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Table 1. Categorization of neuropathy by clinical anatomic criteria |
Correct assignment of a patient's disorder at the outset into one of the anatomic-pathologic patterns of neuropathy listed in Table 1 makes correct and efficient diagnosing possible. It reduces a potential list of, perhaps, 100 or more conditions to a much shorter list. Concentrating on this shorter list focuses subsequent evaluation and enhances the chance of identifying the correct diagnosis.
As needed, confirm the anatomic-pathologic pattern of involvement by EMG, quantitative sensory testing, quantitative autonomic testing, radiologic and imaging studies, CSF evaluation, or other evaluations.
Nerve conduction and needle EMG examination is especially useful for such characterization. [5] Whereas lower motor neuron involvement is usually reliably recognized by weakness, atrophy, and fasciculations, sensory involvement, especially when it develops insidiously over time, may come on without the patient (or physician) recognizing it. Also, whether sensory loss is present, and which modality is affected, is often not reliably characterized by the clinical examination. Quantitative sensory testing, determination of the amplitude of the sensory nerve action potential, or morphometric assessment of the sural nerve biopsy specimen may be needed to provide unequivocal evidence of an abnormality of sensation and loss of specific size classes of sensory fibers. Likewise, autonomic deficit is seldom adequately characterized by physicians. The type of autonomic neuron involvement and its distribution can only be adequately evaluated by appropriate quantitative autonomic tests.
Electrodiagnostic studies are particularly helpful in reliable identification of: (1) the anatomic pattern, e.g., root, plexus, or nerve, or combinations; (2) the population of neurons (fibers) involved, e.g., motor or large sensory; (3) the part of neuron involved, e.g., neuronal versus distal axonal; (4) inferred pathologic alterations of fibers: axonal degeneration, segmental demyelination, or conduction block (and sites) (see below); (5) discrimination of motor neuropathy from neuromuscular defect and from myopathy; and (6) regenerative activity. A careful assessment in step 1 also allows the electromyographer to perform a more focused (and perhaps more brief) study, improving both diagnostic accuracy and the efficiency of the EMG.
Quantitative sensory testing [6] is used to detect, or confirm, sensory loss and to identify the modality and class of fibers affected. It permits recognition of sensory dysfunction before it can be recognized clinically and is also useful in recognizing altered stimulus-response characteristic, e.g., hyperalgesia or allodynia.
Autonomic testing [7] is helpful in detection and characterization of various types of autonomic dysfunction and to identify them as central or peripheral. The thermoregulatory sweat distribution test may reveal quite striking neurologic impairment not readily apparent by the clinical examination or by other tests Figure 1 and Figure 2.
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Figure 1. This shows (diagrammatically, left, and photographically, right) the striking and convincing sudomotor abnormalities demonstrated by a thermoregulatory sweat distribution test in a 48-year-old woman referred for a 6-year history of pain, prickling, and allodynia in the hands and left thigh. The sudomotor abnormality mirrored the regions of pain and provided unequivocal evidence of a patchy neuropathic abnormality not as convincingly demonstrated by any other tests. Neurologic examination showed only hypesthesia to touch and hypalgesia to pin prick in the distribution of both median nerves and anterior left thigh. Diffuse hyporeflexia was present. Electrophysiologic testing suggested a patchy sensory neuropathy or neuronopathy. In the thermoregulatory sweat distribution test, localized areas of anhidrosis are revealed by an orange color (the dye has not changed color). As described in text (Example 2), this test was useful in confirming the validity of the patient's symptoms, provided evidence of the multifocal nature of the neuropathic involvement, and suggested the anatomic and pathologic pattern of involvement. |
