Curr Treat Options Neurol (2015) 17:17 DOI 10.1007/s11940-015-0345-6
Multiple Sclerosis and Related Disorders (P Villoslada, Section Editor)
Therapeutic Management of Severe Relapses in Multiple Sclerosis Carolyn Bevan, MD, MS Jeffrey M. Gelfand, MD, MAS* Address * MS Center, Department of Neurology, University of California, 675 Nelson Rising Lane, Box 3206, San Francisco, CA 94158-3206, USA Email: [email protected]
* Springer Science+Business Media New York 2015
This article is part of the Topical Collection on Multiple Sclerosis and Related Disorders Keywords Multiple sclerosis (MS) I MS relapses I Pseudo-relapse I Glucocorticoids I Adrenocorticotropic hormone (ACTH) I Neuroprotection I Neuroreparation I Therapeutic management
Opinion statement While not all multiple sclerosis (MS) relapses require treatment, relapses that are bothersome or that impair function should prompt consideration of timely treatment to restore function and minimize disability. Patients with suspected MS relapses should be evaluated to confirm the diagnosis, exclude other causes of neurological dysfunction, and identify potential triggers for relapse or pseudo-relapse, such as urinary tract infections, fever, or metabolic derangements. The diagnosis of an MS relapse is clinical, but MRI may be useful for confirmation and to evaluate for multifocal disease activity. High-dose oral or intravenous glucocorticoids, with or without an oral taper, are first-line therapy for MS relapses. Adrenocorticotropic hormone (ACTH) provides an alternative to glucocorticoid treatment but is currently much more expensive and does not have proven superiority. If the acute neurological deficits remain severe after steroid treatment, and particularly if there is persistent abnormal contrast-enhancement of the symptomatic lesion on repeat MRI, plasma exchange (PLEX) should be considered as an acute rescue therapy for relapse. In exceptional cases, particularly fulminant or tumefactive disease that fails to improve following treatment with steroids and PLEX, cytoxic agents such as cyclophosphamide or B cell-depleting regimens such as rituximab may be considered, although risk must be carefully weighed and the kinetics of such regimens indicate that they probably serve more to accelerate remission of disease activity than as an immediate relapse remedy. A single dose of natalizumab given as acute therapy for MS relapse was shown not to improve clinical outcomes in a randomized controlled trial. Attention to symptom management and promotion of neurorehabilitation are important aspects of MS relapse care. Neuroprotective and neuroreparative therapies remain under investigation, but are likely to become important complementary elements of relapse therapy in the future. Relapses
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serve as important indicators of MS disease activity. In the context of the emerging treatment paradigm of targeting freedom from evidence of MS disease activity, relapses should prompt consideration of transitioning to a disease-modifying treatment that may offer better efficacy.
Introduction The majority of patients diagnosed with multiple sclerosis (MS) experience a relapsing disease course [1, 2]. A relapse is defined by International Panel (McDonald) criteria as a patient reported or objectively observed attack with characteristics consistent with a demyelinating event lasting greater than 24 h in the absence of fever or infection [3]. Relapses serve as important markers of MS disease activity [2, 4, 5], and all currently available MS immunomodulatory and immunosuppressive diseasemodifying treatments were approved in part due to efficacy in reducing relapse activity as preventive therapy. The diagnosis of MS relapse is clinical, but MRI can be helpful if there is diagnostic uncertainty or to define the extent of new disease activity, which can be multifocal. The radiological correlate of an MS relapse is an active demyelinating lesion on MRI. Active MS lesions on MRI are characterized by abnormal contrast enhancement on post-gadolinium T1 sequences and/or restricted diffusion [6–8]. However, not all active MS lesions on MRI cause symptoms [9]. While subclinical MRI disease activity is a marker of disease progression and may prompt initiation or escalation of preventive diseasemodifying therapy, radiological findings alone are not an indication to initiate acute relapse therapy. On the other hand, MRI activity in MS correlates imperfectly with clinical attacks [10], so treatment decisions must b e b a s ed o n c l i n i c a l j u d g m e n t a nd c l i n i c a l symptomatology. Fever and infection may cause worsening of MS symptoms in the absence of new MS disease activity, a phenomenon referred to as pseudo-relapse. Pseudorelapses are typically characterized by fatigue or malaise or by the reemergence or worsening of neurological deficits that were at one time present [11]. While classically associated with fever or infection, and particularly urinary tract infections that may be otherwise subclinical, pseudo-exacerbations can also be caused by metabolic derangements, especially in patients with other medical comorbidities [12]. Screening for potential causes of pseudo-relapse is an important part of the initial evaluation of suspected relapse to ensure appropriate treatment, to avoid unnecessary steroid exposure,
