Keywords
diabetes mellitus, polyneuropathy, focal neuropathy, autonomic neuropathy, cognitive decline, dementia, stroke, Alzheimer disease, vascular dementia, hypoglycemia, hyperglycemia
Both type 1 and type 2 diabetes mellitus commonly target the nervous system. In the peripheral nervous system, complications include polyneuropathies and focal neuropathies. In the central nervous system, diabetes may be associated with cognitive decline, leukoencephalopathy, and a heightened risk of both stroke and dementia. Acute changes in glycemia are also associated with neurologic signs and symptoms. This chapter summarizes the acute and chronic neurologic complications of diabetes mellitus that clinicians should keep in mind when caring for patients with this disorder.
Acute Neurologic Features
Diabetic Ketoacidosis
Diabetic ketoacidosis (DKA) in patients with type 1 diabetes is a medical emergency that may present with neurologic signs and symptoms. Anorexia, lethargy, thirst, polyuria, vague abdominal pain, and Kussmaul respiration are followed by confusion and a decreased level of consciousness. Rarely, a primary CNS infection, such as bacterial meningitis, accompanies diabetic ketoacidosis. Cerebral edema complicates diabetic ketoacidosis and may present with headache, papilledema, and bilateral abducens neuropathies; it may develop on presentation or during correction of the metabolic disorder. Secondary complications include cerebral infarction, cerebral venous sinus thrombosis, and compression neuropathies.
Nonketotic Hyperosmolar Syndrome
Neurologic symptoms and signs may also herald a nonketotic hyperosmolar syndrome, which is defined as a blood glucose level exceeding 33 mmol/L (600 mg/dl) and a plasma osmolarity greater than 320 mOsm/L, without accompanying acidosis or ketonemia. Polyuria, polydipsia, thirst, fatigue, and generalized weakness are common, and neurologic signs include a decreased level of consciousness, hemiplegia, aphasia, brainstem abnormalities, dystonia, chorea, and seizures. Seizures are often focal and can include tonic, movement- induced, or continuous forms (e.g., epilepsia partialis continua). Unusual neurologic features are visual symptoms, hallucinations, hemichorea, tonic eye deviation, nystagmus, abnormal pupil reactivity, and meningeal signs. The correction of hyperglycemia may be more effective than using antiepileptic agents in the treatment of seizures.
Hypoglycemia
Hypoglycemia most often presents with altered neurologic function. In diabetic subjects, hypoglycemia may occur in the setting of insulin use. A high index of suspicion is required as patients may present with focal neurologic signs or seizures that mimic stroke. Hypoglycemia is defined as a plasma glucose concentration less than 2.7 mmol/L (50 mg/dl), a level which is typically associated with a decline in cognitive function. Premonitory systemic symptoms include anxiety, tachycardia, perspiration, nausea, and tremor, but these signs may be absent in patients taking β-adrenergic–blocking medications or in patients with autonomic neuropathy. Early neurologic symptoms include decreased attention and concentration, drowsiness, poor memory, disorientation, clumsiness, and tremor. Patients may progress to experience seizures and loss of consciousness. Seizures may be focal or generalized and may lead to status epilepticus. Rapid detection through expectant testing and early treatment are essential as severe untreated hypoglycemia is associated with diffuse cortical, basal ganglia, and dentate gyrus damage, leading to permanent disability.
Peripheral Neuropathies
A length-dependent polyneuropathy related to diabetes is typically a chronic, symmetric disorder that targets the distal terminals of axons first. Focal or localized neuropathies of a single plexus or nerve, also known as mononeuropathies, are also common in patients with diabetes and develop from mechanical compression, ischemia, or other, less well-defined causes. Autonomic neuropathy is the other major category of peripheral nervous system dysfunction in these patients.
