Chronic Cryptogenic Sensory Polyneuropathy Clinical and Laboratory Characteristics

ORIGINAL CONTRIBUTION Chronic Cryptogenic Sensory Polyneuropathy Clinical and Laboratory Characteristics

Gil I. Wolfe, MD; Noel S. Baker, MD; Anthony A. Amato, MD; Carlayne E. Jackson, MD; Sharon P. Nations, MD; David S. Saperstein, MD; Choon H. Cha, MD; Jonathan S. Katz, MD; Wilson W. Bryan, MD; Richard J. Barohn, MD

Background: Chronic sensory-predominant polyneu- duration of symptoms of 62.9 months. Symptoms al- ropathy (PN) is a common clinical problem confronting most always started in the feet and included distal numb- neurologists. Even with modern diagnostic approaches, ness or tingling in 86% of patients and pain in 72% of many of these PNs remain unclassified. patients. Despite the absence of motor symptoms at presentation, results of motor nerve conduction studies were Objective: To better define the clinical and laboratory abnormal in 60% of patients, and electromyographic evi- characteristics of a large group of patients with crypto- dence of denervation was observed in 70% of patients. genic sensory polyneuropathy (CSPN) evaluated in 2 uni- Results of laboratory studies were consistent with axo- versity-based neuromuscular clinics. nal degeneration. Patients with and without pain were similar regarding physical findings and laboratory test ab- Design: Medical record review of patients evaluated normalities. Only a few patients (Ͻ5%) had no evi- for PN during a 2-year period. We defined CSPN on dence of large-fiber dysfunction on physical examina- the basis of pain, numbness, and tingling in the distal tion or electrophysiologic studies. All 66 patients who extremities without symptoms of weakness. Sensory had follow-up examinations (mean, 12.5 months) re- symptoms and signs had to evolve for at least 3 mained ambulatory. months in a roughly symmetrical pattern. Identifiable causes of PN were excluded by history, physical Conclusions: Cryptogenic sensory polyneuropathy is a examination findings, and results of laboratory stud- common, slowly progressive neuropathy that begins in ies. We analyzed clinical and laboratory data from late adulthood and causes limited motor impairment. Iso- patients with CSPN and compared findings in patients lated small-fiber involvement is uncommon in this group with and without pain. of patients. Management should focus on rational phar- macotherapy of neuropathic pain combined with reas- Results: Of 402 patients with PN, 93 (23.1%) had CSPN surance of CSPN’s benign clinical course. and stable to slowly progressive PN syndrome. These patients presented with a mean age of 63.2 years and a mean Arch Neurol. 1999;56:540-547

CQUIRED chronic sensory- reditary neuropathies,8 recognition of im- predominant polyneu- mune-mediated neuropathies,9 causes ropathies (PNs) are com- becoming apparent over time,3 and the demon in middle and late velopment of more sophisticated diagnos- adulthood, with an esti- tic approaches. Amated prevalence of more than 3%.1 Most There are few detailed reports of elec- are secondary to readily identifiable causes, trophysiologic findings in the literature, such as diabetes. However, once known but available data suggest that most idio- causes are excluded, a sizable minority re- pathic PN is axonal.5,9 There is less con- main idiopathic. The cryptogenic group sensus on the clinical course for this group was thought to compose as much as 50% of patients. In 1 report,5 most patients (81%) were unchanged or improved after median follow-up of 3 years. Another From the Departments of For editorial comment study10 reported some progression in all Neurology, University of Texas see page 519 71 patients followed up for 4 to 7 years. Southwestern Medical Center, Dallas (Drs Wolfe, Baker, to 70% of PN cases in early series2,3 and Nations, Saperstein, Cha, Katz, 4 5-8 Bryan, and Barohn), and even in 1 recent report. Recent studies have revised this number down to 10% to This article is also available on our University of Texas Health Web site: www.ama-assn.org/neuro. Sciences Center, San Antonio 35%. Likely reasons for the declining per- (Drs Amato and Jackson). centage include better recognition of he-

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 PATIENTS AND METHODS virus or other infections, pertinent toxic or pharmacological exposures, hereditary neuropathy or amyloidosis, and pri- mary amyloidosis were excluded by history and laboratory Medical records were reviewed on all patients evaluated for testing. PN during a 2-year period in our university-based neuro- Nearly all patients underwent routine nerve conduc- muscular clinics. We defined patients with CSPN on the tion studies (NCSs) and needle electromyography (EMG). basis of pain, numbness, or tingling in the distal extremi- Laboratory reference values used for the NCSs are listed ties without symptoms of weakness. Sensory symptoms had in Table 1. Thirty-nine patients underwent QST per- to occur in a roughly symmetrical pattern in the distal lower formed with the Computer-Assisted Sensory Examination extremities or upper extremities or both and evolve for at system (CASE IV; WR Medical Electronics, Stillwater, Minn) least 3 months. On neurologic examination, patients had using a 4, 2, and 1 stepping protocol.11 Fewer patients un- to demonstrate distal sensory deficits to either light touch, derwent QST than NCSs and EMG because routine appli- vibration, position, or pinprick that were not confined to cation of QST was established in only 1 of our laboratories the distribution of an individual peripheral nerve. Slight during the study. The CASE IV system is equipped with distal weakness in foot or hand intrinsic muscles was per- age-matched control values for vibration and cooling sen- mitted as long as motor symptoms were not a presenting sory thresholds. Vibration and cooling thresholds equal to complaint. or greater than the 95th percentile were considered abnor- Routine laboratory tests consisted of a complete chem- mal.12,13 Serum testing for antisulfatide antibodies (Athena istry battery and blood cell count, erythrocyte sedimenta- Diagnostics, Worcester, Mass) was performed in 41 pa- tion rate, antinuclear antibodies, rheumatoid factor, vita- tients, and sural nerve biopsies were performed in 14 pa- min B12 level, thyroid function tests, syphilis serologic tients. screening, and serum protein electrophoresis with immuno- Clinical and laboratory data in patients with pain were fixation electrophoresis. Patients with monoclonal proteins compared with results in the smaller group of patients who were included in the study population only if plasma cell dys- did not report pain. ␹2 Contingency table analysis with the crasias were ruled out after evaluation by an oncologist and Yates correction factor was used for most comparisons. a diagnosis of monoclonal gammopathy of uncertain signifi- When appropriate, the Fisher exact test or Student t test cance (MGUS). Patients were excluded if they had signifi- was substituted. cant abnormal findings on the other laboratory studies. Pa- Symptomatic therapy for painful sensory symptoms tients with identifiable causes of neuropathy such as diabetes, was attempted using a variety of standard pharmacologi- chronic alcohol use, metabolic disturbances, endocrine ab- cal agents. A favorable clinical response was considered pres- normalities, connective tissue diseases including sicca ent if patients reported a significant decrease in or resolu- complex, malignant neoplasms, human immunodeficiency tion of their symptoms.

