Diabetic autonomic neuropathy

Neurology

Clinicals - History

Fact Explanation
Cardiovascular symptoms: exercise intolerance, fatigue, sustained heart rate, syncope, dizziness, light headedness, balance problems Cardiovascular neuropathy is a result of damage to vagal and sympathetic nerves.
The pathogenesis is complex and involves a cascade of pathways activated by hyperglycaemia resulting in neuronal ischaemia and cellular death
Cardiovascular symptoms: exercise intolerance, fatigue, sustained heart rate, syncope, dizziness, light headedness, balance problems
Cardiovascular neuropathy is a result of damage to vagal and sympathetic nerves.
The pathogenesis is complex and involves a cascade of pathways activated by hyperglycaemia resulting in neuronal ischaemia and cellular death
Gastrointestinal symptoms: dysphagia, diarrhea, constipation, loss of bowel control Dysphagia occurs due to reduced contraction amplitudes of the tubular esophagus
Diabetic diarrhea is a result of increased or uncoordinated transit time in the small intestine, bacterial overgrowth, or increased intestinal secretions.
Constipation occurs due to decreased transit time in the large intestine. Loss of bowel control is due to reduced threshold of conscious rectal sensation,decreased resting anal sphincter pressure.
Gastrointestinal symptoms: dysphagia, diarrhea, constipation, loss of bowel control
Dysphagia occurs due to reduced contraction amplitudes of the tubular esophagus
Diabetic diarrhea is a result of increased or uncoordinated transit time in the small intestine, bacterial overgrowth, or increased intestinal secretions.
Constipation occurs due to decreased transit time in the large intestine. Loss of bowel control is due to reduced threshold of conscious rectal sensation,decreased resting anal sphincter pressure.
Genitourinary symptoms: loss of bladder control, urinary tract infection, urinary frequency or dribbling, erectile dysfunction, loss of libido, dyspareunia, vaginal dryness Loss of bladder control occurs by the Inability to sense a full bladder and detrusor muscle hypoactivity.These conditions can progress to overflow incontinence and urinary tract infections.Hyperglycemia alone also can cause increased urine production and incontinence. loss of libido,dyspareunia,vaginal dryness is a result of pelvic plexus neuropathy
Erectile dysfunction in diabetes is multifactorial, including neuropathy,hypogonadism, vascular disease, metabolic control and psychogenic factors.
Diabetic men have impaired neurogenic and endothelium mediated relaxation of penile smooth muscles
Genitourinary symptoms: loss of bladder control, urinary tract infection, urinary frequency or dribbling, erectile dysfunction, loss of libido, dyspareunia, vaginal dryness
Loss of bladder control occurs by the Inability to sense a full bladder and detrusor muscle hypoactivity.These conditions can progress to overflow incontinence and urinary tract infections.Hyperglycemia alone also can cause increased urine production and incontinence. loss of libido,dyspareunia,vaginal dryness is a result of pelvic plexus neuropathy
Erectile dysfunction in diabetes is multifactorial, including neuropathy,hypogonadism, vascular disease, metabolic control and psychogenic factors.
Diabetic men have impaired neurogenic and endothelium mediated relaxation of penile smooth muscles
Sudomotor symptoms: pruritus, dry skin, limb hair loss,anhidrosis,heat intolerance,gustatory sweating Dry skin,hair loss- Poor peripheral circulation (neuronal input to the peripheral vasculature is decreased or absent)
Gustatory sweating-Loss of autonomic supply to auriculotemporal nerve.
Sudomotor symptoms: pruritus, dry skin, limb hair loss,anhidrosis,heat intolerance,gustatory sweating
Dry skin,hair loss- Poor peripheral circulation (neuronal input to the peripheral vasculature is decreased or absent)
Gustatory sweating-Loss of autonomic supply to auriculotemporal nerve.
Endocrine symptoms: hypoglycemic unawareness Impaired catecholamine release prevents the warning signs of hypoglcemia.
counterregulatory response hypoglycemia is reduced due to autonomic dysfunction
Endocrine symptoms: hypoglycemic unawareness
Impaired catecholamine release prevents the warning signs of hypoglcemia.
counterregulatory response hypoglycemia is reduced due to autonomic dysfunction
Eyes: diplopia Loss of autonomic supply to ocular muscles. Eyes: diplopia
Loss of autonomic supply to ocular muscles.
Dizziness while standing up from seated position This is due to orthostatic hypotension (i.e. a decrease in systolic blood pressure of ≥20 mm Hg or diastolic blood pressure of ≥10 mm Hg when standing up.
Vasomotor neuropathy frequently causes orthostatic hypotension by affecting the splanchnic and peripheral vascular beds.
Dizziness while standing up from seated position
This is due to orthostatic hypotension (i.e. a decrease in systolic blood pressure of ≥20 mm Hg or diastolic blood pressure of ≥10 mm Hg when standing up.
Vasomotor neuropathy frequently causes orthostatic hypotension by affecting the splanchnic and peripheral vascular beds.
Poor diabetic control , long duration of diabetes, History of hypertension, dyslipidemia Risk factors for the development of diabetic autonomic neuropathy as damage to the nerves will be increased with time due to longer exposure to hyperglycemia.
The risk is also high in patients who are having other comorbidities which has macrovascular events such as hypertension and dyslipidemia
Poor diabetic control , long duration of diabetes, History of hypertension, dyslipidemia
Risk factors for the development of diabetic autonomic neuropathy as damage to the nerves will be increased with time due to longer exposure to hyperglycemia.
The risk is also high in patients who are having other comorbidities which has macrovascular events such as hypertension and dyslipidemia