Diabetic Polyneuropathy
Diabetic polyneuropathy is the most common form of peripheral neuropathy. With detailed evaluation, approximately 50 percent of both type 1 and type 2 diabetic subjects have the disorder. Symptomatic polyneuropathy may occur in approximately 15 percent of these patients. Lower prevalence numbers have been derived from studies only of hospitalized patients, or studies using exclusively clinical signs of polyneuropathy. Sensory forms predominate, with or without lesser degrees of motor involvement. Positive sensory symptoms are common and include prickling, tingling, “pins and needles,” burning, crawling, itching, electric, sharp, jabbing, and tight sensations in the legs, feet, hands, and fingers. Warm stimuli may be inappropriately perceived as cold, and cold stimuli as warm or hot. Nocturnal burning of the feet accompanies allodynia, defined as the generation of discomfort from normally innocuous stimuli. Many of these symptoms are associated with severe pain, which may become intractable.
Symptoms are generally symmetric and initially confined to the toes, with later spread to more proximal parts of the feet, legs, and fingers ( Fig. 19-1 ). The involvement of the longest sensory axon terminals in the skin results in this “stocking and glove” pattern of sensory symptoms and loss. Negative symptoms include loss of sensation to light touch, pinprick, and temperature. In more severe forms, dense loss of these sensations predisposes patients to the development of foot ulcers. Additional factors that promote foot ulceration include loss of sweating, abnormal foot architecture from muscle wasting, and delayed healing from both macrovascular (atherosclerosis) and microvascular disease.
Motor weakness is less common in early diabetic polyneuropathy but may eventually lead to distal weakness of foot and toe dorsiflexion, predisposing patients to falls. Weakness is accompanied by wasting of the intrinsic foot muscles. Symptoms from concurrent abnormalities of the autonomic nervous system are common and include erectile dysfunction in men, distal loss of sweating, orthostatic symptoms such as “dizziness,” and bowel and bladder dysfunction.
A detailed neurologic examination is essential to the evaluation of diabetic polyneuropathy, providing a low-cost, direct evaluation. While some variation in findings, especially in those patients with very early disease, is expected, the examination remains the gold standard for diagnosis and is not replaced by quantitative methods or electrophysiologic evaluation, which are considered ancillary tests.
On sensory examination, there is distal loss of sensation to light touch, pinprick, cold, and vibration with a 128-Hz tuning fork. Some patients with denser sensory loss are unable to distinguish sharp (pinprick) from dull (analgesia) or to feel light touch at all (anesthesia). The Semmes–Weinstein (10 g) monofilament test is a useful adjunct to the neurologic examination; the filament is pressed against the skin over the dorsum of the great toe or other selected areas of the foot until it bows into a C shape for 1 second, and the patient is asked whether the stimulus is felt. The Rydel–Seiffer tuning fork provides semiquantitative information regarding vibratory sensory perception. Vibratory loss may involve the distal toes, the foot below the ankle, or more extensive territories, depending on its severity. Testing for proprioceptive abnormalities in the toes is often normal except in severe cases.
Distal motor wasting, for example, in the extensor digitorum brevis muscle, and associated weakness especially involving foot and toe dorsiflexion usually accompany more severe sensory loss. Patients may have foot ulcers or, less commonly, a destructive arthropathy from repetitive injury, known as a Charcot joint. Loss of the muscle stretch reflex at the ankle is common in early diabetic polyneuropathy; severe forms lead to loss of all deep tendon reflexes. The feet may be dry from loss of sweating. Patients with concurrent atherosclerosis have loss of distal pulses and sometimes femoral bruits. Orthostatic vital signs should be assessed; in patients with involvement of the autonomic nervous system, a decline of over 20 mmHg in the systolic blood pressure or of 10 mmHg in diastolic pressure indicates postural hypotension.
Diabetic polyneuropathy has been divided into subcategories depending on whether large- or small-fiber involvement occurs. In large-fiber polyneuropathy, there is more prominent loss of sensation to light touch, vibration, and proprioception, and patients may have accompanying ataxia of gait. In small-fiber polyneuropathy, pinprick and thermal appreciation are impaired, and autonomic dysfunction is common, as is neuropathic pain, especially at night. Neuropathic pain can accompany other forms of diabetic polyneuropathy as well.