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Figure 2. Two patterns of abnormality based on the thermoregulatory sweat distribution tests. (Left) There is lack of sweating in a glove glove (upper) and stocking (lower) distribution in a 41-year-old man who developed subacute burning of feet and distal legs and hands 4 months before evaluation (Example 4 in text). The clinical examination was without abnormality. Nerve conduction and EMG changes indicated some abnormality in the distribution of the peroneal nerves (possibly unrelated to the generalized neuropathy). A sural nerve biopsy showed small inflammatory perivascular infiltrates suggestive of an immune process (Step 9). The sudomotor abnormality provided unequivocal evidence of involvement of small fibers and the distribution of the sudomotor deficit (Step 2), which was helpful in differential diagnosis. (Right) The thermoregulatory sweat distribution test shows multifocal anhidrotic regions widely distributed over the surface of the body (Step 2) in a 67-year-old man with neuropathy from leprosy (Example 5 in text). Neuropathic symptoms begun at age 53 with tingling numbness in the right thumb, spread to the entire hand, then to the left hand, and ultimately to both feet. When seen at age 60 years, he reported tingling hands and feet and in patches of his upper limbs, his abdomen, his ear lobes, and his forehead. No weakness or reflex abnormality was found. A skin rash with anesthesia and sudomotor abnormality suggested the diagnosis of leprosy. Biopsy of an ulcerative lesion within the nose demonstrated acid-fast bacilli in macrophages diagnostic of leprosy (Step 9). |
Diagnostic radiography, myelography, CT, and MRI may be useful in anatomic localization (e.g., MRI recognition of lesions in roots, ganglia, or nerves, or of structures impinging on nerve).
Five examples illustrate the value of anatomic-pathologic characterization.
A hypothetic patient is evaluated for arm and hand weakness, developing insidiously for the last 36 months. The patient reports no sensory or autonomic symptoms. On neurologic examination, weakness is recognized in median-innervated muscles of the forearm and hands. No clinical deficit is recognized in reflexes, sensation, or autonomic function. Based on the clinical examination, consideration would need to be given to categories: 12 (multiple mononeuropathy), 13 (motor neuron degeneration), 14 (motor and sensory neuron degeneration), 15 (motor neuropathy), 9 (brachial plexus neuropathy), 18 (polyradiculoneuropathy), and 19 (polyneuropathy) Table 1. Further characterization is needed to decide among these anatomic-pathologic patterns.
Let us assume, for this hypothetical case, that sensory nerve action potential (SNAP) amplitude and sensory conduction velocities are normal, as are quantitative sensory testing results of the hands. This provides evidence against categories 6, 9, 12, and 14. Let us further assume that conduction block was found in the forearm of both median nerves and that the needle EMG features were in keeping with the forearm localization. The likely anatomic-pathologic diagnosis is category 15 (motor neuropathy). The diagnosis would appear to be multiple motor mononeuropathy with persistent conduction block Table 2. In this patient, further categorization led not only to proper assignment into an anatomic-pathologic pattern but to a specific diagnosis.
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Table 2. Diagnoses to be considered when multiple mononeuropathy is the pattern of involvement |
Let us assume that for the hypothetic patient described in the first paragraph, quite different electrophysiologic features were found. Let us assume that abnormalities are found only in upper limbs and encompass both median- and ulnar-innervated muscles. Motor nerve conduction velocities (MNCV) of median and ulnar nerves are at the lower limits of normal, and compound muscle action potential (CMAP) amplitudes are decreased. The SNAP amplitudes are decreased and not dispersed. Needle EMG abnormality is found only in median and ulnar forearm muscles and in keeping with chronic neurogenic change. The latency of F-waves is slightly prolonged but not beyond what is expected from knowing the conduction velocity of nerves in forearm. Vibratory detection threshold (VDT) of the distal phalanx of the index finger is abnormal (>or=to 99th percentile) but cold detection threshold (CTD) and heat-pain 5 (of 10) response of the dorsal hand are within normal limits. These test results show that the process is confined to upper limbs, motor and sensory modalities are involved, multiple nerves are affected (ulnar and median nerves, distal limb involvement, and decreased SNAP amplitudes), and that axonal degeneration rather than segmental demyelination is occurring. The anatomic-pathologic categories that need to be considered are: 19 (polyneuropathy-of upper limbs), and perhaps 14 (motor and sensory neuron degeneration-with distal axonal degeneration). Among the disorders that will need to be considered are: late-onset Tangier disease, hereditary and motor sensory neuropathy of the Hanel type, [8] and other disorders.
