Pathogenesis and presentation of ALS: examining reasons for delayed diagnosis and identifying opportunities for improvement.

Amyotrophic lateral sclerosis (ALS), or Lou Gehrig disease, is a progressive, always-fatal neuromuscular disease characterized by motor neuron degeneration in the brain and spinal cord. As upper and lower motor neurons fail, inability to transmit messages to the muscles causes muscle stiffness, atrophy, and wasting. The incidence of this incurable disease is increasing in the United States, and its prognosis is grim. On average, patients survive about 3 to 5 years from symptom onset. Until recently, few risk factors were known, but some are newly emerging. About 10% of cases are related to genetic variants. Patients who develop ALS often experience diagnostic delays (10-16 months on average), and its heterogeneity contributes to that delay. Diagnosis is based primarily on clinical signs and symptoms and exclusion of other causes of motor neuron dysfunction. Reliable, accessible biomarkers are needed to aid early ALS diagnosis, differentiate from ALS-mimicking diseases, predict survival, and monitor disease progression and treatment response. Misdiagnosing ALS can have devastating consequences, including unnecessary emotional burden, delayed and/or inappropriate treatment, and undue financial burden. The grim prognosis and sure progression to death creates considerable burden and reduces quality of life for patients and caregivers.

Optimizing pharmacologic treatment for ALS to improve outcomes and quality of life.

Just 3 disease-modifying treatments-edaravone, riluzole, and sodium phenylbutyrate and taurursodiol (PB/TURSO)-are currently FDA approved to slow progression of amyotrophic lateral sclerosis (ALS). A fourth therapy has been recently approved under accelerated approval and is contingent upon verification of clinical benefit in confirmatory trials(s). Therapy selection is based largely upon patient characteristics, as guidelines have not been updated since the recent approval of PB/TURSO or accelerated approval of tofersen. Managing ALS symptomatically is important to improve patients' quality of life. Although evidence is lacking for many pharmacologic therapies, providers use symptomatic treatments to address common symptoms including anxiety, depression, emotional lability (pseudobulbar affect), fasciculations, fatigue, insomnia, muscle cramps or spasms, musculoskeletal pain due to immobility, neuropathic type pain, excessive salivation (sialorrhea), spasticity, constipation, and urinary urgency. Emerging agents offer some hope for patients with ALS. Among the drugs, biologics, and interventions under investigation for ALS are an oral tyrosine kinase inhibitor, RIPK1 inhibition, the use of mesenchymal stem cells, antisense oligonucleotides, sequential administration of all experimental treatments in a new study design, and modification of the patient's own mesenchymal stem cells.

Evaluation of Novel Urinary Biomarkers in Beagle Dogs With Amphotericin B-Induced Kidney Injury.

Next-generation urinary protein biomarkers have been qualified to enable monitoring for drug-induced kidney injury in toxicology studies conducted in rats. However, there is limited literature on the utility of these biomarkers in dogs. To add to the existing body of knowledge on the utility of the next-generation drug-induced kidney injury (DIKI) biomarkers, we evaluated the value of these biomarkers for the early detection of DIKI in Beagle dogs using a differentiated nephrotoxicant, Amphotericin B (AmpB). In dogs with AmpB-induced kidney injury, we monitored the response of urinary albumin, total protein, clusterin, kidney injury molecule 1, neutrophil gelatinase-associated lipocalin and N-acetyl-beta-D-glucosaminidase. We also measured blood urea nitrogen, serum creatinine and cystatin C. The results showed that urinary clusterin (up to ∼ 112x) was much more sensitive to AmpB-induced kidney injury relative to other biomarkers. Moreover, other than urinary clusterin and to a much lesser extent urinary albumin and total protein, none of the other biomarkers analyzed in this study were more sensitive than blood urea nitrogen and serum creatinine. The AmpB related tubular alterations were characterized by minimal to mild, multifocal necrosis, degeneration, regeneration, dilatation and mineralization. The mild nature of these histopathologic findings further attested to the sensitivity of urinary clusterin to AmpB-induced kidney injury in dogs. These results will help drug developers make informed decisions when selecting urinary biomarkers for monitoring DIKI in dogs for toxicology studies.

A Cluster Randomized Controlled Trial Testing the Impact of Function and Behavior Focused Care for Nursing Home Residents With Dementia.

