Epidemiology of Spontaneous Cervical Artery Dissection: Population-Based Study.

BACKGROUND: Cervical artery dissection (CeAD) represents up to 15% to 25% of ischemic strokes in people under the age of 50 years. Noninvasive vessel imaging is increasingly used in clinical practice, but the impact on the frequency of detection of CeAD is unknown. In 2006, the yearly incidence rate of CeAD was estimated at 2.6 per 100 000 person-years, but the current incidence is unknown. METHODS: In this population-based retrospective observational cohort study, we utilized the resources of the Rochester Epidemiology Project to ascertain all adult residents of Olmsted County, MN, diagnosed with internal carotid artery dissection and common carotid artery dissection or vertebral artery dissection from 2002 to 2020. Patients with only intracranial involvement or CeAD following major trauma were excluded. Age-adjusted sex-specific and age- and sex-adjusted incidence rates were estimated using the US White 2010 decennial census, with rates expressed per 100 000 person-years. We assessed longitudinal trends by dividing the data into 5-year time intervals, with the last being a 4-year interval. RESULTS: We identified 123 patients with a diagnosis of CeAD. There were 63 patients with internal carotid artery dissection, 54 with vertebral artery dissection, 2 with concurrent internal carotid artery dissection and vertebral artery dissection, and 4 with common carotid artery dissection. There were 63 (51.2%) female patients and 60 (48.8%) male patients. The average age at diagnosis was 50.2 years (SD, 15.1 [95% CI, 20.1-90.5] years). The incidence rate of spontaneous CeAD encompassing all locations was 4.69 per 100 000 person-years (2.43 for internal carotid artery dissection and 2.01 for vertebral artery dissection). The incidence rate increased from 2.30 per 100 000 person-years from 2002 to 2006 to 8.93 per 100 000 person-years from 2017 to 2020 (P<0.0001). The incidence rate for female patients rose from 0.81 per 100 000 person-years from 2002 to 2006 to 10.17 per 100 000 person-years from 2017 to 2020. CONCLUSIONS: The incidence rate of spontaneous CeAD increased nearly 4-fold over a 19-year period from 2002 to 2020. The incidence rate in women rose over 12-fold. The increase in incidence rates likely reflects the increased use of noninvasive vascular imaging.

Trial Readiness of Cavernous Malformations With Symptomatic Hemorrhage, Part I: Event Rates and Clinical Outcome.

BACKGROUND: Cerebral cavernous malformation with symptomatic hemorrhage (SH) are targets for novel therapies. A multisite trial-readiness project (https://www.clinicaltrials.gov; Unique identifier: NCT03652181) aimed to identify clinical, imaging, and functional changes in these patients. METHODS: We enrolled adult cerebral cavernous malformation patients from 5 high-volume centers with SH within the prior year and no planned surgery. In addition to clinical and imaging review, we assessed baseline, 1- and 2-year National Institutes of Health Stroke Scale, modified Rankin Scale, European Quality of Life 5D-3 L, and patient-reported outcome-measurement information system, Version 2.0. SH and asymptomatic change rates were adjudicated. Changes in functional scores were assessed as a marker for hemorrhage. RESULTS: One hundred twenty-three, 102, and 69 patients completed baseline, 1- and 2-year clinical assessments, respectively. There were 21 SH during 178.3 patient years of follow-up (11.8% per patient year). At baseline, 62.6% and 95.1% of patients had a modified Rankin Scale score of 1 and National Institutes of Health Stroke Scale score of 0 to 4, respectively, which improved to 75.4% (P=0.03) and 100% (P=0.06) at 2 years. At baseline, 74.8% had at least one abnormal patient-reported outcome-measurement information system, Version 2.0 domain compared with 61.2% at 2 years (P=0.004). The most common abnormal European Quality of Life 5D-3 L domains were pain (48.7%), anxiety (41.5%), and participation in usual activities (41.4%). Patients with prospective SH were more likely than those without SH to display functional decline in sleep, fatigue, and social function patient-reported outcome-measurement information system, Version 2.0 domains at 2 years. Other score changes did not differ significantly between groups at 2 years. The sensitivity of scores as an SH marker remained poor at the time interval assessed. CONCLUSIONS: We report SH rate, functional, and patient-reported outcomes in trial-eligible cerebral cavernous malformation with SH patients. Functional outcomes and patient-reported outcomes generally improved over 2 years. No score change was highly sensitive or specific for SH and could not be used as a primary end point in a trial.