A 48-year-old woman was referred to us with a 6-year history of pain, prickling, and allodynia of the hands and anterior left thigh. On clinical testing, we found no muscle weakness, generalized hyporeflexia, and hypesthesia and hypoalgesia in the symptomatic regions. MNCV and CMAP amplitudes of ulnar, median, and peroneal nerves were normal. SNAP of ulnar and median nerves were slightly reduced in amplitude. Quantitative sensory tests were not unequivocally abnormal in the hand. A thermoregulatory test was done and showed striking sudomotor abnormalities, which mirrored the patient's localization of pain, prickling, and allodynia (see Figure 1). This demonstration of sudomotor abnormality strengthened the validity of the patient's symptoms, provided evidence of the multifocal nature of the neuropathic process, and suggested an anatomic-pathologic pattern of involvement. The anatomic-pathologic patterns that would need to be considered are: 16 (sensory neuropathy), 17 (autonomic neuropathy), and 8 (polyganglionopathy). In cases such as this, the locus of the pathologic abnormality is not well known. Without detailing the steps we used to characterize the case further, we concluded that this patient had an immune sensory-autonomic neuropathy or polyganglionopathy.
A 41-year-old man developed burning of feet (also distal legs) and fingers and hands 4 months before referral. The clinical examination was without abnormality. Minor electrophysiologic abnormalities of nerve conduction were found in peroneal nerves. The nature and distribution of the symptoms and the results of the sweat distribution test (see Figure 2) provided unequivocal evidence of involvement of small sensory and autonomic nerve fibers. In the epineurium of a sural nerve biopsy specimen (step 9), small mononuclear cell perivascular infiltrates were found. We diagnosed an immune, predominantly sensory and autonomic polyneuropathy.
A 67-year-old man began to have tingling numbness of the right thumb at the age of 53 years. Later the same symptoms spread to the entire hand, then to the right foot and later to both feet. When seen by us at age 60 years, he reported tingling and numbness in hands and feet and in ``patches'' in upper limbs, abdomen, ear lobes, and forehead. No weakness or reflex change was found. Skin rash in regions of sensory loss and the pattern of abnormality in the sweat distribution test (see Figure 2) suggested multifocal involvement of cutaneous sensory and autonomic nerves (categories 16 and 17, Table 1). Biopsy of an ulcerative lesion within the nose demonstrated acid-fast bacilli in macrophages, diagnostic of leprosy.
The list of specific diagnostic possibilities that should be considered when multiple mononeuropathy is the pattern of neuropathy encountered is given in Table 2. For many of the conditions, multiple mononeuropathy is not the characteristic pattern of involvement. To illustrate, a patient with diabetes mellitus is more likely to have polyneuropathy than multiple mononeuropathy. Focusing on this short list of diagnoses makes it more likely that the correct diagnosis will be selected and that few inappropriate tests will be ordered. The age, course, and associated diseases and neurologic and physical findings may limit the differential diagnoses to a few of the conditions listed in Table 2. It may then be possible to focus on one or two highly likely disorders.
The list of conditions that may cause involvement of motor neurons is short Table 3. As in multiple mononeuropathy, many of the diagnostic possibilities are rare or can be readily excluded, allowing the examiner to focus on a few conditions. In other cases, it is not the usual manifestation of the associated disease. To make a specific diagnosis, one needs to consider age of onset, course, associated disease, inheritance, and assess for specific enzyme abnormalities or disease markers.
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Table 3. Diagnoses to be considered when motor neuron degeneration is the pattern of involvement |
To arrive at a diagnosis it is useful to infer pathologic alterations of nerve fibers-fiber loss; axonal degeneration; axonal atrophy, demyelination and remyelination, and axonal degeneration; segmental demyelination; or fiber regeneration. Such inferences can be made from consideration of the kind of symptoms, the distribution and kind of neurologic deficits, the type and distribution of abnormalities of nerve conduction and EMG, quantitative sensory and autonomic tests, nerve biopsy, and other tests (as described in subsequent sections).
