Quantitative assessment of painful diabetic peripheral neuropathy after high-frequency spinal cord stimulation: a pilot study.

OBJECTIVE: Randomized trials have demonstrated efficacy of spinal cord stimulation (SCS) for treatment of painful diabetic neuropathy (PDN). Preliminary data suggested that treatment of PDN with high-frequency SCS resulted in improvements on neurological examination. The purpose of the present study was to explore whether patients with PDN treated with high-frequency SCS would have improvements in lower-extremity peripheral nerve function. DESIGN: Prospective cohort study in an outpatient clinical practice at a tertiary care center. METHODS: Patients with PDN were treated with high-frequency SCS and followed up for 12 months after SCS implantation with clinical outcomes assessments of pain intensity, neuropathic symptoms, and neurological function. Small-fiber sudomotor function was assessed with the quantitative sudomotor axon reflex test (QSART), and large-fiber function was assessed with nerve conduction studies (NCS). Lower-extremity perfusion was assessed with laser Doppler flowmetry. RESULTS: Nine patients completed 12-month follow-up visits and were observed to have improvements in lower-extremity pain, weakness, and positive sensory symptoms. Neuropathy impairment scores were improved, and 2 patients had recovery of sensory responses on NCS. A reduction in sweat volume on QSART was observed in the proximal leg but not at other sites. No significant differences were noted in lower-extremity perfusion or NCS as compared with baseline. CONCLUSIONS: The improvement in pain relief was concordant with improvement in neuropathy symptoms. The findings from this study provide encouraging preliminary data in support of the hypothesis of a positive effect of SCS on peripheral neuropathy, but the findings are based on small numbers and require further evaluation. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT03769675.

Pain and the immune system: emerging concepts of IgG-mediated autoimmune pain and immunotherapies.

The immune system has long been recognised important in pain regulation through inflammatory cytokine modulation of peripheral nociceptive fibres. Recently, cytokine interactions in brain and spinal cord glia as well as dorsal root ganglia satellite glia have been identified important- in pain modulation. The result of these interactions is central and peripheral sensitisation of nociceptive processing. Additionally, new insights and the term 'autoimmune pain' have emerged through discovery of specific IgGs targeting the extracellular domains of antigens at nodal and synaptic structures, causing pain directly without inflammation by enhancing neuronal excitability. Other discovered IgGs heighten pain indirectly by T-cell-mediated inflammation or destruction of targets within the nociceptive pathways. Notable identified IgGs in pain include those against the components of channels and receptors involved in inhibitory or excitatory somatosensory synapses or their pathways: nodal and paranodal proteins (LGI1, CASPR1, CASPR2); glutamate detection (AMPA-R); GABA regulation and release (GAD65, amphiphysin); glycine receptors (GLY-R); water channels (AQP4). These disorders have other neurological manifestations of central/peripheral hyperexcitabability including seizures, encephalopathy, myoclonus, tremor and spasticity, with immunotherapy responsiveness. Other pain disorders, like complex regional pain disorder, have been associated with IgGs against ß2-adrenergic receptor, muscarinic-2 receptors, AChR-nicotinic ganglionic α-3 receptors and calcium channels (N and P/Q types), but less consistently with immune treatment response. Here, we outline how the immune system contributes to development and regulation of pain, review specific IgG-mediated pain disorders and summarise recent development in therapy approaches. Biological agents to treat pain (anti-calcitonin gene-related peptide and anti-nerve growth factor) are also discussed.

Spinal Cord Stimulation for Neuropathic Pain Treatment in Brachial Plexus Avulsions: A Literature Review and Report of Two Cases.

