ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 6, No. 1 Copyright © 1976, Institute for Clinical Science
Diabetic Neuropathy. A Review of Clinical Manifestations. A. M. LAWRENCE, Ph.D., and C. ABRAIRA, M.D. Sections of Endocrinology, Veterans Administration Hospital, Hines, 1L 60141 and Loyola University Stritch School of Medicine, M aywood, IL 60153
ABSTRACT Diabetic neuropathy in some form or other afflicts a majority of patients with diabetes mellitus. Neuropathic disturbance of sensory, motor or autonomic nerves may occur singly or in combination. Cranial nerve and other mononeuropathies generally resolve spontaneously. Autonomic neuropathy which can result in orthostatic hypotension, gastroparesis diabeticorum, nocturnal diarrhea, atonic bladder and impotence, although chronic, may wax and wane in clinical severity. Neuritis, disesthesias and painful sensory neuritis may resolve with good diabetic control; on occasion, diphenylhydantoin has been of therapeutic benefit. Introduction
Clinically manifest neuropathic problems may wax and wane in severity. Symptoms frequently disappear altogether. Diabetic neuropathy may involve the peripheral sensory, motor or autonomic nervous systems. The frequent finding of increased cerebral spinal fluid protein in diabetic neuropathy suggests a more widespread encephalo-myelopathic process. Further more, regional involvement by diabetic neuropathy is frequently a mix or com bination of several specific disorders of the peripheral nerves. In the foot, for example, diabetic anhidrosis, ischemic mononeuropa thies and diabetic motor amyotrophy com bine with a progressive distal poly neuropathy which collectively leads to hypercallosity of the plantar surface, onychogryposis with nail deformity and degeneration, dermal dryness and cracking, neuropathic ulcerations, infection, gangrene and eventual amputation. Diabetic neuropathy mimics many neu
Diabetic neuropathy of varying degree probably afflicts the majority of persons with recognized diabetes mellitus .7,8 For practical purposes, clinically manifest problems which accrue from diabetic neuropathy are evident in more than 50 percent of the American dia betic population. In general, there is no exact correlation between the severity of neuropathic morbidity and the severity or duration of clinically manifest diabetes mellitus. The clinical spectrum of involve ment is wide and may show evidence of generalized sensory or autonomic im pairment or simply be manifest as a local disturbance. In many, manifestations of dia betic neuropathy may appear to predate glu cose intolerance and appreciation of the dia betic origin may be missed because so many patients with diabetic neuropathy may have a normal fasting blood sugar and negative glycosuria. 78
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rologic diseases including amyotrophic lateral sclerosis, pernicious anemia, multiple sclerosis, tabes, syringomyelia and spinal cord tumor. As invasive diagnostic tech niques such as angiography carry sig nificantly greater risk of morbidity in dia betics it is imperative that physicians who see such patients think of the possibility of diabetic neuropathy before proceeding to the ordering of unwarranted and potentially harmful workups. Conversely, it is as im portant not to summarily assign all neuro pathic problems in diabetics to diabetic neuropathy for the obvious reason that dia betics are as heir to bonafide neurologic ail ments as the rest of us. Virtually nothing is known of the patho genesis of diabetic neuropathy. Consensus holds that the metabolic problems of the diabetic state are responsible, but good ex perimental models are not available. Seg mental demyelinization can be seen on mi croscopic examination of peripheral nerves. Some have suggested the disease is inherent to defective Schwann cell function whereas others propose that the disturbance is secon dary to microvasculopathy of the vasa ner vorum or to excessive accumulation of sugar alcohols, such as sorbitol, in peripheral nerves. Remarkably little hard data have been developed in this area, although it is clear in both human and in experimental dia betes that motor nerve conduction velocity is significantly slowed. Diabetic neuropathy can be divided into peripheral sensory, peripheral motor, pe ripheral autonomic and cranial (peripheral) nerve involvement. An alternative clasTABLE I Regional Syndromes in Diabetic Neuropathy
Peripheral sensory and motor neuritis Cranial nerve neuropathy The diabetic foot Urogenital neuropathy (atonic bladder and impotence) Gastrointestinal neuropathy Diabetic dental caries Orthostatic hypotension
TABLE II Clinical Manifestations of Sensory Neuropathy in Diabetes
