Unravelling the etiology of chronic idiopathic axonal polyneuropathy

Polyneuropathy is the most common neuromuscular syndrome. There are many causes
of polyneuropathy, but after extensive investigations no cause can be found in
about one-third of patients: 'chronic idiopathic axonal polyneuropathy' (CIAP).
Althoug CIAP runs a benign and slowly progressive course, it can have a marked
impact on daily functioning and quality of life.
Pathological examination of nerve biopsies from patients with CIAP have shown
endoneurial microvascular changes. A possible pathogenetic mechanism could be
an association with the metabolic syndrome, which is an important determinant
of microvascular disease. Other common etiologies to be considered are chronic
obstructive pulmonary disease (COPD), cardiovascular disease, environmental and
nutritional factors (such as exposure to toxins or alcohol, subtle vitamin B12
deficiency, vitamin B6 toxicity).
However, there is no conclusive evidence that these conditions are importantly
associated with CIAP because most previous studies were small, not
population-based, or uncontrolled.

Hypothesis
CIAP may be caused by microvascular, hypoxic or toxic nerve damage that can be
linked to the metabolic syndrome or other prevalent conditions such as COPD,
cardiovascular disease, environmental or nutritional factors.

Objectives
1. Achieve a complete ascertainment of incident CIAP patients in the middle of
the Netherlands during a three-year period and determine the frequency of CIAP.
2. Establish whether CIAP is associated with the metabolic syndrome, and if so,
which of its components appear to be the most important determinants.
3. Investigate whether prevalent conditions such as COPD, cardiovascular
disease, environmental and nutritional factors contribute to the risk of
developing this disease.

The study may help identify etiological links between chronic idiopathic axonal
polyneuropathy (CIAP) and the metabolic syndrome or other prevalent conditions
in the population, as well as target treatment of this disease that has a
negative influence on quality of life. For example, lifestyle adjustments or
treatment aimed at prevention similar to those in (pre)diabetes and
cardiovascular disease should be considered if the metabolic syndrome plays a
role. Similarly, more rigorous treatment or eradication of other conditions may
also reverse or positively influence the disease course of CIAP. Consequently
the effects of interventions on CIAP could be studied or CIAP could be included
as an outcome parameter in studies on lifestyle interventions.
The study may facilitate the diagnostic process in the large group of patients
with a chronic axonal polyneuropathy, and provide further insight whether CIAP
should still be considered as a singular entity with variable clinical
expression or indeed represents a heterogeneous group of conditions with
specific so far unrecognized etiologies.

A prospective, population-based, case-control study in the middle of the
Netherlands (province of Utrecht). Validated up-to-date questionnaires,
clinical and laboratory (blood) investigations will be used to collect data and
assess risk factors. All analyses will be adjusted for possible confounders.

Burden:
-for patients routine evaluation at the outpatient clinic (conform CBO
guideline 'Polyneuropathie': clinical neurological and neurophysiological
examination, fasting venapuncture), for controls fasting venapuncture (if not
yet done).
-fill out questionaire at home.

Risk:
The risk of the venapuncture is negligible (haematoma at the site of puncture).
The venapuncture will be done at the UMC Utrecht and performed by qualified
personnel (physicians, nurses, laboratory technicians).

In view of the minor burden and negligible risk of the venapuncture this study
is justifiable, because of the effect of CIAP on activities of daily living and
quality of life, the prevalence of possible associated conditions and potential
henceforthcoming therapeutic consequences.