Chronic idiopathic axonal polyneuropathy, exploring pathways to treatment

Polyneuropathy is one of the most common neurological conditions, affecting 1–4% of the population, particularly the elderly. It involves damage to the peripheral nerves, causing symptoms such as sensory disturbances, pain, muscle weakness, and balance problems. When no underlying cause is found after extensive investigation — which occurs in roughly a quarter of patients — the diagnosis is chronic idiopathic axonal polyneuropathy (CIAP).

CIAP typically presents around age 60 with symmetrical sensory symptoms starting in the feet, including tingling, numbness, pain, and walking difficulties. It progresses slowly and significantly impacts daily functioning and quality of life. No proven disease-modifying treatment currently exists.
This thesis explores potential treatment options for CIAP by improving diagnostics, identifying new modifiable risk factors, and reviewing current medication options.

Improving Diagnostics

Vitamin B12 deficiency — Beyond absolute B12 deficiency, a metabolic B12 deficiency can exist where blood levels of vitamin B12 appear normal but the active form is lacking. This thesis shows that measuring MMA is clinically relevant in patients with B12 levels below 300 pmol/L, and that B12 supplementation led to improvement or stabilisation of symptoms in some patients.

Hereditary transthyretin amyloidosis (ATTRv) — This rare but serious and treatable cause of polyneuropathy is caused by a mutation in the TTR gene. Analysis of 338 patients showed that genetic testing for ATTRv is not useful in patients with a typical CIAP presentation, as all ATTRv patients had atypical features at first presentation. Genetic testing is recommended when at least two of the following are present: cardiomyopathy, family history of ATTRv-related conditions, unexplained weight loss over 5 kg, autonomic nervous system dysfunction, bilateral carpal tunnel syndrome, or rapid progression requiring walking aids within 5 years.

Modifiable Risk Factors

Statins — Both a literature review and a case-control study found that statin use does not increase the risk of developing CIAP, which is an important finding given how widely statins are used.

Gluten sensitivity — Gluten-related antibodies were no more prevalent in CIAP patients than in controls, suggesting gluten sensitivity is unlikely to play a role in CIAP. A gluten-free diet therefore does not appear to be a useful therapeutic strategy.

Insulin resistance — A significant new finding is that CIAP patients had higher insulin levels than controls. Insulin resistance was independently associated with CIAP, even after correcting for metabolic syndrome and cardiovascular disease. This suggests that metabolic dysregulation may play a role in the development of CIAP, opening doors for lifestyle and metabolic interventions.

Treatment
A systematic review confirmed there is currently no proven effective treatment for CIAP. Management remains symptomatic, including pain relief, physiotherapy, walking aids, and psychosocial support. Most drug-based evidence is derived from diabetic polyneuropathy research, with limited CIAP-specific data.

Conclusion
CIAP is a common and disabling condition. This thesis demonstrates that treatable causes can be identified more effectively, that insulin resistance could plays a role in disease development, and that further research into CIAP treatment is urgently needed.