diabetic autonomic neuropathy zaven panossian. mbchb, fracp...

Diabetic Autonomic Neuropathy

Zaven Panossian. MBChB, FRACP-----------------------------------------------------------------------------------------------------------------------------------------

Specialist Physician & EndocrinologistCounties Manukau Health

Ms MJ

21 year old NZE woman• Diagnosed with type 1 diabetes at 4 years of age.

– Poor glycaemic control (HbA1c 86 – 135 mmol/mol)– Fear of hypoglycaemia and of weight gain with insulin.– Complicated with microalbuminuria and mild diabetic

retinopathy.

Past Medical history• History of depression, irritability and explosive behaviour.• Probable absence seizures in 2007 – treated with Na valproate.• IQ at the lower end of normal range (80)• Appendicectomy in 2004.

Ms MJ

Diabetes OPC – October 2008.• recurrent nausea, vomiting and early satiety for ~ 6 months.• Lost ~ 4kg in weight.• Chronic constipation• Suspected to have gastroparesis aggravated by hyperglycaemia.• Advised to start pre-meal domperidone and to reduce the

amount of simple carbohydrates in her meals.

Medications.• Insulin glargine (Lantus) 24 U mane / 22 U nocte• NovoRapid 4-6 U pre-meals.• Coloxyl and Senna

February 2009Presented to NSH.• Vomiting and generalized abdominal pain.• No haematemesis, fever or change in bowel habits. • Recent deterioration of glycaemic control.

On examination.• Dry with mild tachycardia (HR 96 bpm) but otherwise well.• Soft abdomen with mild generalised tenderness.• Treated with 1 L of normal saline IV stat and GIK infusion.

Blood tests.• Arterial blood pH 7.35 after rehydration with 1 L normal saline.• Normal FBC and serum creatinine and electrolytes.

February 2009

Reviewed the next morning by Endocrinologist.• Symptoms were thought to be due to gastroparesis.• GIK infusion stopped and regular doses of insulin started.• Started on metoclopramide and erythromycin in addition to

domperidone.

Gastroscopy.• Mild erythematous / exudative gastritis – omeprazole started.• H. pylori – negative.• Coeliac serology - negative• Biopsy – mild chronic inactive gastritis

June-August 2009

Presented to NSH.• Nausea• Abdominal pain• Worsening of chronic

constipation.• Further weight loss ~13 kg.

Abdominal ultrasound • no abdominal pathology.

Treated with• IV antiemetics and IV fluids • Oral laxatives, movicol,

enemas and oral fleet with no improvement

Gastroenterology review

Gastroparesis with possible small bowel dysmotility• Nasojejunal Tube was inserted for feeding

Gastric emptying study (99m Tc labelled pikelets)• Marked slowing of gastric emptying consistent with severe

gastroparesis.

Seen regularly by Gastroenterologist and Dietitian• Tolerated NJ feeding with gradual introduction of oral feeding.

It was decided that she would need a percutaneous endoscopic gastrostomy with jejunal extension (PEG-J) for long term treatment of constipation rather than stoma formation.

Progress

Gradually but slowly improved over the following 2 months• with intermittent nausea and constipation.• recurrent blockage of the NJ tube

Discharged home on:• Movicol sachets – 1 sachet daily via NJT over 1 hour.• Lactulose 20 ml daily• Tube feed (Peptisorb) – 1L via NJT nocte.• Fortisip – 200 ml daily.• Paracetamol 1g PRN QID• Omeprazole suspension 40 mg daily

Follow upGastroenterology OPC – August 2009• Persistent symptoms• The plan for PEG-J was changed to operative jejunostomy

because directly placed endoscopic jejunostmy tube would pass through the stomach and make her stomach function worse.

• Ondansetron 4-8 mg daily PRN.

Diabetes OPC – September 2009• Persistent GI symptoms

– advised to increase Movicol to 1 sachet bd • Paroxysmal palpitations• Orthostatic hypotension.

– Started on Fludrocortisone 0.1 mg daily

November 2009

Laparoscopic insertion of feeding jejunostomy tube.

Ongoing struggle with gastrointestinal symptoms continued.• Since then she has had 25 admissions to NSH

Presenting Problem Admissions

DKA 4

Jejunostomy tube problems 5

Nausea / Vomiting / Constipation / Abdominal pain 9

Other 7

Weight

Main admission

with GI symptoms

HbA1c

Insertion ofJejunostomy

tube

Medications

Buccastem 3mg bdHyoscine butyl bromide 20 mg bdScopoderm dermal patchOmeprazole 40 mg bdCyclizine 50 mg PRN / TDSOndansetron 4-8 mg PRN / BD

Paracetamol 1g PRN QIDIbuprufen 400 mg PRN BD

Lantus 14 U mane / 22 U nocteApidra 2-10 U PRN BD

Fludrocortisone 0.1 mg bd Metoprolol CR 23.75mg daily

Ferodan liquid 10 mls BDQuetiapine 50 mg bd

Introduction

Diabetes mellitus is the most common cause of autonomic neuropathy in the developed world.