Clinicals - Examination

Fact Explanation
Resting tachycardia Damage to the autonomic nerve fibers that innervate the heart and blood vessels
Occurs at a relatively early stage of the disease.
Heart rate of 90-130 beats per minute can be observed and is associated with a reduction in parasympathetic tone followed by increased sympathetic activity as the disease progresses
Resting tachycardia
Damage to the autonomic nerve fibers that innervate the heart and blood vessels
Occurs at a relatively early stage of the disease.
Heart rate of 90-130 beats per minute can be observed and is associated with a reduction in parasympathetic tone followed by increased sympathetic activity as the disease progresses
Pupillary: Pupillomotor function impairment, Argyll-Robertson pupil Loss of autonomic supply to ocular muscles Pupillary: Pupillomotor function impairment, Argyll-Robertson pupil
Loss of autonomic supply to ocular muscles
Orthostatic hypotension Reduction in systolic blood pressure by > 20 mmHg or in diastolic blood pressure by > 10 mmHg 2 min following postural change from supine to standing.
occurs as a result of the impairment of the sympathetic response to postural change secondary to poor norepinephrine response and abnormalities in the baro-receptor sensitivity
Orthostatic hypotension
Reduction in systolic blood pressure by > 20 mmHg or in diastolic blood pressure by > 10 mmHg 2 min following postural change from supine to standing.
occurs as a result of the impairment of the sympathetic response to postural change secondary to poor norepinephrine response and abnormalities in the baro-receptor sensitivity
Abnormal circadian pattern of blood pressure Correlate with postural hypotension due to cardiovascular autonomic neuropathy. blood pressure rises during the night and falls in the early morning Abnormal circadian pattern of blood pressure
Correlate with postural hypotension due to cardiovascular autonomic neuropathy. blood pressure rises during the night and falls in the early morning