Several scales have been developed to grade the severity of diabetic polyneuropathy for clinical trials. The San Antonio criteria are divided as follows: class I is polyneuropathy without signs or symptoms but with abnormalities on electrophysiologic testing, autonomic testing, or quantitative sensory testing (QST); class II includes signs, symptoms, or both. Other scales, not reviewed here, include the Modified Toronto Neuropathy Scale, the Utah Neuropathy Scale, the Michigan Neuropathy Scale, and the Mayo Clinic diabetic polyneuropathy classification.
Testing
In patients with established diabetes mellitus and typical symptoms of polyneuropathy, extensive additional testing may not be required. Exclusion of other causes of sensory polyneuropathy can be accomplished through judicious screening for hypothyroidism, vitamin B 12 deficiency, monoclonal gammopathy, and ethanol abuse. Table 19-1 details an extensive list of alternative diagnoses that may resemble diabetic polyneuropathy.
| Vitamin Deficiency |
|
| Infectious and Inflammatory |
|
| Endocrine |
|
| Drugs and Toxins |
|
| Metabolic |
|
| Congenital/Inherited |
|
| Vascular |
|
| Neoplastic |
|
Electrophysiologic testing is recommended for patients with unexpectedly severe or atypical forms of polyneuropathy including motor-predominant disease, rapidly progressive symptoms, asymmetric signs, or when another neuromuscular condition is suspected. It is important to choose a laboratory with appropriate certification, training, and experience in performing these techniques. Two major components are usually performed: nerve conduction studies and needle electromyography (EMG). In patients with only sensory symptoms and findings, nerve conduction studies alone may be sufficient. Initial changes include reductions in the amplitude and conduction velocity of the sural sensory nerve action potential (SNAP) recorded from behind the ankle. Slowing of conduction velocity in fibular (peroneal) motor nerve axons detected by recording over the extensor digitorum brevis is an additional early abnormality. In severe neuropathy, there may be widespread loss of sensory nerve action potentials and diffuse mild-to-moderate conduction velocity slowing in multiple motor and sensory nerve territories ( Fig. 19-2 ). In some patients with severe involvement, these findings may resemble the changes expected in a demyelinating polyneuropathy such as chronic inflammatory demyelinating polyneuropathy, but there are usually much more striking electrophysiologic features of primary demyelination in chronic inflammatory demyelinating polyneuropathy such as motor conduction block or dispersion of compound muscle action potentials.
Loss of motor axons in more advanced diabetic polyneuropathy is detected by a decline or loss of compound muscle action potentials, initially in the lower and then the upper limbs. In these patients, needle EMG may detect abnormal spontaneous activity, including fibrillation potentials and positive sharp waves, in denervated muscles. In the setting of partial loss of motor axons, remaining fibers will sprout and innervate adjacent denervated muscle fibers; when activated, the motor unit action potentials recorded from these partially denervated muscles are enlarged but reduced in number, indicative of cycles of chronic denervation and reinnervation. Electrophysiologic testing is also valuable in identifying superimposed entrapment, or compression neuropathies, which are discussed below.
To reproducibly detect or track sensory changes, quantitative sensory testing (QST) using a computer interface may be used. While its chief utility is currently for clinical trials, it may offer early detection should better therapy for diabetic polyneuropathy emerge. QST equipment is available from several manufacturers and most use calibrated electronic interfaces to measure thermal thresholds (warm, cold), pain, touch-pressure, and vibration. As expected, these thresholds in the feet are raised in patients with diabetic polyneuropathy.
Specific testing of the autonomic nervous system is available for evaluating coexisting autonomic neuropathy (see Chapter 8 ). In some patients with diabetes mellitus, prominent and apparently selective autonomic damage occurs without polyneuropathy, as discussed later. Since postganglionic autonomic axons are unmyelinated, autonomic function testing may detect small-fiber forms of diabetic polyneuropathy.