This study’s intent was to better define the clinical and tremor were uncommon presentations, accounting and laboratory characteristics of a large group of pa- for only 4 patients. In all, 67 patients presented with tients with chronic cryptogenic sensory polyneuropa- pain and 26 patients presented without pain. Symptoms thy (CSPN) evaluated in 2 university-based neuromus- were confined to the distal lower extremities in 41 cular clinics. In addition to routine electrophysiologic patients (44%). In another 39 patients (42%), initial studies, we analyzed data from quantitative sensory test- symptoms were restricted to the lower extremities for at ing (QST) and immunologic studies. We determined the least several months but later spread to the hands. frequency of CSPN among our referral population and Symptoms confined to the upper extremities were rare, collected data on the clinical course, prognosis, and re- being reported in only 2 patients (2%). In 1 patient, sponse to pharmacological therapy. We also compared symptoms first appeared in the hands and later spread clinical and laboratory data from patients with CSPN with to the feet. Simultaneous development of upper and pain vs those without. lower extremity symptoms occurred in 6 patients (6%). Four patients could not recall the initial distribution of RESULTS their symptoms. Of the 93 patients, 74 (80%) reported progression A total of 402 patients were evaluated for PN in the 2 clin- of their symptoms before our evaluation. The remain- ics during a 2-year period, 93 (23%) of whom (44 women ing patients (20%) believed their symptoms had im- and 49 men) met entry criteria for CSPN. At presenta- proved or reached a plateau. tion, mean age was 63.2 years (range, 37.0-94.0 years), and mean duration of symptoms was 62.9 months (range, EXAMINATION FINDINGS 3.0-240.0 months). Sensory examination demonstrated abnormal results for PRESENTING SYMPTOMS proprioception in 28 patients (30%), light touch in 50 (54%), pinprick in 69 (74%), and vibration in 79 (85%). Pain with numbness or tingling was the most common Pinprick was the most sensitive modality in assessing the presentation (reported in 58 patients), followed by proximal extent of sensory loss, with 58 patients dem- numbness or tingling without pain (22 patients) and onstrating impairment at the calf, 25 at the knee, 30 in pain alone (9 patients) (Figure 1). Gait unsteadiness the hands, and 11 in the forearms (Figure 2). On mo-

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Distal Latency (DL) Amplitude (amp) Conduction Velocity (CV)

No. Abnl No. Abnl Mean ± SD, No. Abnl Total % Nerve† Mean ± SD, ms (Absent) % Abnl Mean ± SD, mV (Absent) % Abnl m/s (Absent) % Abnl Abnl Median motor (n = 74) 3.98 ± 0.75 13 (0) 17.6 7.72 ± 3.04 9 (0) 12.2 51.1 ± 6.7 15 (0) 20.3 33.3 Ulnar motor (n = 72) 3.07 ± 0.46 15 (0) 20.8 8.49 ± 2.73 4 (0) 5.6 54.4 ± 6.6 6 (0) 8.3 29.2 Peroneal motor (n = 82) 5.39 ± 1.60 14 (8) 26.8 2.83 ± 2.51 33 (8) 50.0 40.0 ± 6.9 21 (8) 35.4 52.4 Tibial motor (n = 82) 4.93 ± 1.53 8 (7) 18.3 6.81 ± 5.62 17 (7) 29.3 38.4 ± 6.2 30 (7) 45.1 47.5 Median sensory (n = 78) ND 27 (3) 38.5 ND 32 (3) 44.9 ...... 56.4 Ulnar sensory (n = 76) ND 17 (7) 31.6 ND 14 (7) 27.6 ...... 32.9 Sural sensory (n = 81) 4.10 ± 0.52 8 (38) 56.8 8.17 ± 6.20 µV 18 (38) 69.1 ...... 69.1

*CSPN indicates cryptogenic sensory polyneuropathy; abnl, abnormal; ND, not determined (because both orthodromic and antidromic methods were used to obtain data); and ellipses, data not calculated. Reference laboratory values are as follows: median motor: amp Ͼ4mV,DLϽ4.5 ms, CV Ͼ48 m/s; ulnar motor: amp Ͼ5mV,DLϽ3.4 ms; CV Ͼ48 m/s; peroneal motor: amp Ͼ2mV,DLϽ6.0 ms, CV Ͼ38 m/s; tibial motor: amp Ͼ2mV,DLϽ6.0 ms, CV Ͼ38 m/s; and sural sensory: amp Ͼ6µV,DLϽ4.5 ms. †Not all nerves were studied in each patient, hence the different n values.