BACKGROUND: At least 50% of individuals who suffer a brachial plexus avulsion (BPA) will develop chronic pain, frequently more debilitating than their functional limitations. Similar to other neuropathic pain states, BPA pain is often refractory to pharmacological agents. Despite spinal cord stimulation (SCS) first being used for BPA in 1974, there have been no published literature reviews examining the current evidence of SCS for the treatment of neuropathic pain following BPA. In addition to a clinical review of the literature for this indication, we also share our experience with high-frequency SCS (HF-SCS) for BPA-related pain. METHODS: MEDLINE and EMBASE databases were searched. All published articles including at least one BPA individual treated with SCS for pain treatment were included. RESULTS: The initial search identified 288 articles, of which 13 met inclusion criteria for a total of 41 patients. These patients were primarily male and underwent SCS with reported improved pain scores. CASE REPORTS: HF-SCS leads were percutaneously placed in two male patients who suffered BPA from traumatic injuries. At follow-ups of 13 and eight months, respectively, both patients continued to report an improvement in their pain. CONCLUSIONS: Despite published reports showing benefit for pain control in patients with BPA, the overall low quality, retrospective evidence included in this review highlights the need for a rigorous prospective study to further address this indication.

Occipital neuralgia associates with high cervical spinal cord lesions in idiopathic inflammatory demyelinating disease.

BACKGROUND: The association of trigeminal neuralgia with pontine lesions has been well documented in multiple sclerosis, and we tested the hypothesis that occipital neuralgia in multiple sclerosis is associated with high cervical spinal cord lesions. METHODS: We retrospectively reviewed the records of 29 patients diagnosed with both occipital neuralgia and demyelinating disease by a neurologist from January 2001 to December 2014. We collected data on demographics, clinical findings, presence of C2-3 demyelinating lesions, and treatment responses. RESULTS: The patients with both occipital neuralgia and multiple sclerosis were typically female (76%) and had a later onset (age > 40) of occipital neuralgia (72%). Eighteen patients (64%) had the presence of C2-3 lesions and the majority had unilateral symptoms (83%) or episodic pain (78%). All patients with documented sensory loss (3/3) had C2-3 lesions. Most patients with progressive multiple sclerosis (6/8) had C2-3 lesions. Of the eight patients with C2-3 lesions and imaging at onset of occipital neuralgia, five (62.5%) had evidence of active demyelination. None of the patients with progressive multiple sclerosis (3/3) responded to occipital nerve blocks or high dose intravenous steroids, whereas all of the other phenotypes with long term follow-up (eight patients) had good responses. CONCLUSIONS: A cervical spine MRI should be considered in all patients presenting with occipital neuralgia. In patients with multiple sclerosis, clinical features in occipital neuralgia that were predictive of the presence of a C2-3 lesion were unilateral episodic symptoms, sensory loss, later onset of occipital neuralgia, and progressive multiple sclerosis phenotype. Clinical phenotype predicted response to treatment.

Amyotrophic lateral sclerosis and anesthesia: a case series and review of the literature.

PURPOSE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to death due to respiratory failure. This report describes the perioperative characteristics of ALS patients who underwent procedures with anesthesia at our institution. METHODS: We reviewed perioperative records of ALS patients who underwent procedures with anesthesia from January 1, 2014, through December 31, 2015. RESULTS: Seventy-eight patients underwent 89 procedures (71 procedures with monitored anesthesia care and 18 with general anesthesia), including 45 gastrostomy tube placements and 18 bone marrow biopsies. Three patients had prolonged duration of postoperative intubation related to preexisting respiratory muscle weakness, and one patient with bilateral pneumothorax required tracheal reintubation for respiratory distress. Four patients had prolonged duration of hospitalization. Three patients were hospitalized for ALS-related complications, and one patient was hospitalized for respiratory distress when pneumoperitoneum developed after gastrostomy tube placement. Three of these patients died of complications attributable to ALS within 30 days of the procedure. Twenty-nine (32.6%) procedures required minimal sedation (e.g., bone marrow biopsy, cataract surgery) and were performed on an ambulatory basis. CONCLUSION: When caring for patients with ALS, the perioperative team must be prepared to treat potentially complex medical conditions that may not be directly related to the procedure and anesthetic management. However, minor procedures performed with minimal sedation may be safely performed on an ambulatory basis.

Erythromelalgia: Identification of a corticosteroid-responsive subset.

