INTRODUCTION — Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the central nervous system that is a leading cause of disability in young adults.
Despite dramatic advances in the clinical assessment of MS due to the widespread availability of brain and spine magnetic resonance imaging, our understanding of the basic etiology of the disease remains limited. Full control of the disease and the repair of damaged myelin are key objectives for current and future investigators.
The treatment of acute exacerbations (also known as attacks or relapses) of MS is reviewed here. Other aspects of MS treatment are discussed separately. (See "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults" and "Treatment of secondary progressive multiple sclerosis in adults" and "Symptom management of multiple sclerosis in adults".)
DEFINITION AND TERMINOLOGY — An MS exacerbation or relapse is defined as a monophasic clinical episode with patient-reported symptoms and objective findings typical of MS, reflecting a focal or multifocal inflammatory demyelinating event in the central nervous system, developing acutely or subacutely, with a duration of at least 24 hours, with or without recovery, and in the absence of fever or infection [1].
MS exacerbation, relapse, flare, and attack are synonyms [1]. The term "clinically isolated syndrome" (CIS) is also synonymous when used to denote the first clinical episode of MS; a CIS resembles a typical MS relapse but occurs in a patient not known to have MS. The term "relapse" is most often used for subsequent clinical attacks in a patient already diagnosed with MS. Since relapses may be multifocal or have a fluctuating onset and course, a period of clinical stability or improvement lasting at least 30 days is required to distinguish separate relapses [2].
EVALUATION
Clinical features — Relapses in MS are highly variable and may include one or multiple neurologic deficits involving sensory disturbance, motor weakness, visual disturbance, imbalance, fatigue, or cognitive difficulty [2]. Common presentations include the following:
●Unilateral optic neuritis, manifesting with painful, monocular visual loss consisting of visual blurring or scotoma
●Painless diplopia due to internuclear ophthalmoplegia (occasionally bilateral) or, less commonly, a sixth nerve palsy
●Brainstem or cerebellar syndrome, such as diplopia described above, ataxia with gaze-evoked nystagmus, vertigo, unilateral facial numbness, or paroxysmal episodes of dysarthria or vertigo
●Partial transverse myelitis, usually with predominant sensory symptoms, including a partial Brown-Sequard syndrome; other manifestations can include sphincter symptoms, with bladder involvement (eg urge incontinence) more common than bowel, and erectile dysfunction
Symptoms usually develop over the course of hours to days and then gradually remit (even if untreated) over the ensuing weeks to months, though remission may not be complete.
Assessment and diagnosis — Patients with a suspected MS relapse should be evaluated for fever and infection. A complete neurologic history and examination is necessary to assess for changes in cognition, vision (including visual acuity, color vision, and eye movements), strength, sensation, coordination, and gait [3]. Findings should be compared with the baseline from prior neurologic evaluations to determine if there is are changes consistent with an MS relapse.
In patients with MS, the diagnosis of a relapse is determined on clinical grounds based upon the symptoms and neurologic examination. An MRI is not obligatory if the clinical suspicion for an MS relapse is high or if the relapse is mild (eg, sensory only). If an MRI of the brain and/or spinal cord is obtained at the time of a relapse, it will often show a corresponding new lesion that enhances with the administration of gadolinium (image 1). An MRI can definitively document that the patient is having a relapse and distinguish an MS attack from a "pseudorelapse," the temporary worsening of existing MS symptoms caused by increased body temperature, underlying infection, metabolic disturbance, or medical illness.
Differential diagnosis — Demonstration of an enhancing lesion in the brain or spinal cord that correlates with new or worsening MS symptoms can help distinguish an MS attack from a "pseudorelapse," the temporary worsening of existing MS symptoms caused by increased body temperature (due to infection, heat exposure, or exercise), underlying infection (eg, urinary tract or upper respiratory infection), metabolic disturbance, or medical illness.
