Dallas Forshew

Practice Parameter update: The care of the patient with amyotrophic lateral sclerosis: Drug, nutritional, and respiratory therapies (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology

Objective: To systematically review evidence bearing on the management of patients with amyotrophic lateral sclerosis (ALS). Methods: The authors analyzed studies from 1998 to 2007 to update the 1999 practice parameter. Topics covered in this section include slowing disease progression, nutrition, and respiratory management for patients with ALS. Results: The authors identified 8 Class I studies, 5 Class II studies, and 43 Class III studies in ALS. Important treatments are available for patients with ALS that are underutilized. Noninvasive ventilation (NIV), percutaneous endoscopic gastrostomy (PEG), and riluzole are particularly important and have the best evidence. More studies are needed to examine the best tests of respiratory function in ALS, as well as the optimal time for starting PEG, the impact of PEG on quality of life and survival, and the effect of vitamins and supplements on ALS. Recommendations: Riluzole should be offered to slow disease progression (Level A). PEG should be considered to stabilize weight and to prolong survival in patients with ALS (Level B). NIV should be considered to treat respiratory insufficiency in order to lengthen survival (Level B), and may be considered to slow the decline of forced vital capacity (Level C) and improve quality of life (Level C). Early initiation of NIV may increase compliance (Level C), and insufflation/exsufflation may be considered to help clear secretions (Level C).

Systemic immune system alterations in early stages of Alzheimer's disease.

Immune activation and inflammation play significant roles in the pathogenesis of Alzheimers disease (AD). To test whether AD patients showed systemic manifestations of inflammation, blood from 41 patients with early stages of AD and 31 aged-match elderly controls were evaluated. Cellular markers for monocyte/macrophage (MO) activation and CD8 T lymphocyte were increased in early AD patients. Expression of monocyte CCR2, the receptor for monocyte chemoattractant protein-1 (MCP-1), was decreased; however, plasma MCP-1 levels were significantly increased and were related to the degree of MO activation in AD. These findings suggest that AD pathogenesis may be influenced by systemic immunologic dysfunction and provides potential immunologic targets for therapeutic intervention.

Phase II screening trial of lithium carbonate in amyotrophic lateral sclerosis Examining a more efficient trial design

Objective: To use a historical placebo control design to determine whether lithium carbonate slows progression of amyotrophic lateral sclerosis (ALS). Methods: A phase II trial was conducted at 10 sites in the Western ALS Study Group using similar dosages (300–450 mg/day), target blood levels (0.3–0.8 mEq/L), outcome measures, and trial duration (13 months) as the positive trial. However, taking riluzole was not a requirement for study entry. Placebo outcomes in patients matched for baseline features from a large database of recent clinical trials, showing stable rates of decline over the past 9 years, were used as historical controls. Results: The mean rate of decline of the ALS Functional Rating Scale–Revised was greater in 107 patients taking lithium carbonate (−1.20/month, 95% confidence interval [CI] −1.41 to −0.98) than that in 249 control patients (−1.01/month, 95% CI −1.11 to −0.92, p = 0.04). There were no differences in secondary outcome measures (forced vital capacity, time to failure, and quality of life), but there were more adverse events in the treated group. Conclusions: The lack of therapeutic benefit and safety concerns, taken together with similar results from 2 other recent trials, weighs against the use of lithium carbonate in patients with ALS. The absence of drift over time and the availability of a large database of patients for selecting a matched historical control group suggest that use of historical controls may result in more efficient phase II trials for screening putative ALS therapeutic agents. Classification of evidence: This study provided Class IV evidence that lithium carbonate does not slow the rate of decline of function in patients with ALS over 13 months.

Quality improvement in neurology: Amyotrophic lateral sclerosis quality measures Report of the Quality Measurement and Reporting Subcommittee of the American Academy of Neurology

Amyotrophic lateral sclerosis (ALS) is a lethal, progressive neurodegenerative disease characterized by loss of motor neurons.1 Patients with ALS lose function in the limbs, speech, swallowing, and breathing muscles. The cause of the disease is still not known for most patients. Approximately 25,000 people in the United States have ALS, and 5,000 people are diagnosed with ALS annually in the United States.1 Most patients die from respiratory failure 2 to 5 years after onset of symptoms. Cognitive dysfunction is seen in 20% to 50% of patients.2 The disease burden for patients and caregivers is enormous. The average cost of care has been estimated at

Gene expression profiling in peripheral blood mononuclear cells from patients with sporadic amyotrophic lateral sclerosis (sALS)

50,000 per patient per year.3

Factors correlated with NPPV use in ALS.