BACKGROUND: Corticosteroids (CS) may benefit certain patients with erythromelalgia. OBJECTIVES: Our objective was to determine clinical predictors of corticosteroid-responsive erythromelalgia. METHODS: Patients with erythromelalgia who received CS were identified and stratified into corticosteroid nonresponders (NRs), partial corticosteroid responders (PSRs), complete corticosteroid responders (CSRs), and steroid responders (SRs = PSRs + CSRs). In the study variable analysis, P < .05 was considered statistically significant. RESULTS: The median (interquartile range) age of the 31-patient cohort was 47 years (26-57 years), and 22 (71%) were female. Fourteen (45%) were NRs, 17 (55%) SRs, 8 (26%) PSRs, and 9 (29%) CSRs. A subacute temporal profile to disease zenith (<21 days) was described in 15 (48%) patients, of whom 13 (87%) were SRs (P = .003; odds ratio [OR] = 0.069 [95% confidence interval {CI}, 0.011-0.431]). Six (67%) CSRs reported a disease precipitant (eg, surgery, trauma, or infection; P = .007; OR = 12.667 [95% CI, 2-80.142]). SR patients received CS sooner than NR at 3 (3-12) versus 24 (17-45) months (P = .003). A high-dose CS trial (≥200 mg prednisone cumulatively) was administered to 17 (55%) patients, of whom 13 (76%) were SRs (P = .012; OR = 8.125 [95% CI, 1.612-40.752]). LIMITATIONS: This was a retrospective case series. CONCLUSION: An infectious, traumatic, or surgical precipitant and subacute presentation may portend CR erythromelalgia. A transient "golden window" where CS intervention is useful may exist before irreversible nociceptive remodeling and central sensitization occurs.

Clinical, electrophysiologic, and imaging features of zoster-associated limb paresis.

INTRODUCTION: Paresis is a long-recognized complication of herpes zoster, but there has been comparatively little study of zoster-associated limb paresis (ZALP). METHODS: In this study we reviewed 49 Mayo Clinic patients with ZALP. RESULTS: The mean age of onset was 71 years, 67% were men, and the lower limb was affected in 55%. The mean weakness score was 2.0 (0 = normal strength, 4 = plegia). Most patients developed postherpetic neuralgia (PHN, 92% at 1 month and 65% at 3 months), and the average minimum duration of weakness was 193 days. ZALP was caused by radiculopathy (37%), plexopathy (41%), mononeuropathy (14%), and radiculoplexus neuropathy (8%). MRI demonstrated nerve enlargement, T2 signal prolongation, or enhancement in a majority (64%) of affected plexi and peripheral nerves. CONCLUSIONS: ZALP is associated with considerable weakness. It typically lasts at least several months, localizes to plexus or peripheral nerve in 63%, and is associated with high rates of PHN.

Diaphragm depth in normal subjects.

INTRODUCTION: Needle electromyography (EMG) of the diaphragm carries the potential risk of pneumothorax. Knowing the approximate depth of the diaphragm should increase the test's safety and accuracy. METHODS: Distances from the skin to the diaphragm and from the outer surface of the rib to the diaphragm were measured using B mode ultrasound in 150 normal subjects. RESULTS: When measured at the lower intercostal spaces, diaphragm depth varied between 0.78 and 4.91 cm beneath the skin surface and between 0.25 and 1.48 cm below the outer surface of the rib. Using linear regression modeling, body mass index (BMI) could be used to predict diaphragm depth from the skin to within an average of 1.15 mm. CONCLUSIONS: Diaphragm depth from the skin can vary by more than 4 cm. When image guidance is not available to enhance accuracy and safety of diaphragm EMG, it is possible to reliably predict the depth of the diaphragm based on BMI.

Therapeutic strategies for cancer treatment related peripheral neuropathies.