In addition to pseudorelapse, an attack should be distinguished from alternative conditions including transient paroxysmal symptoms (eg, Lhermitte phenomenon, tonic spams, trigeminal neuralgia), day-to-day fluctuations, functional neurologic symptoms, and neurologic disorders other than MS [2]. (See "Manifestations of multiple sclerosis in adults", section on 'Paroxysmal symptoms'.)
APPROACH TO TREATMENT
Indications — Indications for treatment of an acute relapse (MS exacerbation, attack) in patients with MS include functionally disabling symptoms with objective evidence of neurologic impairment such as loss of vision, diplopia, weakness, and/or cerebellar symptoms. Mild sensory attacks may not require treatment, although symptomatic relief with analgesics and glucocorticoid treatment is sometimes necessary because of patient discomfort (eg, due to paresthesia).
Goals of treatment — The main goal of treatment is to speed recovery time from the attack. However, acute treatment has no apparent benefit for improving long-term disability or for reducing the risk of subsequent attacks [4].
MS relapses may lead to residual, permanent disability [5]. Patients with active MS who manifest disease activity by either clinical relapses or recent magnetic resonance imaging (MRI) lesions (and/or new or unequivocally enlarging lesions) should be offered treatment with disease-modifying therapy. This is discussed separately. (See "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults" and "Treatment of secondary progressive multiple sclerosis in adults" and "Treatment of primary progressive multiple sclerosis in adults" and "Disease-modifying therapies for multiple sclerosis: Pharmacology, administration, and adverse effects".)
Initial therapy with glucocorticoids — We recommend high-dose, short-term glucocorticoid therapy for patients with an acute MS exacerbation that results in neurologic symptoms and increased disability or impairments in vision, strength, cerebellar function, or significant sensory disturbances. Before starting therapy, acute infection (particularly of the urinary tract) should be ruled out, and any active infection should be treated, since glucocorticoids are immunosuppressive and may exacerbate infection.
Options for intravenous methylprednisolone or oral prednisone are listed below. Where available, corticotropin injection gel is an alternative when glucocorticoids are not an option. (See 'Alternative therapy with ACTH' below.)
Intravenous methylprednisolone — Three- to seven-day courses of intravenous methylprednisolone, 500 to 1000 mg daily, with or without a short prednisone taper, are used most commonly [6,7]. Our preferred regimen is intravenous methylprednisolone 1000 mg daily for five days, though this may be truncated for minor relapses where patients have symptomatic relief with fewer than five treatments.
Oral prednisone — An alternative is a three- to seven-day course of oral methylprednisolone, 1000 mg daily, or oral prednisone, 1250 mg daily, with or without a short taper. Our preferred regimen is oral methylprednisolone (1000 mg) without an oral taper. Oral dosing requires many tablets (eg, up to 31 tablets daily of methylprednisolone 32 mg tablets to reach a dose of approximately 1000 mg) but some patients prefer oral therapy rather than intravenous therapy, as the latter requires an intravenous line, sitting still for a few hours while the medication is infused, and potentially being admitted to the hospital.
The bioavailability of oral prednisone (1250 mg) appears to be equal to that of intravenous methylprednisolone (1000 mg) [8]. However, one study found a higher peak concentration after a single dose of intravenous methylprednisolone than after a single dose of the oral formulation [8]. The clinical significance of the peak concentration for efficacy is unknown.
Adverse effects — Short-term high-dose glucocorticoid therapy is associated with relatively few side effects in most patients, although mental status changes, increased susceptibility to infection, and gastric disturbance are potential complications. Psychiatric adverse effects can include increased depressive, manic, and hypomanic symptoms [9]. To mitigate these adverse effects, strategies include the prophylactic use of a proton pump inhibitor in the morning and/or low-dose clonazepam at night while on glucocorticoid treatment. Patients with diabetes mellitus may need to be hospitalized to monitor glucose levels.
