Intensive Evaluation of Referred Unclassdied Neuropahes Yields Improved Diagnosis

Peter James Dyck, MD, Karen F. Oviatt, and Edward H. Lambert, MD, PhD

Intensive evaluation of 205 cases of undiagnosed neuropathy in a center with special approaches and facilities permitted classification of 76% of the patients. Inherited disorders accounted for 42% of the series, 21% of the patients were shown to have inflammatory-demyelinating polyradiculoneuropathy, and 13% had neuropathies as- sociated with other disorders. A considerable improvement in diagnosis was possible from evaluation of the kin of the patients with undiagnosed neuropathy. Analysis of the frequency and type of various sensorysymptoms also was helpful in distinguishing between acquired and inherited neuropathies.

Dyck PJ, Oviatt KF, Lambert EH: Intensive evaluation of referred unclassified neuropathies yields improved diagnosis. Ann Neurol 10:222-226. 1981

The differential diagnosis of a patient with peripheral neuropathy commonly faces the neurologist. In our experience, neurologists say that they can categorize approximately one-half of such cases. Reports on surveys of the relative frequency of various types of polyneuropathy in hospital patients also indi- cate a relatively high percentage of “idiopathic” cases--320/o of Prineas’s [lo] series of 91 patients, 70% of Mathews’s [9] series of 46 patients, and 56% of Rose’s [ 111 series of 80 patients. Because a vari- able number of these patients had inflammatory- demyelinating polyradiculoneuropathy (such as the Guillain-BarrC syndrome), the actual frequency of undiagnosed neuropathies (as used in this paper) is lower than has been reported. Assuming that a sizable number of uncategorized patients can be classified by more intensive evaluation and with spe- cial facilities available in centers expert in such diag- nostic procedures, what categories of diagnosis are most commonly missed? How can physicians im- prove their diagnostic record? What clues are helpful in improving the diagnosis of unclassified neurop- athies?

To provide answers to these questions, we analyzed 205 patients with undiagnosed neuropathy referred mostly from the United States and Canada, mainly by neurologists, between 1972 and 1979. They were intensively studied, particularly by evaluation of kin, to detect inherited neuropathy, and had pathological and biochemical examination of various tissues to detect diseases known to affect nerve. We have the impression that this group contained more chronic cases than would be encountered in a hospital popu-

lation. The insights gained may therefore apply more generally to causes of chronic undiagnosed neurop- athy .

Material and Methods Between March 1, 1972, and March 31, 1979,205 patients with uncharacterized neuropathies were referred directly to one of us for diagnosis and management. Patients with obvious causes of neuropathy such as those associated with diabetes, nutritional deficiency, or alcoholism were not sent to our center for evaluation. Other patients with neuropathies of unknown cause, seen in association but under the primary care of neurological colleagues at the Mayo Clinic and on the four hospital neurology services associated with the Clinic, are not included because of the increased variability and extent of assessment inherent in evaluation by different physicians. Of the referring physi- cians, 795% were neurologists, 4% were neurosurgeons, 7% were internists, and 10% were general practitioners or in another specialty.

In taking the history, problems were listed in the order of importance perceived by the patient. Patients were then asked to elaborate on their symptoms; at this stage of the interview we avoided asking about specific symptoms and did not provide alternative words. Next patients were questioned about specific motor, sensory, and autonomic symptoms. For the motor system they were asked specifically about weakness, atrophy, cramps, and dysfunc- tion in tasks of daily living. For the sensory system the words and phrases patients used to describe their symp- toms were recorded in quotation marks. Patients were then asked to elaborate on symptoms which they had described as “numb,” “dead,” “lifeless,” and “pain.” Their replies were again recorded in quotation marks. Later, we sys- tematically inquired whether they experienced symptoms

From the Peripheral Nerve Laboratory, Mayo Medical School and Foundation, Rochester, MN 55901.

Received Sept 29, 1980, and in revised form Dec 3. Accepted for publication Dec 19, 1980. Address reprint requests to Dr Dyck.

222 0364-5 134/81/090222-05$01.25 @ 1981 by the American Neurological Association

of “asleep numbness” and about deficits of feeling, clumsi- ness, and various types of pain. For the autonomic system they were queried about blurred vision, light-headedness on assuming the erect position (postural hypotension), ability to sweat, ability to maintain normothermia in hot weather, bowel and cardiac dysfunction, and impotence and sphincter continence. Neurological disability such as muscle weakness, reduction of myotatic reflexes, or reduc- tion of cutaneous sensation was graded as mildly (- l ) , moderately (-2), or severely (-3) diminished or as absent ( - 4 ) . The results were summated in a standard form de- scribing both sides of the body and gave a single neurologi- cal disability score [ 7 ] .