OPINION STATEMENT: Chemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity associated with multiple chemotherapeutic agents. CIPN may have a detrimental impact on patients' quality of life and functional ability, as well as result in chemotherapy dose reductions. Although symptoms of CIPN can improve with treatment completion, symptoms may persist. Currently, the treatment options for CIPN are quite limited. Duloxetine, a serotonin-norepinephrine reuptake inhibitor, has the most evidence supporting its use in the treatment of CIPN. Other agents with potential benefit for the treatment of established CIPN include gabapentinoids, venlafaxine, tricyclic antidepressants, and a topical gel consisting of the combination of amitriptyline, ketamine, and baclofen; none of these, however, has been proven to be helpful and ongoing/future studies may well show that they are not beneficial. The use of these agents is often based on their efficacy in the treatment of non-CIPN neuropathic pain, but this does not necessarily mean that they will be helpful for CIPN-related symptoms. Other nonpharmacologic interventions including acupuncture and Scrambler therapy are supported by positive preliminary data; however, further larger, placebo-controlled trial data are needed to confirm or refute their effectiveness.

Management options for established chemotherapy-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating condition associated with a variety of chemotherapeutic agents. Clinicians are cognizant of the negative impact of CIPN on cancer treatment outcomes and patients' psychosocial functioning and quality of life. In an attempt to alleviate this problem, clinicians and patients try various therapeutic interventions, despite limited evidence to support efficacy of these treatments. The rationale for such use is mostly based on the evidence for the treatment options in non-CIPN peripheral neuropathy syndromes, as this area is more robustly studied than is CIPN treatment. In this manuscript, we examine the existing evidence for both CIPN and non-CIPN treatments and develop a summary of the best available evidence with the aim of developing a practical approach to the treatment of CIPN, based on available literature and clinical practice experience.

Impact of preoperative therapy on patterns of recurrence in pancreatic cancer.

BACKGROUND: A theoretical advantage of preoperative therapy in pancreatic adenocarcinoma is that it facilitates the early treatment of micrometastases and reduces postoperative systemic recurrence. METHODS: Medical records of 309 consecutive patients undergoing resection of adenocarcinoma in the head of the pancreas were reviewed. Survival was calculated using the Kaplan-Meier method. Associations between preoperative therapy and patterns of recurrence were determined using chi-squared analysis. RESULTS: Preoperative therapy was administered to 108 patients and upfront surgery was performed in 201 patients. Preoperative therapy was associated with a significantly longer median disease-free survival of 14 months compared with 12 months in patients submitted to upfront surgery (P = 0.035). The rate of local disease as a component of first site of recurrence was significantly lower with preoperative therapy (11.3%) than with upfront surgery (22.9%) (P = 0.016). Preoperative therapy was associated with a lower rate of hepatic metastasis (21.7%) than upfront surgery (34.3%) (P = 0.026). Preoperative therapy did not affect rates of peritoneal or pulmonary metastasis. CONCLUSIONS: Preoperative therapy for pancreatic cancer was associated with longer disease-free survival and lower rates of local and hepatic recurrences. These data support the use of preoperative therapy to reduce systemic and local failures after resection.

Corticosteroid Therapy in Acute and Subacute Arachnoiditis - A Case Series.

Arachnoiditis is difficult to treat. Patients are often left frustrated after many failed trials of conservative therapies without symptom resolution. Surgery may provide symptom relief for a short period of time, but their pain often returned. Herein, we present three cases of acute arachnoiditis following three different pain procedures: epidural blood patch, IDDS implant, and epidural steroid injection. The patients were diagnosed and treated with corticosteroids within 10 days of the procedure. Two patients were treated with the same oral steroid regiment, while the third patient was treated with both oral and IV steroid. All three patients had good outcomes at the completion of their steroid therapy. This case series may provide insight into treating acute and subacute arachnoiditis from pain interventions.

Two-dimensional ultrasound imaging of the diaphragm: quantitative values in normal subjects.