From knowing the anatomic distribution of neurologic abnormality, the classes of nerve fibers involved, the level of involvement within neurons, and the likely pathologic changes of nerve fibers, a restricted list of diagnostic possibilities can be drawn up.
Noting the tempo of onset and subsequent course provides clues to diagnosis. Consider disorders in which motor neurons are selectively involved Table 3. An acute paralytic disease syndrome following fever and acute constitutional symptoms suggests the diagnosis of poliomyelitis or Guillain-Barre syndrome Table 3. In either case, maximal weakness develops in days or weeks. In motor neuron disease, the disorder develops progressively over months or over a few years. Distal progressive muscular atrophy usually begins late in the first decade, or in later decades, and develops insidiously over many years.
A monophasic course is typical of Guillain-Barre syndrome, proximal diabetic neuropathy, truncal radiculopathy of diabetes, some cases of inflammatory polyganglionopathy, single toxic exposure, herpes zoster infection, and others. A fluctuating course is characteristic of intermittent compression of nerves (e.g., spinal stenosis, carpal tunnel syndrome, or inherited tendency to pressure palsy), immune disorders like chronic inflammatory demyelinating polyneuropathy, some inborn errors of metabolism that exacerbate under conditions of metabolic stress (e.g., acute intermittent porphyria), and intermittent exposure to toxins (e.g., lead, arsenic, thallium, mercury).
To illustrate this step, consider the patient who has subacutely developed difficulty in walking over 4 months. He reports that knees buckle when he walks and upper limbs are needed to arise from a chair. He also reports persistent numbness and tingling of his toes and fingers. On neurologic examination, he has symmetric generalized weakness of upper and lower limb muscles, areflexia, and distal stocking-glove sensory loss of tactile, vibration, and joint motion sensation in distal aspects of all four limbs. Even without further study, the pattern is indicative of a chronic polyradiculoneuropathy (pattern 18, Table 1). To assess for specific varieties of chronic polyradiculoneuropathy, further testing is needed, beginning with EMG studies. If nerve conduction velocities are reduced, both motor and sensory axons are involved, and there is evidence of dispersion or block of the compound action potentials, the broad category of chronic inflammatory demyelinating polyradiculoneuropathy becomes a likely possibility.
Persistent ``prickling'' and ``asleep numbness'' is typical of acquired neuropathies. [9] Lack of these symptoms suggests either that sensory neurons (fibers) are not involved or that the neuropathy developed insidiously over many years. Lack of prickling, therefore, suggests inherited neuropathy, although the lack of prickling may also suggest a chronic acquired neuropathy, e.g., some cases of chronic inflammatory demyelinating polyneuropathy (CIDP), amyloidosis, monoclonal gammopathy of undetermined significance (MGUS) neuropathy, and others.
Insidious progression of a disorder over years strongly favors an inherited cause. [9] Delay or failure of the patient or the family to recognize obvious major deficits (because of its insidious development) is characteristic of inherited neuropathy. A typical phenotype (e.g., peroneal muscular atrophy, spinocerebellar degeneration, congenital sensory and autonomic neuropathy) also favors an inherited cause. Some bony and cutaneous abnormalities (pes equinovarus, congenital hip displacement, angiokeratoma corporis, nodules at the tip of the tongue [(in multiple endocrine neoplasia, 2b {MEN 2b}]) may be suggestive of specific inherited disorders. A focused family history in which one systematically inquires and records the medical history of grandparents, parents, aunts and uncles, cousins, and descendants often provides clues that can then be pursued by telephone interview (and even a limited assessment of the ability to walk on toes, on heels, arise from a kneeled position, and similar functional evaluations). An asymmetric pattern favors an acquired process.