and to avert mislabeling such patients as nonresponders to immunomodulatory therapy. The presence of a possible trigger of pseudo-relapse does not necessarily exclude concomitant relapse, and in some cases infections may even trigger MS attacks [13], but identification of a possible cause of pseudo-relapse should at least lead to targeted treatment of the likely trigger followed by neurological reassessment. While MS relapses are, by definition, self-limited, some relapses can cause significant morbidity and recovery can be incomplete. On neuropathology, acute MS lesions are also associated with early axonal injury that can be irreversible [14]. An ideal acute treatment for MS relapse would promote rapid recovery of neurological function and prevent permanent injury from the offending lesion. Not all relapses necessarily need to be treated, but relapses that are bothersome or substantially impair function should prompt consideration of timely treatment to restore function and minimize disability. There is no established scale to grade the severity of MS relapses, but a recent trial of oral glucocorticoids for MS attacks used a 1- to 2.5-point increase in the Expanded Disability Status Scale (EDSS) to define a moderate relapse and a greater than or equal to 3-point increase in EDSS to define a severe relapse [15]. While there are numerous high quality, low risk of bias clinical trials of disease-modifying treatments in MS, there are many fewer trials examining MS relapse management. When treatment for relapse is indicated, high dose glucocorticoids are the first-line treatment [16]. While IV administration of high-dose glucocorticoids was favored historically, oral glucocorticoids at bioequivalent high doses are increasingly used in clinical practice due to ease of administration and cost effectiveness. Intravenous methylprednisolone 1000 mg daily for 3 days or oral methylprednisolone 1250 mg daily for 3 days both lowered the EDSS score in patients experiencing moderate to severe relapse in a head-tohead randomized controlled comparison that demonstrated statistical non-inferiority of oral compared to IV administration at bioequivalent doses for the treatment of MS relapses [15].
Curr Treat Options Neurol (2015) 17:17 Adrenocorticotropic hormone (ACTH) is included in some MS relapse treatment algorithms [17, 18]. Various trials and meta-analyses show that ACTH exhibits similar efficacy in relapse recovery in comparison to highdose glucocorticoids [16, 19, 20]. Because of a marked difference in cost without proven superiority, however, the current role of ACTH in the management of MS relapses remains unclear. Plasma exchange (PLEX) provides additional benefit in recovery from severe MS and acute inflammatorydemyelinating disease attacks in patients with insufficient improvement following treatment with steroids [21–23]. In a classic trial of PLEX in the treatment of refractory inflammatory-demyelinating relapses, patients were treated with seven exchanges, every other day, for a total of 14 days [22]. More recently, partly in an attempt to minimize length of hospital stay, some clinicians offer daily exchanges with close monitoring of hematologic markers and careful monitoring for other complications. If significant acute disability persists after treatment with glucocorticoids and plasma exchange, careful analysis of risk-benefit should be undertaken before further acute therapy is offered. In a randomized, double-blind multicenter trial, a single dose of natalizumab administered soon after the onset of MS relapse did not speed up clinical recovery, although there was a reduction in
Page 3 of 14 17 gadolinium enhancement lesion volume on MRI [24]. Cytotoxic agents like cyclophosphamide [25] or B celldepleting agents like rituximab may have some role as rescue therapy in particularly aggressive, fulminant, or tumefactive disease, but are only used exceptionally in this context and may serve more to accelerate induction of disease activity than as a truly acute treatment. Induction strategies with mitoxantrone [26] or alemtuzumab [27] have also been proposed for the treatment of aggressive MS, but their possible role as a rapid rescue therapy for acute relapse remains unclear, and these treatments are not currently used in this context. Hematopoetic stem cell transplant (HSCT) is an experimental treatment that may have some role in the management of severe MS as a preventive therapy [28, 29] but does not have an established role for treatment of acute relapse. Any evidence of new disease activity, and particularly a clinical relapse, should prompt a review of the patient’s current disease-modifying treatment strategy. Better control of relapse activity earlier in the disease course has been shown to correlate with lower long-term disability status [4, 30]. In addition to pharmacological treatment, care should be taken to address symptom management and promote neuro-rehabilitation with the goal of improving function, comfort, and quality of life.