INTRODUCTION: Real time ultrasound imaging of the diaphragm is an under-used tool in the evaluation of patients with unexplained dyspnea or respiratory failure. METHODS: We measured diaphragm thickness and the change in thickness that occurs with maximal inspiration in 150 normal subjects, with results stratified for age, gender, body mass index, and smoking history. RESULTS: The lower limit of normal diaphragm thickness at end expiration or functional residual capacity is 0.15 cm, and an increase of at least 20% in diaphragm thickness from functional residual capacity to total lung capacity is normal. A side to side difference in thickness at end expiration of > 0.33 cm is abnormal. Diaphragm thickness and contractility are minimally affected by age, gender, body habitus, or smoking history. CONCLUSIONS: This study confirms previous findings in much smaller groups of normal controls for quantitative ultrasound of the diaphragm and provides data that can be applied widely to the general population.

Outcome and natural history of patients with stage IV colorectal cancer receiving chemotherapy without primary tumor resection.

BACKGROUND: There is a trend toward nonsurgical management of patients with nonobstructing metastatic (stage IV) colorectal cancer (CRC), although some will eventually undergo surgery. We examined patients with metastatic CRC who were managed with an intact primary tumor. METHODS: An institutional review board (IRB)-approved database was retrospectively reviewed. All patients presenting with stage IV CRC from 2000 to 2008 were identified and analyzed. RESULTS: Among the 255 patients identified, 112 were taken directly to the operating room for either primary tumor resection or colostomy/bypass. Among the remaining 143 patients, 97 were managed without developing primary tumor-related symptoms, and 14 (9.8%) developed significant primary tumor-related symptoms necessitating operative or endoscopic management. Of the patients who developed symptoms, oxaliplatin and/or irinotecan was used among 71.4% of patients, and bevacizumab in 50%. Forty-two patients in the series underwent elective primary tumor resection after receiving chemotherapy. No independent predictors for development of primary tumor-related symptoms could be identified after controlling for age, gender, tumor location, number of metastatic sites, and type of chemotherapy. Median overall survival was 34 months for those who underwent elective primary tumor resection after chemotherapy, and 16 months for those who failed chemotherapy and developed symptoms. CONCLUSIONS: Among patients with metastatic CRC without an initial indication for surgery, incidence of obstruction or perforation after initiating chemotherapy was low (9.8%). No predictors of primary tumor-related complications could be identified. Survival was favorable among the highly selected cohort of patients who underwent elective primary tumor resection after chemotherapy.

Phase II trial of neoadjuvant/adjuvant imatinib mesylate for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumors: long-term follow-up results of Radiation Therapy Oncology Group 0132.

BACKGROUND: Imatinib inhibits the KIT and PDGFR tyrosine kinases, resulting in its notable antitumor activity in gastrointestinal stromal tumor (GIST). We previously reported the early results of a multi-institutional prospective trial (RTOG 0132) using neoadjuvant/adjuvant imatinib either in primary resectable GIST or as a planned preoperative cytoreduction agent for metastatic/recurrent GIST. METHODS.: Patients with primary GIST (≥5 cm, group A) or resectable metastatic/recurrent GIST (≥2 cm, group B) received neoadjuvant imatinib (600 mg/day) for approximately 2 months and maintenance postoperative imatinib for 2 years. We have now updated the clinical outcomes including progression-free survival, disease-specific survival, and overall survival at a median follow-up of 5.1 years, and we correlate these end points with duration of imatinib therapy. RESULTS: Sixty-three patients were originally entered (53 analyzable: 31 in group A and 22 in group B). Estimated 5-year progression-free survival and overall survival were 57% in group A, 30% in group B; and 77% in group A, 68% in group B, respectively. Median time to progression has not been reached for group A and was 4.4 years for group B. In group A, in 7 of 11 patients, disease progressed >2 years from registration; 6 of 7 patients with progression had stopped imatinib before progression. In group B, disease progressed in 10 of 13 patients>2 years from registration; 6 of 10 patients with progressing disease had stopped imatinib before progression. There was no significant increase in toxicity compared with our previous short-term analysis. CONCLUSIONS: This long-term analysis suggests a high percentage of patients experienced disease progression after discontinuation of 2-year maintenance imatinib therapy after surgery. Consideration should be given to studying longer treatment durations in intermediate- to high-risk GIST patients.

