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Chronic Idiopathic Axonal Polyneuropathy and Successful Aging of the Peripheral Nervous System in Elderly People
Alexander F. J. E. Vrancken, MD;
Hessel Franssen, MD, PhD;
John H. J. Wokke, MD, PhD;
Laurien L. Teunissen, MD;
Nicolette C. Notermans, MD, PhD
Arch Neurol. 2002;59:533-540.
ABSTRACT
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Background Chronic idiopathic axonal polyneuropathy (CIAP) is a frequent neurologic
disorder in elderly persons. In view of the aging population, it is important
to know the long-term prognosis of CIAP.
Objectives To determine if CIAP is influenced by the superposition of the effects
of aging and to evaluate the severity of CIAP according to the disease duration.
Design Controlled cohort study.
Setting Outpatient clinic for neuromuscular diseases at the University Medical
Center Utrecht, Utrecht, the Netherlands.
Participants and Methods One hundred twenty-seven patients with CIAP and 108 age-matched control
subjects were included. We defined CIAP on the basis of symmetrical distal
sensory or sensorimotor symptoms and signs with evolution over at least 6
months, exclusion of causes by history taking, results of clinical and laboratory
investigations, and electrophysiologic findings that agreed with the diagnosis
of axonal polyneuropathy.
Results No important neurologic or electrophysiologic differences were found
between patients with early-onset (before the age of 65 years) and late-onset
(at or after the age of 65 years) CIAP, but patients with early-onset CIAP
who had a short disease duration (<10 years) experienced more disability
than patients with late-onset CIAP who had a similar disease duration. Old
controls (age of 65 years or older) more often had symptoms, sensory signs
in the legs, absent ankle jerks, and lower mean distal amplitudes of compound
muscle action potentials and sensory nerve action potentials than young controls
(aged <65 years). Absence of the sural nerve sensory nerve action potentials
or presence of spontaneous muscle fiber activity in the anterior tibial muscle
was common in patients with CIAP (51% and 60%, respectively), but exceptional
(both 2%) in controls.
Conclusions Neither aging of the peripheral nervous system nor disease duration
affects CIAP to a considerable degree, but CIAP has a greater influence on
the daily life of nonretired patients with early-onset CIAP. The diagnosis
of axonal polyneuropathy is probably supported best by either the absence
of the sural nerve sensory nerve action potentials or the presence of spontaneous
muscle fiber activity in the anterior tibial muscle.
INTRODUCTION
AFTER extensive investigations, no cause can be identified in 10% to
20% of the patients who have polyneuropathy.1-5
In most of these patients the polyneuropathy presents insidiously in the sixth
decade of life with predominantly sensory or sensorimotor symptoms and a slowly
progressive course. Electrophysiologic studies invariably show axonal polyneuropathy.
For this clinical entity the term "chronic idiopathic axonal polyneuropathy"
(CIAP) has been introduced.6 Others have used
"cryptogenic (sensory) polyneuropathy."3, 5
Severe disability or ambulatory impairment has not been observed 5 to 10 years
after disease onset.2-3,5-6
Neurologic symptoms and signs suggestive of polyneuropathy occur more
frequently with successful aging.7-12
Also, there is a decline of nerve conduction parameters.8, 11, 13-19
Furthermore, age-related degenerative changes have been demonstrated in pathologic
studies of peripheral nerves in subjects without peripheral nervous system
disease.20-21
The age-dependent decline could affect the clinical course of CIAP with
differential consequences regarding disability and prognosis for younger and
older patients. However, it is unknown whether CIAP with onset at a younger
age differs from CIAP with onset at an older age. Moreover, the disease duration
could obscure the influence of aging. To our knowledge, the severity of CIAP
after a long disease duration (which is more likely to occur in patients with
disease onset at a younger age) has not been studied before. The aims of this
study were to determine if CIAP is influenced by the superposition of the
effects of aging and to evaluate the severity of CIAP according to disease
duration. We compared the neurologic symptoms and signs, disability status,
and electrophysiologic parameters of 127 patients with CIAP with those of
108 successfully aged control subjects.
