Heterogeneity in Measures of Illness among Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Is Not Explained by Clinical Practice: A Study in Seven U.S. Specialty Clinics.

Background: One of the goals of the Multi-site Clinical Assessment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (MCAM) study was to evaluate whether clinicians experienced in diagnosing and caring for patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) recognized the same clinical entity. Methods: We enrolled participants from seven specialty clinics in the United States. We used baseline data (n = 465) on standardized questions measuring general clinical characteristics, functional impairment, post-exertional malaise, fatigue, sleep, neurocognitive/autonomic symptoms, pain, and other symptoms to evaluate whether patient characteristics differed by clinic. Results: We found few statistically significant and no clinically significant differences between clinics in their patients' standardized measures of ME/CFS symptoms and function. Strikingly, patients in each clinic sample and overall showed a wide distribution in all scores and measures. Conclusions: Illness heterogeneity may be an inherent feature of ME/CFS. Presenting research data in scatter plots or histograms will help clarify the challenge. Relying on case-control study designs without subgrouping or stratification of ME/CFS illness characteristics may limit the reproducibility of research findings and could obscure underlying mechanisms.

Physiological assessment of orthostatic intolerance in chronic fatigue syndrome.

BACKGROUND: Orthostatic intolerance-OI is common in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-ME/CFS. We used a 10-min passive vertical lean test as orthostatic challenge-OC and measured changes in vitals and end tidal CO2 (eTCO2). An abnormal physiologic response to OC was identified in 60% of the 63 patients evaluated from one to three times over several years. Hypocapnia, either resting or induced by OC, was the most frequent abnormality, followed by postural orthostatic tachycardia. OBJECTIVE: Evaluate the physiologic response of patients with ME/CFS to a standardized OC. DESIGN: Respiratory and heart rate, blood pressure and eTCO2 were recorded twice at the end of 10-min supine rest and then every minute during the 10-min lean. Hypocapnia was eTCO2 ≤ 32 mmHg. Orthostatic tachycardia was heart rate increase ≥ 30 beats per minute compared with resting or ≥ 120 BPM. Orthostatic hypotension was decreased systolic pressure ≥ 20 mmHg from baseline. Tachypnea was respiratory rate of  ≥ 20 breaths per minute-either supine or leaning. Questionnaire data on symptom severity, quality of life and mood were collected at visit #2. PATIENTS: 63 consecutive patients fulfilling the 1994 case definition for CFS underwent lean testing at first visit and then annually at visit 2 (n = 48) and 3 (n = 29). MEASURES: Supine hypocapnia; orthostatic tachycardia, hypocapnia or hypotension. RESULTS: The majority of ME/CFS patients (60.3%, 38/63) had an abnormality detected during a lean test at any visit (51%, 50% and 45% at visits 1, 2 and 3, respectively). Hypocapnia at rest or induced by OC was more common and more likely to persist than postural orthostatic tachycardia. Anxiety scores did not differ between those with and without hypocapnia. CONCLUSIONS: The 10-min lean test is useful in evaluation of OI in patients with ME/CFS. The most frequent abnormality, hypocapnia, would be missed without capnography.

Vagal nerve stimulation as a possible non-invasive treatment for chronic widespread pain in Gulf Veterans with Gulf War Illness.

