Elsevier

The Lancet Neurology

Volume 6, Issue 10, October 2007, Pages 903-912
The Lancet Neurology

Review
Primary-progressive multiple sclerosis

https://doi.org/10.1016/S1474-4422(07)70243-0Get rights and content

Summary

About 10–15% of patients with multiple sclerosis (MS) present with gradually increasing neurological disability, a disorder known as primary-progressive multiple sclerosis (PPMS). Compared with relapse-onset multiple sclerosis, people with PPMS are older at onset and a higher proportion are men. Inflammatory white-matter lesions are less evident but diffuse axonal loss and microglial activation are seen in healthy-looking white matter, in addition to cortical demyelination, and quantitative MRI shows atrophy and intrinsic abnormalities in the grey matter and the white matter. Spinal cord atrophy corresponds to the usual clinical presentation of progressive spastic paraplegia. Although neuroaxonal degeneration seems to underlie PPMS, the pathogenesis and the extent to which immune-mediated mechanisms operate is unclear. MRI of the brain and spinal cord, and examination of the CSF, are important investigations for diagnosis; conventional immunomodulatory therapies, such as interferon beta and glatiramer acetate, are ineffective. Future research should focus on the clarification of the mechanisms of axonal loss, improvements to the design of clinical trials, and the development of effective neuroprotective treatments.

Introduction

Multiple sclerosis (MS) is a common, chronic neurological disease of young adults, with a prevalence of between 1 in 500 and 1 in 1500 of the population in Europe, North America, and Australasia. The clinical course is variable, although most patients develop significant locomotor disability 15–30 years after onset. In the past decade, disease-modifying treatments that reduce the frequency of acute relapses and the white-matter lesions seen on MRI have been made available, although their long-term effects are not known. The ability to modify beneficially at least a part of the disease pathology is important to define patient groups that might or might not benefit from therapeutic interventions.

The main clinical subtypes of MS were defined 20 years ago as relapsing-remitting MS (RRMS) and chronic progressive MS. The former is characterised by episodes of acute neurological deterioration (relapses), followed by partial or complete recovery (remission); the latter is characterised by steady progressive deterioration in neurological function over months or years. Although most cases of chronic progressive MS start as RRMS, in some patients there is a steady progression from onset, without relapses. The recognition that there are notable differences in MRI findings in the brain between these two progressive forms of MS1 preceded the more general use of the terms primary-progressive MS (PPMS) and secondary-progressive MS (SPMS), to distinguish these forms of progressive disease. In 1996, a formal classification of MS clinical subgroups was proposed that included both PPMS and SPMS,2 and this classification has become widely accepted (panel 1).

The classification of disease subtype—relapsing-remitting, secondary progressive, or primary-progressive—is highly relevant because of differences in prognosis and because disease-modifying treatments are effective only in predominantly relapsing MS. The diagnosis and differential diagnosis of PPMS can be a challenge, with a spectrum of disorders that differ from those considered in the diagnosis of relapse-onset MS. Although most of the major clinical subgroups fall within the framework of a single disease (MS), there is, nevertheless, evidence for differences in their pathology and pathogenic mechanisms. This Review of PPMS will survey recent literature on epidemiology, natural history, genetics, pathology, pathogenesis, and MRI findings, and consider the clinical manifestations, diagnosis, and management of this disorder (table 1).

