*5.3.5. Hypoglycemia unawareness and associated autonomic failure*

Autonomic neuropathy is associated with more severe hypoglycemic events [126, 127] and the loss of symptoms prompting awareness of hypoglycemia [128, 129]. However, the jury is still out on whether autonomic neuropathy actually causes a loss of counter-regulatory responses to hypoglycemia [130]. Hypoglycemia associated autonomic failure (HAAF) can occur in the absence of autonomic neuropathy [126, 131, 132]. Conversely, diabetic autonomic neuropathy is observed in the absence of hypoglycemia symptom loss [131, 133]. Additionally, reversal of hypoglycemia symptom awareness is observed after strict avoidance of hypoglycemia for a relative short period of times, i.e. several weeks to months [134-136]. This would all appear to suggest that autonomic neuropathy is not a causative factor in hypoglycemia unawareness, i.e. the loss of the counter-regulatory responses to hypoglycemia. However, in the presence of autonomic neuropathy and in combination with HAAF a greater reduction in counterregula‐ tory response hypoglycemia is observed than in hypoglycemia unawareness without auto‐ nomic neuropathy [130]. Furthermore, the recovery of hypoglycemia awareness symptoms with strict avoidance of hypoglycemia is not as complete in those with autonomic neuropathy [128]. Even with the recovery of awareness symptoms, the epinephrine response to hypogly‐ cemia is only partially recovered and even less so in those with autonomic neuropathy [130]. In aggregate, this suggests that autonomic neuropathy is not the predominate cause of hypoglycemia unawareness but does enhance its severity and may play a partial etiologic role. standing position and the blood pressure response to a sustained hand grip reflects sympa‐

Diabetic Neuropathy

345

http://dx.doi.org/10.5772/55372

Assessment of autonomic neuropathy affecting the gastrointestinal track can be done by endoscopy and scintographic measurement of esophageal bolus transit time for esophageal dysfunction; scintography, isotope breath tests, and ultrasonography for gastroparesis; hydrogen breath test for diabetic diarrhea; barium enema for constipation; and anorectal manometry, endoanal ultrasonography, colon transit tests, digital examination of the rectum,

Erectile dysfunction can be assessed by taking a case history, such as with the International Index of Erectile Dysfunction, by physical examination including examining of external genitalia, blood tests including measurement of testosterone levels, measurement of nocturnal penile tumescence, and Doppler studies [2, 117, 140]. The Female Sexual Function Index has been used to evaluate sexual dysfunction in women with type 1 diabetes [124]. Vaginal plethysmography has also been used to directly assess vaginal lubrication in women with

Post void residual volume can be assessed by transurethral catherization or non-invasively via ultrasound [142]. Bladder sensation and upper urinary tract dilation can be assessed with cystometry and voiding cystometrogram. Uroflometry can be used to assess urinary flow rate and sphincter function. A urine culture should also be done to assess bacteria cystitis. In women, a urogynecological examination should be done in order to exclude pelvic prolapse.

Assessment of sudomotor function can be done with the Quantitative Sudomotor Axon Reflex Test (QSART), thermoregulatory sweat test, or the sympathetic skin response. The thermo‐ regulatory sweat test can be used to assess the pattern and distribution of anhydrosis [143]. The QSART is used to assess postganglionic sudomotor nerve function [119, 143]. The sympathetic skin response assesses postganglionic sudomotor sympathetic nerve fibers [144].

Treatment and management of diabetic autonomic neuropathy includes tight glycemic control [4]; however, the primary focus is on alleviation of symptoms [4, 101]. Manage‐ ment of orthostatic hypotension consists of educating the patient in strategies to avoid or address reversible causes of hypotension, increased fluid and salt consumption supplement‐ ed with mineralocorticoid therapy, pharmacotherapy with sympathomimetic agents, and wearing clothing such as compression stockings that increase venous return [2, 101, 118]. Antioxidants and cardioselective beta-blockers may be beneficial in cardiac autonomic

For patients with esophageal dysmotility, proton pump therapy is conventionally used [119]. Fluid consumption immediately after consumption of medications should be advised in order to avoid pill-induced esophagitis in these patients [119]. Diets low in fat and soluble fiber may be beneficial in patients with gastroparesis [2, 119], although pharmaco‐ therapy with prokinetic agents is the mainstay of therapy [119]. Insulin pump therapy may

thetic nervous system function [2].

diabetes [141].