PARTICIPANTS AND METHODS
PATIENTS AND CONTROLS
A total of 127 patients (87 men and 40 women) with CIAP and 108 successfully
aged controls (72 men and 36 women) were included. Fifty-seven patients with
CIAP also participated in a quality-of-life study.22
Patients were referred to our outpatient department for neuromuscular diseases
after previous evaluation by other neurologists. The diagnosis of CIAP was
made according to the following criteria2, 4:
(1) symmetrical distal sensory or sensorimotor symptoms and signs of the limbs,
compatible with polyneuropathy; (2) insidious onset and slow or no progression
of the disease over at least 6 months; (3) no identifiable cause after extensive
clinical and laboratory investigations; (4) no indication of hereditary polyneuropathy;
and (5) electrophysiologic findings that agreed with the diagnosis of axonal
polyneuropathy.
Controls were recruited from relatives or friends of patients visiting
our clinic and had to be free of diseases or conditions known to be associated
with polyneuropathy. They had not previously consulted a neurologist for symptoms
or signs.
Patients were classified into 2 groups—those with disease onset
before the age of 65 years (hereafter referred to as the "early-onset CIAP
group" [n = 61 patients]) and those with disease onset at 65 years or older
(hereafter referred to as the "late-onset CIAP group" [n = 66 patients]).
Disease onset was defined as the age at which the symptoms or signs were first
noted by the patient to be consistently present. Controls were classified
into a group of persons younger than 65 years at study enrollment (hereafter
referred to as the "young controls" [n = 47 subjects]), and a group of persons
65 years or older at study enrollment (hereafter referred to as the "old controls"
[n = 61 subjects]). The cutoff was set at the age 65 years, because it coincided
with the usual retirement age and health expectancy (ie, the average age at
which a person can still be expected to be disability-free or in good self-reported
health) in the Netherlands.23
To evaluate if early-onset CIAP is different from late-onset CIAP, the
data at referral were compared. To study the relationship between the disease
duration and the severity of CIAP, the latest clinical data of 89 patients
who had a short disease duration (<10 years) were compared with the data
of 38 patients who had a long disease duration ( 10 years). To determine
the normal manifestations of successful aging, young controls were compared
with old controls. To evaluate the differences between CIAP and successful
aging, patients with late-onset CIAP were compared with old controls. Comparison
of patients with early-onset CIAP with young controls was considered inappropriate,
because part of the patients with early-onset CIAP had already reached the
age of 65 years at the time of study enrollment. The study protocol was approved
by the Medical Ethical Committee of the University Medical Center Utrecht,
Utrecht, the Netherlands.
CLINICAL EVALUATION
In all patients and controls, history taking and clinical examination
(muscle strength, sensory function, tendon reflexes, and the Romberg test)
were performed in a standardized fashion.4, 22
A detailed inquiry was made about specific motor and sensory symptoms (Table 1), medical history, medication use,
and toxic substance exposure. The occurrence of polyneuropathy in family members
was thoroughly queried, and affected family members underwent neurologic and
electrophysiologic examination, if necessary. If this could not rule out the
possibility of a hereditary neuropathy, subjects were excluded.
