Diabetic Demyelinating Polyneuropathy Responsive to Intravenous Immunoglobulin Therapy FREE

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 CIDP^{24 - 26} ), we performed a prospective open-label pilot study of IVIG therapy in patients with DM-CIDP.

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}

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).

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.

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 χ² 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.

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.

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.

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.

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%).

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.

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).

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.

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 others^{43 - 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.

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@med.miami.edu).