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Diabetic Demyelinating Polyneuropathy Responsive to Intravenous Immunoglobulin Therapy
Khema R. Sharma, MD;
John Cross, MD;
D. Ram Ayyar, MD;
Alberto Martinez-Arizala, MD;
Walter G. Bradley, DM, FRCP
Arch Neurol. 2002;59:751-757.
ABSTRACT
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Background There is growing evidence that idiopathic chronic inflammatory demyelinating
polyneuropathy (CIDP) and polyneuropathy in patients with diabetes mellitus
(DM) that meets the electrophysiological criteria for CIDP (DM-CIDP) have
many similarities.
Objective To evaluate whether DM-CIDP responds to intravenous immunoglobulin (IVIG)
therapy.
Patients and Methods Twenty-six patients (mean [SD] age, 64 [8.9] years; age range, 40-80
years) with type 2 DM (n = 25), who met the electrophysiological criteria
for CIDP, were given IVIG therapy (400 mg/kg body weight per day for 5 days)
in a prospective open-label pilot study. All patients had quantitative evaluation
using the Neuropathy Impairment Score at baseline and at the end of 4 weeks
from the initiation of IVIG therapy.
Results The mean Neuropathy Impairment Score improved significantly from baseline
(mean [SD], 61.5 [26.0] points) to the end of the fourth week (33 [29.6] points; P<.00l). This clinically significant improvement occurred
in 21 (80.8%) of the 26 patients. Conduction block occurred in 11 (42.3%)
of the 26 patients; improvement in the Neuropathy Impairment Score was more
frequent in patients who had a conduction block (11 of 11 patients) than in
those who did not (10/15 [66.7%]; P = .03). Adverse
reactions to IVIG included reversible renal dysfunction in 3 patients, flulike
symptoms in 5, headache in 5, and chest pain and shortness of breath in 1.
Conclusion Although IVIG therapy seemed to improve DM-CIDP in this uncontrolled
trial, a controlled trial is required for confirmation of our findings.
INTRODUCTION
WE HAVE recently reviewed previous reports of the occurrence of demyelination,
as detected by electrophysiological (EP) studies, in diabetes mellitus (DM)
and have shown that 11.8%1 to 18%2-3
of the patients with DM met the EP criteria for chronic inflammatory demyelinating
polyneuropathy (CIDP). We found that 18% of the patients with DM met the EP
criteria for CIDP. The odds of the occurrence of CIDP were 11 times higher
in diabetic subjects than in nondiabetic subjects. We also found that the
odds for the occurrence of DM among patients with CIDP were more than 20 times
higher than in patients with myasthenia gravis, and in those with amyotrophic
lateral sclerosis.2-3
We have also reviewed the immunological features of neuropathies associated
with DM.3-21
Immunotherapy, including intravenous immunoglobulin (IVIG), has been reported
to be effective in some patients with several types of diabetic neuropathy.8-9,12-14,17-21
Based on these reports, and the fact that IVIG therapy has been used effectively
in several immune-mediated diseases (Guillain-Barré syndrome,22 dermatomyositis,23
and CIDP24-26),
we performed a prospective open-label pilot study of IVIG therapy in patients
with DM-CIDP.
PATIENTS AND METHODS
PATIENT SELECTION
Patients with DM and a demyelinating polyneuropathy fulfilling the EP
criteria for CIDP27 were recruited prospectively
between April 1, 1997, and October 31, 2000, at the University of Miami–Jackson
Memorial Medical Center. The diagnosis of DM-CIDP was established by (1) the
presence of insulin- or noninsulin-dependent DM28;
(2) the presence of a chronic, progressive, or relapsing, motor, sensory,
or sensory-motor polyneuropathy of at least 2 months' duration associated
with hyporeflexia or areflexia; and (3) EP criteria for demyelinating neuropathy
as defined by the American Academy of Neurology Ad Hoc Subcommittee AIDS Task
Force 1991,27 except that the criteria for
partial conduction block were more stringent, as recommended by the American
Association of Electrodiagnostic Medicine29
and other investigators.18, 30
Details of the clinical and EP features of these patients are described elsewhere.3 In brief, nerve conduction and electromyographic studies
were performed in at least 3 limbs, which included one affected and the contralateral
limb, using standard techniques. We measured motor nerve conduction and corresponding
F waves in 4 or more of the following nerves: tibial, peroneal, median, ulnar,
radial (near nerve needle stimulation), and sciatic (near nerve needle stimulation).
