Investigating chemotherapy induced peripheral neuropathy (CIPN) and its treatment, using functional Magnetic Resonance Imaging (fMRI)

Background Chemotherapy Induced Peripheral Neuropathy (CIPN) is a debilitating neuropathy caused by commonly used chemotherapeutics. Clinically, the problem of CIPN is compounded by difficulties with diagnosis and limited treatment options. The pathophysiology of CIPN remains elusive, with current mechanistic postulates focused mainly on the peripheral nervous system. However, animal and human models of non-CIPN neuropathic conditions have shown the brain to be central to the development and maintenance of painful neuropathy. Moreover, evidence suggests that aberrant activity in key regions of the brain and brainstem could denote individual vulnerability for chronic pain states. The impact of the brain on CIPN development is unknown. Assessment of drug efficacy using brain imaging can provide sensitive readouts and is increasingly used in clinical trials. Aims Firstly, to prospectively explore the structure and function of the brain in cancer patients prior to chemotherapy administration, using functional magnetic resonance imaging (fMRI), in order to determine whether baseline differences exist between patients who progress to CIPN as compared to those who do not. Secondly, to develop a pilot study using fMRI to investigate a topical treatment for CIPN, in order to assess the feasibility of setting up a study with this kind of design. Methods To address the first aim of this thesis a prospective cohort study (the CIPN fMRI Study) was developed. Cancer patients scheduled to receive neurotoxic chemotherapy treatment including oxaliplatin, carboplatin, carbotaxol, or cisplatin, were recruited from three NHS trusts in Scotland, to undergo a high resolution (3 tesla) functional MRI scan, at a single time point prior to commencement of chemotherapy. During the scan structural, resting state and functional data were collected. Functional data involved the presentation of punctate stimuli (using a 256mN von Frey filament), above the patients’ right medial malleolus. While receiving the punctate stimuli, patients viewed images that had neutral or positive emotional content or a baseline coloured image with no content. Sample size was based on previously successful pain fMRI studies and pragmatic estimates. Acute CIPN was defined clinically by common toxicity criteria as necessitating a chemotherapy dose reduction or cessation. Data were analysed using FMRIB’s Software Library (FSL) version 5, 2015. Standard data pre-processing (brain extraction, registration, B0 unwarping, motion correction, and denosiing with FIX) was carried out. Structural analysis was conducted using FIRST. Resting state analysis utilised FSL’s MELODIC tool, and a non-parametric group comparison was made following a dual regression approach. FEAT was used for both first and second level functional analyses. Group comparisons were made using a mixed effects analysis (z threshold 2·3 and 2, regions considered significant at p<0·05, cluster corrected). The group was split by sex to explore known sex differences in pain processing. To address the second aim of this thesis, a pilot fMRI randomised controlled trial (MINT3 Study) was designed. Approvals from ethics and research and development were sought and obtained. Data collection forms were developed. An fMRI experiment was proposed and a single pilot scan was conducted and analysed. Results 30 patients were recruited for the CIPN fMRI study (mean age 60·4 years, [95% Confidence Interval: 57.4-63.4, 17 women). Two patients had lung cancer, nine had gynecological malignancies and 18 had colorectal cancer. 17 patients developed acute CIPN. Structural analysis showed that patients who developed CIPN had a smaller volume of the Nucleus Accumbens (NAc). Resting state analysis did not show clear differences between those who developed CIPN and those who did not. Finally, functional analysis showed that patients who did not develop CIPN had greater activation in the superior frontal gyrus when viewing positive emotional images as compared to those who did progress to CIPN. Region of interest analysis showed that female patients who developed CIPN had greater activity in their mesencephalic pontine reticular formation (MPRF). Male patients who progressed to CIPN had decreased activity in their thalamus. Feasability of the MINT3 study set up and fMRI paradigm was assessed. Interpretation Differences in brain structure and function are evident between patients who developed CIPN and those who did not. Crucially, the regions identified, in particular the NAc, have been postulated to denote a vulnerability for progression to pain states. Although the findings need further confirmation they suggest a paradigm shift in terms of CIPN as a clinical problem. Specifically, it appears that certain individuals can be considered as having increased risk of CIPN development prior to chemotherapy administration. This risk relates to the baseline structure, and function of their brains. Finally, the set up of the MINT3 fMRI study showed that this kind of study design is acceptable in terms of ethical and R&D approvals and a single healthy volunteer pilot

An Exploratory Study into Objective and Reported Characteristics of Neuropathic Pain in Women with Chronic Pelvic Pain