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Table 1. Neurologic Symptoms at Study Enrollment in Patients With CIAP
and Control Subjects*
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Manual muscle strength testing was scored with the Medical Research
Council (MRC) scale in the subject's forearms, hands, lower legs and feet
(ie, wrist extensors, finger extensors, finger flexors, interossei muscles,
anterior tibial muscle, gastrocnemius muscle, peroneal muscles, and the long
extensor muscle of the big toe). Summation of the MRC scores could total a
maximum of 80. Sensory function was examined and scored bilaterally. Pinprick
and light touch sense were scored as follows: normal, 4; distal to wrist/ankle
abnormality, 3; distal half forearm/leg abnormality, 2; distal to elbow/knee
abnormality, 1; and above the elbow/knee abnormality, 0. Vibration sense (128-Hz
tuning fork perception) was scored as follows: normal perception on middle
finger (at least 15 seconds)/or big toe (at least 10 seconds), 4; decreased
or absent on middle finger/big toe, but with perception on styloid/malleolus,
3; absent on styloid/malleolus, but with perception on elbow/knee, 2; absent
on elbow/knee, but with perception on clavicle/crista iliaca, 1; and absent
on clavicle/crista iliaca, 0. Joint position sense (perception of movement
at distal interphalangeal joint of middle finger/big toe)was scored as follows:
immediate or normal perception, 2; delayed or diminished perception, 1; and
absent perception, 0. Summation of all sensory scores could total a maximum
score of 56. Sensory scores were dichotomized at the following values: pinprick/light
touch/vibration sense below 7 (abnormal) vs 7 or 8 (normal), joint position
sense below 3 (abnormal) vs 3 or 4 (normal). Disability status was scored
using the modified Rankin scale.24
LABORATORY INVESTIGATIONS
Extensive laboratory tests were performed in all patients to exclude
any cause of the polyneuropathy.1-2,4
Additional studies (eg, radiography of the chest or spinal axis or cerebrospinal
fluid analysis) were done when indicated and the findings or results had to
show no abnormality or be within a normal range. Sural nerve biopsy was performed
if there was any suggestion, based on clinical or laboratory findings, of
an underlying disorder such as vasculitis or amyloidosis. Laboratory investigations
were not performed in controls.
ELECTROPHYSIOLOGIC STUDIES
Nerve conduction studies with surface electrodes and concentric needle
electromyography according to standard techniques25
were consistent with axonal polyneuropathy in all patients. In 96 patients
and 49 controls additional standardized conduction studies were performed
after warming the participants' limbs for 30 minutes in water of 37°C.26-27 Motor conduction was investigated
in the median nerve up to the axilla, and in the tibial nerve up to the knee;
sensory conduction on distal stimulation was investigated in the median and
sural nerve.27 Concentric needle electromyography
was performed in the anterior tibial muscle. Criteria for demyelination were
as described previously.27
STATISTICAL ANALYSIS
Frequencies were compared with  2 test statistics. For
differences between not normally distributed continuous variables (ie, age
and disease duration) and ordinal or scaled variables (ie, motor and sensory
sum scores, modified Rankin scores), the Kolmogorov-Smirnov test or Mann-Whitney
test were used, respectively. The means of normally distributed variables
(electrophysiologic parameters) were compared using the t test. Statistical significance was set at P<.05.
RESULTS
Age distributions at study enrollment of patients and controls are shown
in Figure 1. The men-women ratio
was 2:1 in patient and control groups.
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Figure 1. Age distributions at study enrollment
of patients with chronic idiopathic axonal polyneuropathy (gray shaded bars)
and control subjects (solid bars).
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CLINICAL EVALUATION OF PATIENTS WITH CIAP
Profiles of symptoms and signs are shown in Figure 2A. In all patients the polyneuropathy had started distally
in the legs; at the time of referral, 60 patients had symptoms distally in
the legs and hands.
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Figure 2. Symptoms and signs of patients
with chronic idiopathic axonal polyneuropathy (CIAP) (A) and control subjects
(B) for pure sensory (gray shaded bars), pure motor (open bars), and sensorimotor
(solid bars) functions.
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All patients had distal sensory signs in the legs, and 55 had sensory
signs in the hands. Weakness of distal leg muscles was noted in 80 patients,
and 17 also had weakness of the hand muscles. A total of 62 patients with
signs distally in the legs also had signs in the hands.