A broad constellation of symptoms occurs, affecting cardiovascular, urogenital, gastrointestinal, pupillomotor, thermoregulatory, and sudomotor systems.

With the exception of pain, these autonomic manifestations of diabetes• are responsible for the most troublesome and disabling features

of diabetic peripheral neuropathy, and• result in a significant proportion of the mortality and morbidity

associated with the disease.

Patterns of Diabetic Neuropathy

Spectrum of DANCardiovascular.

Gastrointestinal.

Abnormal Pupillary Responses.• Decreased dark adaptation.

Sudomotor.• Distal anhydrosis and Heat intolerance.

Genitourinary.• Neurogenic Bladder dysfunction.• Sexual / erectile dysfunction and Retrograde ejaculation.

Neuroendocrine.• Reduced Glucagon secretion in responses to hypoglycemia.• Delayed Epinephrin secretion in responses to hypoglycemia

Prevalence of DAN

Estimates of the prevalence of diabetic autonomic neuropathy are dependent on the criteria used for diagnosis and the specific population under study. • Few studies of diabetic autonomic neuropathy are without

referral or selection bias.

In a longitudinal, community-based study of 133 newly diagnosed type 2 diabetic patients (Toyry et al., 1996) parasympathetic dysfunction, determined by heart rate variability test abnormalities, was present• In 4.9% of subjects at diagnosis, and• in 65% after 10 years of follow-up.

Mechanisms of Diabetic NeuropathyCallaghan et al, Lancet Neurology 2012, 11.

Cardiovascular Autonomic Neuropathy

Diabetic CAN has diverse manifestations and is associated with a significant amount of the morbidity and mortality of diabetes.

Increased resting heart rate• most likely due to the vagal cardiac neuropathy that results in

unopposed cardiac sympathetic nerve activity.

A decrease in heart rate.

A fixed heart rate• due to progressive dysfunction of the cardiac sympathetic

nervous system.

Cardiovascular Autonomic Neuropathy

Orthostatic Hypotension• The most incapacitating manifestation of autonomic failure.• A common feature of diabetic CAN. • A consequence of efferent sympathetic vasomotor denervation

that causes reduced vasoconstriction of the splanchnic and other peripheral vascular beds.

• Thus, in response to postural change, excessive pooling occurs in the splanchnic region, pelvis, and dependent areas.

Diminished cardiac acceleration and cardiac output.• particularly in association with exercise.

CAN and Mortality

Numerous studies over the years have provided evidence of an increase in overall mortality and sudden death in patients with diabetic autonomic neuropathy.

Estimates for the mortality associated with CAN range from 27% to 56% over 5–10 years.

In a meta-analysis of 15 studies a significant association between cardiovascular autonomic neuropathy (CAN) and subsequent mortality was observed.

The relative risk for mortality was stronger for those studies for which two or more measures were used to define CAN.

The EURODIAB Prospective Complications Study

A recent prospective study of the EURODIAB cohort of 2787 type 1 diabetic patients confirmed that abnormal autonomic function was an independent risk factor for future mortality.

(Soedamah-Muthu et al., 2008).

CAN was defined as• loss of heart rate variability with a RR ratio of<1.04, and/or• postural hypotension with a fall in systolic BP of 20 mmHg.

This study showed that autonomic neuropathy was associated with a standardized hazard ratio of 2.40 [1.32–4.36]) that exceeded the value of the traditional risk factors (age, waist–hip ratio, pulse pressure, and non-HDL cholesterol)

CAN and Mortality

Autonomic dysfunction may cause or contribute to death by several possible mechanisms.

• Absent or altered perception of myocardial ischemia.

• Deficient hemodynamic response to cardiovascular stresses such as surgery, infection, and anaesthesia.

• Increased predisposition to cardiac arrhythmias due to QT interval dispersion.

• Alterations in sympathetic–parasympathetic cardiac innervation balance.

• Focal myocardial regions of sympathetic denervation and re-innervation.