OBJECTIVE: The purpose of this study was to test the effectiveness of the Function and Behavior Focused Care for the Cognitively Impaired (FBFC-CI) intervention on function, physical activity, and behavioral symptoms among nursing home residents with dementia, and to explore the adoption of the intervention at the facility level. DESIGN: This study was a clustered, randomized controlled trial with a repeated measures design that was implemented in 12 nursing homes randomized to either treatment (FBFC-CI) or educational control [Function and Behavior Focused Care Education (FBFC-ED)]. SETTING AND PARTICIPANTS: Twelve nursing homes (6 treatment and 6 control) and 336 residents (173 treatment and 163 control) with moderate to severe cognitive impairment. MEASURES: Outcomes included functional ability (Barthel Index), physical activity (actigraphy and survey), behavioral symptoms (Resistiveness to Care Scale, Cohen-Mansfield Agitation Inventory, Cornell Scale for Depression in Dementia), and psychotropic medication use. RESULTS: The participants were 82.6 (SD = 10.1) years of age, mostly female, and were moderate to severely cognitively impaired (Mini-Mental State Exam of 7.8, SD = 5.1). There was a significantly greater increase in time spent in total activity (P = .004), moderate activity (P = .012), light activity (P = .002), and a decrease in resistiveness to care (P = .004) in the treatment versus control group at 4 months. There was no change in mood, agitation, and the use of psychotropic medications. There was some evidence of adoption of the intervention at treatment sites. CONCLUSIONS AND IMPLICATIONS: This study provides some support for the use of the FBFC-CI Intervention to increase time spent in physical activity and decrease resistive behaviors during care commonly noted among nursing home residents with moderate to severe cognitive impairment.

Does lumbar arthrodesis compromise outcome of total hip arthroplasty?

INTRODUCTION: This matched cohort study aims to determine whether the presence of a spinal arthrodesis (SA) compromises outcome of total hip arthroplasty (THA) and whether the outcome is better if THA is performed before- (THA-1st) or after- SA (THA-2nd). METHODS: This is a single centre, multi-surgeon, review of prospective data. Thirty-seven patients (47 hips) that had SA and 1° THA(s), formed the cases (26 THA-1st; 21 THA-2nd). Most cases had 1-level SA (n = 24). Controls were patients without SA that had THA, over the same period matched for age, gender and prosthesis type. Outcome measures included complication-, revision- rates, Oxford-Hip- and Harris-Hip-Scores (OHS/HHS) (Δ: difference between pre- and post-operative scores). This is a single-centre, multi-surgeon, review of prospective data. RESULTS: At a mean follow-up of 6 years, more complications were seen in cases of THA and SA compared with controls without SA (7 vs. 2) (p = 0.03). Consequently, more cases were revised (n = 4) compared with controls (n = 0) (p = 0.02). There were no differences in functional outcome between cases and controls (p = 0.1-0.6). No differences in complications- (4/26 vs. 3/21; p = 1.00) or revision- rates (2/26 vs. 2/21; p = 1.00) were seen between THA-1st and THA-2nd Groups. The THA-1st Group had higher pre- and post-operative OHS/HHS, compared to the THA-2nd Group. However, no significant difference in ΔOHS (24 vs. 17) and ΔHHS (39 vs. 26) were seen between the THA-1st and THA-2nd Groups (p = 0.1). CONCLUSIONS: Patients with THA and SA, had increased rates of revision; but no differences in patient-reported outcome measures (PROMs) were detected. Addressing the hip pathology first may be associated with improved functional outcome.

Outcomes of Hip Arthroplasty After Failed Hip Arthroscopy: A Case-Control Study.

BACKGROUND: Hip arthroscopy is increasingly being used in joint preservation surgery with clear benefits in the treatment of prearthritic conditions. A number of patients, however, will still go on to require subsequent hip arthroplasty, and at present, little evidence exists determining the impact that prior hip arthroscopy may have on the outcomes of a subsequent arthroplasty. METHODS: Using prospectively collated data, we identified 35 patients who had a hip arthroplasty (22 total hip arthroplasties and 13 hip resurfacing arthroplasties) after prior ipsilateral hip arthroscopy (cases). Cases were matched for age, gender, and prosthesis type with 70 controls (patients who received a primary arthroplasty over the same period, without prior arthroscopy). Outcome measures included range of movement, implant survival, complications, and functional outcome (Oxford Hip Score and Harris Hip Score). RESULTS: There was no demonstrable difference in improved range of motion after hip arthroplasty between the 2 groups, across any axis of movement (flexion, extension, internal/external rotation, abduction, and adduction; P = .07-.78). There was no significant difference in complication rate (P = .72). Overall 7-year implant survival was 85.9% (95% confidence interval [CI], 75-95.8). There was no difference in survival between cases (87.6%; 95% CI, 73.5-100) and controls (86.3%; 95% CI, 74.6%-98.0%; P = .2). Ten of the 11 revision arthroplasties performed were due to adverse reactions to metal debris in metal-on-metal hip resurfacing arthroplasty cases (P = .01). There was no difference in improvement of functional outcome postarthroplasty between groups (P = .48-.76). CONCLUSION: This study demonstrates that hip arthroscopy does not adversely influence outcome of a subsequent hip arthroplasty.