Needle electromyography was performed in affected limbs.
Patients with diabetic amyotrophy or lumbosacral plexopathy were excluded.
Similarly, patients with typical diabetic chronic distal sensory neuropathy
were excluded, except for those who developed new symptoms of progressive
weakness involving proximal and distal muscles. Patients with concomitant
disease (cancer, hepatitis, kidney failure, Lyme disease, paraproteinemia,
other preexisting endocrinopathies, connective tissue disorder, vitamin B12 and folic acid deficiency, heavy metal toxic reactions, and human
immunodeficiency virus infection) were excluded. No patient had a family history
of neuropathy.
All patients had screening laboratory studies, including anti-GM1 and
anti-MAG antibody titers and a glycosylated hemoglobin level. Cerebrospinal
fluid sample studies, including cell count (including mononuclear and polymorphonuclear
cells and cytology for malignancy), glucose level, protein level, and IgG
index, were obtained in 24 patients and were increased in all but 1 patient.
No patient underwent a nerve biopsy. We did not require either an examination
of the cerebrospinal fluid or a nerve biopsy specimen for the diagnosis of
DM-CIDP; unlike requirements for idiopathic CIDP,27
since the main focus of this study was on the EP abnormalities and clinical
profile of these patients. The cerebrospinal fluid protein concentration is
increased in a substantial proportion of patients with other types of diabetic
neuropathy (axonal neuropathy or lumbosacral plexopathy).9, 11-12
Sural nerve biopsy specimen abnormalities as criteria for demyelination lack
sensitivity and specificity (40%-50%).31-32
STUDY DESIGN
The study was a 4-week, open-label pilot study. Patients were examined
by the same neurologist at study enrollment and at 4 weeks after treatment
with IVIG, which was given at a dose of 400 mg/kg body weight per day for
5 days. Each participant signed an informed consent form. After completion
of the clinical trial, patients were seen every few months, with a mean follow-up
of 25 months (range, 1-42 months).
NEUROLOGICAL EVALUATION
All patients had quantitative evaluation using the Neuropathy Impairment
Score (NIS)33 at baseline, at the end of 4
weeks of IVIG therapy, and at the subsequent follow-up visits. The NIS summates
the deficits in strength, sensation, and reflexes that are found on neurological
examination. Deficits in strength were scored from 1 (25% deficit) to 4 (100%
deficit); deficits in sensation and reflexes were scored as 0 (no deficit),
1 (decreased function), or 2 (absent function). The neuropathy severity (based
on the NIS) was graded as mild with an NIS of 15 to 25 points; moderate with
an NIS of 26 to 50 points; and severe with an NIS of 51 points or higher.
STATISTICAL ANALYSIS
Stat View II (Abacus Concepts Inc, Berkeley, Calif) was used for data
analysis. We determined the statistical significance of differences between
categorical variables using a  2 or Fisher exact test as appropriate
and for differences, continuous variables using a 2-tailed t test. The primary outcome measure in this study was changes from
baseline to 4 weeks in the mean NIS. We defined the criteria indicating improvement
as more than a 5-point decrease in the NIS.34-35
All data are expressed as mean value (SD). These data were adjusted for multiple
comparisons (Bonferroni correction). Statistical significance for all analyses
was defined as P<.05.
RESULTS
CLINICAL FEATURES
Sixteen men and 10 women with a mean age of 64 (8.9) years (age range,
40-80 years) were enrolled in the study (Table 1). All except 1 patient had adult-onset type 2 DM (disease
duration, 13.2 [11] years; range, 0-35 years), which required insulin therapy
in 2 patients, a combination therapy of insulin and oral hypoglycemic agents
in 6 patients, oral hypoglycemic agents in 16 patients, and diet control alone
in 2 patients.27 The mean neuropathic symptoms'
duration in these patients was 24 (2.9) months (range, 2-240 months). One
patient had an unsuccessful course of corticosteroid therapy for 2 months
given 4 weeks prior to participation in this study; the remaining patients
had not been previously treated with any immunotherapy. All of the patients
had good control of DM in the preceding months, with no change in medication
or in the percentage of glycosylated hemoglobin. Seventeen (65.4%) of the
26 patients had vascular complications. These include retinopathy in 6 patients,
mild nephropathy in 3, peripheral vascular disease in 3, coronary artery disease
in 3, hypertension in 12, and previous cerebrovascular accident in 2, occurring
6 and 12 months prior to enrollment in this study. Five (4 patients with type
2 DM) (19.2%) of the 26 patients had mild to moderate autonomic dysfunction
(erectile dysfunction, 4 patients; gastroparesis, 1 patient). Four patients
(all having type 2 DM) had preexisting predominantly sensory peripheral neuropathy
of 4 to 7 years' duration before the onset of the new symptoms of progressive
weakness of extremity muscles.