Stocking-glove paresthesia Unrecognized injury: burns, trauma, Charcot foot Metatarsal calluses Neuropathic foot ulcerations Loss of Achilles tendon reflex Impaired two-point discrimination
sification considers the clinical area in volved, namely, the cranial nerves, the vascular tree, the urogenital tract, the gas trointestinal tract, the diabetic foot and dia betic teeth (table I). The remainder of this article is devoted to a brief synopsis describing these particular clinical entities, their diagnosis and some approaches to management. Peripheral Sensory Neuropathy in Diabetes Mellitus As shown in table II, the most common objective disturbance in peripheral sensory neuropathy is diminished appreciation of vi bratory sensation and loss of the Achilles tendon reflex. In its mildest form, patients with this involvement complain of tingling, numbness and paresthesias of the feet and ankles. This sensory neuropathy of diabetes is of a stocking-glove distribution. Although relatively asymptomatic, loss of 2 point dis crimination may render the blind diabetic patient unable to learn Braille, and difficul ties with proprioceptive sensation may hamper a previously effective typist. Some patients suffer from a distressful disesthesia characterized by a burning and searing sensation aggravated by any light contact of the skin with trousers, pajamas, or bed clothes. Pain and disesthesia are generally most severe during the early morning hours of sleep. These disesthesias may be so severe and unrelenting that the patient becomes suicidal; narcotics may need to be used. In the absence of disesthesias the patient may
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D iabetic Cranial N erve N europathy Commonly, the third, sixth an d /o r fourth cranial nerves fail to function. Bell’s palsy is m ore comm on in diabetes. Involvem ent of cranial nerves is frequently sudden in onset, one sided and painful. Ptosis and in terference with lateral gaze develop, but the pupillary reflex remains intact because the third nerve lesion is a peripheral phe nomenon. Cranial nerve involvem ent often precedes any overt evidence of m etabolic abnorm ality by m onths or even years. It has been suggested that these particular cranial nerves are m ore vulnerable to injury because of their long intracranial extension. Cranial nerve involvem ent alm ost inevitably abates spontaneously w ithout treatm ent of any kind.
Figure 1. Neuropathic foot ulceration. Taken from Implications of Hyperglycemia, p. 20, copyright Pfizer Laboratories.
have relative anesthesia of the distal extrem ities, especially of the feet. This may result in injury which is not acutely appreciated, as for example, second and third degree burns of the hands and feet or other types of contact injury which may ultim ately lead to tissue necrosis, gangrene, and need for am putation (figure 1). No current therapy is available for dia betic sensory neuropathy. Peculiarly, in some patients, the initiation of diabetic con trol with drugs or with insulin may seem to usher in symptoms. In many, if not most patients, these abate with tim e and good dia betic control. Diabetic m anagem ent and non-opiate analgesics generally suffice. In re cent years sodium dephenylhydantoin 100 mg tid3 or clofibrate 500 mg tid have been claimed effective in some.
D iabetic Peripheral M otor N europathy Not infrequently, in diabetics, there will be some atrophy of the interosseus muscles (table III), m ore evident in the feet than in the hands. On occasion, wasting of the small muscles of the hand can be striking with marked atrophy of the interosseus, thenar and hypothenar muscles bilaterally. Patients may be unable to use their hands for or dinary personal needs or for occupations requiring even the grossest m anual dexterity. Very rarely, in elderly m en with mild dia betes, widespread muscle wasting, severe anorexia, weight loss and pain are en countered. This syndrom e of diabetic neuro pathic cachexia3 has a variable prognosis but TABLE III Clinical Manifestations of Motor Neuropathy in Diabetes
Extraocular muscle palsies Bell's palsy Atrophy interosseous muscles Diabetic cachexia Peripheral muscle atrophy (femoral, sciatic, median, ulnar and radial nerves in order of frequency)
