Cryptogenic sensory peripheral neuropathy (CSPN) affects 5-10% of those over 40 years old, resulting in reduced quality of life due to pain, sensory loss, imbalance, and fall related injuries. CSPN is a significant cause of patient morbidity, for which there exists no disease altering therapy. Clinically similar to early diabetic neuropathy, it is characterized by preferential injury to small axons, and frequently results in prominent sensory loss and neuropathic pain. Injury to small axons is reflected in reduced intraepidermal nerve fiber density (IENFD). While the precise etiology of CSPN is unknown, and likely multifactorial, accumulating evidence indicates that obesity, dyslipidemia, and insulin resistance/prediabetes (metabolic syndrome) are linked to CSPN risk. Patients with CSPN have an elevated risk of metabolic syndrome and patients with prediabetes have an elevated risk of CSPN. Obesity and dyslipidemia also significantly increase the risk of neuropathy among diabetic patients. Animal models support the hypothesis that obesity and prediabetic levels of glucose dysregulation cause neuropathy. A growing literature suggests that exercise improves nerve regenerative capacity, results in increased IENFD and improves neuropathic pain among patients with CSPN and prediabetes. Cumulatively, these data support the hypothesis that metabolic syndrome is linked to neuropathy risk, CSPN is potentially reversible, and aggressive metabolic management may be an effective strategy to enhance nerve regeneration and improve patient symptoms. However, currently available lifestyle interventions are very difficult to employ in a clinical setting due to poor compliance and attrition from the necessary behavioral changes. Development of better pharmacologic approaches is a major priority. Recent data suggest that gain of function in voltage gated sodium channels plays a role in CSPN and other common forms of neuropathy. Topiramate is a promising therapeutic approach to CSPN. Clinical trials of this anticonvulsant agent in diabetic neuropathy suggest improvement in pain and quality of life, and also in measures of peripheral nerve function including sensory testing and IENFD. Topiramate has multiple potentially neuroprotective effects. It induces significant weight loss at the dose proposed in this study, and also improves insulin resistance. These effects are greatest among obese patients. Topiramate also blocks voltage gated sodium channels. It has been extensively studied for the treatment of epilepsy and migraine and is generally safe and well tolerated. Several studies suggest a potential benefit for neuropathic pain associated with diabetic neuropathy. Small studies suggest topiramate therapy not only results in improved pain, but also improves QOL and preferentially impacts measures of small fiber function, including an increase in IENFD. Data from animal models of diabetes also support its potential therapeutic efficacy. While topiramate has multiple potential mechanisms of action (weight loss, improved insulin sensitivity, sodium channel modulation), the fact that each would be expected to have benefit in CSPN and its potential to differentially impact small fiber injury, which is characteristic of CSPN, support its further evaluation as a disease altering therapy. The Topiramate for CSPN (TopCSPN) Study will randomize 125 CSPN patients to 100 mg of topiramate daily or matched placebo. Treatment will last 24 months. IENFD and the Norfolk Quality of Life ? Diabetic Neuropathy (NQOL-DN) will be co-primary outcome measures. A major secondary goal of the TopCSPN study is to evaluate the clinical meaning of IENFD and other commonly employed surrogate measures of neuropathy. The results of the CSPN Study promise to immediately impact patient care and facilitate future peripheral neuropathy clinical trials.

Public Health Relevance

Cryptogenic sensory peripheral neuropathy (CSPN) affects 5-10% of Americans. CSPN causes progressive injury to the very longest nerves of the body resulting in pain, loss of balance, and fall related injury. There is no FDA approved treatment for CSPN or its symptoms. Our previous research has found that CSPN can be detected and followed by examining nerves that reach to the skin using a small punch biopsy of the skin outer layers. These cutaneous nerves can be injured by high blood glucose, obesity and high triglycerides, but have the potential to regrow in response to treatments that improve these metabolic conditions. Topiramate is an FDA approved medication for seizures, migraine headaches and medical weight loss (in combination with phentermine). It causes weight loss and improves the body's sensitivity to insulin. It also reduces the activity of sodium channels (or pores) in the nerves. Both of these effects are expected to improve CSPN. The proposed study will randomize participants with CSPN to oral topiramate or a matched placebo (?sugar pill?) two years to see if treatment reduces loss of nerve fibers in the skin and also improves patient quality of life.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Cordell, Janice
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Utah
Schools of Medicine
Salt Lake City
United States
Zip Code
Stino, Amro M; Smith, Albert G (2017) Peripheral neuropathy in prediabetes and the metabolic syndrome. J Diabetes Investig 8:646-655