Investigations - Diagnosis

Fact Explanation
Heart rate response to standing and to the Valsalva maneuver Heart rate response to standing- The R-R interval is measured at beats 15 and 30 after the patient stands
A 30:15 ratio of less than 1.03 is abnormal
Heart rate response to Valsalva maneuver-
The patient forcibly exhales into the mouthpiece of a manometer, exerting a pressure of 40 mm Hg
for 15 seconds
A ratio of longest to shortest R-R interval of less than 1.2 is abnormal
Heart rate response to standing and to the Valsalva maneuver
Heart rate response to standing- The R-R interval is measured at beats 15 and 30 after the patient stands
A 30:15 ratio of less than 1.03 is abnormal
Heart rate response to Valsalva maneuver-
The patient forcibly exhales into the mouthpiece of a manometer, exerting a pressure of 40 mm Hg
for 15 seconds
A ratio of longest to shortest R-R interval of less than 1.2 is abnormal
Tests of blood pressure control Systolic blood pressure response to standing-
Systolic blood pressure is measured when the patient is lying down and 2 minutes after the patient
stands
A fall of more than 30 mm Hg is abnormal
A fall of 10 to 29 mm Hg is borderline
Diastolic blood pressure response to isometric exercise- The patient squeezes a handgrip dynamometer to establish his or her maximum.The patient then squeezes the grip at 30% maximum for 5 minutes.A rise of less than 16 mm Hg in the contralateral arm is abnormal
Tests of blood pressure control
Systolic blood pressure response to standing-
Systolic blood pressure is measured when the patient is lying down and 2 minutes after the patient
stands
A fall of more than 30 mm Hg is abnormal
A fall of 10 to 29 mm Hg is borderline
Diastolic blood pressure response to isometric exercise- The patient squeezes a handgrip dynamometer to establish his or her maximum.The patient then squeezes the grip at 30% maximum for 5 minutes.A rise of less than 16 mm Hg in the contralateral arm is abnormal
Gastroduodenoscopy To exclude pyloric or other mechanical obstruction( in assessing the gastrointestinal autonomic function) Gastroduodenoscopy
To exclude pyloric or other mechanical obstruction( in assessing the gastrointestinal autonomic function)
Anorectal manometry To exclude other causes for constipation ( to evaluate sphincter tone) Anorectal manometry
To exclude other causes for constipation ( to evaluate sphincter tone)
Assessment of renal functions and cystometry To exclude other causes of bladder dysfunction Assessment of renal functions and cystometry
To exclude other causes of bladder dysfunction
Penile-brachial pressure index Penile blood flow can be measured by Doppler flow studies of the dorsal penile arteries, and the ratio is Penile-brachial pressure index. low value indicates vascular disease Penile-brachial pressure index
Penile blood flow can be measured by Doppler flow studies of the dorsal penile arteries, and the ratio is Penile-brachial pressure index. low value indicates vascular disease
Hormonal evaluation (luteinizing hormone, testosterone, free testosterone, prolactin) To exclude other causes of erectile dysfunction. Hormonal evaluation (luteinizing hormone, testosterone, free testosterone, prolactin)
To exclude other causes of erectile dysfunction.