Thirty-five patients used walking aids such as a cane, adjusted shoes,
ankle-foot orthoses, or a wheeled walker. One patient used a wheelchair because
of a hemiparesis from cerebral infarction. The scores on the modified Rankin
scale were as follows: 1, 70 patients; 2, 52 patients; and 3, 5 patients.
No patients had modified Rankin scores of 4 or 5.
Patients with early-onset CIAP significantly more often had tingling
or prickling, pain, numbness or a cotton-wool sensation, muscle cramps, stiffness,
and weakness (Table 1), but there
were no statistically significant differences in the presence of signs (Table 2).
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Table 2. Neurologic Signs at Study Enrollment in Patients With CIAP
and Control Subjects*
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CLINICAL SEVERITY IN SHORT AND LONG DISEASE DURATION
In patients with early-onset CIAP who had a short disease duration,
modified Rankin scores were significantly higher than in patients with late-onset
CIAP who had a short disease duration (Table 3). In patients with late-onset CIAP who had a short disease
duration, sensory and motor total scores of the legs were significantly higher,
and modified Rankin scores were significantly lower than in patients with
late-onset CIAP who had a long disease duration (Table 3).
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Table 3. Severity of CIAP in Short and Long Duration of Disease*
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CLINICAL EVALUATION OF CONTROLS
Symptoms and signs were also found in controls, and more often in old
controls (Figure 2B). In 54 controls
symptoms were located distally in the legs, and 26 (6 young and 20 old controls; P .01) had symptoms in the hands as well.
In 70 controls (25 young and 45 old controls; P.02)
sensory signs were found distally in the legs, and 17 (5 young and 12 old
controls; P.01) also had sensory signs in the
hands. Muscle strength of the arms and legs was normal in all but 2 controls
(ages 73 and 74 years) who had an MRC grade 4 weakness of the long extensor
muscle of the big toe or anterior tibial muscle.
The walking aids used by 2 controls (ages 79 and 80 years) were a cane
and a wheeled walker. The modified Rankin scores for the control subjects
were as follows: 0, 51 controls; 1, 54 controls; and 2, 3 controls. No controls
had a modified Rankin score of 3 or higher.
Old controls significantly more often mentioned tingling or prickling
and weakness (Table 1). Furthermore,
old controls had significantly lower sensory total scores of the legs (Table 2), and they significantly more often
had abnormal light touch and vibration sense, and absent ankle tendon reflexes
(Figure 3; sensory functions were
considered abnormal if the sensory scores in the arms or legs were below 7
for pinprick, light touch, or vibration sense, and below 3 for position sense).
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Figure 3. A, Neurologic signs of aging in
young (open bars) and old control subjects (shaded bars). B, For comparison,
the same signs seen in patients with early onset (gray shaded bars) and late
onset of chronic idiopathic axonal polyneuropathy (CIAP) (solid bars).
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CLINICAL COMPARISON OF PATIENTS WITH LATE-ONSET CIAP WITH OLD CONTROLS
In general, patients with late-onset CIAP significantly more often had
symptoms and signs as well as significantly lower sensory and motor total
scores (Table 1 and Table 2). However, old controls significantly more often had pure
motor symptoms (0 patients with late-onset CIAP and 23 old controls; P<.001) or pure sensory signs (23 patients with late-onset
CIAP and 46 old controls; P<.001).
In the legs of old controls pinprick (75%), light touch (82%), and vibration
sense (83%) abnormalities were restricted to the feet, whereas in patients
with late-onset CIAP these rates were significantly lower, that is, 38%, 47%,
and 63%, respectively (P<.001 for all rates).
Patients with late-onset CIAP significantly more often used walking aids (P.01) and had significantly higher modified Rankin
scores (P<.001).
STANDARDIZED ELECTROPHYSIOLOGIC STUDIES
None of the electrophysiologic parameters in patients or controls fulfilled
our criteria for demyelination. Table 4 summarizes the findings of the standardized electrophysiologic
studies in 96 patients with CIAP and 49 controls.