Phage K exposure generates phage-neutralizing activity in a rabbit model-humoral receptiveness may impact efficacy of phage therapy.

Phage therapy has not been established in the clinical routine, in part due to uncertainties concerning efficacy and immunogenicity. Here, three rabbits were immunized against staphylococcal phage K to assess viral potency in the presence of immunized serum. Three rabbits received weekly intramuscular injections of ~1010±1 pfu/mL phage K. Phage K-specific IgG formation was measured by an enzyme-linked immunosorbent assay (ELISA); phage inactivation was assessed by calculating K-rates. Using transmission electron microscopy (TEM) and immunogold labeling, antibody binding to phage K was visualized. This was numerically assessed by objective imaging analysis comparing the relative distances of each gold particle to the nearest phage head and tail structure. Immunization led to a strong IgG response, plateauing 7 days after the last phage injection. There was no significant correlation between K-rate and antibody titer over time. TEM showed IgG binding to the head structure of phage K. Image analysis showed a significant reduction in relative distances between antibodies and phage head structures when comparing samples from day 0 and day 28 (P < 0.0001). These results suggest that while individual serum analysis for antibodies against therapeutic phage bears consideration prior to and with prolonged therapy, during phage application, the formation of specific antibodies against phage may only partially explain decreased phage potency in the presence of immunized serum. Instead, other factors may contribute to an individual's "humoral receptiveness" to phage therapy. Future investigations should be directed toward the identification of the humoral factors that have the most significant predictive value on phage potency in vivo.

Mitochondrial myopathies diagnosed in adulthood: clinico-genetic spectrum and long-term outcomes.

Mitochondrial myopathies are frequently recognized in childhood as part of a broader multisystem disorder and often overlooked in adulthood. Herein, we describe the phenotypic and genotypic spectrum and long-term outcomes of mitochondrial myopathies diagnosed in adulthood, focusing on neuromuscular features, electrodiagnostic and myopathological findings and survival. We performed a retrospective chart review of adult patients diagnosed with mitochondrial myopathy at Mayo Clinic (2005-21). We identified 94 patients. Median time from symptom onset to diagnosis was 11 years (interquartile range 4-21 years). Median age at diagnosis was 48 years (32-63 years). Primary genetic defects were identified in mitochondrial DNA in 48 patients (10 with single large deletion, 38 with point mutations) and nuclear DNA in 29. Five patients had multiple mitochondrial DNA deletions or depletion without nuclear DNA variants. Twelve patients had histopathological features of mitochondrial myopathy without molecular diagnosis. The most common phenotypes included multisystem disorder (n = 30); mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (14); limb myopathy (13); chronic progressive external ophthalmoplegia (12); and chronic progressive external ophthalmoplegia-plus (12). Isolated skeletal muscle manifestations occurred in 27%. Sixty-nine per cent had CNS and 21% had cardiac involvement. Mutations most frequently involved MT-TL1 (27) and POLG (17); however, a wide spectrum of established and novel molecular defects, with overlapping phenotypes, was identified. Electrodiagnostic studies identified myopathy (77%), fibrillation potentials (27%) and axonal peripheral neuropathy (42%, most common with nuclear DNA variants). Among 42 muscle biopsies available, median percentage counts were highest for cytochrome C oxidase negative fibres (5.1%) then ragged blue (1.4%) and ragged red fibres (0.5%). Skeletal muscle weakness was mild and slowly progressive (decline in strength summated score of 0.01/year). Median time to gait assistance was 5.5 years from diagnosis and 17 years from symptom onset. Thirty patients died, with median survival of 33.4 years from symptom onset and 10.9 years from diagnosis. Median age at death was 55 years. Cardiac involvement was associated with increased mortality [hazard ratio 2.36 (1.05, 5.29)]. There was no difference in survival based on genotype or phenotype. Despite the wide phenotypic and genotypic spectrum, mitochondrial myopathies in adults share similar features with slowly progressive limb weakness, contrasting with common multiorgan involvement and high mortality.

