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Diabetic Autonomic Neuropathy
Zaven Panossian. MBChB, FRACP
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Specialist Physician & Endocrinologist
Counties 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 2009
Presented 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 up
Gastroenterology 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
Weight
Main
admission
with GI
symptoms
HbA1c
Insertion of
Jejunostomy
tube
Medications
Buccastem 3mg bd
Hyoscine butyl bromide 20 mg bd
Scopoderm dermal patch
Omeprazole 40 mg bd
Cyclizine 50 mg PRN / TDS
Ondansetron 4-8 mg PRN / BD
Paracetamol 1g PRN QID
Ibuprufen 400 mg PRN BD
Lantus 14 U mane / 22 U nocte
Apidra 2-10 U PRN BD
Fludrocortisone 0.1 mg bd
Metoprolol CR 23.75mg daily
Ferodan liquid 10 mls BD
Quetiapine 50 mg bd
Medications
Buccastem 3mg bd
Hyoscine butyl bromide 20 mg bd
Scopoderm dermal patch
Omeprazole 40 mg bd
Cyclizine 50 mg PRN / TDS
Ondansetron 4-8 mg PRN / BD
Paracetamol 1g PRN QID
Ibuprufen 400 mg PRN BD
Lantus 14 U mane / 22 U nocte
Apidra 2-10 U PRN BD
Fludrocortisone 0.1 mg bd
Metoprolol CR 23.75mg daily
Ferodan liquid 10 mls BD
Quetiapine 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 DAN
Cardiovascular.
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
Spectrum of DAN
Cardiovascular.
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 Neuropathy
Callaghan 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 reinnervation.
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 Hypotension
Treatment 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 Therapies
Erythropoietin
• 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.
Erythromycin
Erythromycin’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 downregulation 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.
Antiemetics
The 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.
Antiemetics
Transdermal 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 Pain
The 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 suggesting
efficacy, 2 randomized, controlled trials
showed 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