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Table 4. Standardized Electrophysiologic Findings in 96 Patients With
CIAP and 49 Control Subjects*
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Standardized Electrophysiologic Studies of Patients With CIAP
In patients with late-onset CIAP the mean distal motor latency of the
tibial nerve was significantly longer. Absence of the sural nerve sensory
nerve action potential (SNAP) or the presence of spontaneous muscle fiber
activity (ie, fibrillation potentials, positive sharp waves, or complex repetitive
discharges) in the anterior tibial muscle were found in most patients (72%)
(33 patients with early-onset CIAP and 36 patients with late-onset CIAP).
Standardized Electrophysiologic Studies of Controls
In old controls the mean distal compound muscle action potential amplitude
of the tibial nerve and the mean distal SNAP amplitudes of the median nerve
and sural nerve were significantly lower. The SNAP of the sural nerve was
absent in 1 old control (age 84 years). In another old control (age 67 years)
concentric needle electromyography of the anterior tibial muscle showed positive
sharp waves at 1 insertion site.
Electrophysiologic Comparison of Patients With Late-Onset CIAP With
Old Controls
In patients with late-onset CIAP the mean distal motor latencies were
significantly longer, and the mean distal compound muscle action potentials,
SNAP amplitudes, the mean motor nerve conduction velocities and sensory nerve
conduction velocities were significantly lower. Absence of the sural nerve
SNAP or the presence of spontaneous muscle fiber activity in the anterior
tibial muscle were found significantly more often in patients with late-onset
CIAP.
COMMENT
There were no important differences in clinical features, electrophysiologic
parameters, or disease course between patients with early-onset and late-onset
CIAP. Patients with early-onset CIAP who had a short disease duration had
worse modified Rankin scores than patients with late-onset CIAP who had a
long disease duration. Basic activities of daily living appear fairly resistant
to aging, whereas complex or instrumental activities of daily living (eg,
preparing meals, housekeeping, occupational skills) are less so.28
The modified Rankin score is an overall disability scale that integrates these
levels of activities of daily living. The polyneuropathy probably has a more
negative influence on the daily life of the nonretired patients with early-onset
CIAP, although they are not more severely affected than the retired patients
with late-onset CIAP. The low total scores of the legs and the worse modified
Rankin scores in patients with late-onset CIAP who had a long disease duration
are fallible because of the small sample size. The advanced age (at least
75 years old) of patients with late-onset CIAP who had a long disease duration
is less likely to provide an explanation, because the scores are equally low
in patients with early-onset CIAP who had a similar disease duration. Moreover,
as we have shown, age does not importantly affect CIAP, nor are the neurologic
impairments or disability in successfully aged old controls of such severity
that they can be expected to have a significant influence. In the successfully
aged person 65 years and older, there is a decline of sensory function distally
in the legs, ankle reflexes are more often absent, and electrophysiologic
studies most notably show lower distal compound muscle action potentials and
SNAP amplitudes.
Similar to others,7, 11, 29
we evaluated each sensory modality by simple techniques. Measurement of the
perception time of the vibratory stimulus from a 128-Hz tuning fork was validated
earlier by De Michele et al.30 Our normal perception
time values of 15 seconds at the middle finger and 10 seconds at the big toe
are of similar magnitude as their mean perception times at the ankle and wrist.
