Changes in saccadic intrusions over time as an objective biomarker to follow ALS disease progression.

Objective: Saccadic Intrusions (SIs) are abnormal eye movements during gaze fixation. Studies have indicated the clinical relevance of SIs, especially of square wave jerks (SWJ) in ALS. We used a software-based platform to extract SIs as a part of an interventional drug trial. The objective was to examine SIs' change over time as a potential biomarker of ALS disease progression. Methods: 28 ALS patients (61.95 ± 8.6 years) were assessed with the revised ALS Functional Rating Scale (ALSFRS-R) and with an oculometric test. Changes of SIs over time and correlations with ALSFRS-R and its bulbar subscale were calculated. A power calculation was conducted to understand the practical implications of results. Results: A significant increase of SWJ over trial duration was observed, with an increase in frequency (mean rise of 0.14 ± 0.28, p < 0.01), amplitude (0.001 ± 0.0016 degrees, p < 0.005), overall duration of SWJ (0.13 ± 0.25, in %, p < 0.01), and in their relative part out of all intrusions (0.18 ± 0.32, in %, p < 0.005). Negative correlations were found with the bulbar subscale (R=-0.43, -0.41, -0.39 and -0.47, respectively, p < 0.001). The required sample size for observing a 40% reduction in bulbar aspects when using the oculometric test (α = 0.05 and ß = 0.8), was found to be 150 patients per arm, compared with 200 patients using the bulbar subscale. Conclusions: Evaluation of saccadic intrusions during fixation was able to detect disease progression over time, correlated with ALSFRS-R bulbar subscale. Eye movements can potentially serve as an objective biomarker in ALS clinical trials and reduce the required sample size to show clinical effect of therapies.

Oculometric measures as a tool for assessment of clinical symptoms and severity of Parkinson's disease.

Abnormalities of oculometric measures (OM) are widely described in people with Parkinson's disease (PD). However, knowledge of correlations between abnormal OM, disease severity and clinical assessment in PD patients is still lacking. To evaluate these correlations, PD patients (215 patients, mean age 69 ± 9.1 years, 79 females) with severe (H&Y > 3) and mild to moderate (H&Y ≤ 2) disease, and 215 age-matched healthy subjects were enrolled. All patients were evaluated using MDS-UPDRS and an oculometric test using computer vision and deep learning algorithms. Comparisons of OM between groups and correlations between OM and MDS-UPDRS scores were calculated. Saccadic latency (ms) was prolonged in patients with severe compared with mild to moderate disease (pro-saccades: 267 ± 69 vs. 238 ± 53, p = 0.0011; anti-saccades: 386 ± 119 vs. 352 ± 106, p = 0.0393) and in patients with mild to moderate disease versus healthy subjects (pro-saccades: 238 ± 53 vs. 220 ± 45, p = 0.0003; anti-saccades: 352 ± 106 vs. 289 ± 71, p < 0.0001). Error rate (%) was higher among patients with severe (64.06 ± 23.08) versus mild to moderate disease (49.84 ± 24.81, p = 0.0001), and versus healthy subjects (49.84 ± 24.81 vs. 28.31 ± 21.72, p = 0.00001). Response accuracy (%) was lower for patients with severe (75.66 ± 13.11) versus mild to moderate disease (79.66 ± 13.56, p = 0.0462), and versus healthy subjects (79.66 ± 13.56 vs. 90.27 ± 8.79, p < 0.0001). Pro- and anti-saccadic latency, error rate and accuracy were correlated with MDS-UPDRS scores (r = 0.32, 0.28, 0.36 and -0.30, respectively, p < 0.0001) and similar correlations were found with its axial subscore (R = 0.38, 0.29, 0.44, and -0.30, respectively, p < 0.0001). Several OM were different in patients under levodopa treatment. OM worsened as PD severity increases, and were correlated with MDS-UPDRS scores. Using OM can be implemented for PD patients' assessment as a tool to follow disease progression.

Correlation between oculometric measures and clinical assessment in ALS patients participating in a phase IIb clinical drug trial.

Objective: Oculometric measures (OM) can be extracted from eye movements during presentation of visual stimuli. Studies have indicated the benefit of OM in assessment of neurological disorders, including Amyotrophic Lateral Sclerosis (ALS). We used a new software-based platform for the extraction of OM during patients' assessment. Our objective was to examine the correlation between OM and clinical assessment as a part of a clinical drug trial. Methods: 32 ALS patients (mean age 60.75 ± 10.36 years, 13 females), were assessed using a validated score (ALSFRS-R), and a novel software-based oculometric platform (NeuraLight, Israel) as a part of a clinical drug trial. Correlations of ALSFRS-R with OM were calculated and compared with matched healthy subjects' data (N = 129). Results: A moderate correlation was found between ALSFRS-R and corrective saccadic latency (R = 0.52, p = 0.002). Fixation time during smooth pursuit and peak velocity during pro-saccades were both worse in ALS patients versus healthy subjects (mean (SD)=0.34(0.06) vs. 0.3(0.07), p = 0.01, and 0.41(0.05) vs. 0.38(0.07), p = 0.04, respectively). Patients with bulbar symptoms (N = 14) had a decreased pro-saccade gain compared with patients without bulbar symptoms (mean (SD)=0.1 (0.04) vs. 0.93 (0.07), p = 0.01), and a larger error rate of anti-saccade movement (mean (SD)=0.42 (0.21) vs. 0.28 (0.16), p = 0.04). Conclusions: Oculometric measures correlated with the clinical assessment and were different from data of healthy subjects. Further studies are warranted to establish the role of oculometrics in the evaluation of patients with ALS and other neurodegenerative disorders, and its possible use in clinical trials.

