The Efficacy Of Intravenous Immunoglobulin Therapy In Treatment Induced Neuropathy Of Diabetes

Treatment induced neuropathy of diabetes (TIND), also referred to as insulin neuritis, is
thought to be a rare iatrogenic cause of neuropathy that occurs in the setting of rapid
glycemic control in individuals with a history of prolonged hyperglycemia.

In a recent paper, the investigators reported that a systematic review of all patients seen
in a tertiary diabetic neuropathy referral center resulted in the diagnosis of TIND in >10%
of patients seen over a 5 year period of time. These individuals developed symptoms of
neuropathy as a consequence of a sudden improvement in glycemic control. The neuropathy
associated with TIND is a painful small fiber and autonomic neuropathy of acute onset, but is
also associated with the simultaneous development of retinopathy and nephropathy.

TIND differs from the most prevalent generalized neuropathy of diabetes, the distal
sensory-motor polyneuropathy, in several respects. The neuropathic pain has an acute onset,
appearing within 8 weeks of glycemic change in contrast to the more insidious onset in the
Diabetic sensorimotor polyneuropathy (DSP). The pain in TIND is more severe, and poorly
responsive to interventions including opioids, whereas most patients with DSP respond to
non-opioid interventions. Although the distribution of the pain is length dependent in
individuals with TIND, it is frequently far more extensive than in DSP and the associated
allodynia and hyperalgesia are much more prevalent. Autonomic symptoms and signs are common,
prominent and appear acutely, in contrast to the relatively lower prevalence, gradual onset
and slow progression in DSP. Finally, both the pain and autonomic features may be reversible
in some patients.

The pathogenic mechanisms whereby this change in glucose results in nerve damage and/or
dysfunction are not known. Proposed mechanisms include endoneurial ischemia due to epineurial
arterio-venous shunts, apoptosis due to glucose deprivation, microvascular neuronal damage
due to recurrent hypoglycemia and ectopic firing of regenerating axon sprouts, but these
possibilities are unproven. A potential role for inflammation as a cause of TIND is supported
by studies showing an increase in pro-inflammatory cytokines provoked by experimental
hypoglycemia. This is reinforced by the association of hyperalgesia with prior exposure to
hypoglycemia.

Other microvascular complications are commonly seen in patients with TIND. The simultaneous
development of TIND, retinopathy and nephropathy in our cohort suggests a common systemic
mechanism likely resulting in microvascular disease. Prior reports of 'early worsening
retinopathy' associate a greater risk of retinopathy development with every percentage point
decrease in the glycosylated hemoglobin, a result that parallels the neuropathy development
in TIND. Furthermore, a link between hypoglycemia, production in pro-inflammatory cytokines,
and the development of retinopathy has been proposed.

Treatment induced neuropathy is an iatrogenic cause of an acute, painful autonomic neuropathy
in patients with poor glycemic control. Although the underlying mechanism is not yet known,
there is a clear relationship between a rapid rate of glycemic control and the development of
microvascular complications. Our preliminary data on upregulation of cytokines in individuals
with TIND, and the similar findings noted in early worsening retinopathy, suggest the
possibility that early intervention may improve outcomes.

The investigators have studied over 100 individuals with TIND in a longitudinal fashion. The
characteristic disease progression is well described and related to the magnitude of the
change in HbA1c. All patients develop severe neuropathic pain and progressive small fiber and
autonomic neuropathy. The neuropathy progresses over 18-24 months and then may gradually
improve.

The investigators have studied 4 patients with TIND that developed the acute onset of
autonomic and peripheral neuropathy in the setting of rapid glycemic control. All 4
individuals had regular detailed neurological examinations, skin biopsy analysis of nerve
fiber density, autonomic function testing and retinal examinations.

