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Efficacy of Intravenous Immunoglobulin in Patients With IgG Monoclonal Gammopathy and Polyneuropathy
Kenneth C. Gorson, MD;
Allan H. Ropper, MD;
David H. Weinberg, MD;
Robert Weinstein, MD
Arch Neurol. 2002;59:766-772.
ABSTRACT
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Context The optimal treatment of patients with neuropathy associated with IgG
monoclonal gammopathy of undetermined significance is unknown. Plasma exchange
has been shown to be effective but alternative therapies have not been systematically
evaluated.
Objective To report our experience with intravenous immunoglobulin (IVIG) in patients
with IgG monoclonal gammopathy of undetermined significance polyneuropathy.
Design Retrospective review of clinical and electrodiagnostic features of 20
consecutive patients treated with IVIG over an 8-year period.
Setting Academic medical center.
Main Outcome Measures Medical Research Council strength (maximum, 40 points) and sensory (maximum,
26 points) scores, modified Rankin Disability Scale score.
Results There were 14 men and 6 women (mean age, 65 years; age range, 36-82
years). The mean strength score was 35.6 points and the mean sensory score
was 15.8 points prior to therapy. After IVIG therapy, the mean strength score
increased by 1.1 points (P = .22) and the sensory
score increased by 1.7 points (P = .11). Eight patients
(40%) improved by 2 points or more in their motor or sensory score and 1 point
or more in the modified Rankin Disability Scale score and were considered
IVIG therapy responders. They had a shorter duration of symptoms (P = .03), numb hands (P = .02), and falling
episodes (P = .02), and had greater proximal leg
weakness (P = .02) compared with nonresponders. In
IVIG therapy responders, the ulnar motor conduction velocity was slower, ulnar
and peroneal distal motor latencies were prolonged, and the frequency of conduction
block was higher (13 of 36 motor nerves in responders vs 6 of 53 in nonresponders, P = .008).
Conclusions Intravenous immunoglobulin therapy was beneficial in 8 (40%) of our
20 patients with polyneuropathy and IgG monoclonal gammopathy of undetermined
significance. Proximal leg weakness, short duration of symptoms, and demyelinating
features on electrodiagnostic studies were associated with a response to IVIG
therapy.
INTRODUCTION
THE POLYNEUROPATHY associated with monoclonal gammopathy of undetermined
significance (MGUS) is thought to be immune-mediated in some cases.1-3 The evidence for a connection
between MGUS and a neuropathy is strongest for those patients with an IgM
paraprotein; approximately half of these patients have antibodies directed
against epitopes on peripheral nerve myelin (eg, antimyelin-associated glycoprotein
antibodies).1-5
The relationship between IgG-MGUS and polyneuropathy is less certain, and
many of the latter cases have been considered indistinguishable from idiopathic
chronic inflammatory demyelinating polyneuropathy (CIDP).6-11
Although plasma exchange apparently has been effective in the polyneuropathy
associated with IgG-MGUS,12 the role of other
immunomodulating therapies has not been evaluated systematically. There have
been reports of patients improving with corticosteroid therapy, alone or in
combination with cytotoxic therapy, 13-16
and with intravenous immunoglobulin (IVIG).10-11,16
We reviewed our treatment experience with IVIG in patients with IgG-MGUS polyneuropathy
with attention to clinical, electrodiagnostic, and immunological features
that may have been associated with a response to treatment.
PATIENTS AND METHODS
PATIENT SELECTION
Clinical, laboratory, and electrophysiological information were collected
uniformly and reviewed retrospectively for consecutive patients with an IgG-MGUS
neuropathy who were seen by the Neuromuscular Service at St Elizabeth's Medical
Center, Boston, Mass, from January 1, 1992, through December 31, 2000 and
were treated with IVIG. Immunoelectrophoresis or immunofixation electrophoresis
with quantitation of serum immunoglobulins and  and  light
chains was obtained in all patients using a high-resolution agarose gel technique
according to the procedure described previously.17
Monospecific antisera to IgM, IgG, IgA, and and light chains
were used and immunoglobulins were quantified with nephelometry. The amount
of the IgG monoclonal protein was less than 3.0 g/L and the level of the paraprotein
remained stable on repeated testing in all patients. Serum autoantibodies
directed against myelin-associated glycoprotein, sulfatide, and GM1 were measured
in 19 patients. One patient had a low titer (1:2700) of antisulfatide antibodies;
in the remaining 18 patients, antibodies were not detected. Most patients
were evaluated by a hematologist (R.W.) and underwent a radiographic skeletal
survey, bone marrow aspirate and biopsy, fat pad biopsy, urine immunoelectrophoresis,
and chest and abdominal computed tomographic scans that excluded a plasma
cell dyscrasia and lymphoproliferative disorder, and none developed such a
condition at the time of last follow-up. Those with a history of concurrent
medical illnesses associated with polyneuropathy (eg, diabetes mellitus, nutritional
deficiencies, malignancy, human immunodeficiency virus infection, alcohol
dependence, or connective tissue diseases), medication or toxic exposures
known to cause neuropathy, or a family history of neuropathy also were excluded.