An increased incidence of fractures has been reported in patients undergoing repeated glucocorticoid therapy; baseline and yearly bone density scans are recommended for these individuals. (See "Prevention and treatment of glucocorticoid-induced osteoporosis", section on 'General measures'.)
Efficacy — The evidence for the benefit of glucocorticoid treatment of MS relapses is supported by several randomized controlled trials.
●Placebo controlled trials – A systematic review and meta-analysis published in 2000 identified six randomized controlled trials comparing methylprednisolone or adrenocorticotropic hormone (ACTH) with placebo in a total of 377 patients with acute exacerbations of MS [10]. Methylprednisolone was tested in four trials with 140 patients; it was administered orally in one trial (500 mg daily for five days followed by a 10-day taper), and intravenously in three trials (500 mg daily or 1000 mg daily for five days in two trials, and 15 mg/kg daily for three days in the third). Compared with placebo, patients treated with ACTH or methylprednisolone had a significant reduction in the risk of either worsening or not improving within five weeks from randomization (odds ratio [OR] 0.37, 95% CI 0.24-0.57). In a subgroup analysis by drug, both methylprednisolone treatment and ACTH treatment reduced the risk of worsening or not improving within five weeks.
●Oral versus intravenous glucocorticoids – Small randomized trials comparing oral versus intravenous glucocorticoids for acute MS attacks have found no important differences in benefit [11,12]. In a double-blind non-inferiority randomized trial (COPOUSEP) that enrolled 199 adults with relapsing-remitting MS who had a relapse within the previous 15 days, there was no significant difference between treatment with oral or intravenous high-dose methylprednisolone (1000 mg once a day for three days) for the outcome of improvement in disability scores by day 28 [13]. In addition, there was no significant difference between treatment groups in the rate of recurrent relapses at six months.
Another randomized trial of 80 patients with acute MS relapse compared oral methylprednisolone (48 mg daily for seven days, followed by 24 mg daily for seven days, and finally by 12 mg daily for seven days) versus intravenous methylprednisolone (1000 mg daily for three days) [14]. There was no statistical difference between the treatment groups for any of the outcome measures. In an assessor-blinded trial, 40 patients with an acute MS attack were randomly assigned to treatment with either oral or intravenous high-dose methylprednisolone at 1000 mg daily for five days [15]. At one week, both groups showed a similar reduction of gadolinium-enhancing lesions on brain MRI. At four weeks, both groups showed a similar improvement in clinical status.
●Patients with optic neuritis – Though previous studies suggested oral glucocorticoids were less effective than intravenous glucocorticoids for patients with optic neuritis, a randomized trial of 55 subjects found that oral prednisone (1250 mg) was equivalent to intravenous methylprednisolone sodium succinate (1000 mg) for patients with optic neuritis [16]. However, some experts continue to recommend intravenous rather than oral glucocorticoids for patients with acute optic neuritis. (See "Optic neuritis: Prognosis and treatment".)
Alternative therapy with ACTH — For patients who cannot tolerate high-dose glucocorticoids or have poor venous access or who prefer self-injection, repository corticotropin injection gel, a purified form of bovine or porcine adrenocorticotropic hormone (ACTH), is available in the United States (as HP Acthar Gel) and several other countries. It is administered by intramuscular (IM) or subcutaneous (SQ) injection. Various dosing schedules have been used in trials and in clinical practice for adults with acute MS exacerbations, generally starting corticotropin at 80 to 120 units daily by IM or SQ injection for one week followed, or not followed, by a taper [17]. Our preferred regimen is corticotropin injection gel 80 units daily for one week followed by a tapering schedule over a second week (eg, total dosage: 80 units for seven days, 40 units for four days, and 20 units for three days). The IM and SQ administration of corticotropin appear to be bioequivalent [18].
The benefit of ACTH is probably similar to that of intravenous methylprednisolone (see 'Efficacy' above). However, corticotropin injection gel is much more expensive than equivalent doses of methylprednisolone or prednisone.