Two additional forms of testing, not in routine clinical use for diabetic polyneuropathy, also evaluate small-fiber involvement. These include skin biopsy, using a 3-mm punch to count the number of epidermal axons, and corneal confocal microscopy, which is a noninvasive measure of unmyelinated axons in the cornea.
Biopsy of the sural nerve is not indicated for the routine evaluation of diabetic polyneuropathy and should be reserved for the diagnosis of unusual or progressive neuropathies that are atypical and suspected to be from another cause. In diabetes, sural nerve biopsies show loss of myelinated and unmyelinated axons that can accompany microvascular basement membrane thickening, endothelial cell reduplication, or vessel occlusion. These biopsies typically leave the patient with a sensory deficit and therefore should be considered judiciously.
Cerebrospinal fluid (CSF) examination is not routinely indicated for typical diabetic polyneuropathy, although when performed it may show an elevated CSF protein concentration without pleocytosis. Imaging studies are used to exclude spinal cord disease, spinal stenosis, or other central disorders whose symptoms may occasionally resemble diabetic polyneuropathy.
Differential Diagnosis
A number of neurologic disorders may resemble diabetic polyneuropathy. Other polyneuropathies with prominent sensory involvement are listed in Table 19-1 . As diabetes mellitus is very common, a detailed neurologic examination is essential to exclude other syndromes in these patients; for example, spinal cord disease may present with limb tingling and numbness, but other signs of upper motor neuron dysfunction are usually present on examination. Lesions at the cervicomedullary junction may cause sensory symptoms that begin in one limb and then progressively involve all four limbs. “Pseudoneuropathy” is a term used to describe the combination of lower limb sensory symptoms from spinal stenosis with upper limb tingling caused by carpal tunnel syndrome. It is important to identify patients with chronic inflammatory demyelinating polyneuropathy because they may respond to immunomodulatory therapies.
Pathogenesis
A number of mechanisms have been proposed to play a role in the pathogenesis of diabetic peripheral neuropathy, all with limited definitive evidence usually explored in rat and mouse models of diabetes. Excessive flux of polyols (sugar alcohols), especially sorbitol, through the aldose reductase pathway is one such proposed mechanism. Aldose reductase inhibitors or protein kinase C inhibitors that interrupt this pathway have unfortunately been shown to have limited clinical benefit. Free radical oxidative stress and mitochondrial dysfunction along with impaired antioxidant defenses likely contribute to neuronal damage. Diabetic microangiopathy may lead to ischemic damage of neurons and axons, although this mechanism may occur later in the illness rather than serving as a primary trigger. Trophic mechanisms that support neurons are also impaired in diabetes. To date, clinical trials with nerve growth factor, neurotrophin-3, and brain-derived neurotrophic factor have all been disappointing. An intriguing alternative is insulin itself, an important growth factor which is neurotrophic; its receptors are widely expressed in most neurons of the peripheral nervous system. Intranasal insulin can access the CSF and through this route can reverse experimental diabetic neuropathy.
Treatment
Despite extensive experimental work, no therapy is currently available to arrest or reverse diabetic polyneuropathy. Tight control of hyperglycemia helps to reduce the incidence of polyneuropathy and its progression. Aldose reductase inhibitors have been tested extensively as a means of reversing sorbitol accumulation in peripheral nerves and associated metabolic abnormalities, but their overall impact has been disappointing. Daily foot inspection for injuries and early ulceration is recommended. Treatment for neuropathic pain associated with diabetic polyneuropathy is available and is discussed later.
Focal Mononeuropathies
Focal neuropathies involving single peripheral nerves are common in diabetes. Many of these mononeuropathies develop at sites of entrapment or compression, but others are of uncertain origin or may develop from nerve trunk ischemia.
Carpal Tunnel Syndrome
Carpal tunnel syndrome arises from compression of the median nerve at the wrist beneath the transverse carpal ligament, often following repetitive use of the wrist. It is characterized by tingling, pain, and numbness in the thumb, index, and middle fingers, especially at night or on awakening. Asymptomatic carpal tunnel syndrome (electrophysiologic diagnosis) can be detected in 20 to 30 percent of diabetics, but symptomatic carpal tunnel syndrome is present in only 6 percent. Carpal tunnel syndrome is the most common entrapment neuropathy in diabetic and nondiabetic patients. Women are more susceptible than men, and the dominant hand is more commonly involved that the nondominant hand.