Investigations - Management

Fact Explanation
Test for heart-rate variability-Check the response to Valsalva maneuver Depends on the symptoms and signs.
Monitor every year for response to treatment
Test for heart-rate variability-Check the response to Valsalva maneuver
Depends on the symptoms and signs.
Monitor every year for response to treatment
Measure blood pressure standing and supine Monitor response to treatment of postural hypotension - reduction in systolic blood pressure by > 20 mmHg or in diastolic blood pressure by > 10 mmHg 2 min following postural change from supine to standing Measure blood pressure standing and supine
Monitor response to treatment of postural hypotension - reduction in systolic blood pressure by > 20 mmHg or in diastolic blood pressure by > 10 mmHg 2 min following postural change from supine to standing
upper-GI endoscopy or barium series Monitor response to treatment of gastrointestinal dysfunction
to rule out structural or mucosal abnormalities of the GI tract
upper-GI endoscopy or barium series
Monitor response to treatment of gastrointestinal dysfunction
to rule out structural or mucosal abnormalities of the GI tract
Cystometrogram Bladder sensation and upper urinary tract dilation can be assessed with cystometry and voiding cystometrogram Cystometrogram
Bladder sensation and upper urinary tract dilation can be assessed with cystometry and voiding cystometrogram
Sweat test used to evaluate the integrity of central and peripheral sympathetic sudomotor pathways from the central nervous system to the cutaneous sweat glands. Asymmetric sweat patterns and anhidrotic areas are noted in autonomic failure Sweat test
used to evaluate the integrity of central and peripheral sympathetic sudomotor pathways from the central nervous system to the cutaneous sweat glands. Asymmetric sweat patterns and anhidrotic areas are noted in autonomic failure
Lipid profile Important to assess other co morbidities in order to prevent cardiovascular adverse events.
targets - LDL-Cholesterol <100 mg/dL, HDL-Cholesterol >50 mg/dL, and triglycerides <150 mg/dL
Lipid profile
Important to assess other co morbidities in order to prevent cardiovascular adverse events.
targets - LDL-Cholesterol <100 mg/dL, HDL-Cholesterol >50 mg/dL, and triglycerides <150 mg/dL
Test for heart-rate variability Screening depends on the symptoms and signs.
Check the response to Valsalva maneuver,response to standing
If negative: repeat yearly
If positive: apply appropriate diagnostic tests, treat symptoms
Test for heart-rate variability
Screening depends on the symptoms and signs.
Check the response to Valsalva maneuver,response to standing
If negative: repeat yearly
If positive: apply appropriate diagnostic tests, treat symptoms
urine culture Bladder dysfunction can cause recurrent urinary tract infection, pyelonephritis urine culture
Bladder dysfunction can cause recurrent urinary tract infection, pyelonephritis
Ultra sound scan abdomen Postvoid ultrasound to assess residual volume and upper-urinary tract dilation Ultra sound scan abdomen
Postvoid ultrasound to assess residual volume and upper-urinary tract dilation
Cystometrogram Cystometry and voiding cystometrogram to measure bladder sensation and volume pressure changes associated with bladder filling with known volumes of water and voiding Cystometrogram
Cystometry and voiding cystometrogram to measure bladder sensation and volume pressure changes associated with bladder filling with known volumes of water and voiding

Management - Supportive

Fact Explanation
Tight glycemic control Reduces the prevalence of autonomic dysfunction and slows the deterioration of R-R variation. Tight glycemic control
Reduces the prevalence of autonomic dysfunction and slows the deterioration of R-R variation.
Physical activity at least 150 minutes of moderate-intensity aerobic physical activity or at least

90 minutes of vigorous aerobic exercise per week is recommended in order to reduce cardiovascular adverse events.

The physical activity should be distributed over at least 3 days per week, with no more than 2 consecutive inactive days.
Physical activity
at least 150 minutes of moderate-intensity aerobic physical activity or at least

90 minutes of vigorous aerobic exercise per week is recommended in order to reduce cardiovascular adverse events.

The physical activity should be distributed over at least 3 days per week, with no more than 2 consecutive inactive days.

Management - Specific

Fact Explanation
Treatment of cardiac autonomic neuropathy Beta-blockers s that are cardioselective (eg:atenolol, metoprolol, acebutolol)-
Opposing the sympathetic stimulus, and thereby restore the parasympathetic-sympathetic balance.
ACE inhibitors-Increase heart-rate variation and decrease mortality in patients with mild microalbuminuria.
Treatment of cardiac autonomic neuropathy
Beta-blockers s that are cardioselective (eg:atenolol, metoprolol, acebutolol)-
Opposing the sympathetic stimulus, and thereby restore the parasympathetic-sympathetic balance.
ACE inhibitors-Increase heart-rate variation and decrease mortality in patients with mild microalbuminuria.
Treatment of orthostatic hypotension Non pharmacological-
Wear supportive stockings to increase venous return,
Cautioned to get out of bed slowly,
To avoid hot baths,
To take their insulin injections while lying down,
perform physical counter-manoeuvres (leg crossing, stooping and squatting), increase fluid and salt intake.

9-fluorohydrocortisone and supplementary salt- May benefit for some patients with orthostatic hypotension.But not effective until edema settles,therefore carries a rick of heart failure.

Clonidine- An alpha-2 agonist, can treat a deficiency of alpha-2 adrenergic receptor in patients with orthostatic hypotension.