Assessing response to initial therapy — While there are no clear guidelines or standards for determining the response to relapse treatment, one approach is to assess recovery in terms of how much the patient has returned to their baseline before the relapse. Residual disability that prevents a return to pre-relapse level of function may be considered to be a poor response.
The degree of symptom resolution and recovery may vary according to the timing of post-relapse functional assessment [19]. Patients experiencing day-to-day improvement during a five-day course of high-dose glucocorticoid treatment may be expected to continue to improve in the following days to weeks after treatment. In contrast, patients who have disabling deficits with little or no objective improvement or with worsening after three to seven days may benefit from another treatment course, as discussed below.
Treatment of refractory relapse — For patients with a poor response to initial treatment, we suggest plasma exchange (PLEX) (see 'Plasma exchange' below). Other options for a second treatment course after a poor response to initial with high-dose glucocorticoid therapy include ACTH (see 'Alternative therapy with ACTH' above), a second cycle of high-dose glucocorticoid therapy, or immunoadsorption (see 'Immunoadsorption' below) where available. Intravenous immune globulin has been tried, but one small randomized trial found no benefit [20].
Plasma exchange — We suggest treatment with PLEX for patients with acute, severe neurologic deficits caused by MS attacks who have a poor response to treatment with high-dose glucocorticoids [21,22]. One author (JH) uses PLEX particularly for patients with large, tumefactive lesions causing severe deficits such as hemiplegia, paraplegia, quadriplegia, coma, aphasia, or acute severe cognitive dysfunction, and for patients with optic neuritis and severe visual impairment (acuity worse than 20/400) [23]. Such relapses are uncommon but not extraordinarily rare.
●Administration – PLEX is administered daily or every other day for a total of three to seven treatments (eg, seven treatments given every two days over 14 days, or daily treatment for five to seven days).
●Adverse effects – In experienced centers, complications from PLEX are uncommon and generally mild; rarely patients may experience potentially severe complications such as anaphylaxis, catheter infection and thrombosis, bleeding, hypotension, cardiac arrhythmias, and a toxic reaction to the citrate used in the procedure. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Complications".)
●Efficacy – PLEX may be beneficial in patients with acute central nervous system (CNS) inflammatory demyelinating disease who do not respond to glucocorticoid therapy. In the only formally reported clinical trial, 22 patients with CNS demyelinating disease (12 with MS) were randomly assigned to either active PLEX or sham treatment, with a total of seven treatments, given every two days over 14 days [24]. Moderate or greater improvement in neurologic disability occurred during 8 of 19 (42 percent) courses of active treatment compared with 1 of 17 (6 percent) courses of sham treatment. Improvement occurred early in the course of treatment and was sustained on follow-up. However, four of the patients who responded to the active treatment experienced new attacks of demyelination during six months of follow-up. In an earlier randomized controlled trial of 116 patients with MS, a subgroup analysis of patients with relapsing forms of MS showed that plasma exchange led to faster improvement in disease exacerbations than sham plasma exchange [25].
Based mainly upon the results of this trial, guidelines from the American Academy of Neurology state that plasmapheresis should be considered for the adjunctive treatment of exacerbations in patients with relapsing forms of MS [23]. Nonrandomized studies have suggested benefit as well. In a series of 90 patients with MS or a clinically isolated syndrome suggestive of MS who had acute relapses, a clinical response to PLEX was observed in 72 percent [26]. The presence of gadolinium-enhancing lesions on MRI before treatment best predicted response to treatment [26].
Immunoadsorption — Immunoadsorption is a method of apheresis that removes circulating autoantibodies. In contrast to PLEX, which nonselectively removes plasma proteins from circulation, immunoadsorption selectively binds and removes immunoglobulins. Treatment requires a large bore intravenous catheter, similar to PLEX. High cost and restricted availability limit the use of this therapy.
