Treatment-induced Neuropathy of Diabetes in Youth: Case Series of a Heterogeneous and Challenging Complication

Case Series of a Heterogeneous and Challenging Complication

Eirene G. Alexandrou; Sarah D. Corathers; Amit Lahoti; Jacob Redel; Siobhan Tellez; Nana-Hawa Yayah Jones; Ahlee Kim


J Endo Soc. 2020;4(12) 

In This Article


In this series we describe 7 cases of TIND in children and young adults treated at 2 pediatric centers, increasing recognition of TIND as a complication of pediatric diabetes. Prior to our report, only 2 pediatric cases had been published,[4,7] indicating that the occurrence of TIND is more than the paucity of literature suggests. By raising awareness, we hope to enhance detection and timely management of this distressing and potentially debilitating condition. TIND should be considered in patients with diabetes who present with acute neuropathy or autonomic symptoms following rapid correction of hyperglycemia defined as >2% decline in HbA1c over 3 months. If TIND is suspected, interdisciplinary care comprised of an endocrinologist, neurologist, and pain management physician or physical therapist should be coordinated.

Our cases reinforce the inciting events in TIND development, its varied course, unique treatment challenges, and continued limitations. In accordance with previous reports,[1–8] all of our patients with TIND had a significantly elevated baseline HbA1c ranging from 12.1% to >14% (109 mmol/mol to >130 mmol/mol) with a >2% decline over 1 to 3 months (Table 1). TIND impacted both those with recent and remote diabetes. Within our population, 57% had new-onset diabetes and the remaining had lived with diabetes for 3 to 5 years. Despite the preponderance of T1D within our group, clinicians should remain cognizant that this condition also impacts those with T2D. Our cases also underscore the medical complexity of TIND. All presentations were complicated by autonomic symptoms (gastrointestinal 100%; cardiovascular 14%; genitourinary 14%). Microvascular complications were also present in 43% of our patients; all had microalbuminuria and 2 out of the 3 had nonproliferative retinopathy. For those patients that were not due for microvascular screening per American Diabetes Association guidelines,[9] testing was performed only if symptoms were expressed, such as retinal screening for those with vision changes. Patients with retinal changes subsequently had microalbuminuria screening, as the presence of one microvascular complication may indicate another. The early microvascular changes detected in our patients with new-onset diabetes highlights the importance of screening for these conditions in all TIND presentations, despite duration of diabetes. Another unique finding was the presence of motor symptoms in 2 patients (cases 4 and 6). The loss of motor axons associated with neurogenic muscle atrophy has been documented as a late consequence of DPN;[10] however, motor deficits have yet to be reported in TIND. Although case 4 had 3 years of poorly controlled diabetes, the acute onset and resolution of his neuropathic and sensorimotor symptoms is inconsistent with DPN. Given our limited understanding of TIND's pathophysiology, small sample size, and the challenge of performing neurological exams in young children, we are unable to definitively conclude if motor deficit is a new, underrecognized manifestation of pediatric TIND. Lastly, treatment response in this condition is varied, as shown here. Some of our patients experienced spontaneous resolution of symptoms without treatment or worsening glycemic control (29%), while others experienced resolution of pain within 5 to 12 months of starting medical therapy (57%) or unremitting pain despite intervention (14%) (Table 1). We are unable to explain the variable and at times incomplete response to treatment. This may be driven by underlying genetic modifiers that have yet to be elucidated or could also be a reflection of the lower doses of gabapentin prescribed, in contrast to a maximum daily dose of 3600 mg.[11] Furthermore, the most severe and persistent presentation (case 5) also had anorexia nervosa, which may have played a role in stagnating his recovery.

Although our cases clearly describe characteristics of pediatric TIND, reporting on its prevalence is beyond the scope of this series, as cases were identified through individual providers as opposed to unbiased, retrospective chart review. We speculate that the condition may occur more commonly in those with new-onset diabetes, as initiation of insulin results in rapid improvements in glycemic control in contrast to a patient who has been on insulin for several years (unless adherence to therapy changes). Despite the estimated incidence of diabetes nearing 34.2 per 100 000 youths per year,[12] reasons as to why TIND is not more commonly reported, especially in comparison to adults, demonstrates the need for further scientific exploration. Part of this could be driven by under-reporting of symptoms in a pediatric population. The detection of neuropathic symptoms may improve by standardized application of screening tools with age-appropriate language for those presenting with rapidly improved glycemic control. Additional studies are also needed to determine genetic predisposition to TIND as well as other modifiers that may endow protection in youth with diabetes.

At this time, we remain underpowered to define any additional risk factors in TIND development or propose novel prevention and treatment strategies. Gradual control of hyperglycemia was speculated as a potential preventive measure for TIND; however, this has never been studied. Therefore, patients with diabetes should continue to be approached according to guidelines, with aggressive insulin therapy to reduce the risk of development and progression of microvascular complications.[9] Secondly, in those that develop TIND, permissive hyperglycemia for symptomatic resolution is inadvisable, given the increased risk of permanent microvascular complications.[6] There remain no consensus guidelines for management of TIND and the approach to these patients, as evidenced by our cases, continues to be varied. Our cases demonstrate that extensive evaluation, including sophisticated imaging, may be pursued; however, nearly all these studies were negative. This brings to light the need for established guidelines to streamline diagnostic workup, while promoting timely identification of TIND and minimizing the burden placed on patients, providers, and the medical system by excessive diagnostics. Until future studies can further elucidate the mechanisms contributing to TIND, the mainstay of treatment continues to be supportive care and stable glycemic control within recommended targets.[4,12]