Assessing Discomfort in American Adult Intensive Care Patients.

BACKGROUND: While in the intensive care unit, critically ill patients experience a myriad of distressing symptoms and stimuli leading to discomfort, a negative emotional and/ or physical state that arises in response to noxious stimuli. Appropriate management of these symptoms requires a distinct assessment of discomfort-causing experiences. OBJECTIVES: To assess patient-reported discomfort among critically ill patients with the English-language version of the Inconforts des Patients de REAnimation questionnaire, and to explore relationships between demographic and clinical characteristics and overall discomfort score on this instrument. METHODS: This study had a cross-sectional, descriptive, single-cohort design. The convenience sample consisted of alert and oriented patients aged 18 years or older who had been admitted to intensive care units at a Midwestern tertiary referral hospital and were invited to participate. An 18-item questionnaire on physiological and psychological stimuli inducing discomfort was administered once. Each item was scored from 0 to 10, with the total possible discomfort score ranging from 0 to 100. Descriptive statistics were used to analyze participants' demographic and clinical characteristics and questionnaire responses. RESULTS: A total of 180 patients were enrolled. The mean (SD) overall discomfort score was 32.9 (23.6). The greatest sources of discomfort were sleep deprivation (mean [SD] score, 4.0 [3.4]), presence of perfusion catheters and tubing (3.4 [2.9]), thirst (3.0 [3.3]), and pain (3.0 [3.0]). CONCLUSIONS: Intensive care unit patients in this study reported mild to moderate discomfort. Additional research is needed to design and test interventions based on assessment of specific discomfort-promoting stimuli to provide effective symptom management.

Evaluation of Sonicate Fluid Culture Cutoff Points for Periprosthetic Joint Infection Diagnosis.

Introduction: Implant sonication is useful for recovery of periprosthetic joint infection (PJI) pathogens in culture, but exact cutoff points for definition of clinically significant sonicate fluid culture results vary from study to study. The aim of this study was to define ideal sonicate fluid culture cutoff points for PJI diagnosis. Methods: Sonicate fluid cultures from hip and knee prosthesis components removed between February 2007 and December 2020 were studied. Prosthesis components were placed in solid containers in the operating room; in the clinical microbiology laboratory, 400 mL Ringer's solution was added, and containers subjected to vortexing, sonication and then vortexing, followed by centrifugation. Concentrated sonicate fluid was plated on aerobic and anaerobic solid media, and culture results reported semiquantitatively, as no growth, <20, 20-50, 51-100, or >100 CFU/10 mL sonicate fluid. Sonicate cultures from cement spacers and cultures yielding more than 1 microorganism were excluded. Sensitivity and specificity of each cutoff point was evaluated. Results: A total of 1448 sonicate fluid cultures were evaluated, 68% from knees and 32% from hips. PJI was present in 644 (44%) cases. Sensitivity of sonicate culture was 75.0% at <20 CFU/10 mL, 55.3% at ≥20 CFU/10 mL, 46.9% at >51 CFU/10 mL, and 39.8% at >100 CFU/10 mL. Specificity was 78.2%, 99.8%, 100%, and 100%, at the 4 cutoff points, respectively. Conclusions: A cutoff point for sonicate fluid culture positivity of ≥20 CFU/10 mL is suitable for PJI diagnosis.

A comparison of phage susceptibility testing with two liquid high-throughput methods.