Because the objectives of seeing this group of patients were, first, to attempt to diagnose their problem and help them manage it, second, to learn better approaches to diag- nosis and management, and third, to discover underlying mechanisms, it was not necessary to perform the same lab- oratory tests and procedures on each patient. However, all patients were evaluated by neurological history, neurologi- cal examination, evaluation of conduction in motor and sensory fibers of limb nerves, needle electromyography of selected limb muscles, and, as these systems became available, computer-assisted sensory examination (usually in the most affected acral part: foot, hand, or face).

Diagnostic tests and procedures were individualized. For neuropathies associated with metabolic disease, intoxica- tion, or deficiency, a temporal association between the dis- ease process and neuropathy, as well as characteristic clini- cal and pathological changes and improvement when the abnormality was corrected, was sought. A tissue diagnosis was required for neuropathies with distinctive pathologi- cal changes in nerve or other tissues, e.g., necrotizing angiopathy, amyloidosis, sarcoidosis, multiple myeloma, neuroaxonal dystrophy, and lipidoses such as metachro- matic leukodystrophy and Krabbe’s disease [2, 41. For paraneoplastic neuropathies, a tissue diagnosis of the asso- ciated neoplasm, temporal relationship to the development of the neuropathy, and failure to detect another cause were required for diagnosis. In neuropathies associated with a known inborn error of metabolism, the characteristic syndrome and biochemical evidence were required for diagnosis 11 21.

From previous experience we knew that persons with in- herited neuropathy frequently are unaware that their dis- order is inherited, even when it is obvious from examina- tion of kin [8]. Therefore, for patients in whom a diagnosis could not be made from initial evaluation and laboratory tests and for those with a phenotype suggesting inherited neuropathy, a detailed kinship history was recorded. The name of the relative, sex, age, whether alive or dead, known diseases, and particular symptoms and physical characteristics that might suggest neuromuscular disease were noted. Specifically asked about were the presence of high arches, curled-up toes, claw hands, wasting of muscles, polio and arthritis (not infrequently an incorrect diagnosis for inherited neuropathy), kyphosis or scoliosis, plantar foot ulcers, subluxed hips, and other abnormalities of body build. The relatives with symptoms suggestive of inherited neuropathy were then requested to come for an examina- tion. They were evaluated by taking a history and by per-

forming a neurological examination, nerve conduction and needle electromyographic studies, and, in some cases, a fascicular biopsy of sural nerve. If no relatives with sugges- tive symptoms were found, the parents, siblings, and chil- dren were evaluated by these tests.

The diagnosis of inflammatory-demyelinating polyra- diculoneuropathy was based on history, clinical examin- ation, characteristics of spinal fluid, nerve conduction, needle electromyography, pathological abnormalities of nerve biopsy tissue, and exclusion of other causes accord- ing to previously described criteria [ 1, 51. Particularly in the slowly progressive variety, an underlying disease asso- ciated with an increase in monoclonal protein was searched for in most cases and on multiple occasions.

Early in the study it became apparent that in order to recognize neuropathy associated with an increase in monoclonal protein, it was necessary to screen all cases with serum protein electrophoresis and with quantitative electrophoresis of the protein in a 24-hour urine collection. Immunoelectrophoresis was performed on positive serum and urine specimens. Whenever a monoclonal protein was detected, a search was made for an underlying disease such as amyloidosis or myeloma by obtaining biopsied tissue from bone marrow, rectum, and sural nerve.

In the case of multiple mononeuropathy we attempted to discriminate, mainly by the pathological abnormalities found in biopsied nerve or other tissue, between whether the cause was a necrotizing angiopathy, an inflammatory- demyelinating neuropathic process, sarcoidosis, leprosy, emboli, inherited tendency to pressure palsy, or other specific abnormality.

Results Of the 205 neuropathies, 42% were diagnosed as inherited disorders, 2 1 % as inflammatory-demy- elinating polyradiculoneuropathies, and 13%’ as other acquired neuropathies; 24% remained undiag- nosed (Fig 1).

