Diagnosis of DPN is based on history, examination, and, when possible, electrodiagnos-tic testing. The San Antonio Consensus Criteria remain the gold standard for diagnosis, although their use is limited to clinical trials and epidemiological studies (43); the criteria are too exhaustive for routine use in a clinical practitioner's office. The San Antonio Consensus Criteria are based on measurements in each of the following five categories: clinical symptoms, clinical examination, electrodiagnostic studies (EDX), QST, and AFT. EDX, also referred to as nerve conduction studies, are a quantitative and objective measure of peripheral nerve function. A major benefit of EDX is the ability to distinguish whether the origin of neuropathy is axonal or demyelinating. EDX most frequently show a mixed picture in DPN with primarily axonal damage and a low degree of dysmyelination (44). The most common criticism of EDX—that its restriction to large nerve fibers with small fibers is not questioned—is in most cases not valid.
QST assesses the loss of sensory functions which often go unnoticed by both patient and physician. The essence of the QST is the use of quantitative instruments to measure abnormal function with regards to sensing vibration and thermal changes. The simplest QST device is the quantitative 64 Hz tuning fork which measures the intensity of residual vibration on an eight-point scale rather than approximating dysfunction based on time elapsed from tuning fork strike (45). Most clinical trials and epidemiological studies employ the CASE IV system (WR Medical Electronics Co.). The CASE IV system measures both vibration detection threshold (great toe) and cool thermal detection threshold (dorsal foot) using a stepping algorithm; differences are expressed as just noticeable difference units that vary from 1 to 25. A discussion of AFT occurs later in this chapter.
Using the San Antonio Consensus Criteria, a patient has probable neuropathy if he has signs or symptoms and an abnormality of either EDX, QST, or AFT; he has definite neuropathy if he has signs or symptoms and two abnormalities among EDX, QST, or AFT. Because of the quantitative nature of the three groups of tests, patients can be followed longitudinally for a response to a therapeutic intervention or as part of a detailed epidemiological study of DN.
While the San Antonio Consensus Criteria are essential for clinical trials, in routine practice, a careful clinical examination of the feet with assessment of large fiber (vibration perception and proprioception) and small fiber (light touch, pain, and thermal perception) modalities and ankle reflexes is sufficient to make the diagnosis of DPN. Table 2 lists other possible etiologies underlying a distal symmetric polyneuropathy; depending on the patient presentation and history, the practitioner should consider other diagnostic possibilities. As DPN has no unique features from alternate forms of neuropathy, the most frequent unrelated forms of neuropathy that may be mistaken for DPN are B12 deficiency, uremia, hyperthy-roidism, and alcoholic neuropathy. The three clinical pearls of DPN are (i) symmetry, (ii) slow progression, and (iii) sensory deficits more prominent than motor weakness. Deviations from these well-established attributes should be referred to the neurologist as the condition is less likely to be DPN.
In our own outpatient practice, we use the definition of DPN put forth by the American Diabetes Association i.e., "the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes" (1). To assess DPN we employ a simple standardized tool, the Michigan Neuropathy Screening Instrument (MNSI), with a questionnaire and clinical examination, allowing us to compare scores over time in the same patient. The MNSI has been independently tested and validated as a diagnostic tool (46,47) and is currently an important component of the DCCT/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Trial(29,48). The MNSI consists
Table 2 Differential Diagnosis of Diabetic Neuropathy
I. Distal symmetric polyneuropathy a. Metabolic i. Diabetes mellitus ii. Uremia iii. Folic acid/cyanocobalamin deficiency iv. Hypothyroidism v. Acute intermittent porphyria b. Toxic i. Alcohol ii. Heavy metal (Hg, Pb, etc.)
iii. Industrial hydrocarbons iv. Various drugs c. Infectious or inflammatory i. Sarcoidosis ii. Leprosy iii. Periarteritis nodosa iv. Others: Systemic lupus erythematosus d. Others i. Dysproteinemias & paraproteinemias ii. Paraneoplastic syndrome iii. Leukemias and lymphomas iv. Amyloidosis v. Hereditary neuropathies
II. Pains and paresthesias without neurological deficit a. Early small fiber sensory neuropathy b. Psychophysiological disorder (depression, hysteria, etc.)
III. Autonomic neuropathy without somatic component a. Shy-Drager syndrome b. Diabetic neuropathy with mild somatic involvement c. Riley-Day Syndrome d. Idiopathic orthostatic hypotension
IV. Diffuse motor neuropathy without sensory deficit a. Guillain-Barre syndrome b. Primary myopathies c. Myasthenia gravis d. Heavy metal toxicity
V. Femoral neuropathy a. Degenerative spinal-disk disease (Paget's disease of the spine)
b. Intrinsic spinal cord mass lesion c. Equina cauda lesions d. Coagulopathies VI. Cranial neuropathy a. Carotid aneurysm b. Intracranial mass c. Elevated intracranial pressure VII. Mononeuropathy multiplex a. Vasculidites b. Amyloidosis c. Hypothyroidism d. Acromegaly e. Coagulopathies
Source: Adapted with permission from Ref. 91.
Please take a few minutes to answer the questions below about the feeling in your legs Check yes or no based on how you usually feel.
1. Are your legs and/or feet numb?
2. Do you ever have burning pain in your legs and/or feet?
3. Arc your feel too sensitive to loueh? A. Do you get muscle cramps in your legs and/or feet?
5. Do you ever have pnckling feelings in your legs or feet?
6. Docs it hurt when the bedcovers touch your skin?
7. When you get m the tub or shower, arc you able to tell the hot water from the cold water?
8. I lave yon ever had an open sore on your foot? 9 Has youi doctor ever told you that you have diabetic neuropathy?
10. Do you feel weak all over most of the tune?
11. Are your symptoms worse at night?
12. Do your legs hurt when you walk?
13. Arc you able to sense your feet when you walk?
14. Is lite skin on your feet so dry that it tracks open?
15. Have you. ever had an amputation?
Figure 4 MNSI patient questionnaire. Source: Adapted with permission from Ref. 47.
of a 15-point patient questionnaire about sensation and peripheral vascular disease (Fig. 4). Scoring more than seven is the threshold to predict or diagnose DPN. Positive assessment on the MNSI should be followed by an eight-point MNSI clinical examination of the foot including foot inspection and vibration sensation (Fig. 5). Scoring more than two on the clinical examination properly diagnoses DPN with 95% confidence.
Many other tests besides the MNSI are available to diagnose and assess DPN. One frequently used tool developed by Peter Dyck and colleagues in the Rochester Diabetic Neuropathy Study is commonly referred to as the Neuropathy Impairment Score (NIS) plus 7. The simplest component of this scheme is the NIS of the lower limbs; this is an easily applied clinical exam evaluating both sensation and strength in the lower limbs. This can be added to seven quantitative tests to evaluate DPN severity (24), which include EDX and QST. The higher the number of abnormalities among the seven tests, the higher the severity of neuropathy. While the NIS plus 7 tests increase diagnostic accuracy, we prefer the MNSI because of its simplicity and availability to all practitioners.
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