Phage therapy is a promising antibacterial strategy, especially given that drug-resistant bacterial infections are escalating worldwide. Because phages are not active against all strains of a given species, phages being considered for therapeutic use would ideally be tested against bacterial isolates from individual patients prior to administration. Standardized, clinically validated phage susceptibility testing (PST) methods are needed for assessing in vitro phage activity. This study compared two high-throughput liquid-based PST assays. The first, using the Biolog Omnilog™, assessed changes in microbial respiration leading to color changes based on a tetrazolium dye. The second, Agilent BioTek Cytation 7, assessed changes in optical density. Both used 96-well microtiter plate formats. A total of 55 diverse phages with activity against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii, or Enterococcus faecalis were studied against their respective susceptible bacterial hosts and non-susceptible controls, with susceptibility defined based on plaque assay. PST was performed by both assays in replicates, with results compared in terms of hold times (time through which bacterial growth is inhibited by phage compared to controls). Coefficients of variance and interclass correlation coefficients were used to assess inter- and intra-assay reproducibility. Based on a ≤50% coefficient of variance cutpoint, 87% of Biolog and 84% of Agilent assays were considered valid for susceptible bacteria, with 100% considered valid for non-susceptible bacteria by both systems. Using a 8 h hold time cutpoint, 100% of the results matched between the two assays. The interclass correlation coefficient showed 26% excellent agreement, 35% good agreement, and 17% moderate agreement between the two assays for susceptible isolates and 100% excellent agreement for non-susceptible isolates. Overall, the assays compared provided good/fair statistical reproducibility for the assessment of phage susceptibility.

Timing of Anticoagulation Resumption and Risk of Ischemic and Hemorrhagic Complications in Patients With ICH and Mechanical Heart Valves.

BACKGROUND AND OBJECTIVES: In patients with mechanical heart valves and recent intracranial hemorrhage (ICH), clinicians need to balance the risk of thromboembolism during the period off anticoagulation and the risk of hematoma expansion on anticoagulation. The optimal timing of anticoagulation resumption is unknown. We aimed to investigate the relationship between reversal therapy and ischemic stroke, between duration off anticoagulation and risk of ischemic strokes or systemic embolism and between timing of anticoagulation resumption and risk of rebleeding and ICH expansion. METHODS: We conducted a retrospective cohort observational study in 3 tertiary hospitals. Consecutive adult patients with mechanical heart valves admitted for ICH between January 1, 2000, and July 13, 2022, were included. The primary end points of our study were thromboembolic events (cerebral, retinal, or systemic) while off anticoagulation and ICH expansion after anticoagulation resumption (defined by the following criteria: increase by one-third in intracerebral hematoma volume, increase by one-third in convexity subdural hemorrhage diameter, or visually unequivocal expansion of other ICH locations to the naked eye). RESULTS: A total of 171 patients with mechanical heart valves who experienced ICH were included in the final analysis. Most of the patients (79.5%) received reversal therapy for anticoagulation. Patients who received anticoagulation reversal therapy did not have increased risk of thromboembolic complications. Time off anticoagulation was not associated with risk of ischemic stroke; only 2 patients had a stroke within 7 days of the ICH, and both had additional major risk factors of thromboembolism. The rate of ischemic stroke/transient ischemic attack while off anticoagulation was lower than the rate of ICH expansion once anticoagulation was resumed (6.4% vs 9.9%). Furthermore, patients who developed ICH expansion had higher mortality compared with patients who had ischemic stroke while being off anticoagulation (41% vs 9%). Use of intravenous heparin bridging upon resumption of warfarin was strongly associated with increased risk of ICH expansion as compared with restarting warfarin without a heparin bridge. DISCUSSION: Withholding anticoagulation for at least 7 days after ICH may be safe in patients with mechanical heart valves. Heparin bridging during anticoagulation resumption may be associated with increased risk of bleeding.

NLRP3 inflammasome activation and altered mitophagy are key pathways in inclusion body myositis.