AIMS: Widespread pain and headache are common in Gulf War Illness with suboptimal treatments available. We tested the efficacy of non-invasive, transcutaneous vagal nerve stimulation (nVNS) for relief of widespread pain and migraine in Gulf War Veterans with GWI. MAIN METHODS: A 10-week double-blind, randomized controlled trial of nVNS used the gammaCore (ElectroCore, Inc.) compared to sham stimulation with the same device followed by a 10-week open-label follow up with active nVNS. The primary outcome was a numerical pain rating at the end of the blinded period. Secondary outcomes included physical function, migraine frequency and severity, and impression of change during the blinded and open-label periods. Two-factor MANOVA models tested for significant differences between groups from baseline to end of the blinded period and during the open-label period. KEY FINDINGS: Among 27 participants enrolled and issued a nVNS device, there was a slight improvement in pain ratings from baseline to the end of the blinded phase [6.18 (±0.82) vs. 5.05 (±2.3); p = 0.040] which did not differ between active and sham nVNS. Physical function was also slightly improved overall without group differences. There were no significant changes in migraine frequency or severity during the blinded period. Twenty participants started in the open-label phase; no statistically significant changes in pain, physical function, migraine measures, or impression of change were noted during this phase. SIGNIFICANCE: Veterans with GWI actively treated with nVNS reported no improvement in either widespread pain or migraine frequency or severity relative to Veterans with GWI who received sham nVNS.

Multimodal and simultaneous assessments of brain and spinal fluid abnormalities in chronic fatigue syndrome and the effects of psychiatric comorbidity.

The purpose of this study was to investigate whether CFS patients without comorbid psychiatric diagnoses differ from CFS patients with comorbid psychiatric diagnoses and healthy control subjects in neuropsychological performance, the proportion with elevated spinal fluid protein or white cell counts, cerebral blood flow (CBF), brain ventricular lactate and cortical glutathione (GSH). The results of the study did not show any differences in any of the outcome measures between CFS patients with and without psychiatric comorbidity, thus indicating that psychiatric status may not be an exacerbating factor in CFS. Importantly, significant differences were found between the pooled samples of CFS compared to controls. These included lower GSH and CBF and higher ventricular lactate and rates of spinal fluid abnormalities in CFS patients compared to healthy controls. Thirteen of 26 patients had abnormal values on two or more of these 4 brain-related variables. These findings, which replicate the results of several of our prior studies, support the presence of a number of neurobiological and spinal fluid abnormalities in CFS. These results will lead to further investigation into objective biomarkers of the disorder to advance the understanding of CFS.

Multi-Site Clinical Assessment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (MCAM): Design and Implementation of a Prospective/Retrospective Rolling Cohort Study.

In the Multi-Site Clinical Assessment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (MCAM), we relied on expert clinician diagnoses to enroll patients from 7 specialty clinics in the United States in order to perform a systematic collection of data on measures of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS). Healthy persons and those with other illnesses that share some features with ME/CFS were enrolled in comparison groups. The major objectives were to: 1) use standardized questionnaires to measure illness domains of ME/CFS and to evaluate patient heterogeneity overall and between clinics; 2) describe the course of illness, identify the measures that best correlate with meaningful clinical differences, and assess the performances of questionnaires as patient/person-reported outcome measures; 3) describe prescribed medications, orders for laboratory and other tests, and management tools used by expert clinicians to care for persons with ME/CFS; 4) collect biospecimens for future hypothesis testing and for evaluation of morning cortisol profiles; and 5) identify measures that best distinguish persons with ME/CFS from those in the comparison groups and detect subgroups of persons with ME/CFS who may have different underlying causes. Enrollment began in 2012 and is planned to continue in multiple stages through 2017. We present the MCAM methods in detail, along with an initial description of the 471 patients with ME/CFS who were enrolled in stage 1.

Elevations of Ventricular Lactate Levels Occur in Both Chronic Fatigue Syndrome and Fibromyalgia.

BACKGROUND: Chronic fatigue syndrome (CFS) and fibromyalgia (FM) frequently have overlapping symptoms, leading to the suggestion that the same disease processes may underpin the two disorders - the unitary hypothesis. However, studies investigating the two disorders have reported substantial clinical and/or biological differences between them, suggesting distinct pathophysiological underpinnings. PURPOSE: The purpose of this study was to further add to the body of evidence favoring different disease processes in CFS and FM by comparing ventricular cerebrospinal fluid lactate levels among patients with CFS alone, FM alone, overlapping CFS and FM symptoms, and healthy control subjects. METHODS: Ventricular lactate was assessed in vivo with proton magnetic resonance spectroscopic imaging (1H MRSI) with the results normed across the 2 studies in which the data were collected. RESULTS: Mean CSF lactate levels in CFS, FM and CFS+FM did not differ among the three groups, but were all significantly higher than the mean values for control subjects. CONCLUSION: While patients with CFS, FM and comorbid CFS and FM can be differentiated from healthy subjects based on measures of CFS lactate, this neuroimaging outcome measure is not a viable biomarker for differentiating CFS from FM or from patients in whom symptoms of the two disorders overlap.