Treatment Pharmacologic treatment This review focuses on the acute treatment of severe MS relapses (Fig. 1). For a discussion of preventive disease modifying therapy in MS, we refer the reader to a number of excellent summaries [31–33].
Glucocorticoids Glucocorticoids are the first-line acute pharmacological therapy for MS relapses. Glucocorticoids exert a rapid immunosuppressant effect and also reduce CNS swelling. Glucocorticoids appear to promote clinical recovery after MS relapses but do not appear to alter the longer-term course of the disease. The Optic Neuritis Treatment Trial (ONTT), first reported in 1992, demonstrated that intravenous methylprednisolone 1 g per day for 3 days (administered in the trial as 250 mg every 6 h) followed by an 11-day oral taper promoted faster recovery of visual function as assessed by visual field metrics at 6 months compared to placebo and to lower-dose oral prednisone [34]. In the ONTT, oral prednisone at a lower dose of 1 mg/kg/day for 14 days was associated with an increased risk of subsequent episodes of optic neuritis, although the biological plausibility of that observation remains dubious and controversial [35]. While the ONTT is one of the most familiar and frequently
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Clinical concern for MS relapse
Clinical evaluaon Labs including urinalysis and urine culture Further studies as indicated by history and exam
Relapse
Pseudorelapse
Disabling or parcularly bothersome to paent
Not disabling to paent
Treat with pulse glucocorcoids: Oral or IV
Symptom management
+/- oral taper
No improvement
Treat underlying cause Monitor for improvement and reevaluate
Monitor Re-evaluate DMT Rehabilitaon as indicated
Improvement
Consider plasma exchange if severe acute disability. May also consider extending course of glucocorcoid pulse.
No improvement
Improvement
Recovery aer PLEX may be delayed. May consider repeat steroids. For fulminant disease consider cytotoxic or B-cell depleng therapy.
Fig. 1. An algorithmic approach to treating severe MS relapses.
cited studies in support of the efficacy of steroid treatment for MS exacerbations, it is by no means the only one. Building upon favorable clinical observations published in case series from as early as 1951, Miller et al. in 1961 published a controlled trial of corticotropin (ACTH) in comparison to placebo for MS relapse [36]. Several other trials for MS relapse followed suit examining ACTH [37] and methylprednisolone [38–42] utilizing a range of clinical endpoints,
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and the vast majority showed benefit for shorter-term clinical outcomes. A 2000 Cochrane review concluded that there was evidence of moderate quality to support the efficacy of methylprednisolone in comparison to placebo for the treatment of MS relapses [16]. A number of studies have since demonstrated the non-inferiority of bioequivalent high doses of oral compared to IV steroids for the treatment of MS relapse, and oral treatment is increasingly substituting for IV treatment in many clinical contexts because of ease of administration and lower cost. In a pharmacokinetic study in MS patients, the bioavailability of 1250 mg oral prednisone had a similar area under the curve of drug concentration over 24 h as 1000 mg IV methylprednisolone, although there was a higher and earlier peak concentration with IV administration [43]. The OMEGA trial, a phase IV multicenter randomized controlled trial that enrolled 49 patients with MS, showed that oral methylprednisolone 1250 mg daily was non-inferior to a bioequivalent dose of 1000 mg IV methylprednisolone per day for 3 days on both clinical (EDSS) and radiological (gadolinium-enhanced lesions) endpoints and had a similar safety and tolerability profile [15]. A single-blind randomized controlled trial of oral versus IV methylprednisolone administered 500 mg twice daily for 5 days showed non-inferiority of oral administration for the radiological endpoint of reducing the number of gadolinium-enhanced lesions [44]. An earlier double-blind placebo-controlled trial in 80 patients with MS of 1000 mg IV methylprednisolone versus a lower dose of 48 mg prednisone a day for 7 days followed by a 14-day taper showed no significant difference in clinical disability (EDSS) as an outcome, but this trial was neither designed nor powered as a non-inferiority analysis [45] (see Table 1).