Background: Inclusion body myositis (IBM) is the most prevalent muscle disease in adults for which no current treatment exists. The pathogenesis of IBM remains poorly defined. Inflammation and mitochondrial dysfunction are the most common histopathological findings. In this study, we aimed to explore the interplay between inflammation and mitochondrial dysfunction in IBM patients, highlighting sex differences. Methods: We included 38 IBM patients and 22 age- and sex-matched controls without myopathy. Bulk RNA sequencing, Meso Scale Discovery ELISA, western blotting, histochemistry and immunohistochemistry were performed on frozen muscle samples from the study participants. Results: We demonstrated activation of the NLRP3 inflammasome in IBM muscle samples, with the NLRP3 inflammasome pathway being the most upregulated. On muscle histopathology, there is increased NRLP3 immunoreactivity in both inflammatory cells and muscle fibers. Mitophagy is critical for removing damaged mitochondria and preventing the formation of a vicious cycle of mitochondrial dysfunction-NLRP3 activation. In the IBM muscle samples, we showed altered mitophagy, most significantly in males, with elevated levels of p-S65-Ubiquitin, a mitophagy marker. Furthermore, p-S65-Ubiquitin aggregates accumulated in muscle fibers that were mostly type 2 and devoid of cytochrome-c-oxidase reactivity. Type 2 muscle fibers are known to be more prone to mitochondrial dysfunction. NLRP3 RNA levels correlated with p-S65-Ubiquitin levels in both sexes but with loss of in muscle strength only in males. Finally, we identified sex-specific molecular pathways in IBM, with females having activation of pathways that could offset some of the pathomechanisms of IBM. Conclusions: NLRP3 inflammasome is activated in IBM, along with altered mitophagy particularly in males, which is of potential therapeutic significance. These findings suggest sex-specific mechanisms in IBM that warrant further investigation.

Caregiver recruitment strategies for interventions designed to optimize transitions from hospital to home: lessons from a randomized trial.

Challenges to recruitment of family caregivers exist and are amplified when consent must occur in the context of chaotic healthcare circumstances, such as the transition from hospital to home. The onset of the COVID-19 pandemic during our randomized controlled trial provided an opportunity for a natural experiment exploring and examining different consent processes for caregiver recruitment. The purpose of this publication is to describe different recruitment processes (in-person versus virtual) and compare diversity in recruitment rates in the context of a care recipient's hospitalization. We found rates of family caregiver recruitment for in-person versus virtual were 28% and 23%, respectively (p = 0.01). Differences existed across groups with family caregivers recruited virtually being more likely to be younger, white, have greater than high school education, and not be a spouse or significant other to the care recipient, such as a child. Future work is still needed to identify the modality and timing of family caregiver recruitment to maximize rates and enhance the representativeness of the population for equitable impact.

Healthcare use and out-of-pocket costs for rural family caregivers and care recipients in a randomized controlled trial.

BACKGROUND: Rural family caregivers (FCGs) in the United States often experience high economic costs. This randomized controlled trial compared a transitional palliative care intervention (TPC) to support FCGs of seriously ill care recipients (CRs) to an attention control condition. We evaluated the TPC's effect on healthcare use and out-of-pocket spending for both FCGs and CRs. METHODS: TPC FCGs received teaching, guidance, and counseling via video calls for 8 weeks following CR discharge from the hospital. After discharge, a research assistant called all FCGs once a month for up to 6 months or CR death to collect self-reported healthcare utilization (e.g., outpatient, emergency department, and hospital), out-of-pocket healthcare spending (e.g., deductibles and coinsurance), and health-related travel costs (e.g., transportation, lodging, food) for FCGs and CRs. Incidence rate ratios (IRRs) were estimated using negative binomial regressions. RESULTS: The study included 282 FCG-CR dyads across three U.S. states. Follow-up over the 6-month period was shortened by high CR mortality rates across both arms (29%), but was similar across arms. TPC reduced nights in the hospital for CR (IRR = 0.75; 95% confidence interval [CI] = 0.56-0. 99). Total out-of-pocket spending was not significantly different for TPC versus control. Across both groups, mean out-of-pocket spending for dyads was $1401.85, with healthcare payments contributing $1048.58 and transportation expenses contributing $136.79. TPC dyads reported lower lodging costs (IRR = 0.71; 95% CI = 0.56-0.89). CONCLUSIONS: This study contributes to evidence that palliative care interventions reduce the number of nights in the hospital for seriously ill patients. Yet, overall rural FCGs and seriously ill CRs experience substantial out-of-pocket economic costs in the 6 months following hospitalization. Transitional care intervention design should consider impacts on patient and caregiver spending. CLINICALTRIALS: gov # is NCT03339271.

Implementation Costs of Technology-Enhanced Transitional Palliative Care for Rural Caregivers.