There are a variety of systemic diseases that relate to the cause of neuropathy. Perhaps the most common association is with endocrine disease, e.g., both types of diabetes mellitus, hypothyroidism, acromegaly, adrenoleukodystrophy, MEN 2b, and others. Malnutrition (e.g., in starvation and alcoholism) and specific vitamin deficiencies (B1, B6, and B12) or excess (B6) may result in systemic symptoms and development of a peripheral neuropathy. Finding an associated infection (leprosy, HIV, herpes simplex and zoster, Lyme disease, or syphilis) helps in pinpointing the cause of neuropathy. A history of a preceding upper respiratory infection or recent immunization may suggest the diagnosis of acute infectious inflammatory demyelinating neuropathy or another immune neuropathy. Knowing that neuropathy is associated with the occurrence of a monoclonal protein, lymphoma, myeloma (multiple or osteosclerotic) amyloid, or with certain cancers may provide important clues as to the possible cause of neuropathy. The association of peripheral neuropathy with osteosclerotic myeloma is almost 100%, whereas it generally is not associated with carcinoma or sarcoma. [10] An exepetion is the sensory neuropathy associated with small cell bronchogenic carcinoma. Some hematologic diseases (polycythemia rubra vera, primary thrombocytosis, leukemias), kidney diseases (uremia), hepatic disease (several varieties), and gastrointestinal diseases (e.g., malabsorption) are associated with neuropathy.
In general, we discourage a broadly based search for such underlying diseases as cancer, metabolic disease, deficiency, infection, or intoxications without some clue that such a search may be worthwhile. A difficult decision is how far to extend the search for underlying cancer in the patient with sensorimotor polyneuropathy and such systemic symptoms as cachexia and weight loss. Perhaps the evaluation should extend at least as far, or perhaps a little farther, than is justified for the evaluation of the cachexia and weight loss alone.
Specific patterns of disease may point to the need for a careful search for an associated disease condition. For example, the POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin pigmentation) syndrome should lead to a search for underlying osteosclerotic myeloma. Neuropathy in a patient whose skin has become hyperpigmented should raise the question of adrenal insufficiency (e.g., adrenoleukodystrophy), Castleman's disease, or another endocrine disease. In cases such as these, it is desirable to assess endocrine function, searching intensively for osteosclerotic myeloma. Perform immunofixation tests of serum and urine proteins for monoclonal proteins, assess for long-chain fatty acids (for adrenoleukodystrophy), and assess tissues (nerve, bone marrow, and so on) for specific histologic markers, e.g., storage material.
The degree to which tests should be ordered, and for which indications, is not a simple matter. We order tests depending on the anatomic-pathologic pattern, age, gender, and other clues. Thus, for some patterns, few tests are necessary, whereas for others, intensive testing is desirable. Since in most cases tests are done to rule out a condition, do not expect a high yield. We further suggest that one must be more vigorous in ruling out conditions for which there is efficacious treatment, e.g., infections, immune disorders, malnutrition and specific vitamin deficiencies, intoxications, metabolic conditions, and systemic diseases. In other conditions, an intensive diagnostic evaluation is needed to provide peace of mind, prepare for the future, prevent needless surgery or expensive treatment, or for other reasons.
In a 60-year-old woman with slowly progressive weakness of face and hands, heat and pain loss over cranial and cervical dermatomes, and absent SNAPs in upper limbs check for a severe decrease in high-density lipoproteins to recognize late-onset Tangier disease.
The patient with generalized sensory symptoms consisting of prickling and burning should raise the question of whether the process might be in spinal cord tracts, roots, ganglia, or nerves. In step 1, distinguish whether sensory modalities of pain and temperature are dissociated from large fiber sensation-a pattern characteristic of an intermedullary lesion or some cases of small-fiber neuropathy. Assuming that large fibers are involved, the amplitude of the SNAPs should separate disorders proximal and distal to spinal ganglia. For assessment of patients suspected of having inflammatory polyganglionopathy, one might want to assess with such tests as ESR, rheumatoid factor (RhF), ANA, extractible nuclear antigen (ENA), anti-nuclear cytoplasmic antibody (ANCA), and anti-neuronal nuclear antibody (ANNA). The degree of tearing could be checked with the Schirmer test or the Rose Bengal test. Biopsy of the lip may be used to assess for inflammation in the region of salivary glands.
