Lipoic acid and secondary progressive multiple sclerosis

There are various reports on work by Dr. Rebecca Spain (leading an Oregon Health & Science University research team) on the use of lipoic acid [LA] on patients with secondary progressive multiple sclerosis. The paper is available on the internet. Published online June 28, 2017. doi: http:/​/​dx.​doi.​org/​10.​1212/​NXI.​0000000000000374. Neurol Neuroimmunol Neuroinflamm September 2017 vol. 4 no. 5 e374.

The conclusion of a study involving 51 participants [27 LA and 24 placebo ]: Lipoic Acid demonstrated a 68% reduction in annualized percent change brain volume [PCBV] and suggested a clinical benefit in SPMS while maintaining favorable safety, tolerability, and compliance over 2 years.

Of the MRI: The following sequences were acquired using a Philips Achieva 3.0T X-series with Quasar Dual gradient systems: (1) 3D high-resolution magnetization-prepared rapid acquisition gradient echo (3D MP-RAGE) with 1 mm3 voxels for high-resolution structural (T1-weighted) information. The upper cervical spinal cord was intentionally included in the series through positioning; (2) 3D fluid-attenuated inversion recovery (3D FLAIR) series with 1 mm3 voxels; (3) conventional 3 mm (0.3 gap) axial 2D proton density/T2-weighted sequences with in-plane resolution 1 mm2; and (4) 3-mm sagittal 2D proton density/T2-weighted spinal cord sequences. No intravascular contrast was used.

The paper also noted:


The reduction in the brain atrophy rate compares favorably with a large phase 3 trial of ocrelizumab (n = 731), reporting a 17.5% reduction in the whole-brain atrophy rate over 120 weeks.26 In contrast to the present study, the ocrelizumab trial included only primary progressive MS patients with more men (51% vs 39%) who were younger (45 vs 59 years), had shorter disease duration (6.5 vs 30 years), and less disability (EDSS 4.7 vs 5.4). The ocrelizumab trial limited inclusion to those with inflammatory CSF, a characteristic not assessed in this study. Other disease-modifying therapy trials in progressive MS populations have not demonstrated robust changes in brain atrophy rates or have not used this outcome measure.27,–,29



One notes that the study by Rebecca Spain recognizes that the disease-modifying agent ocrelizumab [tradename OCREVUS] does lower the rate of brain volume reduction (atrophy) BUT it finds that lipoic acid is more effective in reducing the rate:


From Spain paper:

for 600mg (racemic) lipoic acid: This change corresponds to a 68% reduction in the rate of brain atrophy in LA vs placebo (figure 2A, table 3).

for ocrelizumab : The reduction in the brain atrophy rate compares favorably with a large phase 3 trial of ocrelizumab (n = 731), reporting a 17.5% reduction in the whole-brain atrophy rate over 120 weeks

68/17.5 = 3.89



Consider some background material from Vollmer et al., Journal of the Neurological Sciences
Volume 357, Issues 1–2, 15 October 2015, Pages 8-18:


In this study, the average multiple sclerosis patient receiving first-generation disease-modifying treatment or no disease-modifying treatment lost approximately 0.7% of brain volume/year, well above rates associated with normal aging (0.1%–0.3% of brain volume/year).

(...)

Arnold et al. found that the median percentage change in brain volume from baseline to 24 months was − 0.64% and − 0.77% for delayed-release DMF [Tecfidera] twice daily and thrice daily, respectively [56]. The DMF results show that there is a significant 21% reduction in the PBVC among patients treated with DMF twice daily compared with patients in the placebo arm (p = 0.04).



****Separately, from the Genzyme website:


Through year five, 33 percent and 43 percent of patients who had some disability before receiving Lemtrada in CARE-MS I and CARE-MS II, respectively, had improvement in EDSS score confirmed over at least six months as compared with pre-treatment baseline.