100 1% Numbness or Tingling Toes/Feet With Pain Ankle 10% Numbness or Tingling Calf 3% Without Pain 80 Knee Pain Alone Fingers/Hand Gait Unsteadiness Wrist Tremor Forearm 60 24% 62% 40 % of Patients

0 Figure 1. Presenting symptoms in patients with cryptogenic sensory Vibration Pinprick Light Touch Proprioception polyneuropathy (N = 93). Figure 2. Percentage of patients with cryptogenic sensory polyneuropathy with sensory loss on initial examination (N = 93). Anatomic extent of the tor examination, mild distal weakness was observed in deficit for each sensory modality is represented by bar graphs. 38 patients (41%) and distal muscle atrophy was observed in 14 (15%). Intrinsic foot muscle weakness was present in 35 patients (38%), hand weakness in 17 (18%), of patients. Except for 3 patients, those with abnormal and foot and hand weakness in 14 (15%). Therefore, it motor NCS results in the upper extremities also had ab- was rare to see hand weakness without foot weakness. normal motor responses in the lower extremities. When Deep tendon reflexes were absent in the ankles of 47 pa- absent responses were excluded from analysis, the mean tients (50%), the knees of 14 (15%), the biceps of 7 (8%), values of all NCS variables were within the reference and the triceps of 6 (6%). ranges for our laboratories. No patient had NCS results Follow-up examinations were performed on 66 that satisfied electrophysiologic criteria for demyelinat- patients. Mean follow-up in this group was 12.5 months ing neuropathy.14 (range, 1.0-42.0 months). All 66 patients remained Because sural sensory responses are often reduced ambulatory. Ten patients (15%) had progression on or absent in healthy people older than 60 years,15 we ana- either sensory or motor examination. Only 4 patients lyzed NCS results in this age group separately. Of the 56 (6%) demonstrated increased weakness. Progression abnormal sural study results, 39 (70%) occurred in pa- was more common in those followed up longer than 18 tients 60 years or older, with 29 being absent. Thirty- months (7 [33%] of 21 patients), two of whom had seven of these 39 patients had other abnormal findings motor progression. on NCSs. The 2 remaining patients had additional laboratory evidence for PN: 1 patient had abnormal vibra- ELECTROPHYSIOLOGIC STUDIES tion and cold thresholds on QST and the other had chronic neurogenic motor unit potentials in the tibialis anterior Results of NCSs are summarized in Table 1. An abnor- on EMG. mal sural sensory amplitude was the most common ab- Needle EMG abnormalities were present in 45 (70%) normality, seen in 69% of patients. The most common of 64 patients, only 1 of whom had EMG abnormalities motor NCS abnormalities were reduced peroneal ampli- restricted to intrinsic foot muscles. The other 44 pa- tudes and reduced tibial conduction velocities. Overall, tients demonstrated abnormalities in the tibialis ante- abnormal sensory NCS results were seen in 77% of pa- rior, medial gastrocnemius, or intrinsic hand muscles. tients and abnormal motor NCS results were seen in 60% Fibrillation potentials were recorded in 27 studies (42%),

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Table 2. Percentage of CSPN Patients With Abnormal Results* Table 3. Clinical and Laboratory Findings in Painful vs Painless CSPN* Abnormal QST 84.6 Abnormal sensory NCS 77.0 Patients Patients Abnormal motor NCS 59.6 With Pain Without Pain Abnormal needle EMG 70.3 (n = 67) (n = 26) P Fibrillation potentials 42.2 Patient demographics Neurogenic motor units 63.1 Male, % 47.8 65.3 .20 Age, mean ± SD, y 62.7 ± 13.0 64.5 ± 13.3 .55 *CSPN indicates cryptogenic sensory polyneuropathy; QST, quantitative Symptom duration, 70.7 ± 56.3 42.9 ± 43.7 .03 sensory testing; NCS, nerve conduction studies; and EMG, mean ± SD, mo electromyography. Physical examination Decreased vibration 56 (84) 23 (88) .79 Decreased pinprick 48 (72) 21 (81) .52 and chronic neurogenic motor unit potentials or re- Normal sensation† and DTRs 8 (12) 1 (4) .44 duced recruitment or both were recorded in 41 (64%). Electrophysiologic tests Table 2 compares the yields of various laboratory tests Abnormal sural sNCS 42/57 (74) 16/24 (67) .71 in the population with CSPN. Abnormal ulnar/median sNCS 35/57 (61) 17/23 (74) .42 Abnormal peroneal/tibial mNCS 32/61 (52) 19/25 (76) .08 Fibrillation potentials 18/45 (40) 9/19 (47) .79 QUANTITATIVE SENSORY TESTING Neurogenic MU potentials 29/45 (64) 12/19 (63) .92 Quantitative sensory tests Quantitative sensory testing was performed on 39 Decreased vibration 18/29 (62) 6/10 (60) Ϸ1.0 patients. Abnormal cold and vibration thresholds were Decreased cold 23/29 (79) 9/10 (90) .65 seen in 22 patients, abnormal cold but normal vibration Decreased vibration and cold 16/29 (55) 6/10 (60) Ϸ1.0 thresholds in 9 patients, and abnormal vibration but Decreased cold only 7/29 (24) 3/10 (30) .70 normal cold thresholds in 2. Results of 6 studies (15%) Decreased vibration only 2/29 (7) 0/10 Ϸ1.0 were normal, 4 of which were in patients with pain. In *Data are given as number (percentage) unless otherwise indicated. CSPN 15 studies with abnormal results, elevated thresholds indicates cryptogenic sensory polyneuropathy; DTRs, deep tendon reflexes; were restricted to the feet in accordance with a length- mNCS, motor nerve conduction study (NCS); sNCS, sensory NCS; and MU, dependent process. Only 1 patient had QST abnormali- motor unit. †Normal sensation for light touch, vibration, and proprioception. ties in the hands but not the feet. Of 33 patients with abnormal QST results, 3 had normal NCS results and presented with painful feet but had abnormal vibration, pain who underwent electrophysiologic testing and QST, light touch, and pinprick thresholds on examination. only 2 (7%) had no abnormalities on either study. No Two patients had abnormal thresholds for cold only patients presenting without pain had normal electro- and 1 patient had abnormal thresholds for cold and physiologic study and QST results. Two patients with- vibration. out pain had normal NCS results, but they did not undergo EMG and QST. COMPARISON OF PATIENTS WITH CSPN WITH OR WITHOUT PAIN OTHER LABORATORY STUDIES