In the patient with multiple mononeuropathy suspected of having necrotizing vasculitis, check for constitutional symptoms and findings such as malaise, weight loss, fever, hypertension, arthralgia, gastrointestinal symptoms, asthma, or renal involvement. Also test for serologic abnormalities (ESR, RhF, ANA, ENA, ANCA). Perform biopsy of tissue, e.g., a cutaneous nerve, to look for the characteristic features of necrotizing vasculitis, evidence of bleeding, and focal fiber loss. To exclude inherited tendency to pressure palsy, search for conduction block at pressure points and a more generalized nerve conduction abnormality, a family history of remitting limb weakness or sensory loss, tomaculae in nerve biopsies, or deletion of 17p11.2 in molecular genetic studies.
This is an extension of step 5. When a specific diagnosis of neuropathy cannot be made, the answer may come from obtaining a detailed kinship history or from examining members of the kindred. Obviously detailed examination of all family members of patients with undiagnosed neuropathy is not practical, but examination of selected members may be. First, record a family tree noting the names, gender, age (or age at death), cause of death, illness, neuromuscular characteristics (pes cavus, atrophied legs, plantar ulcers and so on) of immediate members of the family (grandparents, parents, aunts and uncles, siblings, and children and grandchildren). Next, examine relatives with suggestive symptoms or phenotype. Not infrequently relatives accompany patients and they can be quickly examined. Almost always relatives can be briefly interviewed by telephone (even in cities far removed from the physician's city). In the telephone interview, ask relatives to walk on toes, walk on heels, arise from a kneeled position, and so on. The time spent in such activity should be compensated by third-party payers because it is less expensive and more fruitful in achieving a diagnosis than repeated evaluations of patients or obtaining batteries of biochemical, enzyme, antibody, and other tests. Finally, a formal evaluation of the kindred with neurophysiologic and specialized tests may be needed.
This step is deliberately left until late in the evaluation. It should not be done simply because one is not able to make a diagnosis. It should only be done in a small subset of patients with neuropathy. Clinicians often order a nerve biopsy to differentiate between axonal and demyelinating pathology, a distinction that may be inferred with adequate confidence by electrophysiologic studies (as outlined in earlier steps). Furthermore, it is underrecognized that many ``primary'' demyelinating neuropathies, e.g., CIDP, in which proximal nerve segments are most affected, may manifest themselves only with axonal degeneration or loss at the level of the sural nerve. We think that the main reason to perform a nerve biopsy is to define the presence and type of interstitial pathologic change. From the symptoms, neuropathic deficits, and physiologic tests (nerve conduction and EMG, and quantitative sensory and quantitative autonomic tests), the involvement and type of pathologic alteration of fibers are reasonably inferred. There may be situations when nerve biopsy is used to establish whether fiber degeneration is continuing or to determine unmyelinated fiber change. The nerve biopsy is particularly useful in recognizing inflammation (inflammatory demyelination, necrotizing vasculitis, granuloma, or ganglionitis), infiltration (amyloidosis, lymphoma, or other tumor), infection (leprosy), and unique tissue reactions (tomaculae, excessive glycogen, and other). One chooses a sensory nerve so as not to cause weakness.
In patients who are thought to have chronic inflammatory demyelinating polyradiculoneuropathy, a therapeutic trial of plasma exchange or immune globulin infusion, if associated with unequivocal improvement, tends to bolster the correctness of the diagnosis and provides evidence that the disease responds to treatment. [11] In such patients, after a comprehensive evaluation, a trial of plasma exchange or immune globulin infusion may be justified. Before embarking on such a trial, ensure that baseline evaluations are performed, an adequate treatment program is arranged, and a reassessment (after 6 to 8 weeks and like the baseline evaluation) will be performed. Response to treatment is evaluated by use of quantified and validated tests of symptoms (e.g., Neuropathy Symptoms and Change [NSC]), neuropathic deficits (e.g., Neuropathy Impairment Score [NIS]) and other test (e.g., quantitative sensory test) abnormalities. [12] All assessments should be made independently of previous results and should use standard and objective tests.