Eleven patients received 1 or more immunomodulating therapies before
treatment with IVIG: 7 were treated with plasma exchange, 4 with corticosteroids,
3 with azathioprine, and 2 with cyclophosphamide. Five patients improved transiently
but they developed a relapsing course, warranting a trial of an alternative
therapy (IVIG); the remainder failed to respond to therapy. None received
immunotherapy for at least 2 months prior to treatment with IVIG.
CLINICAL ASSESSMENT
Strength was assessed using the Medical Research Council (MRC) grading
scale (0-5 points) in 8 muscles in the arms and legs (ie, deltoid, extensor
digitorum communis, psoas, and tibialis anterior muscles, on both sides) with
a maximum possible MRC strength score of 40 points, comparable to previous
studies.7-8,13, 18-24
Vibration, joint position, and pinprick sensation were graded semiquantitatively
in the first distal interphalangeal and metatarsal joints bilaterally using
a modified version of the Neurological Impairment Scale as follows: 2 points,
normal; 1 point, reduced; and 0 points, absent. The presence of sensory ataxia
was assessed by the Romberg sign, graded as present (0 point), equivocal (swaying
with eyes closed but able to maintain balance for 5 seconds; 1 point), or
absent (2 points); the maximum possible sensory score was 26 points.7, 18-19,23-25
To assess the affect of the neuropathy on daily functional activities,
the modified Rankin Disability Scale was used, similar to prior neuropathy
studies,7-8,13, 17, 20-24
as follows: 0 indicates asymptomatic; 1, nondisabling symptoms that do not
interfere with daily activities; 2, slight disability, unable to carry out
all activities but still able to look after oneself; 3, moderate disability,
requiring assistance with some activities but able to walk without assistance;
4, moderately severe disability, unable to walk without assistance and unable
to attend to one's own bodily needs without assistance; and 5, severe disability,
totally dependent, requiring constant nursing care and attention.
ELECTROPHYSIOLOGICAL ASSESSMENT
Electrophysiological studies were performed at the time of initial evaluation
according to methods previously described.26
Motor conduction studies were performed using supramaximal percutaneous stimulation
with surface electrode recordings. Sensory nerve action potentials were recorded
following antidromic stimulation using ring (median and ulnar) or bar (sural)
electrodes; skin temperature was maintained at 32°C. The median, ulnar,
and peroneal motor nerves and median, ulnar, and sural sensory nerves were
sampled in most patients. Partial conduction block was defined as a 20% or
more baseline-to-peak amplitude reduction between proximal and distal sites
of motor nerve stimulation, excluding sites prone to compression.27 Needle electrode examination included sampling of
at least one distal and proximal muscle in the arm and leg, using a semiquantitative
assessment of motor unit potentials and abnormal spontaneous activity.
IVIG THERAPY
All patients were treated with at least 1 course of IVIG at a dosage
of 2 g/kg, administered over 2 to 5 days. Twelve patients received 1 course
of IVIG therapy, 3 received 2 courses, and 5 had 3 cycles of therapy (administered
monthly for 3 consecutive months). To assess a response to treatment, motor
and sensory scores and the modified Rankin Disability Scale score were determined
at the time of the maximum deficit before the initial treatment and at the
time of maximal improvement after IVIG therapy, or at the last follow-up for
patients who did not respond to IVIG therapy. Because most patients had a
predominantly sensory neuropathy, improvement was defined as an increase of
2 points or more in the motor or sensory score, and improvement of 1 point
or more in the modified Rankin Disability Scale score. Patients were classified
as treatment responders or nonresponders. The mean duration of follow-up was
44 months (median, 33 months; range, 4-144 months). Relapse after receiving
IVIG therapy was defined as worsening after improvement with a decline of
2 points or more in either the motor or sensory score, and increase (worsening)
of 1 point or more in the modified Rankin Disability Scale score.