Of 93 patients, 67 (72%) presented with pain and 26 pre- Monoclonal proteins were present in 4 of 83 patients who sented without pain. Clinical and laboratory data for these underwent serum protein and immunofixation electro- 2 groups are compared in Table 3. A longer duration phoresis. The paraprotein was IgA-␬ in 2 patients, IgG-␬ of symptoms in patients presenting with pain (mean ± SD, in 1 patient, and IgG-␭ in 1 patient. All 4 patients were di- 70.7 ± 56.3 months) vs those without pain (mean ± SD, agnosed as having MGUS. Antisulfatide antibodies were 42.9 ± 43.7 months) reached statistical significance. How- negative in all 41 patients tested. Cerebrospinal fluid (CSF) ever, no physical or laboratory abnormality was more com- was examined in 5 patients, and results were normal in 4 mon to either clinical group at PϽ.05. Lower extremity patients. One patient had an elevated CSF protein level of motor NCS results were more frequently abnormal in pa- 89 mg/dL. He was diagnosed with a small-fiber sensory- tients presenting without pain but at P = .08. Abnormal predominant PN and had normal motor examination find- sensory NCS results, EMG findings, and vibratory thresh- ings, normal serum protein and immunofixation electro- olds on examination and QST were seen at similar fre- phoresis results, and no evidence of demyelination on NCSs. quency in both groups. Only 8 (12%) of 67 patients with Of the 14 patients who underwent sural nerve bi- pain had intact reflexes and normal sensation for light opsy, histological findings showed axonal degeneration touch, vibration, and proprioception. This compared with in 13 (93%). One biopsy sample showed prominent 1 (4%) of 26 patients without pain. Of the 8 patients pre- evidence of demyelination with lesser features of axonal senting with pain who had normal large-fiber modali- degeneration. ties on examination, only 2 patients had normal NCS findings. Five of the patients with CSPN with pain had THERAPEUTIC RESPONSE completely normal NCS and EMG findings, and another 6 patients had normal NCS results, but EMG was Empiric treatment for painful paresthesia or dysesthesia not performed. Among the 27 patients with CSPN with was attempted with a variety of agents, including tri-

