate regimen is required. • Review management with culture results. Step down therapy. Group 1 and 2 patients on discharge from hospital. • All non viable tissue, bacterial biofilm and infected bone and bone sequestra will have been debrided from the wound usually at the DFC-T. • Deep tissue samples and bone cultures will help guide antibiotic therapy particularly if MRSA, ESBLs or polymicrobial infections present. • Once the wound and patient are stable discharge should occur with further follow up at the DFC-T. • A switch to oral antimicrobial therapy should take place except under exceptional circumstances. Diabetic Foot Ulcer Multidisciplinary Care Team • Diabetologist • Vascular Surgeons • Interventional Radiologists • DSNs (Hospital) • TVNS • Ward Staff Nurses • Medical Photographers • • • • • Microbiologists Radiologist Orthopaedic Surgeon Podiatrist Plaster Room Technician • District and TV Nurses • DSNs (Community) Broad Outcomes • A high quality diabetic foot service should ensure: – No or very few major limb amputations relating to neuropathic ulceration – No or very few major limb amputations relating to infection – All or the vast majority of amputations should come from those who have both (1) Severe ischaemia and (2) Diffuse inoperable peripheral vascular disease Types of Pain • • • • • Nociceptive pain Inflammatory pain Neuropathic pain Combination of different pain modalities dysfunctional pain Neuropathic Pain • Non functional/non protective • Reaction of the nervous system itself to nervous system damage (i.e. it’s a disease state) • Peripheral nerve damage e.g. Herpes Zoster, painful diabetic neuropathy • Central nerve damage (MS, CVAs, spinal cord injury) Prevalence of neuropathic pain Nervous system damage Diabetes 30% to 50% Type 1> Type 2 Chemotherapy 10 to 40% HIV 30% Radiculopathies 30% neuropathic H. Zoster 30% PHN Stroke 5% Carpal tunnel syndrome 15% pop. risk Comorbidity associated with peripheral neuropathic pain Difficulty sleeping 60% 55% Lack of energy Drowsiness 39% Concentration difficulties 36% Depression 33% Anxiety 27% 18% Poor appetite 0 10 20 30 40 50 60 70 % patients with moderate to severe discomfort due to neuropathic symptoms (n=126) 1. Meyer-Rosberg K, Kvarnström A, Kinnman E et al. Eur J Pain 2001; 5(4): 379–389 Signs and symptoms of neuropathic pain Sign/Symptom Description (example) Spontaneous symptoms Spontaneous pain1 Persistent burning, intermittent shock-like or lancinating pain Dysesthesias2 Abnormal, unpleasant sensations, e.g. shooting, lancinating, burning Parasthesias2 Abnormal, but not unpleasant sensations, e.g. tingling Stimulus-evoked symptoms Allodynia2 Painful response to a non-painful stimulus, e.g. warmth, pressure, stroking Hyperalgesia2 Heightened response to painful stimulus, e.g. pinprick, cold, heat Hyperpathia2 Delayed, explosive response to any painful stimulus 1. Baron R. Clin J Pain. 2000; 16(2 Suppl): S12–S20 2. Merskey H, Bogduk N (Eds). Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms (2nd Ed). Seattle: IASP Press, 1994 SKIN Non-neural cell e.g. Keratinocyte TRPA1 TRPM8 ASIC TRPVs 5-HTR P2X TRKA GPCRs Soma in DRG VGCC Nocisensors Spinal Cord Substancia Gelatinosa mast cell SKIN Noxious e.g. tissue damage, hot or acid surface etc 0.4 to 50 m/s (c fibre) (A beta) TRPA1 NSC TRPM8 TRPV3 TRPV3 5-HT ATP 5-HT ATP ATP ATP ASIC TRPVs 5-HTR P2X TRKA VGCC GPCRs bradykinin ATP bradykinin bradykinin bradykinin Receptor Potential Action Potential Threshold reached Ca++ Noxious Stimulus bradykinin TRPV3 5-HT ATP TRPA1 TRPM8 ASIC TRPVs 5-HT P2X TRKA GPCRs Na+ k+ VGCC Ca++ Descending Modulatory Pathways and a complex set of interneurones modulate the raw nociceptor signal ….. .. . …. . ..... . . .. AMPA .. . ... . mGluR .... .. ; NMDA ... ... .