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may regress spontaneously with full and uneventful recovery. The Neuropathic Diabetic Foot Discreet calluses over one or more inferior metatarsal heads (figure 1 ) are almost path ognomonic of diabetic heritage or of the diabetic state .1 The reason for this de velopment is not entirely clear, but interosseus muscle atrophy and contracture are frequently apparent and this phe nomenon results in an extension, claw-like position of the toes. The resultant effect is that the protective subcutaneous fat pad is drawn forward and away from the metatarsal heads which then bear the patient’s full weight during standing and walking. At times, these calluses become enor mously heaped up. Once higher than the surface of the ball of the foot, they become the full weight-bearing fulcrum of the foot. This adds to the callus growth. In time, this will lead to deep tissue necrosis and to the development of neuropathic ulcerations (figure 1). Such ulcers may develop awesome dimensions because they are so anesthetic that they cause the patient to delay medical attention. The painless quality is clearly neuropathic in origin. Indeed, it is possible to debride surgically these areas without anesthesia. Virulent bacteria may infect these ulcers and initiate local osteomyelitis, TABLE IV Clinical Manifestations of Autonomic Neuropathy in Diabetes
Neurogenic bladder Impotence Gastroparesis diabeticorum Gastric beozoars Nocturnal diarrhea Fecal incontinence Constipation Orthostatic hypotension Dental caries (anesthetic) Hypoglycemia proneness
cellulitis and threat of impending sepsis which may require amputation. Early education, impressing upon the patient the need for adequate foot care, would avoid most of these complications. Well fitting shoes, daily bathing in a gentle soap, careful drying between the toes, pumice stone abrasion of calluses, appro priate cutting or filing of the toenails and im mediate medical attention to contact inju ries, blisters, infections, or other threats to foot health could probably avoid the ma jority of amputations in our diabetic popu lation. Once a neuropathic ulcer has de veloped on the ball of the foot, long-term avoidance of weight bearing and local cleansing care are the prime resorts to effective cure. Once healed, vigilance is re quired and cushioned sole pads become mandatory. A metatarsal arch support may help to keep the problem from re-emerging. The Charcot foot is also seen in some dia betics. This condition results in inappro priate use of the “insensitive” foot in such a way that dislocation of small joints and avul sion of tendons and muscle detachments de velops. The end result in an extraordinarily unstable distal appendage, a bag of bones, which on x-ray will show a mixture of severe small joint degenerative disease and bone resorption. The use of braces and crutches may buy time for fibrous ankylosis of these injured joints and for return of some mod icum of stability to the foot. Urogenital Diabetic Neuropathy Neurogenic bladder and diabetic impo tence (table IV) are very common but fre quently not suspected by the patient’s phy sician .4,5 A large number of diabetic patients have abnormally low bladder tone requiring a greater than normal volume before the urge to urinate develops. In some patients, this can reach the point of virtual bladder paralysis and volumes of over 5000 cc have been recorded (figure 2). Presentation may
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Figure 2. Atonic bladder from Diabetes Mellitus: Theory & Practice by Ellenberg & Rifkin, figure 39-7 on p. 833. Copyright 1970. Used with permission of McGraw-Hill Book Company.
be with a large intra-abdominal mass or with a complaint of intermittent constipation be cause of pressure of the distended bladder on the sigmoid colon. Any degree of neuro pathic bladder adds significantly to the risk of cystitis and ascending pyelonephritis in these patients. Once the diagnostic suspicion of an atonic bladder is confirmed by cystometrogram, mild cases can be treated by having the patient void every four hours by applying suprapubic pressure. If the situation is more severe and the bladder virtually paralyzed with overflow incontinence, Foley catheter drainage for several days may be required to help restore bladder tone. Any accom panying urinary tract infection must be ag gressively treated. If marked bladder disten tion repeats itself, then surgical interruption
of the internal bladder sphincter becomes mandatory. This operation causes retrograde ejaculation because of incompetency of the internal sphincter, a problem that can be controlled by exerting a Valsalva maneuver during ejaculation. To a diabetologist, impotence (failure to initiate or sustain an erection for successful coitus) in the presence of avowed libido is diabetic in origin until proven otherwise. Penile erection requires stimulation of the second, third and fourth sacral component of the parasympathetic nerves, and impo tence in diabetics is presumed to be due to autonomic neuropathy involving the Nervi Erigentes. More than 50 percent of diabetic men suffer from diabetic impotence, and this situation may precede the actual diagnosis of diabetes. This condition may revert spon taneously; in others, clofibrate 500 mg tid may be helpful for reasons which are not clear. Good diabetic control and elimi nation, where possible, of contributing psy chic stress or drugs