STATISTICAL ANALYSIS
Intravenous immunoglobulin therapy responders were compared with nonresponders
to identify clinical, laboratory, or electrophysiological features that may
have been associated with a response to IVIG therapy. The Fisher exact test
(2-sided) was used to compare categorical responses and the Kruskal-Wallis
analysis of variance or Wilcoxon-matched sign rank test was used to compare
nonparametric ordinal and continuous variables. P .05
was considered statistically significant.
RESULTS
PATIENTS
There were 14 men and 6 women with a mean age of 65 years (age range,
36-82 years). The average duration of symptoms prior to treatment with IVIG
was 27 months (range, 1-120 months). Most had a preponderantly sensory polyneuropathy
with reports of numbness (17 patients), gait unsteadiness (16 patients), paresthesias
(14 patients), and neuropathic pain (9 patients). Fifteen reported weakness
in the hands (9 patients) or legs (15 patients).
RESPONSE TO IVIG THERAPY
The initial mean MRC score was 35.6 points and the follow-up score improved
by an average of 1.1 points (follow-up mean MRC score, 36.7 points; P = .22, Table 1).
The MRC score improved by 2 or more points in 7 patients, remained unchanged
in 7, and worsened in 6 after IVIG therapy (Table 2). The initial mean sensory score was 15.8 points and improved
by an average of 1.7 points (follow-up mean sensory score, 17.5 points; P = .11). The sensory score improved by 2 points or more
in 9 patients, was unchanged in 7, and worsened in 4 (Table 2).
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Table 1. IgG-MGUS Polyneuropathy: Response to IVIG Therapy*
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Table 2. IgG-MGUS Polyneuropathy: Clinical Features
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Eight patients (40%) had a 2-point or greater improvement in either
the sensory or motor score, and all 8 had a 1-point or greater improvement
(reduction) in the modified Rankin Disability Scale score, and were, therefore,
classified as IVIG therapy responders (Table 2 and Table 3).
These patients had a shorter duration of symptoms at the time of the initial
evaluation (mean, 7 months vs 41 months for nonresponders, P = .03), and more often reported numbness in the hands and episodes
of falling (Table 3). The IVIG
therapy responders also had greater proximal leg weakness (mean psoas MRC
score, 3.9 points vs 4.8 points for nonresponders, P
= .02) prior to therapy. In the IVIG responder group, the mean MRC score improved
by 4.4 points (vs -1.1 points in nonresponders, P<.001), and the mean sensory score improved by 6.5 points (vs -1.4
points for nonresponders, P<.001, Table 3).
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Table 3. IgG-MGUS Polyneuropathy: IVIG Therapy Responders vs Nonresponders*
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The 12 patients who had only 1 IVIG infusion had a mean improvement
of the MRC score of 2.7 points compared with a mean decrease of 1.3 points
in those who received 2 or 3 infusions (P = .01).
Similarly, the mean sensory score increased by 3.5 points in patients who
received 1 infusion compared with a mean reduction of 0.9 points in patients
who received 2 or 3 infusions (P = .03).
ELECTRODIAGNOSTIC AND LABORATORY FEATURES
Several electrodiagnostic abnormalities were associated with a response
to IVIG therapy (Table 4). In
those who responded to IVIG therapy, the mean ulnar motor amplitude was lower,
the ulnar conduction velocity was substantially slower, the ulnar and peroneal
motor distal latencies were prolonged, and the frequency of conduction block
was higher (Table 4). Sensory
nerve action potentials were frequently absent in both groups.
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Table 4. IgG-MGUS Polyneuropathy: Nerve Conduction Studies*
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Nine patients had at least 1 demyelinating abnormality on electromyographic
(EMG) studies. Using strict research criteria for the diagnosis of CIDP,27 we found that only 2 patients fulfilled criteria
for definite CIDP (clinical, electrodiagnostic, cerebrospinal fluid, and nerve
biopsy requirements), and neither improved with IVIG therapy, although both
also had substantial axon loss seen on EMG and in nerve biopsy specimens.
Three patients had probable CIDP (a nerve biopsy specimen was not obtained
but all other criteria were satisfied), and all improved after IVIG therapy;
2 others had possible CIDP (the result of a cerebrospinal fluid sample was
normal or a lumbar puncture was not performed, neither had a nerve biopsy
specimen obtained, but clinical and EMG criteria were satisfied), and both
responded to IVIG therapy. Two others had a mixed axonal and demyelinating
polyneuropathy that did not satisfy EMG criteria for CIDP, and neither patient's
condition improved with treatment. In summary, 7 patients fulfilled the criteria
for possible or probable CIDP (lacking cerebrospinal fluid or biopsy material
to qualify for definite CIDP), and 5 (71%) improved with IVIG therapy.