Screening

Screening for CAN should be performed • At the diagnosis of type 2 diabetes, and• 5 years after the diagnosis of type 1 diabetes

Diabetic patients should be evaluated for the presence of CAN.• Features of cardiac autonomic dysfunction

– Unexplained tachycardia, – Orthostatic hypotension, and– Poor exercise tolerance, or

• Other symptoms of autonomic dysfunction. • History of poor glycaemic control.• Diabetic Peripheral Neuropathy.• Cardiovascular risk factors.• Macro- and microvascular diabetic complications.

Diagnosis

Questionnaires.• Have been developed to investigate orthostatic symptoms and

their severity in dysautonomic conditions

Cardiovascular autonomic reflex tests.• Heart rate response to

– deep breathing, standing, and Valsalva manoeuvre.• Blood pressure response to standing.

Multigated angiography (MUGA) thallium scan.

123I metaiodobenzylguanidine (MIBG) scan.

Treatment

The risk of diabetic autonomic neuropathy can be reduced with improved control of blood glucose, plasma lipids and BP.

A recent follow-up of the Diabetes Control and Complications Trial (DCCT) cohort reported persistent benefit of prior intensive therapy on the prevalence and incidence of CAN.

Prevalence• 13–14 years after the conclusion of the DCCT, the prevalence of autonomic

neuropathy was– 28.9% in the former intensively treated group, and– 35.2% in the former conventional group (p = 0.018).

Incidence• Prior DCCT intensive therapy reduced the risks of incident CAN by 31% (odds

ratio 0.69, 95% CI 0.51–0.93).

Treatment

Lifestyle modifications.• Intensive diabetes therapy retards the development of CAN in

type 1 diabetes.• Intensive multifactorial cardiovascular risk intervention retards

the development and progression of CAN in type 2 diabetes.

Treatment based on pathogenetic concepts.• Only limited data on a pathogenetically oriented

pharmacotherapy are available in CAN patients.• Phase II randomized controlled trials have shown favourable

effects on HRV indices using the anti-oxidant α-lipoic acid, vitamin E, and C-peptide.

• Further studies are needed to confirm these findings.

Orthostatic HypotensionTreatment of orthostatic hypotension is required only when symptomatic• The therapeutic goal to minimize postural symptoms rather than to restore

normotension.

Non-pharmacological measures• Identify other causes, e.g. volume depletion.• Avoid, when possible, drugs exacerbating postural symptoms, such as psychotropic

drugs, diuretics, and α-adrenoreceptor antagonists.• Behavioural strategies such as• Gradual staged movements with postural change• Mild isotonic exercise.• Head-up bed position during sleep• Physical manoeuvres (e.g. leg crossing, stooping, squatting, and tensing muscles)• Use of portable folding chairs.• Increased fluid and salt intake if not contraindicated.• Avoidance of large meals rich in carbohydrates.• Use of elastic garment over the legs and abdomen.

Pharmacotherapy

If symptoms persist despite these measures, a pharmacological treatment should be considered.

Several drugs have efficacy in the treatment of neurogenic orthostatic hypotension.• Midodrine.• Fludrocortisone.• Erythromycin.

The potential risks of a drug should be weighed against its possible benefit, including• the balance between the goal of increasing standing blood

pressure and the avoidance of a marked supine hypertension.

Midodrine

A peripheral selective α1-adrenergic agonist .

Is a 1st line drug that exerts a pressor effect through both arteriolar constriction and venoconstriction of the capacitance vessels.

The dosing should be individually tailored (10 mg bd – qid).• the first dose taken before arising, and• use avoided several hours before planned recumbence.

Adverse events are pilomotor reactions, pruritus, supine hypertension, bradycardia, GI symptoms, and urinary retention.

Midodrine is the only medication approved by the FDA for the treatment of symptomatic orthostatic hypotension and is now under reconsideration.

Fludrocortisone

9-α-fluorohydrocortisone is another first-choice drug.

Acts through• sodium retention• a direct constricting effect on partially denervated vessels, and• an increase in the water content of the vessel wall leading to a

reduced distensibility.

Possible adverse effects include• supine hypertension• hypokalaemia.• congestive heart failure, and peripheral oedema.

The initial dose should be 0.05–0.1 mg daily• with individual titration to 0.1–0.3 mg daily.

Other TherapiesErythropoietin• was proposed to increase standing BP via several mechanisms:• Increasing red cell mass and central blood volume• Correcting the anaemia frequently associated with severe CAN, and• Neurohumoral effects on the vascular wall and vascular tone

regulation.• It can be administered in diabetic patients with haemoglobin levels

under 110 g/L with an haemoglobin target of 12 g/L followed by lower maintenance doses.

Desmopressin acetate - a vasopressin analogue.

Somatostatin analogues.

Caffeine.

