One hundred and five healthy volunteers were recruited from hospital personnel, relatives and friends of patients, at sports accommodations, and informal meetings for the elderly. Inclusion criteria were: no pain or other neurological complaints, no history of alcohol abuse, no diseases that may cause sensory deficit or pain sensation, and normal findings at neurological examination .
Patients referred to the Maastricht Sarcoidosis Management Centre, a referral centre for sarcoidosis in The Netherlands, were screened for eligibility. We included 91 patients in the study. Inclusion criteria were: diagnosis of sarcoidosis , lucid consciousness, no alcohol abuse, no usage of immunosuppressant drugs in the past 6 months, no diseases that may cause sensory deficit, and no signs of central nervous system involvement or large fibre neuropathy (no abnormal nerve conduction studies). After inclusion, patients were categorised as either “no SFN”, or, when having SFN symptoms as “possible SFN”. A patient was classified as having SFN symptoms when he or she reported at least one of the following symptoms, not otherwise explained: burning pain in extremities, dry mouth or eyes, changes in sweating, flushes, gastrointestinal dysfunction (constipation, diarrhea), cardiac complaints (palpitation, dizziness at standing up), urogenital dysfunction (sexual dysfunction, incontinence) .
The NPS was designed to assess distinct pain qualities associated with neuropathic pain and has been used in peripheral neurological conditions . The questionnaire rates ten different aspects of pain on a numerical 0–10 scale. Addressed are intensity and unpleasantness of pain in general; intensity of sharpness, hotness, dullness, coldness, skin sensitivity, itching; and intensity of surface and deep pain.
The horizontal visual analogue pain scale (VAS) is a 10-cm horizontal line, depicting no pain at the left and worst pain ever at the right side. Patients mark their pain intensity at the line. It is considered to reliably assess a patient’s experience .
The original Composite Autonomic Symptom Scale (COMPASS), validated in patients with autonomic failure and non-autonomic neuropathies, correlates well with autonomic function tests . Its 73 questions concern different aspects of the autonomic system: orthostatic intolerance and reflex syncope, secretomotor, vasomotor, pupillomotor, urogenital, gastrointestinal, and sleep difficulties.
Translation and modification
The translation of the NPS and mCOMPASS was performed according to the international guidelines . Some domains of the COMPASS were simplified by a clinimetrician (ISJM), and questions on female sexuality were added, reflecting an equivalent score for male sexuality, resulting in a 65 item modified scale (mCOMPASS), with a sum score of 200 for both men and women.
All participants underwent skin biopsy for intraepidermal nerve fibre density (IENFD) determination according to European guidelines . Biopsies were taken 10 cm above the lateral malleolus. Normative values were used to determine normal versus impaired IENFD findings . Patients were further divided into subgroups according to the presence of symptoms combined with skin biopsy results: group A, patients without SFN symptoms; B, patients with SFN symptoms but normal IENFD; and C, patients with SFN symptoms and reduced IENFD. We expected those with both symptoms and reduced IENFD to be most affected, IENFD being considered an objective tool to diagnose SFN [11, 12].
Study design and statistics
The study was approved by the medical ethical committee of the Maastricht University Medical Centre (Central Committee for Human Related Research, identifier number p06.0066L/MEC 05-224), in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. Informed consent was obtained from all participants prior to the study. All patients were examined at the Maastricht University Medical Centre. Examination took take place in a comfortable, temperature-controlled room. Questionnaires were provided with written instructions. Healthy controls were requested to complete the mCOMPASS. Data collection, entry, and management were performed using the Teleform automated processing system.
Reliability and validity studies
Patients completed the NPS and mCOMPASS twice, within 2–4 weeks, without having access to their previous answers (test–retest reliability; weighted kappa-statistic (κ) measures) . We examined the discriminatory validity of the NPS in the various patients’ subgroups in relation to severe pain, defined as a numerical rating score >5 on a NPS question (Chi-square test). Correlation studies between the NPS (item pain intensity) and VAS pain scales were also performed (convergent validity of NPS; Spearman’s Rank tests). For the mCOMPASS domains, subgroups comparison (one-way ANOVA + Bonferonni corrections) was performed. All analyses were performed using Stata 10.0 for Windows XP.