Treatment Induced Neuropathy of Diabetes: Underrecognized But on the Rise?

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Treatment-induced neuropathy of diabetes (TIND), also called insulin neuritis, may be more common than previously thought, according to a review published in the October issue of Current Diabetes Reports.¹ Past research has suggested that TIND has an incidence of about 1%, but the review cites more recent research that indicates that up to 10.9% of study participants may meet the criteria for the condition. In the largest retrospective review to date, researchers found that 104 of 954 individuals evaluated from 2008 to 2012 at a tertiary care diabetic neuropathy clinic met criteria for TIND.²

TIND is a painful acute neuropathy that affects autonomic and small somatosensory nerve fibers, causing autonomic symptoms such as orthostatic hypotension or syncope along with burning or shooting pain that typically affects the extremities but may be more generalized. Patients may also experience worsening of microvascular disease, including retinopathy and nephropathy. The condition can affect people with type 1 diabetes mellitus (T1D) or type 2 diabetes mellitus (T2D) who have had a prolonged period of hyperglycemia. It usually begins 4 to 6 weeks after rapid normalization of glucose levels when initiating intensive glycemic control with insulin, oral agents, or (rarely) extreme diet control. In fact, the Gibbons and Freeman² study found that development of TIND was tied to how rapidly HbA1c dropped: a decrease of 2% to 3% over 3 months was linked to 20% absolute risk for TIND, while a decrease of more than 4% was linked to over 80% increased absolute risk.

Pain in TIND is usually more severe and more refractory to therapy than that of polyneuropathy of diabetes. Moreover, the autonomic symptoms of TIND are more prevalent and more severe. TIND also develops more rapidly, while symptoms of diabetic polyneuropathy are more insidious and may develop over years.

While TIND is usually self-limiting-symptoms gradually improve within weeks to months-the condition is usually extremely painful and often treatment-resistant.  One case series found that participants rated the pain as 10 on a scale of 1 to 10, despite combined treatment with 2 to 3 analgesics.³ However, some patients may experience longer-term symptoms, especially those with poorly controlled diabetes. A recent study of 26 individuals with T1D found that about 27% with unstable glycemic control continued to have worsened neuropathy and microvascular complications 7 to 8 years after experiencing TIND.⁴

While the etiology remains unclear, various mechanisms have been proposed. Current hypotheses include immunological or inflammatory response to insulin, hemodynamic changes similar to those found in retinopathy, ischemia of the connective tissue around the nerve sheath, microvascular damage and cell death related to hypoglycemia, and nerve regeneration after normalization of glucose levels leading to abnormal nerve firing.

TIND has been known for quite some time: it was first described by Caravati in 1933. But doctors may start to see more TIND cases for several reasons. First, the diabetes epidemic may mean that the sheer number of people at risk for TIND has increased. Also, recent recommendations for more intensive glycemic control following publication of results from the Diabetes Control and Complications Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) trials may mean that physicians are starting to see more cases of TIND. Physician reimbursement tied to achieving rapid (and sometimes too rapid) glycemic control may add another complicating factor. Finally, lack of awareness about TIND may have led some clinicians to overlook the link between rapid change in glycemic control and acute neuropathy.

“The subsequent incorporation of HbA1c measures in physician quality measurement programs and the growing role played by physician performance measures in physician ratings by payers, social media, and other stake holders has reinforced the emphasis on lowering HbA1c values. Further, it is likely that some previously reported cases of acute painful neuropathy and acute autonomic neuropathy in diabetic subjects may have been unrecognized cases of TIND,” writes Chistopher Gibbons, MD, of Harvard Medical School.² He advises slower correction of hyperglycemia, along with appropriate glycemic control to avoid long-term complications.

Take Home Points
• Recent findings suggest that TIND (ie, insulin neuritis), may be more common than previously thought, is associated with rapid rates of blood glucose normalization, and may produce long-term symptoms in people with inadequately controlled diabetes
• TIND is an acute neuropathy that typically causes extreme burning or shooting pain in the extremities, autonomic symptoms, and worsening of retinopathy, or nephropathy in people with T1D or T2D who have recently initiated intensive glycemic control with insulin or oral agents after prolonged periods of hyperglycemia
• TIND is usually self-limiting and refractory to multiple analgesics
• Cases of TIND may be increasing related to the increased prevalence of diabetes and recent recommendations for more intensive glycemic control; further study is needed.

References:

1. Gibbons CH. Treatment-induced neuropathy of diabetes. Curr Diab Rep. 2017;17:127.
2. Gibbons CH, Freeman R. Treatment-induced neuropathy of diabetes: an acute, iatrogenic complication of diabetes. Brain. 2015;138:43-52.
3. Gibbons CH, Freeman R. Treatment-induced diabetic neuropathy: a reversible painful autonomic neuropathy. Ann Neurol. 2010;67:534-541.
4. Gibbons CH. Treatment induced neuropathy of diabetes-Long term implications in type 1 diabetes. J Diabetes Complications. 2017;31:715-720.