Survival and associated comorbidities in inclusion body myositis.

OBJECTIVE: To evaluate survival and associated comorbidities in inclusion body myositis (IBM) in a population-based, case-control study. METHODS: We utilized the expanded Rochester Epidemiology Project medical records-linkage system, including 27 counties in Minnesota and Wisconsin, to identify patients with IBM, other inflammatory myopathies (IIM), and age/sex-matched population-controls. We compared the frequency of various comorbidities and survival among groups. RESULTS: We identified 50 IBM patients, 65 IIM controls and 294 population controls. Dysphagia was most common in IBM (64%) patients. The frequency of neurodegenerative disorders (dementia/parkinsonism) and solid cancers was not different between groups. Rheumatoid arthritis was the most common rheumatic disease in all groups. A total of 36% of IBM patients had a peripheral neuropathy, 6% had Sjögren's syndrome and 10% had a haematologic malignancy. T-cell large granular lymphocytic leukaemia was only observed in the IBM group. None of the IBM patients had hepatitis B or C, or HIV. IBM patients were 2.7 times more likely to have peripheral neuropathy, 6.2 times more likely to have Sjögren's syndrome and 3.9 times more likely to have a haematologic malignancy than population controls. IBM was associated with increased mortality, with a 10-year survival of 36% from index, compared with 67% in IIM and 59% in population controls. Respiratory failure or pneumonia (44%) was the most common cause of death. CONCLUSIONS: IBM is associated with lower survival, and higher frequency of peripheral neuropathy, Sjögren's syndrome and haematologic malignancies than the general population. Close monitoring of IBM-related complications is warranted.

Correction to: Is the new ASNM intraoperative neuromonitoring supervision "guideline" a trustworthy guideline? A commentary.

The article Is the new ASNM intraoperative neuromonitoring supervision "guideline" a trustworthy guideline? A commentary, written by Stanley A. Skinner, Elif Ilgaz Aydinlar, Lawrence F. Borges, Bob S. Carter, Bradford L. Currier, Vedran Deletis, Charles Dong, John Paul Dormans, Gea Drost, Isabel Fernandez­Conejero, E. Matthew Hoffman, Robert N. Holdefer, Paulo Andre Teixeira Kimaid, Antoun Koht, Karl F. Kothbauer, David B. MacDonald, John J. McAuliffe III, David E. Morledge, Susan H. Morris, Jonathan Norton, Klaus Novak, Kyung Seok Park, Joseph H. Perra, Julian Prell, David M. Rippe, Francesco Sala, Daniel M. Schwartz, Martín J. Segura, Kathleen Seidel, Christoph Seubert, Mirela V. Simon, Francisco Soto, Jeffrey A. Strommen, Andrea Szelenyi, Armando Tello, Sedat Ulkatan, Javier Urriza and Marshall Wilkinson, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 05 January 2019 without open access. With the author(s)' decision to opt for Open Choice the copyright of the article changed on 30 January 2019 to © The Author(s) 2019 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. The original article has been corrected.

Incidence and disease burden of chemotherapy-induced peripheral neuropathy in a population-based cohort.

OBJECTIVE: To assess disease burden of chemotherapy-induced peripheral neuropathy (CIPN), which is a common dose-limiting side effect of neurotoxic chemotherapy. Late effects of CIPN may increase with improved cancer survival. METHODS: Olmsted County, Minnesota residents receiving neurotoxic chemotherapy were identified and CIPN was ascertained via text searches of polyneuropathy symptoms in the medical record. Clinical records were queried to collect data on baseline characteristics, risk factors, signs and symptoms of CIPN, medications, impairments and International Classification of Diseases, Ninth Revision (ICD-9) diagnostic codes for all subjects. RESULTS: A total of 509 individuals with incident exposure to an inclusive list of neurotoxic chemotherapy agents between 2006 and 2008 were identified. 268 (52.7%) of these individuals were determined to have CIPN. The median time from incident exposure to first documented symptoms was 71 days. Patients with CIPN received a neuropathy ICD-9 diagnosis in only 37 instances (13.8%). Pain symptoms and use of pain medications were observed more often in patients with CIPN. Five-year survival was greater in those with CIPN (55.2%) versus those without (36.1%). Those with CIPN surviving greater than 5 years (n=145) continued to have substantial impairments and were more likely to be prescribed opioids than those without CIPN (OR 2.0, 1.06-3.69). CONCLUSIONS: Results from our population-based study are consistent with previous reports of high incidence of CIPN in the first 2 years following incident exposure to neurotoxic chemotherapeutic agents, and its association with significant pain symptomatology and accompanied long-term opioid use. Increased survival following exposure to neurotoxic chemotherapy and its long-term disease burden necessitates further study among survivors.