Effect of Milnacipran Treatment on Ventricular Lactate in Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Trial.

UNLABELLED: Milnacipran, a serotonin/norepinephrine reuptake inhibitor, has been approved by the US Food and Drug Administration for the treatment of fibromyalgia (FM). This report presents the results of a randomized, double-blind, placebo-controlled trial of milnacipran conducted to test the hypotheses that a) similar to patients with chronic fatigue syndrome, patients with FM have increased ventricular lactate levels at baseline; b) 8 weeks of treatment with milnacipran will lower ventricular lactate levels compared with baseline levels and with ventricular lactate levels after placebo; and c) treatment with milnacipran will improve attention and executive function in the Attention Network Test compared with placebo. In addition, we examined the results for potential associations between ventricular lactate and pain. Baseline ventricular lactate measured by proton magnetic resonance spectroscopic imaging was found to be higher in patients with FM than in healthy controls (F1,37 = 22.11, P < .0001, partial η(2) = .37). Milnacipran reduced pain in patients with FM relative to placebo but had no effect on cognitive processing. At the end of the study, ventricular lactate levels in the milnacipran-treated group had decreased significantly compared with baseline and after placebo (F1,18 = 8.18, P = .01, partial η(2) = .31). A significantly larger proportion of patients treated with milnacipran showed decreases in both ventricular lactate and pain than those treated with placebo (P = .03). These results suggest that proton magnetic resonance spectroscopic imaging measurements of lactate may serve as a potential biomarker for a therapeutic response in FM and that milnacipran may act, at least in part, by targeting the brain response to glial activation and neuroinflammation. PERSPECTIVE: Patients treated with milnacipran showed decreases in both pain and ventricular lactate levels compared with those treated with placebo, but, even after treatment, levels of ventricular lactate remained higher than in controls. The hypothesized mechanism for these decreases is via drug-induced reductions of a central inflammatory state.

Intrathecal baclofen therapy: complication avoidance and management.

PURPOSE: Intrathecal baclofen (ITB) therapy is an accepted treatment modality for spasticity and dystonia. Several complications related to ITB have been described, including mechanical malfunctions, infections, cerebrospinal fluid fistula, and baclofen withdrawal or overdose. In this study, we present our institutional experience with ITB therapy, emphasizing complication avoidance and lessons learned. METHODS: The charts of 87 patients treated with ITB therapy were retrospectively reviewed. The primary surgical technique, complication type and timing, method of treatment, and outcome were analyzed. RESULTS: Thirteen out of 76 (17.1%) patients primarily treated at our department had 25 complications. The first complication occurred 17.5-30.9 months (mean 24.2±6.7) after the pump implantation. Additional four patients with pumps placed elsewhere had six complications and were subsequently treated by our group. The main complications were: catheter fracture (11), subcutaneous fluid collection (5), lumbar wound/CSF infection (3), lumbar catheter or connector protrusion (3), pump malfunction (3), distal catheter migration outside the thecal sac (2), and baclofen withdrawal (1). Of the patients in the NYULMC group, six were treated by a single surgical procedure, six underwent multiple surgical procedures, and one was managed conservatively. In retrospect, changing the surgical technique, or adding an abdominal binder may have prevented 17 complications (54.8%). There were two deaths that were unrelated to the ITB therapy. CONCLUSION: ITB therapy is associated with complications, many of which require additional surgery. Some of these complications are avoidable by adhering to a strict surgical technique and a proper criterion for patient selection.