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Table 1. Clinical Features and Laboratory Data of 26 Patients With
Diabetes Mellitus (DM) and Chronic Inflammatory Demyelination Polyneuropathy*
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The main clinical features (Table
1) were worsening limb weakness (23 patients), sensory symptoms
(all patients), pain (12 patients), and poor balance (2 patients). Almost
all patients had weakness in both upper and lower limbs, and of those patients
almost half had the typical proximal more than distal weakness of CIDP.
The mean motor deficit score was 36.5 (19.8) (range, 10-83). The combined
(sensory and motor deficit) mean NIS was 59.6 (26.7) points (range, 25-125
points). The spectrum of neuropathy severity in our patients varied from mild
(1 patient), to moderate (9 patients), to severe (16 patients), with 8 patients
(30.8%) able to walk without aids, 5 patients (19.2%) able to walk only with
aids, and 13 patients (50%) unable to walk.
EP RESULTS
Nerve conduction study findings are summarized in Table 2. All patients fulfilled at least 3 of the 4 criteria for
demyelination, but there was a wide range of EP abnormalities (Table 3). A total of 148 motor nerves were examined (Table 2, which excludes details about the 2 facial nerves; Table 3). Distal latencies were prolonged
in 82 (55.4%) of the 148 nerves tested, conduction velocity was slowed in
89 (60.1%), and F waves were prolonged or absent in 112 (75.7%; Table 3). Conduction block was demonstrated in at least 1 nerve
in 11 patients (42.3%; Table 3).
Temporal dispersion was observed in at least 1 nerve in 10 patients (38.5%);
and 4 of these patients with temporal dispersion also had associated conduction
block (Table 3). An abnormality
of the sural sensory nerve was present in all patients (slowed conduction
velocity in 7 patients, decreased amplitude in 3 patients, and absent response
bilaterally in 16 patients; Table 3).
The tibial motor potential was absent in 23.8% of those nerves tested, and
the peroneal potential was absent in 40.0% of those nerves tested (Table 3). The mean summated compound muscle
action potential amplitude (normalized for number of nerves studied in a patient)
was higher in patients with conduction block (4.9 [1.8] µV) than in
those without conduction block (4.0 [1.7] µV, P
= .05). There was no difference in motor deficit score between patients with
conduction block (36.9 [19.4] mV) and those without (36.0 [20.9] mV, P = .90). Conduction block occurred equally among patients
with mild, moderate, or severe neuropathy. Needle electromyographic examination
was performed in the affected limbs in all patients and it revealed subacute
to chronic neurogenic changes.
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Table 2. Electrodiagnostic Study Results*
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Table 3. Summary of Abnormal Nerve Conduction Findings*
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RESPONSE TO IVIG THERAPY
The average NIS of the 26 patients improved significantly from baseline
(59.6 [26.7] points; range, 25-125.0 points) to 4 weeks after IVIG therapy
(33.0 [29.6] points; range, 3-119 points; P<.001).
The changes in the NIS for individual patients are shown in Figure 1. The improvement in NIS (motor component) was observed
on the third day of treatment in 3 patients (11.5%), on fifth day of treatment
in 4 patients (15.4%), and after the completion of the 5-day IVIG course in
the remaining patients. In 21 (80.8%) of the 26 patients the improvement in
NIS was more than 5 points after 4 weeks. Of the remaining 5 patients, 1 patient's
score improved by 5 points, 1 by 4 points, 2 had no change, and 1 had a decrease
of 6 points. There was significant (P = .01) improvement
in lower limb motor function 4 weeks after IVIG therapy compared with baseline
as indicated by the number of patients in the following groups: able to walk
without aid (13 [50%] of the 26 patients at 4 weeks vs 30.8% at baseline),
requiring an aid to walk (10 [38.5%] of the 26 patients vs 19.2% at baseline),
and requiring a wheelchair (3 [11.5%] of the 26 patients vs 50% at baseline).
