The Efficacy and Safety of Dorsal Root Ganglion Stimulation as a Treatment for Neuropathic Pain: A Literature Review.

OBJECTIVE: Dorsal root ganglion stimulation (DRGS) received its first regulatory approval (CE marking in Europe) in late 2011, and so its use is now almost six years old. Several thousand patients have already been treated, and a landmark trial in lower limb complex regional pain syndrome (CRPS) and causalgia has recently been published. METHODS: In this review we have summarized the literature to date on the use of DRGS in the treatment of neuropathic pain. RESULTS: The results so far are encouraging, with reports of successful use in treating a wide range of indications including postsurgical pain, CRPS, and phantom pain. Treatment of failed back surgery syndrome (FBSS) appears less successful. The therapy is still young, and long term results are not yet available. There is now good randomized clinical trial (RCT) evidence that DRGS provides superior pain relief to spinal cord stimulation for CRPS and causalgia of the lower limb, and produces stimulation that is more posturally stable, with more precise paraesthesia coverage. However evidence of this quality for other indications and pain locations is lacking. CONCLUSION: There is now Class A RCT evidence that DRGS provides superior pain relief to SCS for CRPS and causalgia of the lower limb. In the coming years we hope that randomized controlled trials will be performed on an indication-by-indication basis, which, together with the publication of longer term follow-up data, will provide a more complete understanding of the role of DRGS in the treatment of neuropathic pain syndromes.

The impact of long-course chemoradiotherapy on the myenteric plexus, neuromuscular functions and responses to prokinetic drugs in the human rectum.

BACKGROUND & AIMS: The long-term effects of chemoradiotherapy on human rectum are poorly understood. The aims were to investigate changes in inflammatory status, myenteric neuron numbers/phenotype, neuromuscular functions and prokinetic drug efficacy. METHODS: Macroscopically normal proximal-to-mid rectum was obtained from 21 patients undergoing surgery for bowel cancer, 98 days (range: 63-350) after concurrent capecitabine and pelvic radiotherapy, and 19 patients without chemoradiotherapy. Inflammatory status was measured by H&E, CD45 staining and qPCR. Myenteric neurons were examined by immunohistochemistry. Neuromuscular functions and drug efficacy were studied using exogenous agents and electrical field stimulation (EFS) to activate intrinsic nerves. RESULTS: Inflammation was not detected. Numbers of myenteric ganglia/neurons were unchanged (11.7 ± 2.4 vs. 10.3 ± 2.2 neurons/mm myenteric plexus with/without chemoradiotherapy) as were the numbers of cholinergic/nitrergic neurons. EFS stimulated cholinergic and nitrergic neurons so the contractile response of the muscle was the sum of both but dominated by cholinergic (causing contraction) or less often, nitrergic activity (relaxation), followed, after termination of EFS, by neuronally mediated contraction. Inhibition of nitric oxide synthase (by L-NAME 300 µM) more clearly defined EFS-evoked contractions. The 5-HT4 agonist prucalopride 10 µM and the cholinesterase inhibitor donepezil 1 µM, respectively increased and greatly increased the composite contractile response to EFS (measured as 'area-under-the curve') and the contractions isolated by L-NAME (respectively, by 22 ± 14% and 334 ± 87%; n = 11/8). After chemoradiotherapy, nitrergic-mediated muscle relaxations occurred more often during EFS (in 29.8 ± 6.1% preparations vs. 12.6 ± 5.1% without chemoradiotherapy, n = 21/18). With L-NAME, the ability of prucalopride to facilitate EFS-evoked contraction was lost and that of donepezil approximately halved (contractions increased by 132 ± 36%; n = 8). CONCLUSIONS: Several months after chemoradiotherapy, the rectum was not inflamed and myenteric neuron numbers/phenotype unchanged. However, nitrergic activity was increased relative to cholinergic activity, and prokinetic-like drug activity was lost or greatly reduced. Thus, chemoradiotherapy causes long-term changes in neuromuscular functions and markedly reduces the efficacy of drugs for treating constipation.

Expression of p16 Within Myenteric Neurons of the Aged Colon: A Potential Marker of Declining Function.

Human colonic neuromuscular functions decline among the elderly. The aim was to explore the involvement of senescence. A preliminary PCR study looked for age-dependent differences in expression of CDKN1A (encoding the senescence-related p21 protein) and CDKN2A (encoding p16 and p14) in human ascending and descending colon (without mucosa) from 39 (approximately 50: 50 male: female) adult (aged 27-60 years) and elderly donors (70-89 years). Other genes from different aging pathways (e.g., inflammation, oxidative stress, autophagy) and cell-types (e.g., neurons, neuron axonal transport) were also examined. Unlike CDKN1A, CDKN2A (using primers for p16 and p14 but not when using p14-specific primers) was upregulated in both regions of colon. Compared with the number of genes appearing to upregulate in association with temporal age, more genes positively associated with increased CDKN2A expression (respectively, 16 and five of 44 genes studied for ascending and descending colon). Confirmation of increased expression of CDKN2A was sought by immunostaining for p16 in the myenteric plexus of colon from 52 patients, using a semi-automated software protocol. The results showed increased staining not within the glial cells (S100 stained), but in the cytoplasm of myenteric nerve cell bodies (MAP2 stained, with identified nucleus) of ascending, but not descending colon of the elderly, and not in the cell nucleus of either region or age group (5,710 neurons analyzed: n = 12-14 for each group). It was concluded that increased p16 staining within the cytoplasm of myenteric nerve cell bodies of elderly ascending (but not descending) colon, suggests a region-dependent, post-mitotic cellular senescence-like activity, perhaps involved with aging of enteric neurons within the colon.

Prediction of stroke thrombolysis outcome using CT brain machine learning.

A critical decision-step in the emergency treatment of ischemic stroke is whether or not to administer thrombolysis - a treatment that can result in good recovery, or deterioration due to symptomatic intracranial haemorrhage (SICH). Certain imaging features based upon early computerized tomography (CT), in combination with clinical variables, have been found to predict SICH, albeit with modest accuracy. In this proof-of-concept study, we determine whether machine learning of CT images can predict which patients receiving tPA will develop SICH as opposed to showing clinical improvement with no haemorrhage. Clinical records and CT brains of 116 acute ischemic stroke patients treated with intravenous thrombolysis were collected retrospectively (including 16 who developed SICH). The sample was split into training (n = 106) and test sets (n = 10), repeatedly for 1760 different combinations. CT brain images acted as inputs into a support vector machine (SVM), along with clinical severity. Performance of the SVM was compared with established prognostication tools (SEDAN and HAT scores; original, or after adaptation to our cohort). Predictive performance, assessed as area under receiver-operating-characteristic curve (AUC), of the SVM (0.744) compared favourably with that of prognostic scores (original and adapted versions: 0.626-0.720; p < 0.01). The SVM also identified 9 out of 16 SICHs, as opposed to 1-5 using prognostic scores, assuming a 10% SICH frequency (p < 0.001). In summary, machine learning methods applied to acute stroke CT images offer automation, and potentially improved performance, for prediction of SICH following thrombolysis. Larger-scale cohorts, and incorporation of advanced imaging, should be tested with such methods.