Zoster-associated mononeuropathies (ZAMs): a retrospective series.

INTRODUCTION: Zoster-associated limb paresis is an uncommon complication of herpes zoster (HZ) and one whose precise pathophysiologic mechanism is poorly understood. Occasionally, the paresis results from a zoster-associated mononeuropathy (ZAM). METHODS: Mayo Clinic records between 1996 and 2010 were reviewed for patients with ZAM whose clinical, electrophysiologic, and radiographic features were then abstracted. RESULTS: Ulnar (2), median (3), femoral (1), and sciatic (2) mononeuropathies were identified. Most patients had moderate to severe weakness in affected muscles, and most had post-herpetic neuralgia (88% at 1 month and 71% at 4 months). The minimum duration of weakness was prolonged (mean, 281.9 days; range, 45-1242 days). Nerve magnetic resonance imaging (MRI) was abnormal, demonstrating nerve enlargement (4/4 cases), T2 signal hypertintensity (2/4 cases), or enhancement (1/4 cases). CONCLUSIONS: While ZAM is an uncommon occurrence following cutaneous HZ, it is associated with significant weakness, high rates of post-herpetic neuralgia, and prolonged morbidity.

Hematoma risk after needle electromyography.

INTRODUCTION: Although needle electromyography (EMG) appears to be a relatively safe procedure based primarily on clinical experience, no evidence-based guidelines exist for EMG procedures in patients taking anticoagulant or antiplatelet medications. We sought to determine whether there is an increased risk of hematoma formation after EMG of potentially high-risk muscles in patients taking anticoagulant or antiplatelet agents. METHODS: After undergoing routine EMG, if any of seven predetermined high-risk muscles were tested, study subjects then underwent ultrasound to evaluate for hematoma formation. RESULTS: Patients were divided into three groups based on medication (warfarin, aspirin/clopidogrel, no blood-thinning medication), with at least 100 muscles examined per group. Two small, subclinical hematomas were seen on ultrasound; there was no difference in hematoma risk between groups (P = 0.43). CONCLUSIONS: Our findings suggest that hematoma formation from standard needle EMG is rare even in high-risk muscles, which have been avoided historically in anticoagulated patients.

Comparative Effectiveness of Landmark-guided Greater Occipital Nerve (GON) Block at the Superior Nuchal Line Versus Ultrasound-guided GON Block at the Level of C2: A Randomized Clinical Trial (RCT).

OBJECTIVES: The purpose of this single center, prospective randomized controlled trial was to compare clinical outcomes between an ultrasound-guided greater occipital nerve block (GONB) at the C2 vertebral level versus landmark-based GONB at the superior nuchal line. METHODS: Patients with occipital neuralgia or cervicogenic headache were randomized to receive either a landmark-based GONB with sham ultrasound at the superior nuchal line or ultrasound-guided GONB at the C2 vertebral level with blinding of patients and data analysis investigators. Clinical outcomes were assessed at 30 minutes, 2 weeks, and 4 weeks postinjection. RESULTS: Thirty-two patients were recruited with 16 participants in each group. Despite randomization, the ultrasound-guided GONB group reported higher numeric rating scale (NRS) scores at baseline. Those in the ultrasound-guided GONB group had a significant decrease in NRS from baseline compared with the landmark-based GONB group at 30 minutes (change of NRS of 4.0 vs. 2.0) and 4-week time points (change of NRS of 2.5 vs. -0.5). Both groups were found to have significant decreases in Headache Impact Test-6. The ultrasound-guided GONB had significant improvements in NRS, severe headache days, and analgesic use at 4 weeks when compared with baseline. No serious adverse events occurred in either group. CONCLUSIONS: Ultrasound-guided GONBs may provide superior pain reduction at 4 weeks when compared with landmark-based GONBs for patients with occipital neuralgia or cervicogenic headache.