Acarbose

Diabetic Gastroparesis

Gastroparesis is a syndrome characterized by delayed gastric emptying in the absence of mechanical obstruction of the stomach.

The cardinal symptoms include:• postprandial fullness.• nausea and vomiting.• bloating.

It was initially described by Kassander in 1958 as “gastroparesis diabeticorum” in patients with type 1 diabetes with gastric retention.

Incidence

Symptoms of gastroparesis are reported by 5%–12% of diabetics.

In a Minnesota study using delayed gastric emptying and typical symptoms as criteria for diagnosis, the cumulative incidence of gastroparesis was• 4.8% in type I diabetes, • 1% in type 2 diabetes, and• 0.1% in non-diabetic people.

The crude incidence rate appears to increase with age.• Diabetic gastroparesis typically develops after diabetes has been

established for 10 years.• Patients with type 1 diabetes are likely to have neuropathy,

nephropathy, or retinopathy.

Natural History and Impact

Once established, diabetic gastroparesis tends to persist, despite amelioration of glycemic control.

Diabetic gastroparesis reduces quality of life scores on all main domains assessed including physical, emotional, mental, social, and bodily functions.

In a study of 86 patients with diabetes who were followed up for at least 9 years, gastroparesis was not associated with mortality after adjustment for other disorders.

• The median time of death was 6 years (range, 1–12).

• The major causes of death were cardiovascular or renal disease

Mechanisms

Gastric emptying requires interactions between• smooth muscle,• enteric and extrinsic autonomic nerves, and• specialized pacemaker cells - the interstitial cells of Cajal (ICC).

Several abnormalities in diabetes may result in gastric motor dysfunction, • autonomic neuropathy• enteric neuropathy involving excitatory

and inhibitory nerves• abnormalities of ICC• acute fluctuations in blood glucose• psychosomatic factors.

Diagnosis

Gastroparesis is diagnosed by demonstrating delayed gastric emptying in a symptomatic patient after exclusion of obstruction and other potential etiologies of symptoms.

Scintigraphy.

• Scintigraphic measurement of the emptying of solids is the current diagnostic method of choice.

Endoscopy.

• In the absence of obstruction, retained food in the stomach after an overnight fast is suggestive of ineffective antral motility and gastroparesis.

• Absence of the antral component of the migrating motor complex is associated with postprandial antral hypomotility.

Management

First line therapy should aim at restoring

• Hydration and electrolytes,• Nutrition (enteral is preferable to parenteral), and• Glycemic control

Nutritional support is often overlooked in gastroparesis patients

• There is a lack of randomised controlled trials assessing the effect of nutritional intervention on outcome.

• Patients are often advised to eat small frequent meals, chew their food well, avoid fiber and consume a diet low in fat.

Prokinetics

The evidence for use of current prokinetics is based on trials performed 2 or 3 decades ago.• Therefore, the level of evidence might not be as good as the

rigorous large trials with validated patient response outcomes required nowadays.

The currently used prokinetics are:

• Metoclopramide (Maxolon®)

• Domperidone (Motilium®)

• Erythromycin

Metoclopramide

Metoclopramide (Maxolon®) is a 5-hydroxytryptamine (5-HT4) receptor agonist and a dopamine receptor antagonist.

In a 3-week, double-blind, multicenter, placebo-controlled trial, metoclopramide was tested in 40 patients with gastroparesis.

• Relative to baseline there was evidence of– reduced nausea, vomiting, fullness, and early satiety.– improved meal tolerance.– significantly improved gastric emptying

However no significant difference was observed between the metoclopramide and placebo treatment arms.

Metoclopramide

Neurologic side effects

• extrapyramidal symptoms of pseudoparkinsonism, akathisia, and acute dystonic reactions.

• tardive dyskinesia– the risk is < 1% - as per national prescription databases.

Proposed principles for use of metoclopramide.

1. metoclopramide should be reserved for patients with documented gastroparesis.

2. it should first be prescribed for a trial period, and the lowest effective dose for the individual patient should be sought.

Domperidone

Domperidone (Motilium®) is a more selective dopamine antagonist with lesser central penetration.

In a double-blind, multicenter comparison of 4 weeks’ treatment of diabetic patients with symptoms of gastroparesis,

• domperidone and metoclopramide were equally effective in alleviating symptoms of diabetic gastroparesis.

• adverse central nervous system effects were more severe and more common with metoclopramide treatment, including somnolence and reduced mental acuity.

ErythromycinErythromycin’s prokinetic effects in gastroparesis involve activating motilin receptors on cholinergic receptors on neurons and smooth muscle.