Association of Long-term Opioid Therapy With Functional Status, Adverse Outcomes, and Mortality Among Patients With Polyneuropathy.

Importance: Polyneuropathy is one of the most common painful conditions managed within general and specialty clinics. Neuropathic pain frequently leads to decisions about using long-term opioid therapy. Understanding the association of long-term opioid use with functional status, adverse outcomes, and mortality among patients with polyneuropathy could influence disease-specific decisions about opioid treatment. Objectives: To quantify the prevalence of long-term opioid use among patients with polyneuropathy and to assess the association of long-term opioid use with functional status, adverse outcomes, and mortality. Design, Setting, and Participants: A retrospective population-based cohort study was conducted of prescriptions given to patients with polyneuropathy and to controls in ambulatory practice between January 1, 2006, and December 31, 2010, to determine exposure to long-term opioid use as well as other outcomes. The latest follow-up was conducted through November 25, 2016. Exposures: Long-term opioid therapy, defined by 1 or multiple consecutive opioid prescriptions resulting in 90 continuous days or more of opioid use. Main Outcomes and Measures: Prevalence of long-term opioid therapy among patients with polyneuropathy and controls. Patient-reported functional status, documented adverse outcomes, and mortality were compared between patients with polyneuropathy receiving long-term opioid therapy (≥90 days) and patients with polyneuropathy receiving shorter durations of opioid therapy. Results: Among the 2892 patients with polyneuropathy (1364 women and 1528 men; mean [SD] age, 67.5 [16.6] years) and the 14 435 controls (6827 women and 7608 men; mean [SD] age, 67.5 [16.5] years), patients with polyneuropathy received long-term opioids more often than did controls (545 [18.8%] vs 780 [5.4%]). Patients with polyneuropathy who were receiving long-term opioids had multiple functional status markers that were modestly poorer even after adjusting for medical comorbidity, including increased reliance on gait aids (adjusted odds ratio, 1.9; 95% CI, 1.4-2.6); no functional status markers were improved by long-term use of opioids. Adverse outcomes were more common among patients with polyneuropathy receiving long-term opioids, including depression (adjusted hazard ratio, 1.53; 95% CI, 1.29-1.82), opioid dependence (adjusted hazard ratio, 2.85; 95% CI, 1.54-5.47), and opioid overdose (adjusted hazard ratio, 5.12; 95% CI, 1.63-19.62). Conclusions and Relevance: Polyneuropathy increased the likelihood of long-term opioid therapy. Chronic pain itself cannot be ruled out as a source of worsened functional status among patients receiving long-term opioid therapy. However, long-term opioid therapy did not improve functional status but rather was associated with a higher risk of subsequent opioid dependency and overdose.

Glutaminase Increases in Rat Dorsal Root Ganglion Neurons after Unilateral Adjuvant-Induced Hind Paw Inflammation.