Three IVIG therapy responders (patients 5, 9, and 12, Table 2) had an axonal neuropathy. In 2, gait disorder was the primary
problem, with imbalance and sensory ataxia related to impaired proprioception
and the presence of the Romberg sign that improved after receiving IVIG therapy.
One patient had distal, symmetric sensory loss and pain in the feet and legs
that resolved after receiving IVIG therapy. Electrodiagnostic studies showed
slightly reduced motor amplitudes in the legs, mild slowing of conduction
velocities, little or no denervation potentials in distal leg muscles, and
absent sural sensory potentials. There were no demyelinating features.
There were no differences in the mean amount of the IgG monoclonal protein
(IVIG therapy responder group, 1.4 g/L; IVIG nonresponder group, 1.3 g/L, P = .75) or cerebrospinal fluid protein concentration (IVIG
therapy responder group, 0.77 g/L; IVIG nonresponder group, 0.52 g/L, P = .56).
TIMING OF IMPROVEMENT, RELAPSE AFTER RECEIVING IVIG THERAPY, AND FOLLOW-UP
In those who responded to IVIG therapy, we observed the onset of improvement
a mean of 3 weeks (range, 1-8 weeks) after receiving IVIG treatment, with
maximum improvement after an average of 6 weeks (range, 2-12 weeks). Six patients
in the IVIG therapy responder group developed a relapsing course and required
periodic maintenance therapy. The mean time to relapse for these patients
was 9 weeks (range, 2-16 weeks, Table 2). The remaining 2 patients (patients 5 and 10, Table 2) had sustained improvement of their condition at the most
recent follow-up (range, 22-48 months).
Three of 12 patients in the nonresponder group have remained stable
at last follow-up and have not received further therapy. The remaining 9 patients
had slowly progressive motor or sensory deficits.
COMMENT
There have been only a few case reports or small case series alluding
to the efficacy of IVIG therapy in patients with IgG-MGUS associated polyneuropathy.10-11,16, 28 Our
systematic review of a larger number of patients indicates that approximately
40% responded to IVIG therapy. The treatment had a positive effect in the
activities of daily living of the 8 patients who responded to IVIG therapy,
as measured by an improved modified Rankin Disability Scale score, and corroborated
by increased strength and sensory scores after receiving therapy compared
with the nonresponders. The improvement we observed in this group of patients
is similar to that of others.10-11,16
Hermosilla et al11 also noted significant clinical
improvement in 4 of 5 patients with IgG-MGUS–associated demyelinating
neuropathy who were treated with IVIG, although most developed a long-term,
relapsing course, comparable to that of most of our patients who responded
to IVIG therapy. Other reports have indicated that the neuropathy of an additional
5 patients improved following treatment with IVIG, but further details were
not provided.10, 16
Data provided in Table 1
suggest that IVIG therapy was not effective in producing statistically significant
improvement in the mean motor or sensory scores of the entire cohort. However,
although ours is the largest report of patients with IgG-MGUS who were treated
with IVIG, the sample size of 20 patients is small and, therefore, clinically
meaningful effects in some patients may be obscured by larger group analysis.18 This only can be clarified by appropriately powered,
prospective studies.
Although both motor and sensory scores improved in the subset of patients
who responded to IVIG therapy, the magnitude of improvement was greatest for
the sensory score. This probably reflects the nature of IgG-MGUS neuropathy
as a preponderantly sensory condition in most patients, rather than a selective
effect of IVIG therapy on sensory nerve function.2, 6, 8-9,14-15
To our knowledge, the relationship of the clinical presentation to the
response to IVIG therapy has not been emphasized previously. We found that
the duration of the neuropathy was considerably longer, on average, in those
who failed to improve with IVIG therapy; this may reflect progressive axon
loss and the likelihood of irreversible nerve injury as the condition advances.
Indeed, patients with greater degrees of demyelination reflected by EMG studies
were more likely to improve with IVIG therapy (see below). Accordingly, our
data suggest that patients with a progressive IgG-MGUS neuropathy may benefit
from early therapy with IVIG, although this also requires confirmation with
prospective trials.
Our experience also suggests that patients who responded to IVIG therapy
did so soon after the first infusion; maximum improvement for the motor and
sensory scores was greater for those patients who had 1 infusion compared
with patients who had 2 or 3 infusions. It may be that those who did not respond
to the first course were simply less likely to respond to additional infusions,
perhaps due to associated axonal degeneration. The timing of improvement in
the IVIG therapy responders is comparable to what has been reported in patients
with CIDP.29 However, 6 of the 7 patients who
improved after 1 infusion developed a relapsing course, and it may be that
patients with demyelinating neuropathies and IgG-MGUS are more likely to respond
to treatment with IVIG early (ie, after a single infusion) and require periodic
retreatment due to relapse.