Within 4 weeks of the onset of neuropathic pain (within 8 weeks of the change in glucose
levels), they were offered a trial of immune globulin administration at a dose of 2grams/kg
divided into 5 doses of 0.4 grams/kg for 5 days. In 3 of 4 patients there was significant
improvement in neuropathic pain (>50%) and autonomic dysfunction with 4 weeks of immune
globulin administration. In addition, there was a clinically significant increase in
intra-epidermal nerve fiber density after 6 months (findings not seen in the large cohort of
individuals that were untreated). One patient did not exhibit any clear improvement in
neuropathic pain or autonomic dysfunction. Prior to immune globulin administration the
investigators measured circulating cytokine levels in these 4 individuals. Those that
responded tended to have higher circulating cytokine levels than that the individual that did
not.

The investigators propose a prospective therapeutic study to determine the efficacy of IVIG
in improving both neuropathic pain and nerve fiber structure and function in individuals with
TIND. In addition, the investigators will attempt to define mechanisms that will predict
success in this trial.

Inclusion Criteria:

- Individuals with a diagnosis of diabetes and treatment induced neuropathy (defined by
the onset of neuropathic pain and signs of small fiber or autonomic neuropathy within
8 weeks of a change in HbA1C exceeding 3 points over 3 months).

- Ages 18-60.

- BMI ≤ 30.

- Nonsmoker.

- Consumption of up to 4 alcoholic beverages per week.

- No history of substance abuse or dependence with 1 year prior to screening.

- Normal ECG.

- Vital Signs within normal range (with the exception of a resting tachycardia which is
expected in all subjects due to neuropathic pain; research subjects with a heart rate
greater than 110 bpm, however, will be excluded).

- CBC, standard chemistry panel within normal limits.

- Standard coagulation studies (within BIDMC laboratory normal limits) including PT,
PTT, platelets.

- D-dimer <0.05 FEU.

Exclusion Criteria:

- Female subjects of childbearing potential with a positive urine pregnancy test.

- BMI >30.

- No other known cause of neuropathy (chemotherapy, toxins, other medical disorder - all
subjects have diabetes so this would not be an exclusionary factor).

- Anticoagulation with warfarin, aspirin & Plavix together or other anticoagulant that
would place subjects at undue risk of bleeding from a skin biopsy. Aspirin or Plavix
alone are not an exclusion criterion.

- Clinically active coronary artery or cerebrovascular disease.

- Cardiac insufficiency (NYHA Grade III-IV), cardiomyopathy, significant cardiac
dysrhythmia requiring treatment, unstable advanced ischemic heart disease.

- History of congenital or acquired coagulopathy or thromboembolic disease before the
age of 55 or arterial thromboembolic disease before the age of 45.

- History of Deep Venous Thrombosis (DVT) and/or Pulmonary Embolism (PE).

- Evidence of lower extremity deep vein thrombosis at screening including limb swelling,
pain or discoloration and or risk of thrombotic event as assessed by Wells criteria.

- Known history of blood hyperviscosity.

- Evidence of severe vascular disease (history of ulceration, poor wound healing,
vascular claudication).

- History of allergic reaction to local anesthesia for skin biopsies or history of
scarring or keloid formation.

- History of renal dysfunction that includes glomerular filtration rate <60 mL/min, or
creatinine of >2.0 mg/dL.

- Known IGA deficiency with antibodies to IgA.

- History of hypersensitivity, anaphylaxis or severe systemic response to
immunoglobulin, blood or plasma derived products.

- Positive Direct Antiglobulin Test (DAT) prior to administration or history of
hemolytic anemia.

- Subject who is unlikely to comply with the study protocol, or in the opinion of the
investigator, would not be a suitable candidate for participation in the study.

Criteria for discontinuation:

- Pregnancy: women of childbearing potential will have a urine pregnancy test at every
visit. Subjects who become pregnant will be discontinued from the study.

- A Grade 3 or higher allergic reaction within 24 hours of IVIG/Placebo infusion.

- Any thromboembolic events (e.g. myocardial infarction, stroke, venous thromboembolism)

- Clinically significant hematologic complications (e.g. hemolysis and/or neutropenia).

- Withdrawal by subject