Hence, our normal values likely classify a larger proportion of elderly persons
as having abnormal vibration sense at the feet. Others have advocated the
use of the Rydel-Seiffer graduated tuning fork and contended that absent vibration
sense at the feet in healthy elderly subject should be considered abnormal.31 However, individuals with absent vibration perception
in at least one of the sites tested were excluded prior to the analysis. Because
vibration perception at the big toe was absent in 28% of our old controls,
we are less inclined to denote this as abnormal in elderly persons. Whatever
sensory testing techniques used, many studies most notably show a decline
of light touch and vibration sense with advancing age.7-11,30-32
Paradoxically, old controls mentioned weakness more often than could
be confirmed by neurologic examination. Weakness on standard neurologic examination
is unusual in successful aging, but a decline of muscle strength can been
demonstrated by more sensitive quantitative techniques (ie, isometric or isokinetic
strength testing).33
The biceps, triceps, and knee jerks are usually retained after the age
of 65 years.9-11,34
Some investigators have asserted that the ankle reflex should also usually
be present after the age of 65 years,35-36
but others have found it to be absent as frequently as in our study.7-11,34, 37
The effort made to obtain the ankle jerk (eg, reinforcement methods) and the
selection and age distribution of controls may contribute to observed response
rates. Because the ankle jerk may often be absent in persons older than 65
years, it is not a good indicator for the presence of polyneuropathy in elderly
people.
The lower mean distal SNAP amplitudes and compound muscle action potentials
in old controls compared with young controls are compatible with normal aging.8, 11, 13, 15-19
We did not find a change with age in distal motor latencies or nerve conduction
velocities unlike others,11, 14, 18-19
which may be because of the inclusion of younger subjects in those studies,
and our rigorous temperature control.
Because absence of the sural nerve SNAP or presence of spontaneous muscle
fiber activity were exceptional in controls but common in patients with CIAP,
either one of these phenomena probably best supports the diagnosis of axonal
polyneuropathy in a clinically suspect individual. Instead of using standard
electrode placement, we palpated the sural nerve at the ankle and placed the
recording electrode over the nerve, which may have contributed to our findings
on the preservation of the sural nerve responses. Also, our findings are reinforced
by other studies that have shown that sural nerve SNAP is absent in only small
proportions (0%-9%) of the control subjects, even after the age of 60 years.14-16,19, 38-44
Studies on the normal electromyography of the intrinsic foot muscles of controls
have shown conflicting results regarding the presence of spontaneous muscle
fiber activity.45-46 Therefore,
we performed electromyography in the anterior tibial muscle, although we are
unaware of normal electromyography studies of this muscle.
CONCLUSIONS
The superposition of aging in the peripheral nervous system does not
importantly affect CIAP. Even after more than 10 years of having the disease,
severe disability (modified Rankin score >3) does not occur. Axonal polyneuropathy
can probably be confirmed best on the basis of the absence of the sural nerve
SNAP or the presence of spontaneous muscle fiber activity in the anterior
tibial muscle. In successfully aged subjects older than 65 years, mild pure
sensory or pure motor symptoms, slight and pure sensory signs confined to
the feet (including absent vibration sense at the big toe), or absent ankle
reflexes can be considered as normal aging manifestations. Our findings are
valuable when informing patients with CIAP about the prognosis. In view of
the aging population, our findings stress the importance of clinical criteria
by which symptoms or signs may be attributed to normal aging or conversely
to polyneuropathy.
AUTHOR INFORMATION
Accepted for publication September 25, 2001.
Author contributions: Study concept and design (Drs Vrancken and Notermans); acquisition of data (Drs Vrancken, Franssen, Teunissen, and Notermans); analysis
and interpretation of data (Drs Vrancken, Franssen, and
Wokke); drafting of the manuscript (Dr Vrancken); critical revision of the manuscript for important intellectual content (Drs Franssen, Wokke, Teunissen, and Notermans); statistical
expertise (Drs Vrancken and Franssen); study supervision (Drs Franssen, Wokke, and Notermans).
Corresponding author: Alexander F. J. E. Vrancken, MD, Department
of Neurology, C03.236, University Medical Center Utrecht, PO Box 85500, 3508
GA Utrecht, the Netherlands (e-mail: a.f.j.e.vrancken{at}neuro.azu.nl).
From the Departments of Neurology (Drs Vrancken, Wokke, Teunissen,
and Notermans) and Clinical Neurophysiology (Dr Franssen), University Medical
Center Utrecht, Utrecht, the Netherlands.
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