**5.5. Management**

neuropathy [2].

protoscopy and sigmoidoscopy for fecal incontinence [2, 139].

#### *5.3.6. Sudomotor autonomic neuropathy*

Abnormalities in thermoregulation are common in type 1 diabetes [137, 138]. The sweat glands are innervated by sudomotor postganglionic unmyelinated sympathetic c-fibers. Autonomic neuropathy affecting sudomotor nerve function results in both anhidrosis and hyperhidrosis. Sudomotor dysfunction manifests symptomatically as dry scaly skin of the limbs and appen‐ dages, heat intolerance, and gustatory sweating. With increasing duration of diabetes, anhidrosis becomes more severe, progressing in a distal to proximal direction [118]. Gustatory sweating, in which there is excessive sweating in the face and trunk in response to eating is thought to result from imperfect reinnervation of postganglionic sudomotor C-fibers following denervation [118].

#### **5.4. Assessment**

Assessment of cardiovascular autonomic nervous system function can be done by measuring heart rate variability, the heart rate response in postural change from lying or sitting to standing, the blood pressure change from lying or sitting to standing, and the diastolic blood pressure response to a sustained hand grip. Heart rate variability can be assessed my meas‐ uring the heart rate response to paced deep breathing, the Valsava maneuver, and spectral analysis. The heart rate response to deep breathing and the heart rate response to a change in posture to the standing position predominately reflect parasympathetic function [2]. The heart rate response to the Valsalva maneuver reflects both parasympathetic and sympathetic function fairly equally [2]. The change in blood pressure from a lying or sitting position to a standing position and the blood pressure response to a sustained hand grip reflects sympa‐ thetic nervous system function [2].

Assessment of autonomic neuropathy affecting the gastrointestinal track can be done by endoscopy and scintographic measurement of esophageal bolus transit time for esophageal dysfunction; scintography, isotope breath tests, and ultrasonography for gastroparesis; hydrogen breath test for diabetic diarrhea; barium enema for constipation; and anorectal manometry, endoanal ultrasonography, colon transit tests, digital examination of the rectum, protoscopy and sigmoidoscopy for fecal incontinence [2, 139].

Erectile dysfunction can be assessed by taking a case history, such as with the International Index of Erectile Dysfunction, by physical examination including examining of external genitalia, blood tests including measurement of testosterone levels, measurement of nocturnal penile tumescence, and Doppler studies [2, 117, 140]. The Female Sexual Function Index has been used to evaluate sexual dysfunction in women with type 1 diabetes [124]. Vaginal plethysmography has also been used to directly assess vaginal lubrication in women with diabetes [141].

Post void residual volume can be assessed by transurethral catherization or non-invasively via ultrasound [142]. Bladder sensation and upper urinary tract dilation can be assessed with cystometry and voiding cystometrogram. Uroflometry can be used to assess urinary flow rate and sphincter function. A urine culture should also be done to assess bacteria cystitis. In women, a urogynecological examination should be done in order to exclude pelvic prolapse.

Assessment of sudomotor function can be done with the Quantitative Sudomotor Axon Reflex Test (QSART), thermoregulatory sweat test, or the sympathetic skin response. The thermo‐ regulatory sweat test can be used to assess the pattern and distribution of anhydrosis [143]. The QSART is used to assess postganglionic sudomotor nerve function [119, 143]. The sympathetic skin response assesses postganglionic sudomotor sympathetic nerve fibers [144].

### **5.5. Management**

*5.3.5. Hypoglycemia unawareness and associated autonomic failure*

*5.3.6. Sudomotor autonomic neuropathy*

denervation [118].