Evidence of efficacy is limited to lower quality studies. An unblinded controlled trial enrolled 61 patients with a glucocorticoid-refractory MS relapse and randomly assigned them to treatment with immunoadsorption or PLEX [27]. Both groups showed improvement as measured by the Multiple Sclerosis Functional Composite (MSFC) score, a scale evaluating the degree of impairment in MS; patients assigned to immunoadsorption showed a larger improvement in MSFC compared with patients assigned to PLEX at four weeks after apheresis but not at earlier time points. The results of two retrospective studies also suggested benefit with immunoadsorption for patients with MS relapses unresponsive to glucocorticoid treatment [28,29].
In a retrospective study of 69 patients with early active demyelinating MS, as demonstrated by brain biopsy, patients with T cell-mediated or T cell plus antibody and complement-mediated autoimmune pathology were more likely to benefit from apheresis with plasma exchange or immunoadsorption than those with primary oligodendrocyte degeneration pathology [30]. These results suggest that pathophysiologic differences in MS lesions play a role in the response to apheresis, but this finding needs confirmation in larger prospective studies and at this point is primarily important for these insights rather than as a practical approach to treatment.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multiple sclerosis and related disorders".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Multiple sclerosis in adults (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Definitions – An MS exacerbation or relapse is defined as a monophasic clinical episode with patient-reported symptoms and objective findings typical of MS, reflecting a focal or multifocal inflammatory demyelinating event in the central nervous system, developing acutely or subacutely, with a duration of at least 24 hours, with or without recovery, and in the absence of fever or infection. MS exacerbation, relapse, and attack are synonyms. (See 'Definition and terminology' above.)
●Clinical features – Relapses in MS are highly variable and may include one or multiple neurologic deficits involving sensory disturbance, motor weakness, visual disturbance (eg, monocular visual loss or diplopia), imbalance, fatigue, or cognitive difficulty. (See 'Clinical features' above.)
●Evaluation and diagnosis – In patients with MS, the diagnosis of a relapse is determined on clinical grounds based upon the symptoms and neurologic examination. An MRI is not obligatory if the clinical suspicion for an MS relapse is high or if the relapse is mild (eg, sensory only). However, demonstration of an enhancing lesion in the brain or spinal cord by MRI that correlates with new or worsening MS symptoms can help distinguish an MS attack from a "pseudorelapse," the temporary worsening of existing MS symptoms caused by increased body temperature, underlying infection, metabolic disturbance, or medical illness. (See 'Assessment and diagnosis' above and 'Differential diagnosis' above.)
●Glucocorticoid treatment – For patients with an acute MS exacerbation (relapse, attack) that results in neurologic symptoms and increased disability or impairments in vision, strength, or cerebellar function, we recommend a short course of high-dose glucocorticoid therapy (Grade 1B). The main goal of treatment is to speed recovery time from the MS attack. However, acute treatment has no apparent benefit for improving long-term disability or for reducing the risk of subsequent attacks. Our preferred regimen is intravenous methylprednisolone 1000 mg daily for five days without an oral taper. However, the data suggest that high-dose oral glucocorticoid regimens are just as effective. Repository corticotropin injection gel, where available, is an alternative for patients with MS exacerbations who cannot tolerate high-dose glucocorticoids or have poor venous access or prefer self-injection. Infection must first be ruled out. (See 'Initial therapy with glucocorticoids' above.)
●Poor response to glucocorticoid treatment – For patients with acute, severe neurologic deficits caused by MS who have a poor response to treatment with high-dose glucocorticoids, we suggest treatment with plasma exchange (Grade 2C). (See 'Treatment of refractory relapse' above.)
●Role of disease-modifying therapy – Patients with relapsing-remitting MS who have current disease activity manifested by clinical symptoms or MRI lesions should be offered disease-modifying therapy. This is discussed separately. (See "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults".)