A greater proportion of patients who had a conduction block (11 of 11 patients)
showed an improvement in NIS in response to the IVIG therapy than of those
who did not have a conduction block (10 of 15 patients; P = .03). Similarly relapses occurred less in the responders who had
a conduction block (1 [9.1%] of 11 patients) than in responders who did not
have a conduction block (5 [50.0%] of 10 patients; P
= .04). There was no difference in the IVIG therapy responders and nonresponders,
or in those who relapsed, for age, sex, duration of DM, duration of neuropathic
symptoms, cerebrospinal fluid protein concentration, percentage of glycosylated
hemoglobin, and NIS. There was no difference in the mean percentage of glycosylated
hemoglobin between baseline (8.3% [2.1%]; range, 5.8%-13.5%) and 4 weeks after
IVIG therapy (8.7% [2.2%]; range, 5.4%-12.8%).
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Note the changes in the Neuropathy Impairment Score (NIS, on vertical
axis; NIS 0, denotes normal neurological examination) from baseline (0 weeks,
on horizontal axis) to the end of 4 weeks of therapy.
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ADVERSE EVENTS
Intravenous immunoglobulin therapy was generally well tolerated. Three
patients (11.5%) developed a reversible decrease in renal function. The serum
creatinine level increased from 0.7 to 2.1 mg/dL (62-186 µmol/L) on
the third day of the treatment in 1 patient, and from 1.4 to 2.4 mg/dL (12-212
µmol/L), and from 1.5 to 2.9 mg/dL (133-256 µmol/L) on the fourth
day of the treatment in the other 2 patients. In all patients the serum creatinine
levels returned to normal with fluid therapy. In one such patient the subsequent
IVIG daily dose was reduced to 200 mg/kg body weight per day, allowing the
IVIG to be given over a longer period. The other 2 patients underwent plasma
exchange of about 2.5 L every other day to complete the 5 treatments, in place
of IVIG therapy (details of the response to plasma exchange are described
in the 2 subsections of the "Observations During Follow-up" section). Other
adverse effects included flulike symptoms in 5 patients, headache in 5, and
chest pain and shortness of breath in 1.
OBSERVATIONS DURING FOLLOW-UP
Responders With or Without Relapse
Twenty-one (80.8%) of the 26 patients who responded to IVIG treatment
were followed up for a mean duration of 26 (10.6) months (range, 1-42 months).
Fifteen of the patients had no relapse of DM-CIDP and required no further
immunotherapy. Six patients had a relapse of DM-CIDP from 9 to 19 months after
the initial IVIG treatment, 1 of whom had a further relapse at 24 months after
the initial course of IVIG therapy. Relapses were less frequent in patients
with a shorter duration of neuropathic symptoms (nonrelapsers, 11.9 [10.2];
range, 2-36 months vs relapsers 35.8 [26.9]; range, 4-84 months; P = .007), and in those who had a conduction block (relapsers 1 [9.1%]
of 11 who had a conduction block vs relapsers 5 [50.0%] of 10 who did not
have a conduction block; P = .04).
Four of the patients had a second course of IVIG therapy for the relapse;
3 had a good response (NIS improvement, 62-41 points; 60-25 points; and 38-12
points), and 1 had a poor response (87-74 points, compared with the response
to the first treatment of 79-34 points). The other 2 patients who relapsed
were treated with plasma exchange because of impaired renal function and their
conditions improved (NIS, 46-33 and 49-29 points). One of the patients who
had received 2 courses of IVIG had a further relapse and received plasma exchange
rather than IVIG therapy because of impaired renal function, and this patient's
condition improved (NIS, 58-22 points).
Nonresponders to IVIG Treatment
Two patients had plasma exchange (5 exchanges given 1 every other day)
and oral prednisone (60 mg/d) after the failure of the initial IVIG therapy,
and their conditions improved slightly (NIS, 29-24 and 76-72 points). Of the
remaining 3 nonresponders, 2 did not respond to a combination of plasma exchange
and oral corticosteroid therapy; the third patient declined further treatment
and the NIS worsened from 56 to 62 points.
