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

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.

Phrenic nerve conduction studies as a biomarker of respiratory insufficiency in amyotrophic lateral sclerosis.

Our objective was to examine the value of phrenic nerve conduction studies (PNCS) in quantifying diaphragm dysfunction in ALS, as no ideal test of respiratory insufficiency exists in ALS. We prospectively recorded bilateral PNCS, forced vital capacity (FVC), maximum inspiratory pressure (MIP), sniff nasal inspiratory pressure (SNIP), respiratory rate, ALSFRS-R, and respiratory symptoms in 100 ALS patients attending our clinic over a nine-month period. Survival data were collected for two years. Results showed that PNCS were reproducible and well tolerated. When the Pamp was abnormal (<0.3 mV), the relative risk of a respiratory rate >18 was 7.2 (95% CI 2.2-37.2, p <0.01) compared with a Pamp ≥0.3 mV. Similarly, the relative risk of orthopnea was 3.5 (95% CI 1.6-8.7, p <0.01) and dyspnea 2.4 (95% CI 1.4-4.0, p <0.01). FVC had the strongest correlation with Pamp (R(2) = 0.48 (p <0.001)). Fourteen of 15 patients with a FVC <50% had a Pamp <0.3 mV. However, eight with a Pamp <0.3 had a FVC >80%. The median survival was 1.07 years when the Pamp was <0.3 mV and >2 years when the Pamp was >0.3 mV (p <0.001). In conclusion, the phrenic Pamp correlated closely with multiple symptoms, signs, and laboratory measures of respiratory insufficiency and may prove to be a useful biomarker of respiratory dysfunction in ALS.

Seeking a measure of clinically meaningful change in ALS.

We sought to identify a method to assess 'clinically meaningful change' perceived by patients, caregivers and clinical raters in relation to changes in ALSFRS-R scores at three-month intervals. In this five-site study, 81 patient-caregiver dyads were interviewed at baseline, three, and six months to assess changes in ALSFRS-R in relation to perceived occurrence of change, its magnitude and impact. Ratings by patients, caregivers and clinical raters were analyzed over three-month intervals within and between respondent groups. We found that patients, clinical raters, and caregivers agreed about 80% of the time about whether change occurred, and in what direction, on each of three visits. The perceived magnitude of change for the four domains measured by the ALSFRS-R was correlated with ratings of impact within respondent groups and across time. We also found moderate associations between changes in ALSFRS-R domain scores and judgments of symptom impact as rated by patient, caregiver and clinical rater. Independent measures (Quality of Life, Goal Assessment Scaling) showed no consistent correlations with ALSFRS-R change scores. In conclusion, the use of scales to assess the perceived magnitude and impact of change corresponding with the domains of the ALSFRS-R may be a step towards understanding of the clinical meaning of changes in that measure.

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

Immune activation and inflammation play significant roles in the pathogenesis of Alzheimer's 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.

A timeline for predicting durable medical equipment needs and interventions for amyotrophic lateral sclerosis patients.

ALS is progressive with increasing patient needs for durable medical equipment (DME) and interventions (gastric feeding tube - PEG, and non-invasive ventilation - NIV). We performed a chart review of deceased patients to determine the time-course of needs and their estimated costs. A timeline of needs was based on when clinic personnel felt an item was necessary. The point in time when an item or intervention was needed was expressed as a percentage of a patient's total disease duration. A wide range of DME and interventions was needed irrespective of site of ALS symptom onset (bulbar, upper, lower extremity), beginning at 10% of disease duration of lower extremity onset and increasing thereafter for all sites. The cumulative probability of costs of items and interventions began at 25%-50% of disease duration and increased to between $18,000 and $32,000 (USD), highest for lower extremity onset due to the cost of wheelchairs. We conclude that a high percentage of ALS patients will need a full spectrum of major DME items and interventions during the second half of disease duration. This results in a linear rise in costs over the second half of the disease duration.

A survey of clinicians' practice in the symptomatic treatment of ALS.

UNLABELLED: Symptomatic management is the mainstay of ALS patient care, but there are few controlled trials of drugs and interventions for common symptoms. METHODS: We queried ALS clinic neurologists to determine drugs and interventions of choice and neurologists' perceived efficacy for 14 symptoms. RESULTS: The results are tabulations of the physicians' four most frequent choices for each symptom, the physicians' perception of efficacy, the average doses and average daily costs. A wide range of drugs and interventions were nominated for management of ALS symptoms. Consensus on treatment was rare for individual symptoms, and efficacy for any symptom was judged moderate at best. A few drugs were recommended for multiple symptoms. Comparisons of perceived efficacy compared to drug costs are informative. DISCUSSION: The results of the survey emphasize the challenges of symptom management in ALS. These data aid clinical management and guide rational choices for randomized controlled trials.

Comparison of instruments addressing quality of life in patients with ALS and their caregivers.

Most quality of life (QoL) instruments for ALS focus on function. An open instrument, the Schedule for the Evaluation of Individual Quality of Life-Direct Weight (SEIQoL-DW) that asks subjects to nominate and rate QoL areas important at the time of evaluation, was given to patients and caregiver spouses. Patients also completed function-based instruments. Correlations were poor between SEIQoL-DW and function-based instruments. SEIQoL-DW scores were worse for caregivers than for patients, probably explained by shifts in patient expectations with disease progression.