Through year five, patients who received Lemtrada in CARE-MS I and II experienced a slowing of brain atrophy as measured by brain parenchymal fraction on magnetic resonance imaging (MRI). In years three, four and five, the median yearly brain volume loss was -0.20 percent or less, which was lower than what was observed during the two-year pivotal studies.



link: http://news.genzyme.com/press-release/treatment-effects-maintained-over-five-years-majority-patients-relapsing-remitting-mul

AND


In the comparator group of the CARE-MS-1 study, the EDSS decreased from baseline (–0.14), whereas an increase of 0.24 was seen in the same group in the CARE-MS-2 study (patients who had failed first-line treatment). The unexpected improvement in EDSS (rather than a slowing in progression) in the comparator group of the CARE-MS-1 study may explain in part why alemtuzumab failed to meet the disability endpoint in the CARE-MS-1 trial. In addition, the low baseline EDSS would also have made it more difficult to detect differences in changes from baseline.

(...)

The drug was found to be more effective in patients with less cerebral inflammation in the pretreatment phase. The authors suggested that the progressive disability and increasing brain atrophy could be attributed to axonal degeneration. This axonal degeneration seemed to depend in part on prior inflammation and progressed despite suppression of inflammation. As a result, subsequent development of alemtuzumab focused on relapsing-remitting MS rather than secondary progressive MS.



link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3959804/


Also, from Filippi M, Rovaris M, Inglese M, Barkhof F, De Stefano N, Smith S et al. Interferon beta-1a for brain tissue loss in patients at presentation with syndromes suggestive of multiple sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet. 2004;364(9444):1489-96.:


A sub-analysis from the ETOMS study that assessed the efficacy of [sc] interferon beta 1-a sc in patients with CIS showed a significant difference in mean annual percentage brain volume change (PBVC) between patients who had disease progression and those who did not (-0.92% and -0.56%, respectively)


ALSO from NeuroImage: Clinical
Volume 13, 2017, Pages 9-15



Indeed, white matter lesion load detected by MRI is only weakly correlated with clinical symptoms (Zivadinov and Cox, 2007). There is a growing body of evidence from both pathology and MRI to suggest that grey matter (GM) degeneration is prevalent in MS (Bermel et al., 2003), (Bakshi et al., 2005), (Chard et al., 2004), (Sanfilipo et al., 2006) and may be a stronger predictor of clinical decline than WM measures (Fisniku et al., 2008; Pirko et al., 2007). I



ALSO, from Journal of Clinical Neuroscience (7 June 2017)


Cognitive impairment affects 40–70% of patients with Multiple Sclerosis (MS), with most frequent deficits of memory, processing speed, attention and executive functions [1,2]. Although cognitive decline can be present from the early stages of the disease, it is more frequent and pronounced in secondary progressive MS (SPMS) [3]. Cognitive impairment is an important predictor of employment status in MS patients [4,5]. Unemployment rates of 50–80% of MS patients have been observed within 10 years of disease onset [2]. A wide range of cognitive domains have been found to be predictive of unemployment in MS patients, including information processing efficiency, memory and executive functions [6].



ALSO, from Neurology, Psychiatry and Brain Research
Volume 22, Issues 3–4, December 2016, Pages 173-177


This study demonstrates that aCC [annualized corpus callosum ] atrophy is associated with severity of cognitive dysfunction in MS patients. Based on a linear multivariate regression we could determine that aCC reduction is a predictive factor for cognitive impairment. We did not find any association between aCCI reduction and gender, age, disease duration as reported in the studies by Martola et al. (2007) and Yaldizli et al. (2011). Over 90% of MS patients display CC structural changes and atrophy (Mesaros et al., 2009). Our study confirms previous imaging study findings. In our investigation CC contracted by a mean of 0.7% per year. This is in the range of 0.8% aCC reduction reported in a recent study (Yaldizli et al., 2011) and is consistent with the annual brain volume loss of 0.5–1.3% measured by other studies in multiple sclerosis patients (Anderson, Fox, & Miller, 2006; Chard et al., 2004; De Stefano, Battaglini, & Smith, 2007; Hardmeier et al., 2003).