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 cyclic antidepressant agents, carbamazepine, phen- bodies to SS-A and SS-B, although we realize that occa- ytoin, and gabapentin. Nineteen (49%) of 39 patients re- sionally seronegative patients with PN related to sicca ported a clinical benefit from tricyclic antidepressant drug complex are incorrectly labeled as cryptogenic using this use, and 10 (50%) of 20 patients reported a benefit from approach. For this reason, it is important to inquire about carbamazepine therapy. Mexiletine hydrochloride treat- new symptoms on follow-up visits and to remain open ment improved sensory symptoms in 2 of 4 patients, and to other diagnostic possibilities. gabapentin treatment improved sensory symptoms in 5 In our study, patients with CSPN had a relatively of 15 patients. Topical capsaicin application was effec- homogeneous PN syndrome beginning in the sixth de- tive in 3 (21%) of 14 patients. Only 1 (9%) of 11 pa- cade of life with long-term stable to slowly progressive tients taking nonsteroidal anti-inflammatory agents and symptoms and axonal features on electrophysiologic and none of 9 patients taking phenytoin sodium noted clini- histological studies. Typical patients had symptoms for cal improvement. several years before evaluation in a neuromuscular clinic. Patients with pain had a longer duration of symptoms. COMMENT We do not have an obvious explanation for this finding, although the onset of positive symptoms such as pain may Chronic PN accounts for a frequent problem referred to be easier for patients to recall than negative symptoms. neurologists and neuromuscular clinics. Although re- Other possibilities are that the patients with CSPN with sults of early series2,3 suggested that 50% or more of pain had less impressive physical findings in early stages chronic PN was idiopathic, these studies were based on or had responded adequately to pain management, thereby younger hospitalized patients, many of whom pre- delaying referral to a specialty clinic. In patients with sented with severe weakness resembling acute or chronic CSPN for whom follow-up examination results were avail- inflammatory demyelinating PNs.2 More recent stud- able, approximately 15% demonstrated progression, but ies5-8 of chronic PN estimate that 10% to 35% are idio- all have remained ambulatory. This pattern is consis- pathic, still a considerable number of patients. In our large tent with previous reports. More than 80% of patients population of PN referrals, 23% were classified as CSPN. with cryptogenic PN in the series by McLeod et al5 were Results of previous studies5,9 found that men are over- unchanged or improved at mean follow-up of 3 years. represented in unclassified PN by as much as 3:1 to 4:1. Half of the patients with idiopathic “small-fiber” neu- Our CSPN population was more evenly divided be- ropathy did not progress during mean follow-up of tween the sexes. There was no male predominance in 2 2 years.17 A plateau phase seems to be particularly studies16,17 of painful idiopathic sensory PN. common in patients with pure sensory PN.9 In the Because cryptogenic PN is essentially a diagnosis of follow-up report by Notermans et al,10 only1of21 exclusion that can be established only after performing patients with sensory neuropathy required an assistive a careful history, thorough neurologic examination, and device for walking after 5 years. Our study suggests, directed laboratory testing, the possibility of overlook- however, that progression on examination will become ing an underlying cause always exists. For instance, re- evident in at least one third of patients as follow-up is evaluation of cryptogenic PN ultimately uncovered a cause extended. Still, debilitating motor impairment seems in 5%10 to 76%18 of previously unclassified patients. Neu- uncommon in our patients with CSPN and in other ropathies related to hereditary factors, diabetes, and al- series. In the study by Prineas,20 in which mean cohol abuse are particularly prone to being missed on ini- follow-up extended to nearly 9 years, no patients tial evaluation. Review of family history and medical became bedridden and most could walk without assis- records alone may miss 30% of hereditary PN.18 By ex- tance. Discomfort or pain was a common symptom, cluding patients with prominent motor involvement from present in 69% of patients in the series by Grahmann et the analysis and performing chemistry batteries, liver func- al,6 65% of patients with sensory PN in the series by tion tests, and serologic screening on all patients, we be- Notermans et al,9 80% of patients with idiopathic small- lieve it is unlikely that neuropathies related to diabetes, fiber PN in the series by Gorson and Ropper,17 and just alcohol abuse, connective tissue disorders, and heredity more than 70% in our patient group. were included in our CSPN population. One could ar- Results of electrophysiologic and pathologic stud- gue that further investigative studies are required be- ies in CSPN indicate an axonal neuropathy. No patients fore labeling a neuropathy cryptogenic. For example, in our series had primarily demyelinating findings on Grant et al19 recently advised that patients with unclas- NCSs or satisfied demyelinating criteria.14 We found ab- sified sensory-predominant PN undergo ophthalmo- normalities on EMG in most patients (70%) who under- logic testing for keratoconjunctivitis sicca to exclude the went needle examination despite the absence of motor possibility of sicca complex or Sjo¨gren syndrome as a symptoms. Therefore, subclinical motor involvement is cause. Because sicca symptoms are often mild and are not often detected on electrophysiologic studies in patients volunteered by patients without direct questioning, this with cryptogenic PN who have only sensory signs. Of the cause may be overlooked. How far one should proceed 14 sural nerve biopsy samples obtained, 13 demon- with diagnostic testing in unclassified PN is a difficult strated typical features of axonal degeneration, includ- question. In the case of sicca complex, our practice is to ing 1 patient with MGUS. directly inquire about dry eye and mouth symptoms and In previous series of idiopathic PN, most patients to obtain an erythrocyte sedimentation rate, rheuma- demonstrated axonal features on electrophysiologic and toid factor, and antinuclear antibodies on all patients. If pathologic studies. Approximately 95% of patients in 2 xerophthalmia or xerostomia is present, we check anti- large series5,9 had axonal features on NCSs. In the series