Although we have not directly compared our 10-step approach with the shotgun or gestalt approaches using a prospective trial and statistical analyses, we think that the 10-step approach is intuitively better. First, there would be little point in obtaining the history and neurologic examination if the information were not used in differential diagnosis. Second, markers are not available for many diseases, and in any case, a physician must ultimately decide whether the presence of a marker correctly identifies the cause of neuropathy in a given patient. An example illustrates this point. A patient with neuropathy is found to have a raised fasting plasma glucose level, e.g., 200 mg/dl, and the HbA1C is 10%-evidence that the patient has diabetes mellitus. Despite this information, the neurologist cannot assume that the neuropathy in this patient is due to diabetes mellitus because the two conditions may occur in the same patient by chance. The judgment that they are causally linked depends additionally on whether the neuropathy follows the pattern of neuropathy found in diabetes mellitus and perhaps on finding retinopathy or nephropathy. Finding retinopathy and nephropathy typical of diabetes mellitus clearly strengthens the notion that neuropathy can also be attributed to diabetes. It is not uncommon for neuropathy encountered in diabetic patients to be caused by something other than diabetes mellitus. Such judgments are possible only when physicians are knowledgeable and experienced regarding the natural history and patterns of diabetic neuropathy.
The neurologic history that focuses on the patient's problem but emphasizes careful questioning about both positive and negative symptoms related to motor, sensory, and autonomic function provides direct evidence bearing on clinical anatomic localization. It ultimately provides much more information bearing on the other steps of testing. In a recent re-review of 100 cases of peripheral neuropathy referred to us, we assessed the influence of the following items of information on correctly identifying the final diagnosis, and the confidence of the diagnosis: (1) referral history; (2) referral examination; (3) referral electrodiagnostic tests; (4) our history; (5) our neurologic examination; (6) our electrodiagnostic tests; (7) our laboratory tests; or (8) our nerve biopsy (Suarez et al., personal communication, with permission). We found that by far the greatest increment in correctly anticipating the final diagnosis was from taking our own history. Confidence that the correct diagnosis had been made increased gradually with the increasing steps of evaluation.
For our approach to be useful and efficient, the physicians (neurologists) must have considerable background information about peripheral nerve anatomy, physiology, pathology, molecular genetics, and clinical neurology so that they may infer the segmental or peripheral nerves involved, the level of such involvement, the pathologic process, and the correct anatomic-pathologic pattern. They will also be able to follow through to a specific diagnosis after the anatomic-pathologic pattern has been chosen. The physician must know much about the natural history of neuromuscular disease, and electrophysiologic and pathologic derangements, and must have had experience in the field. Following the steps of our algorithm precisely will not lead automatically and inevitably to the correct diagnosis. Correct inferences based on extensive clinical, electrophysiologic, and pathologic knowledge must be made.
We do not believe that physicians' assistants, or even general physicians, with little information about neurology, peripheral nerve biology, physiology, or pathology, could use our algorithm expertly to evaluate adequately patients with peripheral neuropathy.
The 10 steps we outline should not be slavishly followed for differential diagnosis. The 10-step approach should be thought of as a mind game in which the neurologist engages during the evaluation of patients. Although we think that neurologists should systematically gather information (by history, examination, and so on), we think it is entirely reasonable that they try to formulate and revise the anatomic-pathologic pattern (and specific diagnosis) continuously while proceeding with the evaluation. In this approach, specific diagnoses are continuously being considered, kept in play, or eliminated as the evaluation proceeds. Neurologists must not become locked into a pattern or diagnosis but must be willing to reconsider all assumptions based on reconsideration of new information. If in doubt, retake the history, reexamine the patient, and reevaluate inferences and assumptions.
The authors gratefully acknowledge the assistance of Carol Overland in preparing the manuscript.
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