Glutamate is a neurotransmitter used at both the peripheral and central terminals of nociceptive primary sensory neurons, yet little is known concerning regulation of glutamate metabolism during peripheral inflammation. Glutaminase (GLS) is an enzyme of the glutamate-glutamine cycle that converts glutamine into glutamate for neurotransmission and is implicated in producing elevated levels of glutamate in central and peripheral terminals. A potential mechanism for increased levels of glutamate is an elevation in GLS expression. We assessed GLS expression after unilateral hind paw inflammation by measuring GLS immunoreactivity (ir) with quantitative image analysis of L4 dorsal root ganglion (DRG) neurons after one, two, four, and eight days of adjuvant-induced arthritis (AIA) compared to saline injected controls. No significant elevation in GLS-ir occurred in the DRG ipsilateral to the inflamed hind paw after one or two days of AIA. After four days AIA, GLS-ir was elevated significantly in all sizes of DRG neurons. After eight days AIA, GLS-ir remained elevated in small (<400 µm²), presumably nociceptive neurons. Western blot analysis of the L4 DRG at day four AIA confirmed the elevated GLS-ir. The present study indicates that GLS expression is increased in the chronic stage of inflammation and may be a target for chronic pain therapy.

Impairments and comorbidities of polyneuropathy revealed by population-based analyses.

OBJECTIVE: To quantify polyneuropathy impairments and comorbidities utilizing the Rochester Epidemiology Project (2010 census = 148,201). METHODS: ICD-9-CM coding identified polyneuropathy cases (2006-2010) and their 5:1 age- and sex-matched controls. Mortality and impairments were evaluated while identifying and adjusting for Charlson Index comorbidities. RESULTS: Overall prevalence of polyneuropathy was 1.66%, and markedly rose to 6.6% in persons older than 60 years. Cases (n = 2,892) had more comorbidities than controls (n = 14,435) with higher median Charlson Index (6 vs 3, p < 0.001). Diabetes with end-organ disease represented the largest increased comorbidity in cases compared with controls (46.8% vs 6.5%). Diabetic polyneuropathy was the most common specific subtype (38.2%). Miscoded idiopathic cases and false-negative controls also commonly had diabetic polyneuropathy. Median modified Rankin Scale score was considerably higher for cases than controls (4 vs 1, p < 0.001). Multiple comorbidities were found associated with polyneuropathy after adjusting for diabetes co-occurrence, including pulmonary disease, dementia, and others. Polyneuropathy was an independent contributor to multiple functional impairments including difficulty walking (odds ratio [OR] = 1.9), climbing stairs (OR = 2.0), using an assistive device (OR = 2.0), fall tendency (OR = 2.4), work disability (OR = 4.2), lower limb amputations (OR = 3.9), and opioid use (OR = 2.7). Prevalent cases had a younger median age at death than controls (80 vs 86 years, p < 0.001), and incident cases had a 6-month shorter survival. CONCLUSIONS: Polyneuropathies have notable neurologic impairments beyond their identified multiple comorbidities. Life expectancy is shortened. Diabetic polyneuropathy is underidentified. The quantified extent of the disease burden and refined comorbidity associations emphasize that greater research efforts and health care initiatives are needed.

Interictal scalp electroencephalography and intraoperative electrocorticography in magnetic resonance imaging-negative temporal lobe epilepsy surgery.

IMPORTANCE: Scalp electroencephalography (EEG) and intraoperative electrocorticography (ECoG) are routinely used in the evaluation of magnetic resonance imaging-negative temporal lobe epilepsy (TLE) undergoing standard anterior temporal lobectomy with amygdalohippocampectomy (ATL), but the utility of interictal epileptiform discharge (IED) identification and its role in outcome are poorly defined. OBJECTIVES: To determine whether the following are associated with surgical outcomes in patients with magnetic resonance imaging-negative TLE who underwent standard ATL: (1) unilateral-only IEDs on preoperative scalp EEG; (2) complete resection of tissue generating IEDs on ECoG; (3) complete resection of opioid-induced IEDs recorded on ECoG; and (4) location of IEDs recorded on ECoG. DESIGN, SETTING, AND PARTICIPANTS: Data were gathered through retrospective medical record review at a tertiary referral center. Adult and pediatric patients with TLE who underwent standard ATL between January 1, 1990, and October 15, 2010, were considered for inclusion. Inclusion criteria were magnetic resonance imaging-negative TLE, standard ECoG performed at the time of surgery, and a minimum follow-up of 12 months. Univariate analysis was performed using log-rank time-to-event analysis. Variables reaching significance with log-rank testing were further analyzed using Cox proportional hazards. MAIN OUTCOMES AND MEASURES: Excellent or nonexcellent outcome at time of last follow-up. An excellent outcome was defined as Engel class I and a nonexcellent outcome as Engel classes II through IV. RESULTS: Eighty-seven patients met inclusion criteria, with 48 (55%) achieving an excellent outcome following ATL. Unilateral IEDs on scalp EEG (P = .001) and complete resection of brain regions generating IEDs on baseline intraoperative ECoG (P = .02) were associated with excellent outcomes in univariate analysis. Both were associated with excellent outcomes when analyzed with Cox proportional hazards (unilateral-only IEDs, relative risk = 0.31 [95% CI, 0.16-0.64]; complete resection of IEDs on baseline ECoG, relative risk = 0.39 [95% CI, 0.20-0.76]). Overall, 25 of 35 patients (71%) with both unilateral-only IEDs and complete resection of baseline ECoG IEDs had an excellent outcome. CONCLUSIONS AND RELEVANCE: Unilateral-only IEDs on preoperative scalp EEG and complete resection of IEDs on baseline ECoG are associated with better outcomes following standard ATL in magnetic resonance imaging-negative TLE. Prospective evaluation is needed to clarify the use of ECoG in tailoring temporal lobectomy.