Tinel sign (tapping over the median nerve at the wrist evokes positive sensory symptoms that resemble the patient’s symptoms distal to the wrist) and Phalen sign (reproduction of tingling by having both wrists flexed and held against each other for 1 minute) may be present, but are nonspecific and insensitive. In mild carpal tunnel syndrome, clinical signs may be absent. Later, sensory loss may occur in the median nerve territory. In more severe carpal tunnel syndrome, weakness and wasting of the abductor pollicis brevis (thenar muscles) develops. Electrophysiologic testing helps to distinguish carpal tunnel syndrome from radiculopathy or other upper limb neuropathies by identifying selective slowing of the conduction of median nerve fibers across the carpal tunnel. Carpal tunnel syndrome may improve with a change in activity and the nocturnal use of wrist splints. Decompression by sectioning the transverse carpal ligament is the only curative procedure. Since diabetes delays nerve regeneration, recovery in diabetics, particularly those with poor glycemic control, may be less robust than in nondiabetics.
Ulnar Neuropathy at the Elbow
Ulnar neuropathy at the elbow presents with pain and sensory symptoms in the medial half of the ring finger and fifth digits, sometimes radiating into the palm as far proximal as the wrist. Sensory loss involves these fingers as well as the medial volar and dorsal hand to the wrist. There may be wasting and weakness of intrinsic ulnar-innervated hand muscles, especially in the first dorsal interosseus muscle, making it difficult for the patient to abduct or adduct the fingers. Manipulation of the ulnar nerve at the elbow may generate tingling that radiates into the hand and reproduces symptoms. Ethanol use and previous elbow trauma or fractures are predisposing factors. The disorder is commonly caused by the patient leaning on the medial elbow, compressing the nerve. The prevalence of ulnar nerve entrapment in patients with diabetes mellitus is estimated to be approximately 2 percent.
Electrophysiologic studies identify slowing of ulnar motor and sensory conduction across the elbow, loss of ulnar sensory nerve action potentials and compound motor action potentials, and sometimes conduction block across the elbow. EMG demonstrates evidence of denervation in affected muscles. Changes in elbow position or protecting the nerve with padding can reverse ulnar neuropathy. There are no controlled clinical trials specifically in diabetic patients to show that surgical decompression improves long-term outcome; however, current clinical practice suggests decompression is a reasonable approach when the lesion is symptomatic, involves motor axons, and is progressive despite conservative measures.
Meralgia Paresthetica
Meralgia paresthetica is an entrapment neuropathy involving the lateral femoral cutaneous nerve of the thigh as it passes under the inguinal ligament. Symptoms are numbness, tingling, prickling, and sometimes pain over the lateral thigh that may be relieved by sitting. Bilateral involvement may occur. Examination findings include loss of sensation to light touch and pinprick over the lateral thigh. The extent of findings may vary from a small patch to most of the lateral thigh from just below the inguinal area to the knee. Hip flexion and knee extension muscle power are preserved, as is the quadriceps stretch reflex. In some patients, a compressive lesion such as an enlarged lymph node, inguinal hernia, or scar from a previous hernia repair is present. Additional risk factors are abdominal obesity, pregnancy, and the wearing of low-riding belts. The differential diagnosis includes diabetic lumbosacral plexopathy (distinguished by weakness and wasting along with loss of the quadriceps reflex), plexopathy secondary to a retroperitoneal lesion, or an L3 or L4 radiculopathy associated with back pain, weakness, positive straight leg raising sign, and loss of the quadriceps reflex. There is no evidence to support benefit from surgical decompression at the inguinal ligament; however, some patients may choose to undergo decompression if weight loss, local anaesthetic, or corticosteroid injections are unhelpful and the pain is intractable. Conservative management of pain and limiting activities that provoke symptoms may allow spontaneous recovery over time.