Among the 86 patients diagnosed as having inher- ited neuropathy, detailed kinship history and medical records were sufficiently strong in 35 cases (41%)) that no direct examination of kin was necessary for confirmation. In this group, the fact that a relative had a neuromuscular disorder was usually known to the patient, but its relationship to his illness had not been appreciated. In 5 1 (59%) of the group, inheri- tance could not be ascertained from kinship history and evaluation of medical records, although sugges- tive history for it was obtained in approximately one-half of the patients. In these cases, relatives were studied by obtaining a neurological history, neu- rological examination, nerve conduction and lim- ited needle electromyographic examination, and, in fewer instances, computer-assisted evaluation of sen- sation and morphometric and pathological evaluation of sural nerve. O n the average, 2.6 (range, 1 to 8) kin per patient were thus evaluated. O n the basis of all types of examination, 24 of these 51 patients were

Dyck et al: Diagnosis of Unclassified Neuropathies 223

F i g 1 . Final rlassification of undragiiosed neuropathies referred betuleev March I , 1972, and March 3 I , 1979.

shown to have kin with a neuropathy. The role of various types of neurological evaluation in the detec- tion of neuropathic abnormality is shown in Table 1. The use of nerve conduction and needle electro- myography, computer-assisted tests of sensation, and nerve biopsy increased the sensitivity of detect- ing neuropathy by 17%. Evaluation of kin did not provide evidence of inheritance in 27 (32%) patients eventually diagnosed as having inherited neuropathy. In these cases, classification into the inherited cate- gory appeared justified because of a characteristic phenotype, natural history, pathological abnormality, or enzyme or biochemical abnormality diagnostic of specific inherited diseases. Failure to detect evidence of inheritance by direct examination of kin is not sur- prising considering the limited number of kin evalu- ated, small size of some sibships, lack of information about parents or siblings in the case of adopted per- sons, and the fact that some of the disorders were recessively inherited. The final diagnosis in these 5 1 cases is shown in Table 2.

Forty-nine of the 205 patients (24!:6) remained undiagnosed even after intensive study and evalua- tion of kin of those who had a suggestive phenotype.

Forty-three (21%) of the 205 patients were diag- nosed as having inflammatory-demyelinating poly- radiculoneuropathy. This category includes mo- tor, sensory, autonomic, and mixed forms of acute inflammatory-demyelinating polyradiculoneuropathy (e.g., the motor variety described by Guillain and Bark) ; chronic inflammatory-demyelinating poly- radiculoneuropathy (including forms with mono- phasic, recurring, and worsening courses); inflam- matory-demyelinating radiculoplexus neuropathy (of brachial and lumbosacral plexuses); and in- flammatory-demyelinating multiple mononeurop- athy.

Tuble 1 . itiethods of Deterting Nruroputhic Abtiornialrties in Kin , by Kinships

Method of Detection

Neurological examination 1515 1 (29.477) Nerve conduction and E M G 18/51 (35.3%) Computerized tests of sensation 7/28 (25.0%) N e r v e biopsy” 519 (55.6%) Combination 2415 1 (47.0960) .‘In 2 of the 5 affected persons this was the only abnormality.

No. of Cases

Table 2. Final Diagnosis of 5 1 PatientJ with Charai.teriJtic Features of Inherited Neuropathy But Wi&orit Knou!ti Inheritnnre

Diagnosis No. of Patients

H M S N , types 1 and 2 24 ( 4 7 5 ) H M S N , type 3 2 ( 4 C t ) P M A , various types 4 ( 8 G ) Spastic paraplegia + 3 tbr;) Spinocerebellar degeneration + 2 (4(-6) Amyloidosis (Indiana type) 1 (2P6) O t h e r 15 (29%)

HMSN = hereditary motor and sensory neuropathy; PMA = progressive muscular atrophy; + = additional clinical features.

Twenty-seven of the 205 patients ( 1 3 q ) were diagnosed as having other kinds of acquired neurop- athy. These included metabolic neuropathies (e.g., diabetes mellitus and myxedema) and neuropathy as- sociated with carcinoma, multiple myeloma, mono- clonal protein, leprosy, and heavy metal intoxica- tion.

We also evaluated the frequency of various motor and sensory symptoms in inherited, inflammatory, and other acquired groups of neuropathies to ascer- tain whether the pattern of symptoms might assist in differential diagnosis. The only helpful motor symp- tom was muscle cramping: cramps of leg and foot muscles were almost three times more frequent among patients with inherited neuropathy (23 of 86, or 26.7%) than in inflammatory-demyelinating polyradiculoneuropathy ( 4 of 43, 9.3%) or other ac- quired neuropathies (7 of 67, 1O.lT’) ( p < 0.01). As anticipated, the most common motor symptoms for all diagnostic groups were those related to weakness of leg and foot muscles.

The order of the three most commonly reported sensory symptoms was the same among the three diagnostic categories. The most common was that of paresthesia (a feeling “like the hand gone asleep,” “like Novocain,” and like nonpainful ”prickling”). The next most common sensory symptom was an un- characterized discomfort in the affected limbs not

224 Annals of Neurology Vol 10 No 3 September 1981

F i g 2. Results from study of biopsied sural nerve of the 45- year-old mother of a 14-year-old son who had a n undiagnosed neuropathy with natural history and findings suggestive of H M S N , type I . The mother and father had no neurological symptoms or signs and no abnormalities on nerve conduction or needle electromyographic studies. Because the mother had slightly higher arches than normal, a fascicular specimen of sural nerve was studied.