… .. Dorsal root ganglion TRPVs 5-HT P2X VGCC GPCRs Nociceptor spinal cord Dorsal root ganglion Low K+ buffering perineuronal rings IL1B PGE2 NO CGRP TRPVs 5-HT ATP 5-HT bradykinin ATP P2X VGCC ATP GPCRs Nociceptor spinal cord TNFa Dorsal root ganglion Low K+ buffering perineuronal rings IL1B PGE2 NO CGRP IL15 MMP 9 TRPVs 5-HT P2X VGCC GPCRs Sub.P platelet activation CGRP Attract Inflammatory mediators, vasodilatation Nociceptor Calor, rubar, dolar spinal cord To Memory To association areas TRPVs 5-HT Direct to Pain pathway P2X GPCRs To Learning response areas VGCC To Emotional response areas spinal cord Neuropathic Pain (1)Direct, Acute Nerve injury Spinal cord descending modulatory pathway Dorsal root ganglion Direct Nerve Injury Ascending e.g. Spinothalamic tract High threshold nociceptor Peripheral Sensitization (1) Direct nerve injury Dorsal root ganglion Spinal cord descending modulatory pathway Retrograde protein transportation e.g. Importin-B, associated with massive transcriptional program activation Nerve injury spontaneous repeated Ectopic action potentials New but rapidly appearing Nav1.7,1.8 and Cav2.2 channels High threshold nociceptor Ascending e.g. Spinothalamic tract high levels of glutamate, SP, CGRP excitatory neurotransmitters Peripheral sensitization (2) Effects on surrounding nerves Dorsal root ganglion Spinal cord descending modulatory pathway sympathetic/ Satellite cells Nitric oxide signalling in DRG local immune activation Inflammatory cytokines from Macrophages and Injured Nerves PAIN Signal to Brain Schwann cell cytokine signalling Various nerve fibres near site of injury, but not injured themselves Worsen neuropathic Pain by reduced threshold and thence increased firing rate into nociceptive range. Significant increase in ion channel numbers. Nearby uninjured nerve terminals are now LOW threshold nociceptors (Hyperalgesia, allodynia) Ascending e.g. Spinothalamic tract Polymorphisms in these ion channels e.g. NaV, 1.7, 1.8 appear to increase risk of developing painful as opposed to painless neuropathy Central sensitization Dorsal root ganglion Spinal cord descending modulatory pathway PAIN Signal to Brain Nerve injury very high excitation stuns and if sustained kills the inhibitory interneurone (hyperexcitation induced apoptosis) Ascending e.g. Spinothalamic tract Central sensitization Dorsal root ganglion Spinal cord descending modulatory pathway Now what would previously have been a sub-threshold impulse is now clear to get through PAIN Signal to Brain Ascending e.g. Spinothalamic tract ‘Activity Dependant Synaptic Plasticity’; ‘Long Term Potentiation’ are methods by which the cord clears a path for frequently used pathways. Great for learning but if the pathway happens to be a pain pathway that’s bad news. Central sensitization Dorsal root ganglion Spinal cord Ongoing Nerve damage The NMDA(R) lowers the electrical threshold for nerve impulse generation. descending modulatory pathway PAIN Signal to Brain Ascending e.g. Spinothalamic Increasing numbers of these receptors appear over time. tract The effect is an increase in the strength of the synapse This is referred to as ‘Wind-up’ whereby intensity and duration of firing rises even though the nerve input is constant. Great for learning but this is really bad news if the pathway is a pain pathway. Neuropathic pain has a major immune and inflammatory component. Ongoing nerve damage PAIN Signal to Brain Dead, dying and stressed out nerve terminals in the spinal cord. Massive immune cell (Microglia) reaction. Inflammatory cytokines and neurotrophic factors sensitize nociceptive neurones Most of the dead and dying cells are unmylinated c-fibres which have limited regenerative capacity Spinal cord Heavily Mylinated ABeta- Fibre: Not normally involved in nociception Spinal cord Dorsal root ganglion Ascending e.g. dorsal column Low threshold e.g. light touch Proprioception Spinal cord Central Sensitization: Ascending e.g. dorsal column Heterosynaptic facilitation Dorsal root ganglion Ongoing nerve damage PAIN pathway Low threshold light touch or vibration sensor Sprouting of CNS terminal into Lamina II section of cord i.e. into nociceptor