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 by Grahmann et al,6 14 of 29 unclassified patients un- Electrophysiologic test results were abnormal in most derwent sural nerve biopsy. All but 1 patient demon- patients with CSPN. Overall, 87% had either abnormal mo- strated axonal degeneration. Six of 9 sural nerve biopsy tor or sensory NCS results. In the few patients with nor- samples in patients with idiopathic small-fiber PN showed mal NCS results, EMG findings were usually normal as well. axonal degeneration, the other 3 being normal.17 Loss of Patients with pain were more likely to have normal NCS myelinated fibers with axonal degeneration and regen- results. Still, 75% of the NCSs in this population were ab- eration were the typical findings on light and electron normal. Our findings differ somewhat from those of the microscopy in another large patient series.5 study by Gorson and Ropper,17 in which 45% of patients with idiopathic distal small-fiber neuropathy had normal electrophysiologic study results. This raises the question, F THE 83 PATIENTS with CSPN tested, only “How common an entity is idiopathic pure small-fiber sen- 4 (5%) had a monoclonal protein, 2 of sory neuropathy?” One might predict that a pure small- whom had slight weakness in the distal fiber neuropathy would occur more often in patients with upper and lower extremities. Hand weak- CSPN with pain. However, most of our population had clini- ness was present in only 17% of patients cal or laboratory evidence of large-fiber involvement, re- Owithout a monoclonal protein. In a recent series,21 pa- gardless of whether pain was present. No physical or labo- tients with idiopathic PN and MGUS tended to have more ratory variable of large-fiber dysfunction was significantly upper extremity involvement. Otherwise, as in our series, more common in patients with or without pain. Only 8 patients with MGUS were difficult to distinguish on clini- (12%) of 67 patients with CSPN with pain had normal light cal and electrophysiologic grounds from those without a touch, vibration, proprioception, and reflex examination paraprotein. The detection of monoclonal proteins in our results. Of these 8 patients, 6 had abnormalities on NCSs. mostly elderly population may be incidental because para- To establish a diagnosis of small-fiber PN in the remain- proteins are found in up to 3% of healthy adults in later ing patients, additional tests such as autonomic studies and life.22 In the series by Notermans et al,21 18% of patients QST can be pursued. Measuring intraepidermal nerve fi- had a monoclonal protein, but patients with sensory and ber density on punch skin biopsy samples is also advo- motor symptoms were included. Results of further analy- cated for this purpose because it provides objective evi- sis suggest that patients with an IgM paraprotein pro- dence of small-fiber loss and is less invasive than sural nerve gressed faster, with more weakness and sensory signs than biopsy examination.16,28-30 However, this novel technique those with an IgA or IgG monoclonal protein.23 None of is available only through a few peripheral nerve laborato- our patients had an IgM paraprotein. ries and is primarily a research tool. We did not detect elevated IgM or IgG antisul- The usefulness of NCSs in the evaluation of idio- fatide antibody levels in any of the 41 tested patients. This pathic PN, especially in patients with a painful, small- contrasts with results of previous reports in which ap- fiber neuropathy, is limited by several factors. First, as men- proximately one quarter of patients with idiopathic sen- tioned earlier, patients with idiopathic painful PN often have sory-predominant neuropathy selected from case rec- normal electrophysiologic study findings.17 Second, the su- ords or a clinic population had antisulfatide antibodies.24,25 ral sensory response may be absent in healthy subjects older Notermans et al,9 however, also failed to detect such an- than 60 years, complicating the interpretation of such a find- tibodies in 70 patients with chronic idiopathic sensory ing in this elderly group of patients.15 In our population, or sensorimotor neuropathy, and results of other re- however, 37 (95%) of 39 patients older than 60 years with ports10,26 confirm their low frequency. Furthermore, the abnormal sural sensory responses had more extensive ab- frequency of IgM antisulfatide antibodies in this popu- normalities on NCSs. Therefore, we rarely encountered the lation was recently revised downward to 0.7%.27 There- ambiguous scenario in which a reduced sural response was fore, our experience and that of others do not support the only abnormality on NCSs in an elderly patient. Fur- the concept that antisulfatide antibodies are a common thermore, the 2 patients with isolated sural abnormalities finding in idiopathic sensory-predominant PN. had additional laboratory evidence for PN on either QST We did not find that CSF studies contributed to the or EMG studies. evaluation of the 5 patients with CSPN who underwent lum- Using standardized controls, QST results for vibra- bar puncture. Results of CSF studies were normal in 4 pa- tion and cold thresholds were abnormal in approxi- tients and showed an elevated protein level in 1 patient who mately 85% of patients tested, a figure similar to a pre- had no clinical or electrophysiologic evidence of an in- liminary report.16 Vibration and cold thresholds were flammatory or demyelinating PN. Similarly, results of CSF abnormal in two thirds of the studies. Cold threshold ab- analysis were largely unremarkable in recent studies of cryp- normalities alone were present in 24% of patients with togenic PN that excluded inflammatory neuropathies. The CSPN with pain and in 30% of patients with CSPN with- mean CSF protein concentration from 73 unclassified pa- out pain. Quantitative sensory testing for cold thresh- tients in the study by Notermans et al9 was 43 mg/dL. Six olds may not be an ideal small-fiber measurement be- (14%) of 44 patients in the series by McLeod et al5 had a cause it presumably assesses both A ␦ and C fibers.31 CSF protein level greater than 100 mg/dL. However, 4 of Quantitative sensory testing of warm or heat pain thresh- these 6 patients were found to have a malignant neo- olds theoretically provides a better measure of C fibers. plasm. In our opinion, CSF examination is of low yield in We do not routinely perform heat pain thresholds in our patients with chronic PN who remain unclassified after rou- laboratory, and CASE IV equipment does not include nor- tine laboratory studies, have minimal motor involvement, mative values for warm thresholds. However, it should and do not demonstrate demyelinating features on NCSs. be emphasized that more than 90% of the population with