The aim of this study was to identify gene expression profiles in peripheral blood mononuclear cells (PBMCs) from sporadic amyotrophic lateral sclerosis (sALS) patients to gain insights into the pathogenesis of ALS. We found that upregulation of LPS/TLR4-signaling associated genes was observed in the PMBCs from sALS patients after short-term cultivation, and that elevated levels of gene expression correlated with degree of peripheral blood monocyte activation and plasma LPS levels in sALS. Similar patterns of gene expression were reproduced in LPS stimulated PBMCs from healthy controls. These data suggest that chronic monocyte/macrophage activation may be through LPS/TLR4-signaling pathways in ALS.

NP001 regulation of macrophage activation markers in ALS: A phase I clinical and biomarker study

In spite of emerging evidence of therapeutic benefit from non‐invasive positive pressure ventilation (NPPV), only a minority of ALS patients use this therapy. We examined factors which correlate with use of NPPV in ALS patients. Data were analyzed from the ALS CARE Database on the use of NPPV in patients with FVC less than 50% of predicted and probable or definite ALS based on modified El Escorial criteria. Of the 403 eligible patients, 146 (36%) used NPPV. NPPV compliance was strongly correlated with symptoms of dyspnea and orthopnea as well as with the use of other therapies including PEG tubes, augmentative speech devices, and riluzole. Male gender and household income >

Phase I clinical trial of safety of L-serine for ALS patients

80,000 were also associated with higher NPPV use. There was no correlation between age, race, type of insurance, forced vital capacity, duration of symptoms, ALSFRS‐R, caregiver burden or quality of life with the use of NPPV. These data suggest that the factors which are most closely associated with NPPV utilization are symptomatic orthopnea and dyspnea. The findings may be useful in designing prospective studies to examine the factors which might explain the underutilization of NPPV and the optimal use of this treatment.

ALS Multicenter Cohort Study of Oxidative Stress (ALS COSMOS): Study methodology, recruitment, and baseline demographic and disease characteristics

Abstract This is a phase I, placebo-controlled, single ascending dose safety and tolerability study of NP001 in patients with ALS. NP001 is a novel regulator of inflammatory macrophages and monocytes. As ALS progression is thought to be related to neuroinflammation, an additional objective of the study was to assess the effects of NP001 administration on monocyte activation markers. Thirty-two ALS patients were enrolled and received either placebo (eight) or one of four (six at each dose) ascending single i.v. doses (0.2, 0.8, 1.6 and 3.2 mg/kg NP001). Patients were monitored for safety, and blood monocyte immune activation markers CD16 and HLA-DR were assessed pre- and 24 h post-dosing. Changes from baseline were calculated. Results showed that NP001 was generally safe and well tolerated. Importantly, a single dose of NP001 caused a dose-dependent reduction in expression of monocyte CD16, a marker of monocyte activation/inflammation. Additionally, monocyte HLA-DR expression was also decreased in those patients with elevated values at baseline. In conclusion, these data indicate that NP001 has an acute effect on inflammatory monocytes in ALS patient blood. The potential for modulation of inflammation in the context of ALS disease progression will require further study with long-term follow-up.

ALS untangled no. 20: The Deanna protocol

Abstract We performed a randomized, double-blind phase I clinical trial for six months on the effects of oral L-serine in patients with ALS. The protocol called for enrollment of patients with a diagnosis of probable or definite ALS, age 18–85 years, disease duration of less than three years and forced vital capacity (FVC) ≥ 60%. Patients were randomly assigned to four different oral twice-daily dose regimens (0.5, 2.5, 7.5, or 15 g/dose). Blood, urine and CSF samples, ALS Functional Rating Scale-Revised (ALSFRS-R) scores and forced vital capacity (FVC) were obtained throughout the trial. Disease progression was compared with matched historical placebo controls from five previous ALS therapeutic trials. Of 20 patients enrolled, one withdrew before receiving study drug and two withdrew with gastro-intestinal problems. Three patients died during the trial. L-serine was generally well tolerated by the patients and L-serine did not appear to accelerate functional decline of patients as measured by slope of their ALSFRS-R scores. Based on this small study, L-serine appears to be generally safe for patients with ALS.