ACTH ACTH gel (repository corticotropin injection) is a purified preparation of porcine adrenocorticotropic hormone (ACTH) in a gelatin suspension administered by IM or SQ injection. ACTH influences both the corticotropic and melanocortin pathways [48]. ACTH first received new drug application approval from the US Food and Drug Administration (FDA) in 1952. MS was added as an indication for ACTH in 1972. When the FDA approved ACTH gel in 2010 under an orphan drug designation for infantile spasms, the FDA permitted the new label to include MS in addition to 17 other “legacy” indications [49]. The relative efficacy of IVMP compared to ACTH for the treatment of MS relapse was compared in a double-blind randomized controlled study in 1989 [19]. The study included 61 patients randomized to either IV methylprednisolone 1 g daily for 3 days or IM ACTH dosed at 80 units for 7 days, 40 units for 4 days, and 20 units for 3 days. Both groups improved over the course of the study without a significant difference in rate of recovery or final outcome at 3 months. A 2000 Cochrane Collaboration review concluded that both IV methylprednisolone and ACTH result in acceleration of recovery and improvement in relapse-related disability [16]. For many years, the cost of ACTH was nominal relative to glucocorticoids. However, in 2007, the cost of ACTH increased to more than $23,000 a vial, and by 2012, the price had reached more than $28,000 a vial [50]. Due to such dramatic cost differentials, the role of ACTH in the routine management of MS relapse remains unclear, and ACTH is not currently part of the standard relapse treatment algorithm in our clinical practice (see Table 2).
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Table 1. Glucocorticoid drug information - Standard dosage IV: methylprednisolone 1000 mg IV daily for 3–7 days (most typically 3–5 days) Oral: methylprednisolone 1250 mg by mouth daily; or prednisone 1000 to 1250 mg by mouth daily; or dexamethasone 160– 200 mg by mouth daily; all for 3–7 days (most typically 3–5 days)—note that special instructions to the pharmacist are often required given the number of pills prescribed per day, as the most concentrated dose per pill of common oral glucocorticoid formulations that pharmacies routinely carry is usually relatively low in this context. For example, the most potent formulations are likely to be prednisone 60 mg pills or dexamethasone 4 mg pills An oral taper may be considered based on relapse severity and clinical context but is not always necessary nor required - Contraindications and cautions Active infection Poorly controlled diabetes (as steroids aggravate hyperglycemia) Recent GI bleed (though the major risk appears to be concomitant use of steroids and NSAIDs, so counsel to avoid NSAID use during the acute steroid course) [46] History of mania, psychosis, severe depression, or suicidality Thromboembolic disorders Major cardiovascular disease Goal of minimizing use in pregnancy when possible and using lowest effective dose when needed - Main drug interactions NSAIDS (may increase risk of GI bleeding) [46] May increase risk of opportunistic infection in combination with other immune suppressive therapies; consider suppressive antiviral therapy with acyclovir or valacyclovir in patients taking fingolimod for MS [47] Avoid live vaccines for at least 1 month post high-dose exposure (although the biggest concern in this context is when the steroid dose is 920 mg/day prednisone equivalent for more than 2 weeks) May cause an increase in INR in patients on warfarin - Main side effects Acute/chronic: insomnia (very common, sleep-promoting medication can be helpful) Acute/chronic: mood disturbance: anxiety, depression, euphoria, mania, psychosis Acute/chronic: avascular necrosis of bone Acute/chronic: osteopenia/osteoporosis risk, fracture risk Acute/chronic: hyperglycemia Acute/chronic: gastritis/GI upset, GI ulcer (especially in combination with NSAIDS) Chronic: skin thinning, easy bruising (purpura), impaired wound healing Chronic: increased risk of infections (consider PCP prophylaxis for long-term use especially if on another form of immunosuppression) Chronic: weight gain Chronic: fluid retention Chronic: cushingoid features, fat redistribution Chronic: menstrual irregularities Chronic: steroid myopathy Chronic: cardiovascular disease Chronic: cataracts Chronic: glaucoma - Cost Oral: relatively inexpensive IV: more expensive when accounting for procedural and facility costs for nursing and infusions (note that IV steroids can be administered to an inpatient or outpatient)