Erythromycin is most effective when given IV at a dose of 3 mg/kg every 8 hours (by IV infusion during a period of 45 minutes to avoid sclerosing veins).

Erythromycin, is associated with tachyphylaxis caused by down-regulation of the motilin receptor.

• This was observed in an open trial of idiopathic and diabetic gastroparesis with acute IV and chronic oral erythromycin.

• Clinical responsiveness drops after 4 weeks; however, some patients continue to experience benefit.

AntiemeticsThe most commonly prescribed antiemetic drugs are• phenothiazines (e.g. prochlorperazine “Stemetil® / Buccastem®”• antihistamine agents

– Cyclizine “Nausicalm®” – Promethazine “Phenergan®”

5-HT3 receptor antagonists – Ondansetron (Zofran®)• There are no studies that compare efficacy of phenothiazines with

newer antiemetics (such as 5-HT3 receptor antagonists ) for gastroparesis;

• clinical practice suggests comparable efficacy for most patients.

Given lower costs, it is reasonable to start with antihistamines and phenothiazines before escalating to more expensive drugs.

AntiemeticsTransdermal Scopolamine• is effective for nausea associated with motion sickness.• Is used for nausea and vomiting of gastroparesis, albeit without peer-

reviewed publications to support this practice.

Aprepitant• Is a Neurokinin receptor-1 antagonist• Is effective in treatment of delayed chemotherapy-induced nausea and

vomiting.• Studies of effectiveness in gastroparesis are not yet available.

Dronabinol• is a synthetic cannabinoid used in practice.• there is risk of hyperemesis on withdrawal.• optimum treatment strategies are unclear.

Abdominal PainThe management of pain remains a challenge, which has not been addressed in clinical trials of patients with gastroparesis.

Tricyclic antidepressants• are often used as first-line therapy for pain in gastroparesis. • are somewhat effective for abdominal pain in functional bowel

disorders.

Second-line approaches• Tramadol - a weak m-opioid receptor agonist

– releases serotonin– inhibits the reuptake of norepinephrine.

• Gabapentin – a g-aminobutyric acid analogue.

TZP-101 – Ghrelin analogue

New Prokinetic Agent

In a study of 10 diabetics with gastroparesis, relative to placebo, it • accelerated gastric emptying of solids (mean acceleration 20%).• shortened the lag time (mean reduction, 34%).• TZP-101 also reduced overall post-meal symptom intensity (24%)

and postprandial fullness (37%).

A more recent analysis compared the effects of TZP-101, at varying IV daily doses (n 17), and placebo (n 6) in patients with severe gastroparesis • TZP-101 (at 80 g/kg) improved symptoms after 4 days• this improvement was sustained at the 30-day follow-up period.

Intrapyloric Botulinum Toxin Injection

Despite several open trials suggestingefficacy, 2 randomized, controlled trialsshowed the same disappointing results,• no efficacy on symptom or objective

end points of gastric emptying.

On the basis of these studies, there is no role for intrapyloric Botulinum toxin injection in the treatment of gastroparesis, despite its extensive use in practice.

Gastric Electrical Stimulation

GES refers to the delivery of high frequency lower energy electrical stimulation to the stomach.

The device was approved by the FDA on the basis of a double-blind study that reported improvement of weekly vomiting frequency and quality of life in 33 patients with diabetic and idiopathic gastroparesis

A recent meta-analysis suggested that among 13 included studies, 12 lacked controls and only 1 was blinded and randomized. • Results showed substantial benefits for high-frequency GES for

the treatment of gastroparesis. • However, caution is necessary in interpreting the results,

because of the limitations of uncontrolled studies.

Venting Gastrostomy or Jejunostomy

Surgically placed venting gastrostomy, with or without a venting enterostomy, has been found to reduce hospitalization rate by a factor of 5 during the year after placement.

Results of endoscopic venting (PEG, direct PEJ) on nutritional outcomes and gastroparesis symptoms have not been formally studied and, therefore, remain unclear.

However, an open-label experience suggests that up to 3 years after venting gastrostomy.• weight can be maintained, and• The total symptom score remain reduced.

Thank You …

Thank You …

References:

Epidemiology, Mechanisms, and Management of Diabetic Gastroparesis. Camilleri. Clinical Gastroenterology and Hepatology, 2011.

Diabetic Gastroparesis – Backwards and Forwards. Chang et al. Journal of Gastroenterology and Hepatology, 2011

Diabetic Gastroparesis: What we have learned and had to unlearn in the past 5 years. Kashyap et al, Gut 2010

diabetic autonomic neuropathy zaven panossian. mbchb, fracp...

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