Glutamate pharmacology and metabolism in peripheral primary afferents: physiological and pathophysiological mechanisms.

In addition to using glutamate as a neurotransmitter at central synapses, many primary sensory neurons release glutamate from peripheral terminals. Primary sensory neurons with cell bodies in dorsal root or trigeminal ganglia produce glutaminase, the synthetic enzyme for glutamate, and transport the enzyme in mitochondria to peripheral terminals. Vesicular glutamate transporters fill neurotransmitter vesicles with glutamate and they are shipped to peripheral terminals. Intense noxious stimuli or tissue damage causes glutamate to be released from peripheral afferent nerve terminals and augmented release occurs during acute and chronic inflammation. The site of action for glutamate can be at the autologous or nearby nerve terminals. Peripheral nerve terminals contain both ionotropic and metabotropic excitatory amino acid receptors (EAARs) and activation of these receptors can lower the activation threshold and increase the excitability of primary afferents. Antagonism of EAARs can reduce excitability of activated afferents and produce antinociception in many animal models of acute and chronic pain. Glutamate injected into human skin and muscle causes acute pain. Trauma in humans, such as arthritis, myalgia, and tendonitis, elevates glutamate levels in affected tissues. There is evidence that EAAR antagonism at peripheral sites can provide relief in some chronic pain sufferers.

Fixative composition alters distributions of immunoreactivity for glutaminase and two markers of nociceptive neurons, Nav1.8 and TRPV1, in the rat dorsal root ganglion.

Most, if not all, dorsal root ganglion (DRG) neurons use the neurotransmitter glutamate. There are, however, conflicting reports of the percentages of DRG neurons that express glutaminase (GLS), the enzyme that synthesizes glutamate, ranging from 30% to 100% of DRG neurons. Defining DRG neuron populations by the expression of proteins like GLS, which indicates function, is routinely accomplished with immunolabeling techniques. Proper characterization of DRG neuron populations relies on accurate detection of such antigens. It is known intuitively that fixation can alter immunoreactivity (IR). In this study, we compared the effects of five formaldehyde concentrations between 0.25% and 4.0% (w/v) and five picric acid concentrations between 0.0% and 0.8% (w/v) on the IR of GLS, the voltage-gated sodium channel 1.8 (Na(v)1.8), and the capsaicin receptor TRPV1. We also compared the effects of five incubation time lengths from 2 to 192 hr, in primary antiserum on IR. Lowering formaldehyde concentration elevated IR for all three antigens, while raising picric acid concentration increased Na(v)1.8 and TRPV1 IR. Increasing IR improved detection sensitivity, which led to higher percentages of labeled DRG neurons. By selecting fixation conditions that optimized IR, we found that all DRG neurons express GLS, 69% of neurons express Na(v)1.8, and 77% of neurons express TRPV1, indicating that some previous studies may have underestimated the percentages of DRG neurons expressing these proteins. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.