344 Type 1 Diabetes

**5.4. Assessment**

Autonomic neuropathy is associated with more severe hypoglycemic events [126, 127] and the loss of symptoms prompting awareness of hypoglycemia [128, 129]. However, the jury is still out on whether autonomic neuropathy actually causes a loss of counter-regulatory responses to hypoglycemia [130]. Hypoglycemia associated autonomic failure (HAAF) can occur in the absence of autonomic neuropathy [126, 131, 132]. Conversely, diabetic autonomic neuropathy is observed in the absence of hypoglycemia symptom loss [131, 133]. Additionally, reversal of hypoglycemia symptom awareness is observed after strict avoidance of hypoglycemia for a relative short period of times, i.e. several weeks to months [134-136]. This would all appear to suggest that autonomic neuropathy is not a causative factor in hypoglycemia unawareness, i.e. the loss of the counter-regulatory responses to hypoglycemia. However, in the presence of autonomic neuropathy and in combination with HAAF a greater reduction in counterregula‐ tory response hypoglycemia is observed than in hypoglycemia unawareness without auto‐ nomic neuropathy [130]. Furthermore, the recovery of hypoglycemia awareness symptoms with strict avoidance of hypoglycemia is not as complete in those with autonomic neuropathy [128]. Even with the recovery of awareness symptoms, the epinephrine response to hypogly‐ cemia is only partially recovered and even less so in those with autonomic neuropathy [130]. In aggregate, this suggests that autonomic neuropathy is not the predominate cause of hypoglycemia unawareness but does enhance its severity and may play a partial etiologic role.

Abnormalities in thermoregulation are common in type 1 diabetes [137, 138]. The sweat glands are innervated by sudomotor postganglionic unmyelinated sympathetic c-fibers. Autonomic neuropathy affecting sudomotor nerve function results in both anhidrosis and hyperhidrosis. Sudomotor dysfunction manifests symptomatically as dry scaly skin of the limbs and appen‐ dages, heat intolerance, and gustatory sweating. With increasing duration of diabetes, anhidrosis becomes more severe, progressing in a distal to proximal direction [118]. Gustatory sweating, in which there is excessive sweating in the face and trunk in response to eating is thought to result from imperfect reinnervation of postganglionic sudomotor C-fibers following

Assessment of cardiovascular autonomic nervous system function can be done by measuring heart rate variability, the heart rate response in postural change from lying or sitting to standing, the blood pressure change from lying or sitting to standing, and the diastolic blood pressure response to a sustained hand grip. Heart rate variability can be assessed my meas‐ uring the heart rate response to paced deep breathing, the Valsava maneuver, and spectral analysis. The heart rate response to deep breathing and the heart rate response to a change in posture to the standing position predominately reflect parasympathetic function [2]. The heart rate response to the Valsalva maneuver reflects both parasympathetic and sympathetic function fairly equally [2]. The change in blood pressure from a lying or sitting position to a Treatment and management of diabetic autonomic neuropathy includes tight glycemic control [4]; however, the primary focus is on alleviation of symptoms [4, 101]. Manage‐ ment of orthostatic hypotension consists of educating the patient in strategies to avoid or address reversible causes of hypotension, increased fluid and salt consumption supplement‐ ed with mineralocorticoid therapy, pharmacotherapy with sympathomimetic agents, and wearing clothing such as compression stockings that increase venous return [2, 101, 118]. Antioxidants and cardioselective beta-blockers may be beneficial in cardiac autonomic neuropathy [2].

For patients with esophageal dysmotility, proton pump therapy is conventionally used [119]. Fluid consumption immediately after consumption of medications should be advised in order to avoid pill-induced esophagitis in these patients [119]. Diets low in fat and soluble fiber may be beneficial in patients with gastroparesis [2, 119], although pharmaco‐ therapy with prokinetic agents is the mainstay of therapy [119]. Insulin pump therapy may also help to improve symptoms in type 1 diabetic patients with gastroparesis [119]. Antibiotic therapy is beneficial in the treatment of diarrhea [2, 119].