region. vibration, light touch stimuli etc now felt as pain. (Allodynia) Inflamed zone Neuropathic Pain • Peripheral sensitization – Internal wind up and soma transcriptional program activation – external spreading • Inflammatory mediators • Wound healing signals • Products of damaged nerve breakdown • Central sensitization – Interneurone apoptosis and rewiring – Wind up of core pain pathway – Heterosynaptic inputs • Central Immunologic activation Ascending Spinothalamic Nociceptive Pathway Somatosensory cortex Hippocampus Thalamus Amygdala (nucleus centralis) Insular Cortex Limbic areas Abnormalities in Thalamic neurone firing rates also noted in diabetic neuropathy. Parabrachial Area (Pontine nuclei) Spinobrachial, Spinothalamic tract Descending Modulation • Emotional and contextual milieu is very important in pain perception • Fear, anxiety, hopelessness may enhance pain while knowledge of great achievement, mortal danger, or determination may eliminate pain completely. • Autonomic responses – heart rate and BP changes, diversion of blood from splanchnic bed to skeletal muscle (fight and flight etc) also occur. Descending Modulatory Pathway Somatosensory Cortex Anterior Cingulate Gyrus Insular Cortex Hippocampus Limbic areas Parahippocampus Amygdala Peri-Aquaductal Grey Matter cannabinoids (circuit breakers) Ventro-Medial Medulla BDNF CCK Opioid Descending Modulatory Pathway Somatosensory Cortex Anterior Cingulate Gyrus Insular Cortex Hippocampus Limbic areas Parahippocampus Amygdala Peri-Aquaductal Grey Matter cannabinoids (circuit breakers) Ventro-Medial Medulla BDNF CCK Opioid Opiates (Enkephalins Endorphins) BDNF CCK cannabinoid circuit breakers ON cells OFF cells 5HT NA Descending Facilitation (5HT-R3) Descending Inhibition a2-R (Pain, Temperature, Autonomic and Motor responses also effected) Combining ascending and descending pathways Anterior Cingulate Gyrus Somatosensory Cortex Hippocampus Parahippocampus Insular Cortex T T Limbic areas A PAG VM PAG PB VM Chronic Neuropathic Pain can become a neurodegenerative condition. 1st Synapse substansia gelatinosa interneurone network So neuropathic pain involves: • primary nerve injury, • peripheral and central sensitization, • descending modulation, • a major immunologic inflammatory component and • finally a neurodegenerative component that can cause permanent CNS damage. Direct nerve injury and other aetiology of Diabetic Neuropathy Metabolic Problems • Ox.phos free radical stress • Fatty acid metabolism • PKC activation • Amino Acid metabolism • AGE - RAGE interactions • Sorbitol/polyol pathway • c-peptide deficiency Aberrant regulation of Neurotrophic factors Axonopathy Schwannopathy Descending modulation Central ischaemia sensitization plasticity degeneration Ischaemia of peripheral nerve Vasa nervorum Immunologic attack • Primary Autoimmune process • Secondary immune following nerve damage inflammatory cytokines Entrapment Medications for neuropathic pain 1st synapse modulation Descending modulatory pathways Presynaptic terminal: Ca2+ VGCaCl Pregabalin Gabapentin Conotoxins Ziconotide Leconotide a2d NA/5HT opioid(R) a1 Alpha2R adrenergic agents e.g. Clonidine Opioids, Methadone SNRIs (Duloxetine*,venlafaxine) Tramadol TCAs Ondoncetron (anti 5HT3R) Postsynaptic terminal: Methadone NMDA Ketamine Dextromethorphan at least some Peripheral nerve action Na+ Vanilloid TRP *Licensed for painful diabetic neuropathy Carbamazepine Lamotrigine Lidocaine Oxcarbazepine Topiramate TCAs Capsaicin Receptor Direct Nerve Potential or Injury ….. .. . …. bradykinin TRPV3 ATP TRPA1 TRPM8 ASIC TRPVs 5-HT P2X TRKA GPCRs Nocisensors Na+ k+ Nav1.7 .. . . .. Na+ Repolarisation VGCC g a2 a1 Ca++ Sodium Channels . . . B d AMPA mGluR NMDA Ketamine Methadone Receptor Direct Nerve Potential or Injury Capsaicin bradykinin TRPV3 ATP TRPA1 TRPM8 ASIC TRPVs 5-HT P2X TRKA GPCRs Nocisensors opioids ….. .. . …. Na+ k+ Nav1.7 .. . . .. Na+ Repolarisation VGCC Sodium Channels Ziconotide g a2 pregabalin gabapentin a1 Ca++ Lignocaine Carbamazepine . . . B d AMPA mGluR NMDA My current Protocol (Diabetic neuropathic pain) 1. 