Evaluation of Pepsinogen I as a Biomarker of Drug-induced Gastric Mucosal Injury in Cynomolgus Monkeys.

Gastric mucosal injury is frequently observed in nonclinical studies of nonhuman primates. Because microscopic evaluation of stomach is generally a terminal procedure, our objective was to determine whether serum pepsinogen I (PG I) could serve as a noninvasive biomarker for detection of gastric mucosal injury in monkey. Serum PG I was measured using a commercial human immunoassay in cynomolgus monkeys ( n = 166) prior to dosing and/or terminally in 11 studies of up to 1 month duration. Mean ( SD) PG I values (ug/L) for monkeys with ( n = 59) and without ( n = 100) gastric mucosal degeneration were 101 (215) and 28 (12.6), respectively. For monkeys with baseline and terminal PG I data, mean ( SD) fold change (ratio of terminal to baseline PG I) for monkeys with ( n = 57) and without ( n = 76) glandular degeneration were 4.1 (11.3) and 1 (0.28). Receiver operating characteristic area under the curve (AUC) data demonstrated moderate diagnostic accuracy for serum PG I for glandular degeneration, AUC ( SE) 0.789 (0.04), with improved diagnostic accuracy as a fold change of baseline, AUC ( SE) 0.816 (0.04), consistent with the large interindividual but low intraindividual variability of serum PG I values in control monkeys. These data demonstrate that serum PG I is a useful biomarker of drug-induced gastric mucosal injury in the cynomolgus monkey.

Rat Urinary Osteopontin and Neutrophil Gelatinase-Associated Lipocalin Improve Certainty of Detecting Drug-Induced Kidney Injury.

Traditional kidney biomarkers are insensitive indicators of acute kidney injury, with meaningful changes occurring late in the course of injury. The aim of this work was to demonstrate the diagnostic potential of urinary osteopontin (OPN) and neutrophil gelatinase-associated lipocalin (NGAL) for drug-induced kidney injury (DIKI) in rats using data from a recent regulatory qualification submission of translational DIKI biomarkers and to compare performance of NGAL and OPN to five previously qualified DIKI urinary biomarkers. Data were compiled from 15 studies of 11 different pharmaceuticals contributed by Critical Path Institute's Predictive Safety Testing Consortium (PSTC) Nephrotoxicity Working Group (NWG). Rats were given doses known to cause DIKI or other target organ toxicity, and urinary levels of the candidate biomarkers were assessed relative to kidney histopathology and serum creatinine (sCr) and blood urea nitrogen (BUN).OPN and NGAL outperformed sCr and BUN in identifying DIKI manifested as renal tubular epithelial degeneration or necrosis. In addition, urinary OPN and NGAL, when used with sCr and BUN, increased the ability to detect renal tubular epithelial degeneration or necrosis. NGAL and OPN had comparable or improved performance relative to Kim-1, clusterin, albumin, total protein, and beta-2 microglobulin. Given these data, both urinary OPN and NGAL are appropriate for use with current methods for assessing nephrotoxicity to identify and monitor DIKI in regulatory toxicology studies in rats. These data also support exploratory use of urinary OPN and NGAL in safety monitoring strategies of early clinical trials to aid in the assurance of patient safety.

Severe motor neuropathy or neuronopathy due to nitrous oxide toxicity after correction of vitamin B12 deficiency.

INTRODUCTION: Nitrous oxide (N2 O) toxicity can cause a sensory predominant myeloneuropathy identical to subacute combined degeneration caused by vitamin B12 deficiency. We describe a patient with a typical vitamin B12 deficiency syndrome after N2 O abuse who recovered and then developed a severe lower motor neuron syndrome following vitamin B12 correction. This suggests N2 O toxicity independent of functional vitamin B12 deficiency. METHODS: Electrophysiological, serological, and clinical evaluations were undertaken in the evaluation of this patient. RESULTS: A 22-year-old man abused N2 O and presented with a dorsal column syndrome with low vitamin B12 and high homocysteine serum levels. He recovered with treatment but presented later with profound motor axonal degeneration and normal vitamin B12, homocysteine, and methlymalonic acid levels. CONCLUSIONS: This case illustrates that N2 O-associated severe motor neuropathy or neuronopathy can develop separately from typical vitamin B12 deficiency dorsal column myelopathy. This syndrome can present when functional measures of vitamin B12 deficiency have normalized.