Somatostatin and somatostatin analogues (octreotide) inhibit the release of vasoactive peptides from the GI tract and thus increase splanchnic vasoconstriction, leading to increase in mean blood pressure
Treatment of orthostatic hypotension
Non pharmacological-
Wear supportive stockings to increase venous return,
Cautioned to get out of bed slowly,
To avoid hot baths,
To take their insulin injections while lying down,
perform physical counter-manoeuvres (leg crossing, stooping and squatting), increase fluid and salt intake.

9-fluorohydrocortisone and supplementary salt- May benefit for some patients with orthostatic hypotension.But not effective until edema settles,therefore carries a rick of heart failure.

Clonidine- An alpha-2 agonist, can treat a deficiency of alpha-2 adrenergic receptor in patients with orthostatic hypotension.

Somatostatin and somatostatin analogues (octreotide) inhibit the release of vasoactive peptides from the GI tract and thus increase splanchnic vasoconstriction, leading to increase in mean blood pressure
Treatment of sudomotor autonomic neuropathy Emolients-Softens skin and prevents dryness Treatment of sudomotor autonomic neuropathy
Emolients-Softens skin and prevents dryness
Treatment of gastrointestinal dysfunction Treatment of gastropariesis should include:
Non pharmacological-Advise to eat multiple small meals (4–6 per day) and to reduce the fat content of their diet to less than 40 g/day.
Prokinetic agents such as metoclopramide,domperidone,erythromycin, and levosulpirid.
Treatment of diabetic diarrhea
1)Fluid and electrolyte balance
2)Antidiarrheal agents (eg, loperamide and diphenoxylate) - can reduce the number of stools, but they may also be associated with toxic megacolon
3)Bacterial overgrowth due to stasis of the bowel may contribute to diarrhea, in which case broad-spectrum antibiotics (e.g., tetracycline and metronidazole) are useful.
Treatment of gastrointestinal dysfunction
Treatment of gastropariesis should include:
Non pharmacological-Advise to eat multiple small meals (4–6 per day) and to reduce the fat content of their diet to less than 40 g/day.
Prokinetic agents such as metoclopramide,domperidone,erythromycin, and levosulpirid.
Treatment of diabetic diarrhea
1)Fluid and electrolyte balance
2)Antidiarrheal agents (eg, loperamide and diphenoxylate) - can reduce the number of stools, but they may also be associated with toxic megacolon
3)Bacterial overgrowth due to stasis of the bowel may contribute to diarrhea, in which case broad-spectrum antibiotics (e.g., tetracycline and metronidazole) are useful.
Treatment of genitourinary tract dysfunction Treating erectile dysfunction
1)Cease taking medications
known to cause erectile dysfunction
2) Phosphodiesterase Type 5 Inhibitors - Sildenafil (Viagra) : work by potentiating the effect of nitric oxide in the penis
3)Vacuum Erection Devices
Treating female sexual dysfunction- Application of vaginal lubricants, including topical estrogen creams
Treating bladder dysfunction-
1)Patients are asked to palpate for their bladder and empty it when it is full
2) Alpha-1 blocker- sphincter relaxation
Treatment of genitourinary tract dysfunction
Treating erectile dysfunction
1)Cease taking medications
known to cause erectile dysfunction
2) Phosphodiesterase Type 5 Inhibitors - Sildenafil (Viagra) : work by potentiating the effect of nitric oxide in the penis
3)Vacuum Erection Devices
Treating female sexual dysfunction- Application of vaginal lubricants, including topical estrogen creams
Treating bladder dysfunction-
1)Patients are asked to palpate for their bladder and empty it when it is full
2) Alpha-1 blocker- sphincter relaxation
Treatment of hypoglycemic unawareness and unresponsiveness Intensive glycemic control therapy- Using very small boluses of long-acting
insulin is recommended
Treatment of hypoglycemic unawareness and unresponsiveness
Intensive glycemic control therapy- Using very small boluses of long-acting
insulin is recommended

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