The natural history of primary progressive multiple sclerosis

Koch, Marcus; Kingwell, Elaine; Rieckmann, Peter; Tremlett, Helen

doi:10.1212/wnl.0b013e3181c5b47f

Cited by 148 publications

(137 citation statements)

References 14 publications

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“…Low inflammatory MRI activity together with the observed low relapse rate is consistent with the currently accepted definition of PPMS 17, 18, 19. Despite the low level of inflammatory activity at the time of inclusion and thereafter, patients had a substantial T2 lesion volume at baseline, indicating previous inflammatory activity, and a high progression rate on‐study, with accelerated brain volume loss.…”

Section: Discussionsupporting

confidence: 83%

Brain atrophy and disability worsening in primary progressive multiple sclerosis: insights from the INFORMS study

Miller

Lublin

Sormani

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo investigate the relationship between brain volume and disability worsening over ≥3 years in the natural history of primary progressive multiple sclerosis using data from the placebo group of the INFORMS trial (n = 487; clinicaltrials.gov NCT00731692).MethodsMagnetic resonance imaging scans were collected annually. Brain volume loss was determined using SIENA. Patients were stratified by baseline normalized brain volume after adjusting for demographic and disease‐burden covariates.ResultsBaseline normalized brain volume was predictive of disability worsening: Risk of 3‐month confirmed disability progression was reduced by 36% for high versus low baseline normalized brain volume (Cox's model hazard ratio 0.64, P = 0.0339; log‐rank test: P = 0.0297). Moreover, on‐study brain volume loss was significantly associated with disability worsening (P = 0.012) and was evident in patients with or without new lesions or relapses. Brain volume loss depended significantly on baseline T2 lesion volume (P < 0.0001). Despite low inflammatory activity at baseline (13% of patients had gadolinium‐enhancing lesions) and throughout the study (mean 0.5 new/enlarging T2 lesions and 172 mm3 T2 lesion volume increase per year), baseline T2 lesion volume was substantial (mean 10 cm3). Lower normalized brain volume at baseline correlated with higher baseline T2 volume and older age (both P < 0.0001).InterpretationBaseline brain volume and the rate of ongoing brain atrophy are significantly associated with disability worsening in primary progressive multiple sclerosis. Brain volume loss is significantly related to baseline T2 lesion volume, but partially independent of new lesion activity, which might explain the limited efficacy of anti‐inflammatory treatment.

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Section: Discussionsupporting

confidence: 83%

Brain atrophy and disability worsening in primary progressive multiple sclerosis: insights from the INFORMS study

Miller

Lublin

Sormani

et al. 2018

Ann Clin Transl Neurol

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“…We found that younger age at onset, previously considered as a good prognostic factor for MS [27] , was associated with longer time to disability. However, several studies have found that despite longer time to disability stages, individuals with younger age at onset reached disability at a younger age [28,29] , results that are supported by our finding when we used age at disability stage as the study outcome (data not shown). Our finding that presence of sensory symptoms at MS onset was associated with better prognosis is consistent with a recent study showing the existence of sensory symptoms at onset as a main factor for favorable prognosis among patients with primary progressive MS [28] .…”

Section: Discussionsupporting

confidence: 87%

Sun Exposure, Vitamin D Intake and Progression to Disability among Veterans with Progressive Multiple Sclerosis

McDowell

Amr²,

Culpepper

et al. 2011

Neuroepidemiology

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Background: Early life events have been suggested to influence multiple sclerosis (MS) susceptibility, and to potentially modulate its clinical course. We assessed vitamin D-related exposures from childhood to disease onset and their associations with MS progression. Methods: Among veterans in the Multiple Sclerosis Surveillance Registry, 219 reported having the progressive form and met the inclusion criteria. Participants reported their past sun exposure, vitamin D-related intake and age at disability milestones using the Patient-Determined Disease Steps (PDDS). The Cox proportional hazards model was used to examine the association between vitamin D-related exposures and time (years) to disability. Results: Low average sun exposure in the fall/winter before disease onset was associated with an increased risk of progressing to a PDDS score of 8 (hazard ratio, HR: 2.13, 95% confidence interval, CI: 1.20–3.78), whereas use of cod liver oil during childhood and adolescence was associated with a reduced risk (HR: 0.44, 95% CI: 0.20–0.96). Conclusions: These results suggest that exposure to vitamin D before MS onset might slow disease-related neurodegeneration and thus delay progression to disability among patients with the progressive subtype.

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“…Therefore, the disease course will progress rapidly, leading to severe disability and dysfunction. 9,33 It was believed that the major hindrance to the repair of demyelination lesions was the failure of oligodendrocytes to unsheathe and preserve axons. 28,[34][35][36][37] Failure to remyelinate is the predominant reason for the axonal and neuronal degeneration that leads to disability.…”

Section: Discussion Promoting Remyelination During the Remission Perimentioning

confidence: 99%

“…6 Patients who suffer primary or secondary progressive MS (PPMS and SPMS), two special clinical types of MS that do not have remission periods, rapidly develop severe disabilities. [7][8][9] The most conspicuous difference between PPMS/SPMS and the classical relapsing-remitting MS is the remission period, when remyelination occurs. The remission stage was defined as a critical window, in which the promotion of remyelination leads to the inhibition of disease progression.…”

Section: Introductionmentioning

confidence: 99%

Thyroid hormone alleviates demyelination induced by cuprizone through its role in remyelination during the remission period

Zhang

Zhan

et al. 2015

Exp Biol Med (Maywood)

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Multiple sclerosis (MS) is a disease induced by demyelination in the central nervous system, and the remission period of MS is crucial for remyelination. In addition, abnormal levels of thyroid hormone (TH) have been identified in MS. However, in the clinic, insufficient attention has been paid to the role of TH in the remission period. Indeed, TH not only functions in the development of the brain but also affects myelination. Therefore, it is necessary to observe the effect of TH on remyelination during this period. A model of demyelination induced by cuprizone (CPZ) was used to observe the function of TH in remyelination during the remission period of MS. Through weighing and behavioral tests, we found that TH improved the physical symptoms of mice impaired by CPZ. Supplementation of TH led to the repair of myelin as detected by immunohistochemistry and western blot. In addition, a sufficient TH supply resulted in an increase in myelinated axons without affecting myelin thickness and g ratio in the corpus callosum, as detected by electron microscopy. Double immunostaining with myelin basic protein and neurofilament 200 (NF200) showed that the CPZ-induced impairment of axons was alleviated by TH. Conversely, insufficient TH induced by 6-propyl-2-thiouracil resulted in the enlargement of mitochondria. Furthermore, we found that an adequate supply of TH promoted the proliferation and differentiation of oligodendrocyte lineage cells by immunofluorescence, which was beneficial to remyelination. Further, we found that TH reduced the number of astrocytes without affecting microglia. Conclusively, it was shown that TH alleviated demyelination induced by CPZ by promoting the development of oligodendrocyte lineage cells and remyelination. The critical time for remyelination is the remission period of MS. TH plays a significant role in alleviating demyelination during the remission period in the clinical treatment of MS.

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The natural history of primary progressive multiple sclerosis

Cited by 148 publications

References 14 publications

Brain atrophy and disability worsening in primary progressive multiple sclerosis: insights from the INFORMS study

Brain atrophy and disability worsening in primary progressive multiple sclerosis: insights from the INFORMS study

Sun Exposure, Vitamin D Intake and Progression to Disability among Veterans with Progressive Multiple Sclerosis

Thyroid hormone alleviates demyelination induced by cuprizone through its role in remyelination during the remission period

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