Long-term (up to 22 years), open-label, compassionate-use study of glatiramer acetate in relapsing-remitting multiple sclerosis.

To evaluate the safety and efficacy of long-term glatiramer acetate (GA) therapy, 46 patients with relapsing-remitting multiple sclerosis (RRMS) were treated for up to 22 years in an ongoing, open-label study. Kurtzke expanded disability status scale (EDSS) was measured every six months, relapses were reported at occurrence and patients self-reported adverse events (AEs). At GA initiation, disease durations ranged from 0-20 years (median 6.0 years) and at data cut-off (October 2004), GA therapy duration ranged from 1-22 years (median 12.0 years). Mean EDSS score increased 0.9 +/- 1.9 from the pretreatment score (3.0 +/- 1.8; P = 0.076). Only 10/28 (36%) patients with baseline EDSS <4.0 had a last observed value >or= 4.0 and 8/34 (24%) with entry EDSS < 6.0 reached EDSS >or= 6.0. A majority (57%) maintained improved or unchanged EDSS scores. Annualized relapse rate decreased to 0.1 +/- 0.2 from 2.9 +/- 1.4 prestudy (P < 0.0001). Of the 18 remaining patients in October 2004 (average disease duration 23 years), 17% with baseline EDSS scores < 4.0 reached EDSS >or= 4.0 and 28% with baseline scores < 6.0 reached EDSS >or= 6.0. Adverse events were similar to those reported in short-term clinical trials. This study shows a low rate of relapses and EDSS progression in RRMS patients on GA for up to 22 years.

On the horizon: possible neuroprotective role for glatiramer acetate.

Inflammation and neurodegeneration characterize the pathogenesis of multiple sclerosis (MS). Slow axonal degeneration, rather than acute inflammation, is considered the cause of chronic disability in MS. The signs of acute axonal damage and loss have been shown to occur early in the lesion development of patients with chronic MS and often correlate with demyelination and inflammation. While immune activity in the central nervous system has traditionally been considered to be a detrimental event in MS, recent studies have found that autoimmune T cells may play an important role in protecting neurons from the ongoing spreading damage. Neuroprotection in MS is a new and evolving concept, and many questions remain with regard to potential targets for therapeutic intervention. Preliminary studies, both in animals and in humans, have suggested that glatiramer acetate (GA) may confer neuroprotective activity in addition to bystander suppression. Additional research is needed to determine if these promising neuroprotective effects correlated with the long-term effect of GA in MS.

Oral glatiramer acetate in experimental autoimmune encephalomyelitis: clinical and immunological studies.

Glatiramer acetate (GA, Copaxone, copolymer 1) for injection is an approved drug for relapsing-remitting multiple sclerosis. The clinical and immunological effects of GA were extensively studied in experimental autoimmune encephalomyelitis (EAE), the experimental animal model for MS. The effect of oral administration of GA was tested in both rodents and primates in acute as well as in chronic relapsing (CR) models of EAE. Oral GA was found to suppress acute EAE induced in rats, mice, and rhesus monkeys. The effect of GA was also tested in several models of CR-EAE: proteolipid protein and myelin oligodendrocyte glycoprotein induced CR-EAE in mice, CR-EAE in Biozzi mice, and CR-EAE in cynomolgus monkeys. In all the murine models, oral treatment with GA initiated at the peak of first relapse reduced the severity of disease and suppressed further relapses. Suppression of EAE with oral GA was associated with marked inhibition of spleen cell proliferation and Th1 cytokine (IL-2 and IFN-gamma) response to the respective autoantigens. GA-specific T cell lines of the Th2/3 type that inhibit EAE induction in vivo, similarly to those induced by injection of GA, could be isolated from spleens of GA-fed mice and rats. Furthermore, as demonstrated previously for GA-specific cells induced by the parenteral route, the orally induced GA-specific cells accumulate in the CNS and secrete in situ Th2 cytokines in response to both GA and MBP as well as brain-derived neurotrophic factor (BDNF). Although a clinical trial in MS with two doses of oral GA in enteric-coated tablets did not show a significant effect either at the clinical or immunological level, the results presented here suggest that oral GA may still be developed into a therapeutic modality in MS.