Extensive VZV Encephalomyelitis without Rash in an Elderly Man.

Introduction. Varicella zoster virus (VZV) encephalomyelitis with cranial nerve involvement is rare. Characteristically it is preceded by a rash and primarily presents in the immunocompromised. The spectrum of VZV neurologic disease is extensive and it is not uncommon to present without rash. We report the case of an elderly otherwise immunocompetent patient who presented with diverse manifestations of VZV CNS infection all occurring without rash. Case Report. A 78-year-old man presented with 1 week of progressive paraparesis and sensory loss, malaise, and fevers. MRI of the neuraxis demonstrated numerous enhancing lesions: intramedullary, leptomeningeal, pachymeningeal, and cranial nerves. Cerebrospinal fluid (CSF) showed a white blood cell count of 420/ µ L with elevated protein (385 mg/dL). CSF VZV qualitative PCR was positive and CSF VZV immunofluorescence assay detected IgM antibody, confirming the diagnosis of VZV encephalomyelitis. Clinical and radiological improvement was observed after intravenous acyclovir treatment. Conclusion. This is a rare report of an immunocompetent patient with extensive VZV encephalomyelitis. We highlight the importance of considering this diagnosis even in the absence of the characteristic rash, and the potential risk of premature discontinuation of antiviral therapy once HSV has been excluded. Prompt recognition and treatment can dramatically reduce morbidity and mortality in patients.

School and community-based childhood obesity: implications for policy and practice.

This introduction to a special issue of the Journal of Prevention and Intervention in the Community on the topic of childhood obesity prevention lays some of the basis for the state of affairs of the childhood obesity epidemic in the United States as of 2012 and the need for and types of existing prevention and intervention efforts underway. At the intersection of public health and community psychology, each of the five articles presents some insights into how prevention and intervention efforts currently underway are fairing and offers some implications for program developers and policy makers to start to turn around the epidemic. Given the key role schools play, successful strategies for engaging schools are presented in the introduction. The authors of this special issue also emphasize the need to involve whole communities in order to attain the intended changes of reductions in overweight and obesity rates and increases in positive health outcomes.

Theory and practice in action: the contributions of Michael Perkins to clinical linguistics.

This article reviews the scholarly contributions of Michael R. Perkins in the discipline of clinical linguistics and provides some indication of the reasons that he has been so successful. Three primary attributes were described through an analysis of his publications.

Spinal cord stroke: acute imaging and intervention.

Spinal cord infarction is an uncommon disease and as such is often a diagnostic challenge for clinicians. It can vary in its onset, severity, outcome, and recovery from patient to patient. Treatment options for this relatively rare condition also remain elusive. Current consensus recommendations are antiplatelet therapy and the symptomatic management of associated complications such as paraplegia and thromboembolic disease. There are multiple studies in surgical literature of a variety of interventions and adjuncts used for reducing the risk of ischemic spinal cord neurological injury, seen most often in the setting of thoracoabdominal aortic repair operations. We report two cases of acute non-surgical-related spinal cord infarcts, where early diagnosis was made and aggressive, early treatments instituted. With often devastating outcomes, we highlight the need for early detection and that interventions, commonly used in preventing neurological injury after high-risk aneurysm repairs, may be beneficial in treating and reducing the severity of disability in acute spinal cord stroke.

Headaches that kill: a retrospective study of incidence, etiology and clinical features in cases of sudden death.

