Residency · Residency · Neurology
Acute MS Relapse Management and Progressive MS
Introduction
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. Distinguishing true relapses from pseudo-relapses and understanding the transition to progressive disease are essential competencies for the neurologist. This lecture covers evidence-based relapse management and the evolving landscape of progressive MS therapeutics.
Defining a True Relapse
A relapse (also called an exacerbation or attack) is defined as a new or worsening neurological deficit lasting more than 24 hours in the absence of fever or infection. It must be separated from a prior event by at least 30 days. Pseudo-relapses are transient symptom worsening triggered by heat (Uhthoff phenomenon), infection, or metabolic stress; they do not represent new inflammatory activity. Before initiating relapse treatment, a urinalysis, CBC, and metabolic panel should always be obtained to exclude infection as a trigger.
Clinical Assessment
The Expanded Disability Status Scale (EDSS) score should be documented at baseline and during the relapse. Gadolinium-enhanced MRI should be performed to confirm new or enlarging lesions when the diagnosis is uncertain. Assessment should cover all functional systems: pyramidal, cerebellar, brainstem, sensory, bowel/bladder, visual, and cerebral.
Acute Relapse Treatment
High-Dose Corticosteroids
Intravenous methylprednisolone 1 g daily for 3-5 days is the standard first-line treatment for acute MS relapses. Oral bioequivalent dosing (for example, 1250 mg oral prednisone) may be used when IV access is impractical. Corticosteroids shorten relapse duration but do not alter long-term disability outcomes. Blood glucose, blood pressure, and mental status should be monitored during infusion. A subsequent oral taper is optional and physician-dependent, with no strong evidence supporting a routine oral taper.
Plasma Exchange (PLEX)
PLEX is reserved for steroid-refractory relapses with severe functional impairment. It typically involves 5-7 exchanges over 10-14 days. It is most effective when initiated early and in patients with acute, severe attacks such as transverse myelitis or severe optic neuritis. Complications include hypotension, coagulopathy, and line-related infections.
Adrenocorticotropic Hormone (ACTH)
ACTH gel is an alternative for patients who cannot tolerate IV steroids. Evidence is limited compared to methylprednisolone, and it is generally considered second-line.
Progressive MS
Classification
Secondary progressive MS (SPMS) is characterized by gradual disability worsening after an initial relapsing-remitting course, with or without superimposed relapses. Primary progressive MS (PPMS) involves progressive disability accumulation from onset without distinct relapses. The transition from RRMS to SPMS is often recognized retrospectively after 6-12 months of sustained worsening.
Pathophysiology of Progression
Progressive MS is driven by a shift from focal inflammatory demyelination to diffuse neurodegeneration, cortical demyelination, and meningeal inflammation. Slowly expanding lesions and brain atrophy are the radiographic hallmarks. Mitochondrial dysfunction, oxidative stress, and iron deposition contribute to ongoing axonal loss.
Disease-Modifying Therapies for Progressive MS
| Therapy | Type of Progressive MS | Key Trial | Key Findings |
|---|---|---|---|
| Siponimod | SPMS (with active inflammation) | EXPAND | Reduced confirmed disability progression |
| Ocrelizumab | PPMS | ORATORIO | First FDA-approved PPMS therapy; greatest benefit in younger patients with inflammation |
| Cladribine | SPMS (limited role) | — | Limited by toxicity profile |
| Mitoxantrone | SPMS (limited role) | — | Cardiotoxicity limits use |
Siponimod has demonstrated reduction in confirmed disability progression in SPMS with active inflammation in the EXPAND trial. Ocrelizumab is the first FDA-approved therapy for PPMS based on the ORATORIO trial, with the greatest benefit seen in younger patients with inflammatory activity. Cladribine and mitoxantrone have limited roles due to their toxicity profiles. B-cell depleting therapies are under investigation in progressive phenotypes.
Symptomatic Management
Spasticity is managed with baclofen, tizanidine, physical therapy, and intrathecal baclofen pump for refractory cases. Fatigue is treated with amantadine, modafinil, and energy conservation strategies. Bladder dysfunction is addressed with anticholinergics, intermittent catheterization, and botulinum toxin for detrusor overactivity. Central neuropathic pain responds to gabapentin, pregabalin, and duloxetine. Cognitive rehabilitation and exercise programs improve quality of life.
Clinical Pearls
Infection must always be ruled out before attributing symptom worsening to a true MS relapse. High-dose IV methylprednisolone hastens recovery but does not change long-term outcomes; PLEX is the rescue therapy for steroid-refractory attacks. The transition to progressive MS is driven by neurodegeneration, and current therapies are most effective when residual inflammatory activity is present. Comprehensive symptomatic management is as important as disease-modifying therapy in progressive MS.
References
- Rae-Grant A, Day GS, Marrie RA, et al. Practice guideline recommendations summary: disease-modifying therapies for adults with multiple sclerosis. Neurology. 2018;90(17):777-788.
- Kappos L, Bar-Or A, Cree BAC, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018;391(10127):1263-1273.
- Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 2017;376(3):209-220.
- Cortese I, Chaudhry V, So YT, et al. Evidence-based guideline update: plasmapheresis in neurologic disorders. Neurology. 2011;76(3):294-300.