OBJECTIVES: Compared to urban family caregivers (FCG), rural FCG experience greater burdens accessing coordinated care for their loved ones during and after hospitalization. The impact of technology-enhanced transitional palliative care (TPC) on caregiver outcomes is currently being evaluated in a randomized control trial. This study evaluates resource use and health system costs of this FCG-focused TPC intervention and potential Medicare reimbursement mechanisms. METHODS: Rural caregivers of hospitalized patients were randomized into an 8-week intervention consisting of video visits conducted by a registered nurse certified in palliative care, supplemented with phone calls and texts (n = 215), or attentional control. Labor costs were estimated for a registered nurse and compared to scenario analyses using a nurse practitioner or social worker wages. Medicare reimbursement scenarios included Transitional Care Management (TCM) and Chronic Care Management (CCM) CPT codes. RESULTS: In the base case, TPC cost was $395 per FCG facilitated by a registered nurse, compared to $337 and $585 if facilitated by a social worker or nurse practitioner, respectively. Mean Medicare reimbursement in the TCM-only scenario was $322 and $260 for high or moderate complexity patients, respectively. Reimbursement in the CCM only scenario was $348 and $274 for complex and non-complex patients, respectively. Reimbursement in the TCM+CCM scenario was $496 and $397, for high/complex and moderate/non-complex patients, respectively. CONCLUSION: TPC is a feasible, low cost and sustainable strategy to enhance FCG support in rural areas. Potential reimbursement mechanisms are available to offset the costs to the health system for providing transitional palliative care to caregivers of patients recently hospitalized.

Transitional Palliative Care for Family Caregivers: Outcomes from a Randomized Controlled Trial.

CONTEXT: Patients receiving inpatient palliative care often face physical and psychological uncertainties during transitions out of the hospital. Family caregivers often take on responsibilities to ensure patient safety, quality of care, and extend palliative care principles, but often without support or training, potentially compromising their health and well-being. OBJECTIVES: This study tested an eight-week intervention using video visits between palliative care nurse interventionists and caregivers to assess changes in caregiver outcomes and patient quality of life. METHODS: This randomized controlled trial, conducted from 2018 to 2022, enrolled adult caregivers in rural or medically underserved areas in Minnesota, Wisconsin, and Iowa. Eligible caregivers included those caring for patients who received inpatient palliative care and transitioned out of the hospital. The intervention group received teaching, guidance, and counseling from a palliative care nurse before and for eight weeks after hospital discharge. The control group received monthly phone calls but no intervention. Caregiver outcomes included changes in depression, burden, and quality of life, and patient quality of life, as reported by the caregiver. RESULTS: Of those consented, 183 completed the intervention, and 184 completed the control arm; 158 participants had complete baseline and eight-week data. In unadjusted analyses, the intervention group and their care recipients showed statistically significant improvements in quality of life compared to the control group. Improvements persisted in adjusted analyses, and depression significantly improved. No differences in caregiver burden were observed. CONCLUSION: Addressing rural caregivers' needs during transitions in care can enhance caregiver outcomes and improve patient quality of life.

MR Imaging Features of Critical Spinal Demyelinating Lesions Associated with Progressive Motor Impairment.