2. In mild pain Paracetamol Duloxetine (SNRI) – NICE supports this as first line in painful diabetic neuropathic pain therapy. 3. 4. 5. 6. 7. Tricyclics - Amitryptline (NICE approved but not licensed), Gabapentin or Pregabalin (both licensed but tolerability variable at effective doses) Carbamazepine/Topiramate/Valproate (none licensed in this class) Morphine Sulphate/Oxycodone (severe pain only) Methadone (when all else has failed) Note: Combination therapy may be required to improve efficiency, limit side effects or dose intervals. (One from each group only). Erectile dysfunction Anatomy Compressed, Endothelial lined sinusoids Tunica Albuginea Urethra Emissary veins and subtunical venous plexus (dilated) septum pectiniforme Expanded blood filled sinusoids Corpus Cavernosum Smooth muscle Corpus Spongiosum (forms the glands penis distally) Crushed/compressed emissary Veins and plexus. Sympathetic nerve Endothelin-1 PGF2a ATII Tonicially contracted smooth Muscle cell Adrenaline Taut actin fibres bound to myosin head in presence of intracellular calcium Endothilium Venous type blood in compressed sinusoid Sympathetic Nerve Endothelial Cell PGF2a (R) Angiotensin II (R)1 Adrenaline Endothelin 1 (R) alpha -1(R) Normal resting state. Vascular Flexibility – ability to quickly flip from one state to another. Smooth Muscle Contraction: crushes the sinusoids and opens the draining veins Detumescence Parasympathetic Nerve (cholinergic) NANC ParaSympathetic nerves PGE1 Nitric Oxide PGE1 Nitric Oxide Nitric Oxide Acetylcholine PGE1 Nitric oxide PGE1 Nitric oxide (e-NOS) Arterial Blood in Filled sinusoid PGE1 Nitric oxide Relaxed Actin fibres dissociated from myosin Nitric Oxide PGE1 Nitric Oxide Nitric Oxide Nitric Oxide PGE1 NANC Parasympathetics Cholinergic Sympathetics c-GMP Relaxation Relaxation c-AMP Corpus Cavernosum Sym. nerves Higher centres Parasym. nerves Cholinregic nerves Angitensin II PGF2a Endothelin 1 Receptors Testosterone PGE1 Alpha 1(R) Secondary Messengers Nitric Oxide PGE1(R) cGMP cAMP SM relaxation SM constriction Degradation (PDE2,3,4.) Degradation (PDE5) Detumescence Erection Angitensin II PGF2a Endothelin 1 Parasym. Cholinregic nerves nerves Sym. nerves Phentolamine Doxazosin Neuropathy ALPROSTIDAL:PGE1 PGE1 Receptors Alpha 1 Higher Testosterone Centres (Caverject; MUSE) Nitric Oxide PGE1(R) Secondary Messengers PDE5i cGMP cAMP (Sildenafil, tadalafil, vardenafil) SM relaxation SM constriction Degradation Detumescence Erection Degradation (PDE2,3,4.) Nonspecific PDEi (Papaverine) Diabetic Gastroparesis • Mild gastric neuromotor dysfunction affects 30 to 50% of patients with diabetes of more than 10 years duration. • Mild dyspepsia, nausea, bloating, • varying degrees of abdominal discomfort • severe syndrome of recurrent vomiting, recurrent severe abdominal pain, weight loss water and electrolyte disorders • Severe reduction on QoL if this occurs. Fundal tone and antral phasic contractions need to be co-ordinated with pyloric and duodenal relaxation. Co-ordination required between •Gastric smooth muscles •Enteric nerve plexus (NANC parasympathics) •Intercalated (basal pacemaker) cells of Cajal) However poor correlation between symptoms and formal gastric emptying studies, implicating other factors. Management • Symptoms, OGD, Gastric sintigraphy Acute care: • Gastric motility agents • Anti emetics (multiple agents, from different classes) • IV insulin, IV fluids, Mg++, K+ • NJ feeding Later: • Excellent metabolic control, CSII Rx in some • Botulinum toxin in some • Gastric electrical stimulation in some Neuropathy • Multi-modal complication of diabetes • Interaction with other morbidities • When severe can be devastating to QoL, very expensive and life threatening – Major limb amputations – Severe Pain syndromes – Sexual Dysfunction – Recurrent severe vomiting syndrome Thank You