COMMENT
The main findings of this prospective open-label pilot trial of IVIG
in patients with demyelinating polyneuropathy were (1) a clinically significant
improvement in neurological functions occurred in most of the patients (80.8%)
by the end of the fourth week of therapy; (2) improvement in neurological
functions was more frequent in patients who had a conduction block than in
those who did not; (3) 6 (28.6%) of 21 responders had a relapse of the neuropathy
9 to 19 months after the initial IVIG therapy; and relapses occurred less
in patients who had a conduction block and a shorter duration of neuropathy;
and (4) most of the patients with relapses responded to further immunotherapy.
Our study was an uncontrolled trial of IVIG in patients with demyelinating
neuropathy meeting the EP criteria for the diagnosis of CIDP. We and others
have advanced strong evidence that CIDP occurs much more frequently in DM
than would be expected by chance.1-3
The relative frequency of CIDP compared with that of other types of neuropathy
in patients with DM will remain unclear until a clinical and EP epidemiological
study is undertaken on a large cohort of patients with DM. However, we have
the impression that clinically significant CIDP is a sufficiently common occurrence
in patients with DM that it should be considered in the differential diagnosis
of any diabetic patient with a worsening, relatively severe neuropathy, particularly
where there is major motor involvement.
It has been established by both uncontrolled and controlled trials that
idiopathic CIDP responds to various forms of immunotherapy, including IVIG.13, 18, 24-26
The mechanism of action of IVIG in treating the autoimmune disorders is uncertain.
Proposed mechanisms include the neutralization of the pathogenic antibodies
by anti-idiotype antibodies,36 attenuation
of complement-mediated tissue damage,37 and
saturation or functional blockade of Fc receptors on macrophages that are
the major effectors of demyelination.38-40
Other mechanisms may include the functional modulation of T lymphocytes and
their production of proinflammatory cytokines,41
and the binding of anti-idiotypic antibodies to antigen receptors on B cells,
thus decreasing autoantibody production.42
It is likely that several of these mechanisms contribute to the short-term
and long-term effects of IVIG therapy in many autoimmune diseases. The results
presented in this article support the contention that DM-CIDP responds as
well as idiopathic CIDP to IVIG therapy, although a controlled trial will
be needed to prove this.
Although IVIG therapy has been found to be safe and effective in most
patients with diabetic demyelinating neuropathy in several reports, including
this study,12-14,17-21
as it has in patients with other autoimmune neuromuscular disorders,22-26
we concur with Hahn et al25 and others43-44 that the potential risks of IVIG
therapy have to be considered carefully in diabetic patients. These risks
include aggravation of abnormal renal function, and precipitation of cardiovascular,
cerebrovascular, and thromboembolic events, particularly in elderly diabetic
patients. The total cost of each course of IVIG therapy (approximately $10 000-$15 000
per patient) also has to be considered. For these reasons we believe it is
important that the frequency of CIDP in DM be clarified, that the diagnosis
of DM-CIDP by EP investigations be based on the strict criteria outlined above,
and that a controlled trial of IVIG therapy for DM-CIDP be undertaken.
AUTHOR INFORMATION
Accepted for publication October 19, 2001.
Author contributions: Study concept and design (Dr Sharma); acquisition of data (Drs Sharma, Cross, Ayyar, and
Martinez-Arizala); analysis and interpretation of data (Drs Sharma,
Martinez-Arizala, and Bradley); drafting of the manuscript (Drs
Sharma, Cross, and Bradley); critical revision of the manuscript for
important intellectual content (Drs Sharma, Ayyar, Martinez-Arizala,
and Bradley); statistical expertise (Dr Sharma); administrative,
technical, and material support (Drs Sharma, Cross, Ayyar, Martinez-Arizala,
and Bradley); study supervision (Drs Sharma and Bradley).
This study was presented in part at the 51st Annual Meeting of the American
Academy of Neurology, Toronto, Ontario, April 20,1999.
We thank Regina Menendez-Choy for help in preparing the manuscript.
Corresponding author: Khema R. Sharma, MD, Department of Neurology,
University of Miami School of Medicine, 1150 NW 14th St, Room 603, Miami,
FL 33136 (e-mail: ksharma{at}med.miami.edu).
From the Department of Neurology, University of Miami School of Medicine,
Miami, Fla.
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