Chronic pelvic pain (CPP) affects 5.7-26.6% women worldwide. 55% have no obvious pathology and 40% have associated endometriosis. Neuropathic pain (NeP) is pain arising as a consequence of a lesion/disease affecting the somatosensory system. The prevalence of NeP in women with CPP is not known. The diagnosis of NeP is challenging because there is no gold-standard assessment. Questionnaires have been used in the clinical setting to diagnose NeP in other chronic pain conditions and quantitative sensory testing (QST) has been used in a research setting to identify abnormal sensory function. We aimed to determine if women with chronic pelvic pain (CPP) have a neuropathic pain (NeP) component to their painful symptoms and how this is best assessed. We performed an exploratory prospective cohort study of 72 pre-menopausal women with a diagnosis of CPP. They underwent a clinician completed questionnaire (DN4) and completed the S-LANSS and PainDETECT™ questionnaires. Additionally QST testing was performed by a clinician. They also completed a patient acceptability questionnaire. Clinical features of NeP were identified by both questionnaires and QST. Of the women who were NeP positive, 56%, 35% and 26% were identified by the S-LANSS, DN4 and PainDETECT™ respectively. When NeP was identified by questionnaire, the associated laparoscopy findings were similar irrespective of which questionnaire was used. No subject had entirely unchanged QST parameters. There were distinct loss and gain subgroups, as well as mixed alteration in function, but this was not necessarily clinically significant in all patients. 80% of patients were confident that questionnaires could diagnose NeP, and 90% found them easy to complete. Early identification of NeP in women with CPP with a simple questionnaire could facilitate targeted therapy with neuromodulators, which are cheap, readily available, and have good safety profiles. This approach could prevent unnecessary or fertility-compromising surgery and prolonged treatment with hormones

Connected consciousness after tracheal intubation in young adults: an international multicentre cohort study

Background: Connected consciousness, assessed by response to command, occurs in at least 5% of general anaesthetic procedures and perhaps more often in young people. Our primary objective was to establish the incidence of connected consciousness after tracheal intubation in young people aged 18e40 yr. The secondary objectives were to assess the nature of these responses, identify relevant risk factors, and determine their relationship to postoperative outcomes. Methods: This was an international, multicentre prospective cohort study using the isolated forearm technique to assess connected consciousness shortly after tracheal intubation. Results: Of 344 enrolled subjects, 338 completed the study (mean age, 30 [standard deviation, 6.3] yr; 232 [69%] female). Responses after intubation occurred in 37/338 subjects (11%). Females (13%, 31/232) responded more often than males (6%, 6/106). In logistic regression, the risk of responsiveness was increased with female sex (odds ratio [OR adjusted ]¼2.7; 95% confidence interval [CI], 1.1e7.6; P¼0.022) and was decreased with continuous anaesthesia before laryngoscopy (OR adjusted ¼0.43; 95% CI, 0.20e0.96; P¼0.041). Responses were more likely to occur after a command to respond (and not to nonsense, 13 subjects) than after a nonsense statement (and not to command, four subjects, P¼0.049). Conclusions: Connected consciousness occured after intubation in 11% of young adults, with females at increased risk. Continuous exposure to anaesthesia between induction of anaesthesia and tracheal intubation should be considered t

Oxaliplatin treatment and peripheral nerve damage in cancer patients: A Polish cohort study

Introduction: Oxaliplatin-induced neurotoxicity is the single main dose-limiting factor in the treatment of colorectal cancer. The degree of neurotoxicity may be either acute and reversible or observed as cumulative and chronic peripheral nerve damage leading to peripheral neuropathy (PNP), walking difficulties, extremity hypersensitivity, tingling and numbness, and increased pain sensation. Aim: The aim of this paper is to determine and compare the ratio of clinical versus subclinical PNP cases in colorectal patients who underwent oxaliplatin treatment. Materials and Methods: Thirty-two colorectal cancer patients were enrolled in the study. Patients received chemotherapy either as folinic acid and 5-fluorouracil and oxaliplatin or capecitabine and oxaliplatin regimen. Electroneurophysiological tests were performed before the treatment and after the 4th cycle when the risk of peripheral nerve damage increases. All patients were subject to a standard neurological examination and a semi-structured questionnaire interview. Results and Discussion: Following oxaliplatin treatment, 21 (66.6%) of all patients presented neurological symptoms and/or electrophysiologically measured signs of PNP; of those, 7 patients (33.4%) displayed only electrophysiological changes and the remaining 14 patients (66.6%) presented fully symptomatic PNP – 4 patients were new neuropathy cases while the other 10 patients were previously diagnosed with PNP and showed signs of further neuronal deterioration and progressing sensory and motor dysfunction. Conclusion: Our study lays ground for further larger scale longitudinal studies on oxaliplatin neurotoxicity and its prevention. We believe that early diagnosis of oxaliplatin-induced neurotoxicity is essential in the prevention of irreversible nerve damage and should be prioritized when assessing and evaluating treatment so that adequate adjustment may be made

Questionnaire outcomes.

<p>Questionnaire outcomes.</p