Although most of our patients who responded to IVIG therapy had a demyelinating
neuropathy, it is of some interest that 3 IVIG therapy responders had electrodiagnostic
features of an axonopathy. Clinically, 2 had a large-fiber, sensory ataxic
neuropathy, and 1 has developed a long-term relapsing course requiring periodic
treatment with IVIG every few months. The timing and degree of improvement
is inconsistent with axonal regeneration, and we can only speculate about
the nature of the clinical response. We did not obtain nerve biopsy specimens
in these patients and, therefore, cannot exclude a demyelinating sensory polyneuropathy
or polyradiculoneuropathy, similar to prior reports.8, 30-33
Most such cases have little or no weakness but demyelinating abnormalities
are found on motor nerve conduction studies, and the diagnosis is usually
confirmed by sensory nerve biopsy specimens demonstrating pathological features
of demyelination.30-33
We postulate that our axonal cases represent a sensory ataxic polyradiculoneuropathy
due to sensory nerve demyelination with loss of the sural sensory nerve action
potential, comparable to the sensory ataxic variant of CIDP that has been
reported to be steroid responsive.32-33
The patients whose conditions improved with IVIG therapy had more frequent
falls at baseline, probably as a consequence of more severe proximal leg weakness
compared with the nonresponders. These observations, along with a higher frequency
of reports of hand numbness, are clinical features that have been commonly
associated with an acquired demyelinating polyneuropathy.26, 34
In the IVIG therapy responder group, 4 of 10 nerve conduction parameters indicated
more severe demyelination compared with nonresponders: specifically, the average
ulnar motor nerve conduction velocity was slower, ulnar and peroneal distal
motor latencies were more prolonged, and the frequency of motor nerve conduction
block was higher. Indeed, we found that 5 (62%) of the 8 IVIG therapy responders
fulfilled strict EMG research criteria for CIDP.27
In contrast, there was no relationship between the amount of the IgG protein
and a response to IVIG therapy. Demyelinating features on EMG studies may
be more relevant than the presence of an IgG monoclonal protein for predicting
a response to IVIG therapy.
Several investigators have suggested that there are few salient features
that distinguish IgG-MGUS neuropathy from idiopathic CIDP.6, 8-10
Both disorders are associated with sensory and motor deficits (although sensory
features seem to predominate in patients with MGUS), a progressive or relapsing
course, demyelinating changes on electrophysiological and pathological studies,
and improvement following treatment with corticosteroids, plasma exchange,
or IVIG.1-3,6-12,14-15,28, 35
The rate of response to IVIG therapy in our patients with IgG-MGUS is comparable
to patients with idiopathic CIDP.8, 29, 35-36
Although proximal and distal limb weakness has been considered a characteristic
feature of CIDP and generally distinguishes these patients from those with
demyelinating IgG-MGUS polyneuropathy,34 as
previously noted, pure sensory variants of CIDP also have been recognized,
making distinction from patients with IgG-MGUS difficult in individual cases.8, 30-33
We conclude that in patients with a polyneuropathy and IgG monoclonal protein,
IVIG therapy is a reasonable alternative to plasma exchange.
AUTHOR INFORMATION
Accepted for publication January 31, 2001.
Author contributions: Study concept and design (Drs Gorson, Ropper, Weinberg, and Weinstein); acquisition
of data (Drs Gorson, Ropper, and Weinstein); analysis
and interpretation of data (Drs Gorson, Weinberg, and Weinstein); drafting of the manuscript (Dr Gorson); critical
revision of the manuscript for important intellectual content (Drs Gorson, Ropper, Weinberg, and Weinstein); statistical expertise (Dr Gorson); obtained funding (Dr Gorson); administrative, technical, and material support (Drs Gorson, Ropper, and Weinstein); study supervision (Drs Gorson, Ropper, Weinberg, and Weinstein).
We thank Alan Pestronk, MD, Washington University, St Louis, Mo, for
measuring the serum autoantibodies directed against myelin-associated glycoprotein,
sulfatide, and GM1 in 19 patients.
Corresponding author: Kenneth C. Gorson, MD, Division of Neurology,
St Elizabeth's Medical Center, 736 Cambridge St, Boston, MA 02135 (e-mail: KGorson{at}aol.com).
From the Divisions of Neurology (Drs Gorson, Ropper, and Weinberg)
and Hematology (Dr Weinstein), St Elizabeth's Medical Center, Tufts University
School of Medicine, Boston, Mass.
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