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Table 2. HP Acthar drug information - Standard dosage HP Acthar 80 units administered intramuscularly or subcutaneously daily for 5–15 days - Contraindications Do not administer intravenously Avoid in systemic fungal infections, ocular herpes simplex, or other active infections Avoid live or live-attenuated vaccines Per labeling, medical conditions including scleroderma, osteoporosis, congestive heart failure, uncontrolled hypertension, primary adrenocortical insufficiency, adrenocortical hyperfunction, sensitivity to proteins of porcine origin Recent surgery GI bleeding, ulcer — avoid concomitant NSAID use - Caution: patients with hypertension, CHF, renal insufficiency - Precautions: increased risk of infection, chronic use may cause Cushing’s syndrome and adrenal insufficiency upon withdrawal. May require taper to discontinue safely. Risk related to mineralocorticoid effects includes elevated blood pressure, salt and water retention, and hypokalemia due to increased excretion of potassium and calcium Hyperglycemia - Main drug interactions May accentuate electrolyte losses associated with diuretic therapy - Main side effects GI bleeding and gastric ulceration Behavioral and mood disturbances including euphoria, insomnia, irritability, mood swings, personality changes, severe depression, psychosis Ophthalmic: cataracts, glaucoma, ocular infections Osteopenia/osteoporosis Fluid retention Alteration in glucose tolerance Elevation of blood pressure Increased appetite and weight gain May cause development of antibodies, risk of hypersensitivity Use in pregnancy: class C. Potentially embryocidal. Excretion in human milk unknown Extremely high cost currently - Special points Enhanced effect in patients with hypothyroidism, hepatic cirrhosis - Cost: very expensive
Interventional procedures Plasma exchange Therapeutic plasma exchange (PLEX) is generally reserved for patients who have severe neurologic deficits caused by inflammatory-demyelinating disease and who fail to recover sufficient neurological function following first-line highdose glucocorticoid treatment. The exchange procedure involves placement of central or peripheral venous access, filtration of the plasma compartment of blood, and substitution of plasma volume with a replacement fluid. PLEX is thought to be beneficial for the treatment of inflammatory disease by removing
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Curr Treat Options Neurol (2015) 17:17 antibodies and other immunologically active products such as immune complexes from the plasma compartment, but PLEX is not thought to directly prevent production of new antibodies or new immunological activity. For indications like MS that are not monophasic, PLEX is best conceived of as an adjunctive or rescue therapy in combination with steroids and not as a substitute for steroids. In 1999, Weinshenker et al. [22] published a randomized controlled trial of PLEX in 22 patients with acute inflammatory-demyelinating attacks, 12 of whom had definitive MS by 1983 criteria and 12 of whom had other demyelinating diseases. Participants enrolled in the study were treated with IV high-dose methylprednisolone for a minimum of 5 days with minimal or no improvement. At the time of treatment with plasma exchange, patients were at least 21 days from the onset of symptoms and 14 days from initiation of corticosteroid treatment. Meaningful improvement in disability was observed in 42 % of treated patients versus 5.9 % of controls (p=0.011). The improvement was sustained on follow-up on days 58 and 208 [22]. While earlier treatment is probably preferable, benefit from PLEX has been observed in some cases in observational analyses even when initiation of plasma exchange occurred 60 days or more after symptom onset [51]. In a series of 153 patients with inflammatorydemyelinating conditions treated with PLEX at the Mayo Clinic, the median time to neurological improvement was 4 days (range, 1 to 100 days) and the odds of improvement were four times greater if there was ring enhancement of the offending lesion on post-gadolinium T1 MRI [21]. Continued improvement has been documented as late as 6 months after completion of plasma exchange in other studies [21, 52]. The major risks of PLEX include those related to securing central venous access, hypotension from volume loss, bleeding secondary to coagulopathy, and infection (particularly related to lines). There is also increased risk of anaphylaxis and infusion-related reactions if donor plasma is needed as a replacement fluid (as opposed to albumin, which is more typical in this context), such as for concomitant treatment of coagulopathy (see Table 3).
