Aaron I. Vinik, MD, PhD, FCP, FACP

Disclosures

December 04, 2002

Question

What is the approach to diagnosing diabetic autonomic neuropathy?

Response from Aaron I. Vinik, MD, PhD, FCP, FACP

Diabetic neuropathy is a heterogeneous disorder that encompasses a wide range of abnormalities affecting both proximal and distal, peripheral sensory and motor, as well as the autonomic nervous system (ANS). The ANS supplies all organs in the body and consists of an afferent and an efferent system, with long efferents in the vagus (cholinergic) and short postganglionic unmyelinated fibers in the sympathetic system (adrenergic). A third component is the neuropeptidergic system, with its neurotransmitters substance P (SP), vasoactive intestinal polypeptide (VIP), and calcitonin gene-related peptide (CGRP), among others.

Diabetic autonomic neuropathy (DAN) can cause dysfunction of every part of the body. "Know DAN and you know the whole of medicine." DAN often goes completely unrecognized by patient and physician alike because of its insidious onset and protean multiple organ involvement. Alternatively, the appearance of complex and confusing symptoms in a single organ system due to DAN may cause profound symptoms and receive intense diagnostic and therapeutic attention. Subclinical involvement may be widespread, whereas clinical symptoms and signs may be focused within a single organ. The organ systems that most often exhibit prominent clinical autonomic signs and symptoms in diabetes include the cardiovascular system, gastrointestinal tract system, genitourinary system, sweat glands, adrenal medullary system, and the ocular pupil (Table 1).

Response from Aaron I. Vinik, MD, PhD, FCP, FACP

 

Cardiovascular

  • Tachycardia, exercise intolerance

  • Cardiac denervation, painless myocardial infarction

  • Orthostatic hypotension

  • Heat intolerance

  • Alterations in skin blood flow

Gastrointestinal

  • Esophageal dysfunction

  • Gastroparesis diabeticorum

  • Diarrhea

Constipation

  • Fecal incontinence

Genitourinary

  • Erectile dysfunction

  • Retrograde ejaculation

  • Cystopathy

  • Neurogenic bladder

Sweating disturbances

  • Areas of symmetrical anhydrosis

  • Gustatory sweating

Metabolic

  • Hypoglycemia unawareness

  • Hypoglycemia unresponsiveness

Pupillary

  • Decreased diameter of dark-adapted pupil

  • Argyll-Robertson-type pupil

 

Disturbances in the ANS may be functional, eg, gastroparesis with hyperglycemia and ketoacidosis, or organic, wherein nerve fibers are actually lost. This creates inordinate difficulties in diagnosing, treating, and prognosticating, as well as establishing true prevalence rates. Tests of autonomic function generally stimulate entire reflex pathways. Furthermore, autonomic control for each organ system is usually divided between opposing sympathetic and parasympathetic innervation, so that heart rate acceleration, for example, may reflect either decreased parasympathetic or increased sympathetic nervous system stimulation.

Since many conditions affect the ANS and autonomic neuropathy is not unique to diabetes, the diagnosis of DAN rests with establishing the diagnosis and excluding other causes. Table 2 elaborates the differential diagnosis of DAN. Diagnostic tests for the evaluation of cardiovascular reflexes are supported by large databases and evidence to establish their use in clinical practice. In addition, the evaluation of postural dizziness (Figure 1) is fairly straightforward and is readily done in clinical practice, as is establishing the cause of gastrointestinal symptoms (Figure 2) and erectile dysfunction. The evaluation of pupillary abnormalities, hypoglycemia unawareness and unresponsiveness, neurovascular dysfunction, and sweating disturbances are for the most part done only in research laboratories, require specialized equipment and familiarity with the diagnostic procedures, and are best left in the hands of those who have a special interest in the area.

Response from Aaron I. Vinik, MD, PhD, FCP, FACP

Figure 1.

The evaluation of postural dizziness in diabetic patients.

Figure 2.

The evaluation of the patient suspected of gastroparesis.

Table 3 presents the diagnostic tests that would be applicable to the diagnosis of cardiovascular autonomic neuropathy. These tests can be used as a surrogate for the diagnosis of autonomic neuropathy of any system, since it is generally rare to find involvement of any other division of the ANS in the absence of cardiovascular autonomic dysfunction (although it does occur).

Response from Aaron I. Vinik, MD, PhD, FCP, FACP

 

Test Method/Parameters
Resting heart rate > 100 beats/min is abnormal.
Beat-to-beat heart rate variation* With the patient at rest and supine (no overnight coffee or hypoglycemic episodes), breathing 6 breaths/min, heart rate monitored by EKG or ANSCORE device, a difference in heart rate of > 15 beats/min is normal and < 10 beats/min is abnormal, R-R inspiration/R-R expiration > 1.17. All indices of HRV are age-dependent.**
Heart rate response to standing* During continuous EKG monitoring, the R-R interval is measured at beats 15 and 30 after standing. Normally, a tachycardia is followed by reflex bradycardia. The 30:15 ratio is normally > 1.03.
Heart rate response to Valsalva maneuver* The subject forcibly exhales into the mouthpiece of a manometer to 40 mmHg for 15 s during EKG monitoring. Healthy subjects develop tachycardia and peripheral vasoconstriction during strain and an overshoot bradycardia and rise in blood pressure with release. The ratio of longest R-R shortest R-R should be > 1.2.
Systolic blood pressure response to standing Systolic blood pressure is measured in the supine subject. The patient stands and the systolic blood pressure is measured after 2 min. Normal response is a fall of < 10 mmHg, borderline is a fall of 10-29 mmHg, and abnormal is a fall of > 30 mmHg with symptoms.
Diastolic blood pressure response to isometric exercise The subject squeezes a handgrip dynamometer to establish a maximum. Grip is then squeezed at 30% maximum for 5 min. The normal response for diastolic blood pressure is a rise of > 16 mmHg in the other arm.
EKG QT/QTc intervals The QTc (corrected QT interval on EKG) should be < 440 ms.
Spectral analysis VLF peak  (sympathetic dysfunction)
LF peak  (sympathetic dysfunction)
HF peak  (parasympathetic dysfunction)
LH/HF ratio  (sympathetic imbalance)
Neurovascular flow Using noninvasive laser Doppler measures of peripheral sympathetic responses to nociception.
* These can now be performed quickly (< 15 min) in the practitioner's office, with a central reference laboratory providing quality control and normative values. VLF, LF, HF = very low-, low-, and high-frequency peaks on spectral analysis. These are now readily available in most cardiologists' practices.
** Lowest normal value of E/I ratio: Age 20-24:1.17; 25-29:1.15; 30-34:1.13; 35-30:1.12; 40-44:1.10; 45-49:1.08; 50-54:1.07; 55-59:1.06; 60-64:1.04; 65-69:1.03; 70-75:1.02 .

 

For example, if one entertains the possibility that the patient has erectile dysfunction due to autonomic neuropathy, then prior to embarking on a sophisticated and expensive evaluation of erectile status, a measure of heart rate and its variability in response to deep breathing would -- if normal -- exclude the possibility that the erectile dysfunction is a consequence of disease of the ANS, and the cause would have to be sought elsewhere. Similarly, it is extremely unusual to find gastroparesis secondary to autonomic neuropathy in a patient with normal cardiovascular autonomic reflexes.

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