**References**

[1] Dyck PJ, Albers JW, Anderson H, Arezzo JC, Biessels GJ, Bril V, et al. Diabetic Poly‐ neuropathies: Update on Research Definition, Diagnostic Criteria and Estimation of

Diabetic Neuropathy

347

http://dx.doi.org/10.5772/55372

[2] Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic Autonomic Neuropathy. Dia‐

[3] Coppini DV, Bowtell PA, Weng C, Young PJ, Sonksen PH. Showing neuropathy is related to increased mortality in diabetic patients-a survival analysis using an accel‐

[4] Boulton AJ, Vinik AI, Arezzo JC, Bril V, Feldman EL, Freeman R, et al. Diabetic Neu‐ ropathies: a statement by the American Diabetes Association. Diabetes Care.

[5] Tesfaye S, Stevens LK, Stephenson JM, Fuller JH, Plater M, Ionescu-Tirgoviste C, et al. Prevalence of diabetic peripheral neuropathy and its relation to glycaemic control and potential risk factors: the EURODIAB IDDM Complications Study. Diabetologia.

[6] Fagerberg SE. Studies on the pathogenesis of diabetic neuropathy. III. Diabetic neu‐ ropathy in relation to diabetic vessel complications. Acta Med Scand. 1957;157(5):

[7] Albers JW, Herman WH, Pop-Busui R, Martin CL, Cleary P, Waberski B. Subclinical neuropathy among Diabetes Control and Complications Trial participants without diagnosable neuropathy at trial completion: possible predictors of incident neuropa‐

[8] England JD, Gronseth GS, Franklin G, Miller RG, Asbury AK, Carter GT, et al. Distal symmetric polyneuropathy: a definition for clinical research: report of the American Academy if Neurology, the Amerian Association of Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology.

[9] Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, et al. The prevalence by staged severity of various types of diabetic neuropathy, retinopathu, and nephrop‐ athy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neu‐

[10] Pop-Busui R, Herman WH, Feldman EL, Low PA, Martin CL, Cleary PA, et al. DCCT and EDIC Studies in Type 1 Diabetes: Lessons for Diabetic Neuropthy Regarding

Metabolic Memory and Natural History. Curr Diab Rep. 2010;10:276-82.

Severity. Diabetes Metab Res Rev. 2011. Epub Jun 21, 2011.

erated failure time model. J Clin Epidemiol. 2000;53(5):519-23.

betes Care. 2003;26:1553-79.

2005;28(4):956-62.

1996;39(11):1377-84.

2005;65(2):199-207.

rology. 1993;43(4):817-24.

thy. Diabetes Care. 2007;30(10):2613-8.

401-6.

Treatment of bladder dysfunction may be behavioral, pharmacological, or surgical. Behavioral management includes pelvic floor exercises to strengthen the muscles of the pelvic floor that support the bladder and urethretha. It also includes a program of scheduled fluid intake and micturition, manual procedures such as the Crede's maneuver, pelvic tapping, the Valsava maneuver, and clean intermittent self-catheterization. Pharmacotherapy includes the use of antimuscarinic agents, cholinergic agents, and tricyclic antidepressants. In cases refractory to non-pharmacological and pharmacological treatment, surgical procedures such as vesicle neck resection, selective pudendal nerve block, unilateral pudendal neurectomy, and sacral neuromodulation may be beneficial [2, 119, 142, 145].

Treatment and management of erectile dysfunction should include psychological counseling; however, pharmacotherapy with the PDE5 inhibitors (sildenafil, vardenafil, tadalafil) is the mainstay of therapy. Intracavernous or intraurethral injections with vasoactive medication, vacuum constriction devices, and penile prosthesis implantation are also options [2, 119]. Vaginal estrogen creams in has been shown to be beneficial in diabetic women with female sexual dysfunction [118].
