Investigation of sensory nerve fibre alterations in people with sciatica

Symptomatic participants will undergo a baseline assessment which includes a clinical examination, quantitative sensory testing, and completion of questionnaires. Skin biopsies will be taken at the time of surgery (in theatre). The initial assessment will be performed in the week prior to surgery and will take approximately 2.5 hours. Healthy control participants will only undergo a baseline assessment including quantitative sensory testing, completion of questionnaires and the taking of skin biopsies. The total visit will take approximately 2.5 hours. a) Clinical examination The participant’s pain history, including pain distribution and pain behaviour will be recorded and a clinical examination for determination of neurological deficits will be conducted (reflex, strength and sensation testing). The clinical examination will be performed by the PI or a research assistant. The time required for the clinical examination: 15 minutes b) Questionnaires Consistent with our previous study (ANZCTR Trial 366797) patients will complete various questionnaires to capture their clinical profile, including: Assessment of pain • Pain intensity of back and leg pain (11- point numerical rating scale (NRS)) • Health care utilisation • Bothersomeness of back and leg pain (NRS) • #Sciatica Bothersomeness Index • #Brief pain Inventory (BPI) 7-item pain interference sub-scale Assessment of functional deficits • Oswestry Disability Index Assessment of neuropathic pain symptoms • painDETECT Questionnaire • #Neuropathic Pain Symptoms Inventory Assessment of psychological factors • *Hospital Anxiety and Depression Scale • *Pain Catastrophizing Scale • Fear avoidance behaviour (Tampa Scale for Kinesiophobia) • Confidence in recovery (‘great deal’, ‘moderate’, ‘no confidence’, ‘do not know’) Assessement of quality of life • *SF-36 • *#EQ-5D-5L Assessment of sleep interference • *Sleep quality (Visual analogue scale) *Questionnaires will also be completed by healthy participants. #Questionnaires will allow comparison to data collected by our collaborator in non-surgical patients with lumbar referred leg pain. The questionnaires will be collected by the PI or a research assistant. c) Quantitative Sensory testing Standardised quantitative sensory testing (QST) will be performed according to the standardised and well validated QST protocol of the German Research Network on Neuropathic Pain (DFNS). The protocol includes the following assessments: cold and warm detection thresholds; the number of paradoxical heat sensations during the procedure of alternating warm and cold stimuli; cold and heat pain thresholds; mechanical detection threshold; mechanical pain threshold; stimulus-response functions: mechanical pain sensitivity and dynamic mechanical allodynia; wind-up ratio; vibration detection threshold; pressure pain threshold. The full test battery will be applied to the lower back and main pain area in the leg on the symptomatic side. Testing of the full test battery will take approximately 25-30 minutes. In the L5/S1 foot dermatomes only thermal, mechanical and vibration detection thresholds will be measured which will take approximately 10 minutes. Prior to testing, participants will be familiarised with the testing methods in a body region which will not be assessed afterwards. The familiarisation will take approximately 10 minutes. The methodology is consistent with our methods in previous studies (ANZCTR trials 366797, 365980). The total time required for the QST will be approximately 1.5 hours. Healthy controls will undergo exactly the same QST procedures as patients. Each healthy control is matched to a specific patient, i.e. the same body regions will be assessed as in the respective patient. c) Skin samples The determination of intraepidermal nerve fibre density (IENFD) in skin biopsies is the gold standard to determine structural integrity of small fibres. Measurement of IENFD is a relatively simple assay which can be performed in relatively innocuous 3mm punch biopsies of skin, a routine dermatological investigation Skin biopsies will be taken by the surgeon at the time of surgery (in theatre) in the lower back and in the leg on the symptomatic side in the same area where the full QST battery had been performed. In each body region (lower back and leg), one skin biopsy will be taken. For healthy controls the skin samples will be taken by a doctor after QST measures have been taken. The skin biopsies will be taken in the same body region where the full QST battery had been performed (lower back and leg). The skin areas will be anaesthetised (1-2ml of 2% lidocaine) prior to the biopsy. Skin punch biopsies will be fresh frozen or fixed with 2% paraformaldehyde-lysine-periodate, as instructed by our AI Schmid (Oxford University), coded with the participant’s ID number and stored in a locked freezer. The skin biopsies will be sent via WorldCourier to our AI in Oxford/UK. Intra-epidermal nerve fibre density reflecting structural small fibre integrity will be established immunohistochemically using protein gene product 9.5 (PGP9.5, panaxonal marker) as previously performed by our collaborator (AI Schmid). Symptomatic participants will be observed up to 12 months after surgery. The 3 months post-surgery assessment will include the same QST procedures as pre-surgery, i.e. the full QST protocol in the participants' lower back, in the pre-surgical main pain area in the leg and the reassessment of detection thresholds in the relevant dermatome. The duration of the QST will be approximately 1.5 hours. In addition participants will have to complete questionnaires to assess pain, functional deficits and neuropathic pain symptoms (see baseline measures). The anticipated duration for the 3 months post-surgery visit is 2 hours. The 12 months follow up will only include the questionnaires as at 3 months. The questionnaires will be sent to the participants. The completion of questionnaires will take approximately 30-40 minutes.