Intercostal or Truncal Radicular Neuropathies
Intercostal neuropathies involve the thorax and abdominal wall and may be ischemic in origin. Patients may present with severe thoracic or abdominal wall pain mistaken for an intra-abdominal or thoracic emergency. Differential diagnoses include herpes zoster without rash or radiculopathy from a segmental structural lesion. Several contiguous territories may be involved unilaterally or bilaterally. Symptoms other than pain include tingling, pricking, lancinating, aching (especially at night), radiation around the chest or abdomen causing a feeling of constriction, and allodynia. Patients may occasionally have asymmetric weakness of the abdominal muscles when sitting up (asymmetric bulging). Men are affected more often than women. Imaging of the spinal cord and roots by magnetic resonance imaging (MRI) with gadolinium should be performed to exclude nerve root compression when a structural lesion is suspected. In some patients, EMG may detect signs of denervation in weak thoracic intercostal or abdominal muscles; such changes commonly are more extensive and may involve the paraspinal muscles at multiple levels. Pain may be severe enough to require treatment, but usually reaches a maximum after several weeks, continues for some months, and then gradually resolves completely. Sensory loss may also slowly resolve with time.
Oculomotor Neuropathy
Oculomotor neuropathy develops in older patients with diabetes, particularly if they are also hypertensive. Symptoms usually involve sudden diplopia and ptosis, with aching pain around or behind the eye. The eye is deviated laterally. The underlying pathology is a vascular lesion that spares the more peripheral pupillomotor fibers, so that the pupil is not involved. A single pathologic study of a patient with oculomotor palsy noted demyelination in the center of the oculomotor nerve within the cavernous sinus. Imaging should include MRI of the brainstem and the course of the oculomotor nerve; MR angiography is indicated to search for evidence of an aneurysm compressing cranial nerve III, although in these cases the pupil is typically involved. Computed tomography (CT) angiography may also be used to exclude aneurysm but there is a risk of contrast nephropathy from the contrast load. Although no specific treatment is available for this neuropathy, spontaneous resolution usually occurs over approximately 3 months. An eye patch prevents diplopia but interrupts binocular depth vision so patients should refrain from driving.
Diabetic Lumbosacral Plexopathy
Diabetic lumbosacral plexopathy (also known as diabetic amyotrophy, radiculoplexus neuropathy, Bruns–Garland syndrome, and proximal diabetic neuropathy) usually develops in patients with type 2 diabetes mellitus, especially in men. It may emerge early in the course of diabetes or following the onset of insulin therapy. Patients without diabetes rarely can develop a similar syndrome. Symptoms are severe and disabling, with impairment in standing and walking. The subacute onset of unilateral intense deep boring or aching muscle pain is typical, sometimes worse at night, located within the muscles of the thigh and often radiating to the back and perineum. These symptoms are followed by weakness and wasting of the proximal thigh muscles including the quadriceps, iliopsoas, hip adductor muscles, and occasionally the anterior tibial muscles (with associated foot drop). Sensory loss and tingling are less prominent. The condition can be distinguished from a femoral neuropathy by the pattern of muscle involvement, which typically includes the medial adductor muscles innervated by the obturator nerve and the iliopsoas muscle innervated directly by the lumbar plexus. Over the months, a slow recovery of muscle power occurs. In some patients, contralateral symptoms may emerge a few weeks after onset. Variations of diabetic lumbosacral plexopathy include symmetric involvement, more prominent foot drop, or apparent worsening of polyneuropathy.
The pathophysiologic mechanism for this form of focal neuropathy is uncertain but may include occlusive changes in microvessels supplying the lumbosacral roots or plexus, or a localized form of vasculitis. Perivascular inflammation, epineurial inflammation, microvessel occlusion, and iron deposition (indicative of intraneural bleeding) accompany loss of axons in biopsies of the sural nerve or cutaneous nerves of the thigh. Imaging studies of the lumbar spinal cord and the lumbosacral plexus, usually with MRI, help to exclude a retroperitoneal compressive plexus lesion.