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 clinical and electrophysiologic examinations detected evi- Table 4. Diagnostic Criteria for CSPN* dence of large-fiber involvement in all but a few patients with painful PN. Thermal threshold testing can de- Inclusion Criteria tect small-fiber dysfunction in most of the remaining Symptoms 30,34,35 Loss of sensation (numbness) or altered sensation patients with PN. (tingling/paresthesia/dysesthesia) or pain beginning in the distal Our findings contrast with those from other stud- extremities (usually with onset in feet before hands) ies of painful small-fiber PN. However, these investiga- Symptoms present for at least 3 mo tors16,30,34 excluded patients with large-fiber involve- No symptoms of weakness ment by requiring normal electrophysiologic study results Symptoms of gait unsteadiness and autonomic dysfunction are allowable and intact strength, proprioception, and deep tendon re- 30 Signs flexes. Because these patients with “pure” small-fiber Sensory signs are present in a symmetrical fashion in distal limbs involvement represent only a fraction of all painful neu- and may include any of the following: loss of vibration, ropathies,30 our experience is likely to be more reflec- proprioception, light touch, pain (pinprick), or temperature tive of routine clinical practice. Hyporeflexia or areflexia may be present but is not required, even at Although by definition the cause of CSPN is un- the ankles Minimal weakness or atrophy is allowable in muscles supplying known, our experience suggests that general diagnostic cri- movement to the finger and toes teria can be developed for these patients. Such criteria should Laboratory studies broadly define the symptoms, signs, and laboratory abnor- Electrophysiology: sensory and motor NCS and needle EMG are malities that are expected and sufficient to arrive at a di- often, but not invariably, abnormal; when abnormal, findings agnosis of CSPN. Table 4 outlines clinical criteria for CSPN indicate a primarily axonal PN Quantitative sensory tests: vibration and temperature thresholds are that we recommend based on our experience and that of often, but not invariably, abnormal other investigators. We chose a mimimum of 3 months of Other studies: if NCS/EMG and QST are normal, other studies sensory symptoms to classify patients as having CSPN. This including skin punch biopsy to measure epidermal nerve fiber excludes patients with an acute sensory neuropathy caused density and autonomic studies including sudomotor tests by a toxic, iatrogenic, or immune-mediated process that (quantitative sudomotor axon reflex test, Silastic imprint testing, sympathetic skin response) and vasomotor tests (heart rate potentially is self-limiting. In our opinion, sensory symp- variability to deep breathing, Valsalva ratio) may provide evidence toms alone are not sufficient to diagnose CSPN. It is at times of peripheral nerve dysfunction difficult to ascertain whether a patient with sensory symp- Blood and urine tests: these should be normal or negative; a toms and normal neurologic examination results actually monoclonal protein by serum protein electrophoresis and/or has neuropathy. Therefore, in this clinical setting, we be- immunofixation electrophoresis is allowable in patients with MGUS lieve that abnormalities on NCSs, EMG, QST, or other studies, including nerve biopsy or punch skin biopsy exami- Exclusion Criteria Any identifiable metabolic, toxic, infectious, systemic, or hereditary nations, are required to diagnose CSPN. By our definition, disorder known to cause PN CSPN is chronic in nature, and whether acute, self- NCS abnormalities consistent with demyelination limited forms exist awaits further study. We suspect that, If a monoclonal gammopathy is present, the presence of an underlying as investigators devote more attention to this previously lymphoproliferative disorder, malignancy, or amyloidosis underemphasized patient group, diagnostic criteria will Weakness on examination other than mild toe and/or finger weakness evolve. Although patients with CSPN share many clinical features, further work will almost certainly elucidate a va- *CSPN indicates cryptogenic sensory polyneuropathy; NCS, nerve conduction studies; EMG, electromyography; PN, polyneuropathy; riety of causes. QST, quantitative sensory testing; and MGUS, monoclonal gammopathy of We found tricyclic antidepressant drug use and car- uncertain significance. bamazepine therapy to have roughly equivalent efficacy in relieving symptoms of painful paresthesias and dys- CSPN had evidence of large-fiber dysfunction, and, there- esthesias. Approximately 50% of patients responded to fore, the addition of warm and heat pain QST would have treatment with either agent. Similar success was found been of diagnostic value in only a few patients. Because with mexiletine hydrochloride treatment in a few pa- many of our patients with CSPN had impaired vibration tients. Each of these agents has demonstrated efficacy in or proprioception responses or both on examination and the treatment of neuropathic pain in double-blinded, abnormal electrophysiologic study findings, the demon- crossover studies of painful diabetic neuropathy.36,37 Gaba- stration of abnormal QST results was adjunctive evi- pentin, a newer antiepileptic drug with a favorable ad- dence for a PN. Although QST has been shown to have verse effects profile, has been effective in a variety of neu- some use as a diagnostic, staging, and outcome measure ropathic pain syndromes, including radiculopathies, in large peripheral neuropathy studies,32,33 its role in rou- postherpetic neuralgia, human immunodeficiency virus tine practice is not established. Furthermore, as a sub- neuropathy, and trigeminal neuralgia,38-40 and has shown jective test dependent on patient attention and coopera- promise in preliminary controlled trials of painful dia- tion, QST is not an ideal measure of small-fiber function. betic neuropathy.41,42 One third of our patients taking In theory, an impaired thermal threshold on QST gabapentin had symptomatic improvement. Topical cap- may represent the only laboratory abnormality in small- saicin use benefits a few patients. Use of phenytoin and fiber PN. However, our experience suggests that this is nonsteroidal anti-inflammatory drugs, in contrast, was an uncommon occurrence. Only 2 (9%) of 23 patients largely of no benefit. In a double-blind, crossover study, with CSPN with pain and abnormal cooling thresholds Saudek et al43 also did not demonstrate efficacy for phen- on QST had normal NCS results. Therefore, thorough ytoin therapy in painful diabetic neuropathy.