OBJECTIVE: The study objective was to analyze cases of sudden death that presented to the National Deptartment of Clinical Neurosciences, Ireland, over a 10-year period (1997-2006) where headache was the presenting symptom. BACKGROUND: Headache is a common yet challenging presentation in clinical neurology. In the vast majority of cases, the cause is trivial and reversible-however, in a few patients it may be indicative of a more sinister intracranial process. Recognizing associated "red flag" features and identifying possible life-threatening causes are crucial in ensuring prompt and appropriate intervention. DESIGN/METHODS: A retrospective study/database of all autopsy cases presenting to the Neuropathology Department in Beaumont Hospital, Dublin, was carried out for the period 1997-2006. Cases were selected with headache as the presenting clinical feature. Traumatic head injuries or known central nervous system (CNS) disorders were excluded. Autopsy and medical reports were reviewed to identify associated red flag features at initial presentation according to the International Classification of Headache Diseases, second edition (ICHD-II) criteria. RESULTS: Fifty-five autopsy cases out of a total of 499 complying with selection criteria were reviewed. Over the 10-year-study period, the number of cases of fatal headaches over time were negatively correlated. The most commonly associated red flag symptoms included age over 50: loss of consciousness and collapse, and worst/thunderclap character of headache. Cause of death at autopsy comprised vascular events 60.4% (N = 29), primary brain tumours/cysts 16.7% (N = 8) and meningitis 6.25% (N = 3). Aneurysms accounted for the majority of vascular cases 22.9% (N = 11), with loss of consciousness, occipital headache, neck pain and a focal neurological deficit seen more commonly in this subset of cases. CONCLUSIONS: Sudden-onset headache is a common and often alarming presentation. The majority of cases are of a benign nature; however, a small proportion may be indicative of a catastrophic etiology. Documenting "red flags" on initial presentation is crucial to acutely identify and treat those at highest risk. The results demonstrate an improving trend among clinicians in recognizing and initiating appropriate interventions in these patients, and highlights particular red flag features common in cases of fatal headaches.

Isolated mononeuropathy multiplex--a rare manifestation of intravascular large B-cell lymphoma.

Intravascular large B-cell lymphoma, also known as angiotrophic large cell lymphoma, is a rare disorder where neoplastic lymphoid cells proliferate within the walls of small- to medium-sized blood vessels. Peripheral neuropathy and other neurological manifestations, including stroke and dementia, are common, but cases of isolated multiple mononeuropathies in the absence of systemic symptoms are distinctly rare. We present an unusual case of biopsy-proved angiotrophic large cell lymphoma presenting exclusively with multiple mononeuropathies.

Research report: variations on the theme of avoidance as compensations during unsuccessful reading performance.

This research report provides additional data, manifestations and discussion about avoidance strategies employed by a language-learning disabled student during reading activities. Rather than seeing avoidance as due to random distractions or oppositional behaviours, these data provide a rationale for viewing many types of avoidance as systematic and compensatory efforts to sustain interactional success in the emergence of linguistic difficulty.

Cerebral tuberculoma in a patient receiving anti-TNF alpha (adalimumab) treatment.

We report a case of a cerebral tuberculoma in a 60-year-old woman with rheumatoid arthritis while receiving the anti-tumor necrosis factor alpha monoclonal antibody, adalimumab (Humira), for active disease. MR brain imaging for dyspraxia revealed a left parietal ring-enhancing lesion, which on resection was shown to be a necrotizing granuloma. There were no associated pulmonary lesions, and the patient was systemically well. Sputum and urine cultures were negative for tuberculosis. The patient was treated with anti-tuberculous medications and made an excellent recovery. We consider this to be the first documented case of tuberculosis involving the central nervous system occurring in the setting of adalimumab treatment.

Co-prescription of gastro-protectants in hospitalized patients: an analysis of what we do and what we think we do.

BACKGROUND: Proton pump inhibitors (PPIs) reduce the risk of upper gastrointestinal hemorrhage (UGIH) associated with the use of many medications. GOALS: To examine how clinicians perceive such risk and whether PPI co-prescribing is based on an accurate assessment. STUDY METHODS: Clinicians in a single teaching hospital were asked to estimate risk of UGIH and comment on PPI co-prescription in hypothetical patients. Records of 160 hospital in-patients (median age; 74 y) were then reviewed to examine PPI prescribing and risk factors for UGIH. RESULTS: In general, clinicians estimated UGIH risk accurately and reported low thresholds for PPI co-prescription. Prescribing records showed regular PPI use increased between admission and discharge of patients from 61/160 (38%) to 93/160 (58%). Ten percent had a prior history of peptic ulcer disease. Proton pump inhibitor prescription was significantly associated with the use of aspirin and clopidogrel. Half of the patients with multiple risk factors for UGIH on admission and almost a third at discharge were not co-prescribed a PPI. CONCLUSIONS: Clinicians generally estimate correctly the risk of UGIH and report a low threshold for prescribing gastro-protection. Despite this, prescribing practice does not consistently take account of relative risk of UGIH. Targeted PPI co-prescribing on the basis of risk factors would lead to more rational PPI use.