BACKGROUND AND PURPOSE: Progressive MS is typically heralded by a myelopathic pattern of asymmetric progressive motor weakness. Focal individual "critical" demyelinating spinal cord lesions anatomically associated with progressive motor impairment may be a compelling explanation for this clinical presentation as described in progressive solitary sclerosis (single CNS demyelinating lesion), progressive demyelination with highly restricted MR imaging lesion burden (2-5 total CNS demyelinating lesions; progressive paucisclerotic MS), and progressive, exclusively unilateral hemi- or monoparetic MS (>5 CNS demyelinating progressive unilateral hemi- or monoparetic MS [PUHMS] lesions). Critical demyelinating lesions appear strikingly similar across these cohorts, and we describe their specific spinal cord MR imaging characteristics. MATERIALS AND METHODS: We performed a retrospective, observational MR imaging study comparing spinal cord critical demyelinating lesions anatomically associated with progressive motor impairment with any additional "noncritical" (not anatomically associated with progressive motor impairment) spinal cord demyelinating lesions. All spinal cord MR images (302 cervical and 91 thoracic) were reviewed by an experienced neuroradiologist with final radiologic assessment on the most recent MR imaging. Anatomic association with clinical progressive motor impairment was confirmed independently by MS subspecialists. RESULTS: Ninety-one individuals (PUHMS, 37 [41%], progressive paucisclerosis 35 [38%], progressive solitary sclerosis 19 [21%]) with 91 critical and 98 noncritical spinal cord MR imaging demyelinating lesions were evaluated. MR imaging characteristics that favored critical spinal cord demyelinating lesions over noncritical lesions included moderate-to-severe, focal, lesion-associated spinal cord atrophy: 41/91 (45%) versus 0/98 (0%) (OR, 161.91; 9.43 to >999.9); lateral column axial location (OR, 10.43; 3.88-28.07); central region (OR, 3.23; 1.78-5.88); ventral column (OR, 2.98; 1.55-5.72); and larger lesion size of the axial width (OR, 2.01;1.49-2.72), transverse axial size (OR, 1.66; 1.36-2.01), or lesion area (OR, 1.14; 1.08-1.2). Multiple regression analysis revealed focal atrophy and lateral axial location as having the strongest association with critical demyelinating lesions. CONCLUSIONS: Focal, lesion-associated atrophy, lateral column axial location, and larger lesion size are spinal cord MR imaging characteristics of critical demyelinating lesions. The presence of critical demyelinating lesions should be sought as these features may be associated with the development of progressive motor impairment in MS.

The clinical spectrum of MELAS and associated disorders across ages: a retrospective cohort study.

Objective: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a severe multisystemic disease, although some have a milder phenotype. We aimed to evaluate the clinical spectrum of this disease from MELAS patients to asymptomatic carriers and identify predictors of severity. Methods: We reviewed 81 patients, who had MELAS or had positive genetics without meeting clinical criteria. Patients who met criteria including lactic acidosis, encephalomyopathy, and stroke-like episodes (SLE) were categorized as MELAS, symptomatic non-MELAS, and asymptomatic. MELAS was further categorized as "standard-onset" if the first stroke-like episode (SLE) occurred before age 40 or "late-onset." Results: Eighty-one patients were included: 42 MELAS (13 late-onset), 30 symptomatic non-MELAS, and 9 asymptomatic. MELAS patients had lower BMI at onset (mean 18.6 vs. 25.1 asymptomatic and 22.0 symptomatic non-MELAS, p < 0.05). There was a trend toward higher serum heteroplasmy in MELAS compared to symptomatic non-MELAS and asymptomatic (means 39.3, 29.3, and 21.8% p = 0.09). Symptomatic non-MELAS had more sensorineural hearing loss as first presenting symptom (51.6% vs. 24.4%, p < 0.05). MELAS had higher prevalence of seizures (88.1% vs. 16.7%, p < 0.05) and shorter survival from onset to death (50% mortality at 25 years vs. 10%, p < 0.05). Late-onset MELAS had longer disease duration from first symptom to first SLE (mean 16.6 vs. 9.3 yrs) and also lived longer (mean age at death 62 vs. 30). Standard-onset MELAS had more neurologic involvement at onset than late-onset (51.7% vs. 15.4%). Late-onset patients had more prevalent diabetes (69.2% vs. 13.8%) and nephropathy (53.8% vs. 10.3%). Patients with late-onset MELAS also had more organ systems involved (mean 4.1 vs. 2.7, p < 0.05). There was a trend toward higher heteroplasmy levels in standard-onset (mean 44.8% vs. 25.3%, p = 0.18). Discussion: Our study highlights the spectrum of MELAS. The lower BMI in MELAS at presentation as well as higher rates of sensorineural hearing loss as initial symptom in symptomatic non-MELAS may be useful clinical markers. While many patients present before age 40 with SLE, some can present with SLE later in life. Standard onset MELAS is more likely to present with neurologic symptoms. Late-onset is more likely to suffer diabetes or nephropathy and have more organ systems involved.