Electrophysiologic studies in diabetic lumbosacral plexopathy show reduction of compound muscle action potential amplitudes recorded over the quadriceps muscle and EMG evidence of denervation in weak muscles. No therapy has been shown to arrest or reverse the motor deficit. Despite the inflammatory changes seen on pathology, the response to immunosuppressive therapy is unproven. Preliminary data suggest that an intravenous course of corticosteroids may shorten the duration of pain but not disability. Patients require intensive pain management that may include opioid use. Physiotherapy and occupational therapy are essential to recovery, and knee bracing helps to prevent falls from leg buckling in the setting of quadriceps weakness.
Other Focal Neuropathies
Other focal neuropathies described in diabetic patients are less common. Bell palsy, presenting with unilateral facial weakness, may be more common in diabetics. Abducens palsy presents with lateral gaze weakness and is seen in older diabetic patients; other causes include compression, trauma, and hypertension. Trochlear palsy presents with diplopia and difficulty looking down and inward due to weakness of the superior oblique muscle; the patient tilts the head to the side opposite the palsy in order to reduce diplopia.
Autonomic Neuropathy
Autonomic neuropathy in diabetes may target one or more components of the autonomic nervous system.
Cardiovascular abnormalities include loss of reflexes such as heart-rate variability in various circumstances including at rest, with the Valsalva maneuver, and following standing. In severe disease, patients may have a fixed, mildly elevated heart rate that resembles a transplanted heart without innervation. More commonly, partial denervation of the heart may contribute to abnormal contractility and arrhythmias. For example, prolonged QTc intervals in patients with type I diabetes may predict an increased risk of mortality. Postural hypotension, from loss of sympathetic control of resistance arterioles, is defined as a decline of systolic pressure of 20 mmHg or more after 1 minute of standing, with associated orthostatic dizziness or fainting; it occurs in 3 to 6 percent of diabetics and may be a late feature of diabetic autonomic neuropathy. Some patients may also have abnormal tachycardia with standing (postural orthostatic tachycardia syndrome), as discussed in Chapter 8 .
Treatment includes stopping or reducing doses of medications that can cause postural hypotension (e.g., tricyclic antidepressants, antihypertensive medications, and other vasodilators); arising from bed or chair slowly; sleeping with the head of bed raised 20 degrees; avoiding prolonged standing; eliminating early morning or postprandial exercise; avoiding prolonged heat exposure, hot baths, or showers; increasing salt and fluid intake; and limiting alcohol intake. Medications used to treat postural hypotension include fludrocortisone, midodrine, and desmopressin ( Chapter 8 ).
The Ewing battery is a set of cardiovascular autonomic tests that includes heart-rate response to the Valsalva maneuver, standing, and to deep breathing, as well as blood-pressure response to standing up and sustained handgrip. Radioiodinated metaiodobenzylguanidine (MIBG) is an injectable marker of sympathetic terminals found in cardiac muscle; loss of uptake in the inferior, posterior and apical portions of the heart occurs in diabetes, indicating sympathetic denervation or dysfunction.
Sexual dysfunction is common in diabetic men. Erectile dysfunction, defined as the inability to achieve or maintain an erection sufficient for sexual intercourse, may occur in over 40 percent. Direct vascular factors, such as atherosclerosis, typically cause erectile dysfunction, but other causes should be excluded including psychologic factors, Peyronie disease, problems with the sexual partner, and medications (e.g., sedatives, antidepressants, and antihypertensives). The additional loss of ejaculation suggests more severe autonomic involvement. Testing includes duplex ultrasonography and nocturnal measurements of penile tumescence. Treatment for erectile dysfunction includes phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil), apomorphine, intracavernosal and intraurethral treatments (e.g., prostaglandin E1, thymoxamine), vacuum devices, and penile prostheses, as is discussed in Chapter 30 .
