The TopCSPN trial is a double blinded randomized placebo controlled study of oral topiramate as a potential disease modifying therapy for cryptogenic sensory peripheral neuropathy (CSPN). Patients with CSPN who also have metabolic syndrome (defined by the ATPIII criteria) who do not have an alternative cause for neuropathy will be potentially eligible. The co primary outcome measures are change in the Norfolk Quality of Life - Diabetic Neuropathy (NQOL-DN) Scale and intraepidermal nerve fiber density (IEFND) at the distal thigh. The treatment phase will last 24 months.

Inclusion Criteria

1. Age 18-80

2. Diagnosis of confirmed symptomatic distal symmetric peripheral polyneuropathy based on the Toronto consensus criteria for probable neuropathy (the presence of unequivocal signs and symptoms of neuropathy)45.

3. Evidence of symptomatic neuropathy based on a screening visit NQOL-DN score of >9.

4. Metabolic syndrome based on modified ATPIII criteria. Specific criteria require 3 of the following 6 to be present at the screening visit.

   • Waist circumference >102 cm for men, >88 cm for women
   • Serum triglycerides of > 150 mg/dl
   • HDL < 40 mg/dl for men, < 50 mg/dl for women
   • Those with either a normal HDL or TRG who are taking a lipid lowering medication for this purpose
   • Blood pressure 130/85 mm Hg or use of anti-hypertension drug
   • Hyperglycemia based on American Diabetes Association (ADA) criteria at screening based on any one or more of the following: fasting plasma glucose > 100 mg/dL (5.6 mmol/L), 2-hour glucose tolerance test > 140 mg/dL (7.8 mmol/L), or hemoglobin A1c > 5.7% .

5. No current or prior history of therapy with topiramate.

6. If female of child-bearing potential (i.e., not surgically sterile or post-menopausal defined as age > 51 years without menses for ≥ 2 years), negative serum pregnancy test at screening and negative urine pregnancy test at baseline visit.

7. Women of child-bearing potential or men with sexual partners of childbearing potential be willing to use an acceptable method of birth control for the duration of the study and for 12 weeks following completion of study drug therapy. Acceptable methods of birth control include abstinence, oral contraceptives, the contraceptive patch, intra-uterine device, the contraceptive ring, and or barrier contraception such as condoms with spermicide.

Exclusion Criteria

1. CSS-PI clinical determination of an alternative cause for peripheral neuropathy (including but not limited to rheumatological disorders, Hepatitis B or C, breast cancer treated with neurotoxic chemotherapy within the past 15 years). All potential subjects will have screening neuropathy labs including assessment for diabetes (Hemoglobin A1c, oral glucose tolerance test), vitamin B12 level, and immunofixation47.
2. Type I diabetes or current use of insulin or use of insulin in the past 3 months.
3. HgA1c > 7.5%. Borderline screening labs can be repeated within two weeks with PPI approval.
4. History of recurrent nephrolithiasis, a single episode of nephrolithiasis within one year prior to screening, or use of ongoing preventative treatment.
5. Family history of a hereditary neuropathy in a first-degree relative.
6. Severe neuropathy: Utah Early Neuropathy Score > 24 at screening
7. Active foot ulceration or a history of a nontraumatic foot amputation.
8. ECG with QTc more than 450 ms in men, or 470 ms in women.
9. Risk of excessive bleeding at the skin biopsy site based on the clinical assessment of the CSS-PI.
10. Chronic corticosteroid use excluding topical or inhaled treatment.
11. Use of a carbonic anhydrase inhibitor (such as acetazolamide) due to risk of nephrolithiasis.
12. Planned bariatric surgery.
13. Use of other weight loss medications.
14. Use of scheduled opiates, or as needed opiate medications more than three times weekly.
15. Use of topical capsaicin products within 16 weeks of screening or at any time on study.
16. Medication change for neuropathy symptoms during the 8 weeks prior to screening; or anticipated change for the duration of study participation.
17. Current use of an intrathecal pain pump or spinal cord stimulator.
18. Screening laboratory creatinine ≥ 2.0 mg/dl.
19. Severe edema, dermatologic or lower extremity condition that would increase risk of skin biopsy.
20. Major depression, bipolar affective disorder, or other mental health disorders that are sufficiently severe to increase adverse event risk or impact neuropathy assessment in the opinion of the responsible site principal investigator.
21. Current suicidal ideation within one year prior to the baseline visit as evidenced by answering "yes" to Questions 4 or 5 on the suicidal ideation portion of the Columbia-Suicide Severity Rating Scale (C-SSRS).
22. Ataxia sufficiently severe to represent an unacceptable fall risk in the opinion of the site principal investigator.
23. A serious medical condition expected to dramatically shorten life span or prevent participation.
24. Any clinically significant condition or illness, which, in the opinion of the CSS-PI, would pose a risk to the subject or might confound the study including metabolic acidosis, bone marrow suppression, blood dyscrasias, bleeding disorder, or closed angle glaucoma.
25. History of alcohol or drug abuse within the past two years, or existing neuropathy related to past drug or alcohol abuse.
26. History of malignancy within five years prior to study enrollment, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.
27. A history of epilepsy.
28. An inability to understand or cooperate with the procedures of the study.
29. Pregnant, or intending to become pregnant, or breastfeeding.