Severe relapses: the role of intravenous immunoglobulin (IVIg) in MS Available evidence does not support IVIg as a treatment for acute MS relapse. Two separate trials evaluating the addition of IVIg to IV methylprednisolone showed no evidence of added benefit of IVIg for treatment of MS relapse [53, 54]. A separate randomized trial evaluating the efficacy of IVIg versus placebo for the treatment of acute optic neuritis showed no benefit [55]. IVIg has been explored as an alternative to steroid treatment in women at risk for increased disease activity in the post-partum period [56, 57], but it should be emphasized that these studies evaluated the use of IVIg as a preventive disease-modifying therapy and did not assess IVIg for acute treatment of relapses. Other investigations of IVIg as a diseasemodifying therapy in MS have been conducted, some of which showed positive results [58, 59]; however, the evidence supporting the utility of IVIg has been questioned in large meta-analyses, [60, 61] and a 2008 randomized placebo-controlled trial of 0.2 and 0.4 mg/kg monthly IVIg showed no benefit as a preventive disease-modifying MS therapy for clinical or radiological endpoints at 1 year [62].
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Table 3. Plasma Exchange (PLEX) treatment - Standard procedure The traditional PLEX treatment protocol for CNS inflammatory-demyelinating disease [22] consists of seven exchange treatments, every other day, for 14 days. In the interest of reducing hospital length of stay and cost, some centers will consider administering five to seven exchanges as frequently as every day with close monitoring for coagulopathy - Complications Hypotension Anemia potentially requiring transfusion Thromboembolic events, including those related to heparin-induced thrombocytopenia Bleeding secondary to coagulopathy (fibrinogen levels are helpful to monitor in advance of reinfusion, especially with accelerated regimens; albumin replacement fluid does not contain fibrinogen) Infection, including line-related sepsis Central venous access-related complications It is advisable to hold ACE inhibitors for at least 24 h due to concern for flushing, GI symptoms, and hypotension, possibly related to the kinin pathway Infusion reactions/anaphylaxis, particularly if the replacement fluid involves donor plasma as opposed to albumin Hypocalcemia and arrhythmia (induced by citrate which is typically used as an anticoagulant in the filtration system or replacement fluid) - Cost/cost effectiveness High cost due to procedural costs, equipment, replacement fluids, blood products, inpatient admission (at some centers), use of central access (at some centers)
Severe relapses: third line and investigational therapies Despite treatment with pulse dose steroids and PLEX, some patients fail to recover fully from relapse symptoms. If residual symptoms remain but the patient has stabilized or begun to recover, it is advisable to defer further acute treatment and monitor for continued improvement over time. If the patient remains significantly disabled or continues to worsen from persistent acute inflammatory activity, however, the evidence becomes less clear regarding further management strategies. Some clinicians will offer another round of steroid treatment in this context, perhaps with a prolonged oral steroid taper. For fulminant or tumefactive demyelinating lesions, which account for a very small subset of MS-related relapses, there may be a role for cytotoxic therapy with agents like cyclophosphamide or B cell depletion with agents such as rituximab [63–66]. Given the kinetics of such therapies, however, their primary effect is probably more of accelerating induction of immunosuppression to prevent subsequent relapse disease activity than acting as true acute rescue treatments for relapse. Myeloablative induction dosing of cyclophosphamide (i.e., 50 mg/kg/day for 4 days) has been shown in small studies in MS to lead to remission of disease activity and improvement in disability [67, 68], and there are reports of the use of such strategies in children [69], although the risks of such therapy in this context require better characterization and such treatment is typically reserved for use in exceptional cases involving fulminant or tumefactive syndromes. Cyclophosphamide can also be given as an intravenous pulse of 500–800 mg/m2 of body surface area every 3–4 weeks without inducing severe myeloablation, but this treatment strategy functions more as a relatively aggressive preventive immunosuppressive therapy and not as an acute