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 We did not use immunosuppressive therapy in our 10. Notermans NC, Wokke JHJ, van der Graaf Y, et al. Chronic idiopathic axonal polyneuropathy: a five year follow up. J Neurol Neurosurg Psychiatry. 1994;57:1525- patients with CSPN. Although literature exists describ- 1527. ing benefits of using corticosteroids, intravenous gam- 11. Dyck PJ, O’Brien PC, Kosanke JL, Gillen DA, Karnes JL. A 4, 2, and 1 stepping maglobulin, and other immunosuppressive agents in id- algorithm for quick and accurate estimation of cutaneous sensation threshold. 17,26 Neurology. 1993;43:1508-1512. iopathic axonal PN, we do not subscribe to their 12. Yarnitsky D. Quantitative sensory testing. Muscle Nerve. 1997;20:198-204. widespread use. The potential for serious adverse events, 13. Dyck PJ, Karnes J, O’Brien PC, Zimmerman IR. Detection thresholds of cutane- the significant monetary expense of some agents, the lack ous sensation in humans. In: Dyck PJ, Thomas PK, Griffin JW, et al, eds. Pe- ripheral Neuropathy. 3rd ed. Philadelphia, Pa: WB Saunders Co; 1993:706-728. of concrete evidence for an autoimmune or inflamma- 14. Cornblath DR, Asbury AK, Albers JW, et al. Research criteria for diagnosis of tory cause for the PN, and the relatively favorable long- chronic inflammatory demyelinating polyneuropathy (CIDP). Neurology. 1991; 41:617-618. term prognosis all argue against administering immu- 15. Wilbourn AJ. Diabetic neuropathies. In: Brown WF, Bolton CF, eds. Clinical Elec- nosuppressive agents to patients with cryptogenic sensory- tromyography. 2nd ed. Boston, Mass: Butterworth-Heinemann; 1993:477-515. predominant PN. 16. Periquet MI, Kissel J, Collins M, et al. A prospective study of painful sensory neuropathies [abstract]. Neurology. 1997;48:A186-A187. In our experience, patients with CSPN follow a stable 17. Gorson KC, Ropper AH. Idiopathic distal small fiber neuropathy. Acta Neurol Scand. course and rarely develop disabling motor deficits despite 1995;92:376-382. the presence of motor nerve involvement on electrophysi- 18. Dyck PJ, Oviatt KF, Lambert EH. Intensive evaluation of referred unclassified neuropathies yields improved diagnosis. Ann Neurol. 1981;10:222-226. ologic studies. Although the mean duration of follow-up 19. Grant IA, Hunder GG, Homburger HA, Dyck PJ. Peripheral neuropathy associ- is limited, 35 of our patients had symptoms of neuropathy ated with sicca complex. Neurology. 1997;48:855-862. for 5 years or longer before our evaluation. All patients with 20. Prineas J. Polyneuropathies of undetermined cause. Acta Neurol Scand Suppl. 1970;44:1-72. follow-up examination results have remained ambula- 21. Notermans NC, Wokke JHJ, van den Berg LH, et al. Chronic idiopathic axonal tory. We found that these patients are often anxious about polyneuropathy: comparison of patients with and without monoclonal gammopa- their future, with many having been told previously by other thy. Brain. 1996;119:421-427. 22. Kyle RA. “Benign” monoclonal gammopathy: a misnomer. JAMA. 1984;251: physicians that their prognosis is bleak and they will be- 1849-1854. come physically incapacitated over time, requiring a wheel- 23. Notermans NC, Wokke JHJ, Lokhorst HM, et al. Polyneuropathy associated with monoclonal gammopathy of undetermined significance. Brain. 1994;117:1385- chair or becoming bedridden. Perhaps the most useful in- 1393. tervention is reassuring these individuals that they are 24. Pestronk A, Li F, Griffin J, et al. Polyneuropathy syndromes associated with se- unlikely to develop disabling motor impairment and that rum antibodies to sulfatide and myelin-associated glycoprotein. Neurology. 1991; 41:357-362. continued physical independence is almost certain. Al- 25. Nemni R, Fazio R, Quattrini A, et al. Antibodies to sulfatide and to chondroitin though such reassurance provides a degree of mental, and sulfate C in patients with chronic sensory neuropathy. J Neuroimmunol. 1993; possibly physical comfort for patients, further studies are 43:79-86. 26. Slogosky SL, Chavin JM, Heiman-Patterson T, Tahmoush AJ. Idiopathic axonal needed to elucidate the underlying pathogenesis of CSPN neuropathy responsive to immunosuppression [abstract]. Ann Neurol. 1995;38: and to develop rational therapeutic strategies for this com- 336. mon form of PN. 27. Lopate G, Parks BJ, Goldstein JM, et al. Polyneuropathies associated with high titre antisulphatide antibodies: characteristics of patients with and without serum monoclonal proteins. J Neurol Neurosurg Psychiatry. 1997;62:581-585. Accepted for publication August 10, 1998. 28. Holland NR, Stocks A, Hauer P, et al. Intraepidermal nerve fiber density in patients with painful sensory neuropathy. Neurology. 1997;48:708-711. We thank Laura L. Herbelin, University of Texas South- 29. Mendell JR, Periquet I, Kissel JT, et al. Distal painful axonal idiopathic neuropa- western Medical Center, Dallas, for assistance with the elec- thy: criteria for diagnosis and distinction from other sensory neuropathies [ab- trophysiologic studies and quantitative sensory testing and stract]. Neurology. 1998;50:A343-A344. 30. Holland NR, Crawford TO, Hauer P, et al. Small-fiber sensory neuropathies: clini- Joan S. Reisch, PhD, University of Texas Southwestern Medi- cal course and neuropathology of idiopathic cases. Ann Neurol. 1998;44:47-59. cal Center, Dallas, for help with statistical analysis. 31. Light AR, Perl ER. Peripheral sensory systems. In: Dyck PJ, Thomas PK, Griffin Reprints: Gil I. Wolfe, MD, Department of Neurol- JW, et al, eds. Peripheral Neuropathy. 3rd ed. Philadelphia, Pa: WB Saunders Co; 1993:149-165. ogy, University of Texas Southwestern Medical Center, 5323 32. 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