such as reserpine, adlactone, and others, which are known to cause impotence, may help as well. Surgical placement of a silicone penile implant6 in creasingly is being used for men with impotency. Diabetic Gastrointestinal Neuropathy Gastroparesis diabeticorum, gastric bezoars, malabsorption, nocturnal diarrhea and constipation are variable manifestations of autonomic neuropathy affecting the digestive tract in diabetics. Gastroparesis diabeticorum is characterized by an enlarged atonic stomach in which ingested and se creted substances are slowly and erratically propelled into the small bowel. Perhaps be cause of these motility abnormalities, dia betic patients are more prone to develop gastric mucobezoars. Clinically, this prob lem may present as recurrent nausea and vomiting, postprandial distress, severe weight loss and debility. An upper gas trointestinal x-ray examination will show
DIABETIC NEUROPATHY— REVIEW OF CLINICAL MANIFESTATIONS
these concretions provided an experienced radiologist is alert to the problem. Papain tablets or fresh pineapple, a source of pa pain, may suffice to dissolve these bezoars but surgical intervention may be required. Diabetic diarrhea, often nocturnal, may emerge as the initial clinical symptom of dia betes mellitus. Small bowel x-rays may show flocculation typical of a malabsorption syn drome and small bowel biopsy may even demonstrate flattened mucosa. No tho roughly successful approach to this diar rheal syndrome, which frequently waxes and wanes, has been proposed. Other Neuropathic Disturbances in Patients with Diabetes Severe orthostatic hypotension with recur ring syncope can develop in some patients with diabetic neuropathy. Study of these patients has revealed a relative paresis of the renin-angiotension-aldosterone system. Au tonomic innervation of the renal jux taglomerular apparatus, the source of renin, is presumed to be defective in these patients as they fail to demonstrate an appropriate renin rise during maneuvers designed to stimulate renin secretion such as salt restric tion. Fortunately for these incapacitated patients, the synthetic salt retaining mineralcorticoid, fludrocortisone acetate, expands blood volume and restores tonus to the vascular system sufficient to ameliorate de vastating symptoms of orthostasis. Serious dental caries in diabetics are likely related to a neuropathic disorder as well. Ba sically there is a tendency for alveolar bone resorption of the dental ridge of both the mandible and the maxilla. Gingival recession exposes the poorly enamalized portion of the tooth cusp to enzymatic and bacterial injury. Because caries in diabetics are anesthetic, the patient may delay dental care until the tooth so loosens from its attachment that it can be extracted by gentle traction. Finally, diabetic patients with evidence of
severe autonomic neuropathy frequently experience marked insulin sensitivity with bouts of unexplained and recurring profound hypoglycemia. These patients act as if they have impaired hormonal and metabolic means of averting or coping with hypo glycemia. It is suspected but not proven that glucagon secretion and hepatic glucose re lease may be deficient owing to malfunction of the autonomic nervous system. Conclusions Consensus holds that diabetic neuropathy is a result of the basic metabolic disturbance in diabetes mellitus. Even so, a careful clinician may encounter clear clinical evi dence of diabetic neuropathy in a patient with what appears to be relatively normal carbohydrate metabolism. As diabetic neuropathy may mimic several serious neu rological disorders, it is important to ap preciate the need to include diabetes mellitus in any differential diagnosis so as to avoid, if at all possible, invasive and potentially noxious diagnostic procedures in these particular patients. References 1. Eliasson, S. G.: Neuropathy and the diabetic foot. The Diabetic Foot. Levin, M. E. and O’Neal, L. W., eds., St. Louis, C. V. Mosby, p. 40, 1973. 2. Ellenberg, M.: Treatment of diabetic neuropathy with diphenylhydantoin. N.Y. State J. Med. 68:2653, 1968. 3. Ellenberg, M.: Diabetic neuropathic cachexia. Dia betes 23:418, 1974. 4. Ellenberg, M.: Diabetic neurogenic vesical dys function. Arch. Intern. Med. 117:348, 1966. 5. Ellenberg, M.: Impotence in diabetes: the neu rologic factor. Ann. Intern. Med. 75:213, 1971. 6. Lash, H.: Silicone implant for impotence. J. Urol. 100:709, 1968. 7. Prockop, L. D.: Diabetic neuropathy. Diabetes Mellitus: Diagnosis and Treatment. Fajans, S. S. and Sussman, K. E., eds., New York, American Diabetes Association, Inc., Vol. Ill, p. 347, 1971. 8. Prockop, L. D. and Pleasure, D. E .: The cellular and molecular basis of neurologic disease. Diabetic Neuropathy. Shy, M., Goldensohn, E., and Apple, S., eds., Philadelphia, Lea and Febiger, 1971.