Gastrointestinal neuropathy is associated with abdominal pain, weight loss, early satiety, postprandial fullness, heartburn, nausea (rarely vomiting), dysphagia, fecal incontinence, diarrhea (which may be nocturnal), and constipation. Esophageal transit and gastric emptying are slowed, a change directly linked to elevated glucose levels. Similarly, small intestine dysmotility develops and may accompany an increased risk of cholelithiasis and cholecystitis. Colonic dysfunction leads to constipation and diarrhea that may be alternating and may be associated with abdominal pain. Anorectal dysfunction with incontinence develops from abnormal internal or external sphincter function, loss of sensitivity, and disrupted anorectal reflexes. A superimposed history of obstetric trauma may particularly predispose diabetic women to this complication. Exclusion of other gastrointestinal problems that can occur in patients with diabetes is important, including esophageal candidiasis, gastric bezoar, Helicobacter pylori infection, anorectal disorders, celiac disease, hemorrhoids, impaired sphincter tone, rectal prolapse, local tumors, ulcers, rectal intussusception, and fecal impaction.
Gastric and intestinal motility studies are carried out using radiography or scintigraphy, manometry, pH recordings, and endoscopy or colonoscopy. Anorectal dysfunction is studied through manometry, ultrasonography, proctoscopy, and sigmoidoscopy. High fiber, low fat diets may facilitate gastric emptying. Pharmacologic treatments of slowed gastric emptying include prokinetic agents (e.g., domperidone, metoclopramide, erythromycin). Cisapride has been withdrawn from the market in many countries because of an increased risk of cardiac arrhythmia and death. For intractable impaired gastric emptying, a temporary or permanent jejunostomy may rarely be required. For diarrhea, opioids (e.g., loperamide, codeine), cholestyramine, fiber, and bulking agents may be useful. Biofeedback may help with fecal incontinence.
Bladder neuropathy leads to loss of bladder sensitivity and later detrusor muscle weakness, both of which contribute to incomplete bladder emptying, recurrent infection, and eventual overflow incontinence (see Chapter 29 ). In late disease, an end-stage, insensitive, non-contractile atonic bladder can result. Symptoms of bladder neuropathy include urgency, nocturia, and incontinence. Other urologic problems such as bladder tumor, infection, urethral stricture, or prostatic hypertrophy should be excluded. Urodynamic studies may be helpful, including urinary tract imaging (e.g., intravenous pyelography), cystography, uroflowmetry, and postvoid ultrasonography to test for residual urine. Pharmacotherapy may include parasympathomimetics and α-adrenergic blockade to relieve sphincter hypertonicity. End-stage dysfunction may require intermittent self-catheterization.
Sudomotor neuropathy , or abnormalities of sweating, can cause stocking and glove distribution anhidrosis, a risk factor for skin ulceration in the feet. Generalized loss of sweating increases heat intolerance. Diabetic subjects may experience inappropriate truncal sweating or gustatory sweating (facial and truncal sweating induced by eating certain foods). Thermoregulatory sweat testing (TST) examines the geographic distribution of sweating; quantitative sudomotor axon reflex testing (QSART) can quantify sweat output using a dehumidified sweat capsule; in diabetes, output may be reduced, absent, excessive, or “hung up” (persistent). The sympathetic skin response is an electrophysiologic surrogate for sweat gland activation. Other measures of sweat output include an analysis of sweat droplet numbers (numbers of functioning sweat glands) and size, skin biopsy to analyze sweat gland innervation, and novel rapid sweat indicator methods. For patients with hypohidrosis or anhidrosis, caution regarding heat exposure should be advised. Moisturizers may be applied to dry feet and hands.
Autonomic neuropathy may cause small pupils, with sluggish or absent pupillary reflexes accompanied by light intolerance. Pupils may be examined by pupillography to measure pupillary diameter, latency to contraction, and velocity of contraction and dilatation.
Patients with diabetes may also have hypoglycemic unawareness because autonomic responses (e.g., sweating, tachycardia) and counterregulatory hormones such as epinephrine fail to increase. Patients may not recognize their impairment and thus fail to take adequate protective measures.
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