Section snippets

Epidemiology and natural history

A presentation of PPMS is seen in 10–15% of patients. Although most patients come from regions where MS is common, such as North America and Europe,3, 4, 5 patients with PPMS have also been reported in other parts of the world.6, 7 The age at onset is about 10 years older than that seen in RRMS (mean 40 years vs 30 years) but similar to the age of onset of SPMS. RRMS is between two and three times more common in men than women; however, there is no gender predominance in PPMS. A progressive

Genetics

Similar HLA associations have been reported in both PPMS and RRMS, and both subtypes are associated with the DR2 haplotype DRB1*1501 in the class II region of the MHC on chromosome 6,14, 15, 16 which was recently confirmed in a large multicenter study of 1339 families.17 Different associations with other HLA antigens have been seen,14, 18 but no consistent profile has been established. No clear associations have been found between haplotype and disease severity, although the authors of a large

Pathology and pathogenesis

Revesz and colleagues22 investigated demyelinated lesions in PPMS and reported that they contained fewer inflammatory cells than the lesions in SPMS. This finding, combined with early MRI studies that showed fewer focal white-matter lesions in PPMS1, led to the notion that pathological features additional to classic inflammatory, demyelinating, white-matter lesions might be important for the disability in PPMS.

The lesions seen in patients with PPMS can show a loss of oligodendrocytes and, in a

Brain

To study MS in vivo, the findings of direct neuro-pathological observations have been supplemented with the indirect pathological inferences from MRI. The first MRI studies showed smaller lesion loads and a lower frequency of gadolinium-enhancing lesions in PPMS compared with SPMS.1, 37 The differences in inflammation and enhancement are quantitative rather than qualitative; studies with triple-dose gadolinium show more gadolinium-enhancing lesions in PPMS than single-dose studies.38

Typical presentation

The clinical feature that distinguishes progressive-onset MS from relapsing-onset MS is the time course over which symptoms develop. In relapsing-onset MS, relapses typically develop rapidly, with symptoms worsening over hours to days, and the symptoms take days to weeks to recede. Progressive-onset MS develops much more slowly: functional impairments increase steadily over months to years and—apart from minor fluctuations—do not reverse.

The most common presentation (80% of patients) is

Prognosis

The studies of the natural history of MS confirm that progression—compared with relapse and remission—is a poor prognostic feature, and there is considerable variation in the reported rates of progression among individuals and groups with different natural histories.5, 8 The average rate of deterioration is the same for PPMS and SPMS, and long periods of relative stability are seen in some patients. The more favourable spectrum should be recognised when counselling patients, to avoid undue

Investigations and diagnostic criteria

MRI is the most useful investigation in patients with suspected progressive-onset MS. In patients with progressive spastic paraplegia, both spinal cord MRI and brain MRI should be obtained. Lesions that are typical for demyelination are usually seen in both locations; however, when the MRI of the brain is negative, spinal cord lesions are of particular diagnostic value.70 T2-weighted imaging, including FLAIR images of the brain, is most sensitive for depicting lesions. Although there are

Differential diagnosis

The main differential diagnosis is progressive spastic paraplegia (panel 2). The differential diagnosis is broad, and includes consideration of the age of the patient (older adults are more likely to have cervical spondylosis), family history (a positive history might indicate hereditary spastic paraplegia, leukodystrophy, or CADASIL [cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy]), and geographical location (human T-cell lymphotropic virus-related

Supportive management

The provision of accurate information and access to support is an essential part of the management of all types of MS. Information specific to disease type should be supplied; for example, information for patients about PPMS is available from the MS Society. Symptomatic treatments and rehabilitation are the same as those for MS in general and are well documented elsewhere.76

Disease-modifying treatment

A short course of high-dose, intravenous methyl-prednisolone is mainly used to shorten the duration of relapses in MS,

Future research priorities

There is a need for effective disease-modifying treatments for progressive forms of MS; the current focus is on strategies for neuroprotection, including sodium channel blockers, glutamate antagonists, and cannabinoids. The UK Medical Research Council is sponsoring a 3 year, placebo-controlled, phase III trial of oral cannabinoids for progressive MS, with disability as the primary outcome measure. Although there is less inflammation than is seen in RRMS, it is still possible that inflammatory

Search strategy and selection criteria

Material for this Review was selected by a PubMed search of English language publications from 2004 until early 2007 with the term “primary progressive multiple sclerosis”. Abstracts were reviewed, and when novel or interesting findings were reported, the full article was reviewed.

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