The compound action potential in vitro (top) showed no ab- normality. The density of myelinatedfibers was near the lower range of normal values, but the size distribution appeared t o be normal (middle). One hundred teasedfibers were evaluated to estimate the percentage of graded pathological abnormalities (bottom). More than 30% of teasedfibers showed greater than 100 96 variability in myelin thickness between internodes, suggesting segmental remyelination after demyelination. This finding indicates subclinical involvement, and it was demon- strated in a member of another kinship.

specified as “burning,” “aching,” “tenderness with use,” or a “stab” or “jab.” The third was an “aching” discomfort. Although the order was the same in the three groups, there was a striking difference in fre- quency. Paresthesias were reported in only 18% of patients with inherited neuropathy but in 7495 of those with inflammatory-demyelinating polyradicu- loneuropathy and 57% of those with other acquired neuropathies ( p < 0.005). The number of patients with “burning,” “aching,” and other types of dis- comfort was lower in inherited (13.1%) and inflam- matory-demyelinating neuropathies (14.0%) than in other acquired neuropathies (30.4%) (0.01 < p < 0.025).

Discussion This study has shown that inherited neuropathies are the most common undiagnosed neuropathies [8, 121.

Dyck et al: Diagnosis of Unclassified Neuropathies 225

The situation can be improved if neurologists (1) take detailed kinship histories, recording skeletal abnor- malities (such as high arches and hammer toes, spine deformity, subluxed hips, and other congenital anomalies) and neuromuscular symptoms (such as difficulty in walking and running, abnormality of gait, difficulty manipulating small objects with the hands, muscle atrophy, trophic ulcers, and sensory symp- toms) and (2) neurologically evaluate kin suspected of having a neuropathy. Evaluation of kin is time- consuming and expensive; nevertheless, it has shown that relatives diagnosed previously as having polio, diabetic neuropathy, idiopathic progressive neuropathy, or arthritis often have inherited neurop- athy. This approach provided reliable evidence of in- heritance in just over one-third of our index cases. Additional evaluation of even a few kin led to detec- tion of inheritance in another one-third of cases; in these, however, the neurological disorder in relatives was often mild, and frequently a detailed examination by nerve conduction and needle electromyography, computer-assisted evaluation of sensation, and nerve biopsy were needed to detect a neuropathic abnor- mality with certainty. In the remaining cases, inher- ited neuropathy was diagnosed on other grounds.

The most common group of inherited neurop- athies that had previously gone undiagnosed was hereditary motor and sensory neuropathy, types 1 and 2 (HMSN-I and -2) [ 3 ] . The index cases with this disorder seldom had the textbook appearance of severe peroneal muscular atrophy, which is actually atypical for HMSN [6]. This and previous studies of the disorder have shown that there is considerable heterogeneity, with features in genetically affected cases ranging from severe peroneal muscular atrophy to no neurological abnormality. We have previously shown that in some patients who are in a direct lineage with more severely affected persons, the only evidence of involvement is low conduction velocity [6]. In this study we encountered 2 patients from separate kinships, without neurological abnormalities and without low nerve conduction velocities, who could be shown to have unequivocally characteristic abnormalities on nerve biopsy (Fig 2). This result is not unexpected since we had previously shown that onIy 42% of children of an HMSN-1 parent had neurological or nerve conduction velocity evidence for the disorder [6] , suggesting that a small percent- age of cases may have an even milder abnormality.

The main reason for failure to diagnose inherited neuropathy is not willful or psychological denial of familial involvement by index patients; it is due to: (1) failure to take an adequate kinship history, (2)

failure by the physician and patient to relate the neurological problem of a relative to that of the pa- tient, and ( 3 ) mild, unrecognized involvement in kin due to genetic heterogeneity. Improved recognition will result when neurologists no longer look for ad- vanced peroneal muscular atrophy to make a diag- nosis but consider inherited neuropathy in all cases, particularly in patients who report increasing clumsi- ness in walking, frequent tripping, toe walking, weak ankles, high arches and hammer toes, and weakness in the use of hands involving dexterity. As compared to persons with inflammatory-demyelinating and other acquired neuropathies, such patients have an increased frequency of leg cramps. In addition, they seldom have paresthesia or “burning” and “bandlike discomfort,” which is more common in other ac- quired neuropathies.

Supported in part by Peripheral Neuropathy Clinical Center Grant NS14304 from the National Institute of Neurological and Com- municative Disorders and Stroke, by a Center Grant from the Muscular Dystrophy Association, and by Mayo, Borchard, Upton, and Gallagher Funds.

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