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Curr Treat Options Neurol (2015) 17:17 treatment option [69, 70]. Mitoxantrone has shown benefit for inducing remission of MS disease activity as an aggressive preventive immunosuppressive therapy, but such benefit is usually outweighed by dose-related lifetime cardiac and hematologic toxicity and is now only rarely used given the availability of other proven disease-modifying treatment options [26, 71]. Rituximab has been reported to be beneficial for tumefactive demyelination in case reports [64, 65]. Alemtuzumab can bring about sustained remission of relapse disease activity as an aggressive preventive disease-modifying therapy, but carries a significant risk of secondary autoimmunity and has not been demonstrated as an acute relapse therapy [27, 72]. Autologous hematopoetic stem cell transplantation (HSCT) remains investigational and has also not been established to promote recovery from acute relapse [28, 29]. While these approaches may prove to be highly efficacious as preventive therapies, their role in promoting rapid recovery from severe relapses has not been established and exposing patients to these treatments during the acute phase of a severe relapse may increase risk of adverse events.
Severe relapses: impact on choice of disease-modifying therapy There are various algorithms for escalating disease-modifying therapies in MS after relapse. As more effective MS treatments become available, the paradigm of disease activity free status (DAFS) or no evidence of disease activity (NEDA) has become an important consideration in MS management [73–75]. If a patient experiences a relapse while off treatment, initiation of a diseasemodifying therapy should be discussed. If a patient experiences a relapse while on an established treatment, transition to a more efficacious disease-modifying agent should be explored.
Severe relapses: symptom management and rehabilitation Though most MS relapses tend to resolve over time with complete or substantial recovery, time to recovery is variable and full recovery to pre-attack baseline may not be achieved [76, 77]. Furthermore, patients and their physicians do not always define recovery in the same way [78]. Care must be taken to identify and manage relapse-related symptoms during both the acute and recovery phases. Management of symptoms like pain, spasticity, or urinary symptoms can greatly increase a patient’s quality of life and allow the patient to participate in physical therapy and regain functional independence more quickly [79–82]. A number of detailed reviews of symptom management strategies in patients with MS have been published and are worthy of study [83–85]. Physical and occupational therapy serve as important tools in expediting a patient’s recovery after an attack and maintaining optimal functional status [86].
Severe relapses: remyelination, neuroprotection, and future directions In spite of aggressive treatment, some patients do not fully recover from severe MS attacks. Emerging therapeutic approaches that promote myelin repair may one day allow for acute or post-acute treatment strategies to reverse damage inflicted by MS attacks. Neuroprotective agents may also prevent or attenuate relapse-related damage [87]. One potentially promising observation and proof of principle for neuroprotective therapy was a 2012 double-blind placebocontrolled trial of recombinant human erythropoietin dosed at 33,000 IU
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intravenously ×3 days given in addition to usual pulse methylprednisolone for the treatment of acute demyelinating optic neuritis, which showed less loss of retinal nerve fiber layer and improved visual-evoked potential latencies at 16 weeks in the erythropoietin-treated group compared to methylprednisolone alone [88]. We envision and hope for a future in which treatment for acute MS relapses will come to consist of combination immunosuppressive, neuroprotective, and reparative strategies.
Acknowledgments Funding was provided through the National MS Society Institutional Clinician Training Award and NIH KL2TR000143.
Compliance with Ethics Guidelines Conflict of Interest Carolyn Bevan declares no conflict of interest. Jeffrey M. Gelfand declares that he has received compensation for medical legal consulting relating to CNS inflammatory disease. Dr. Gelfand has also received compensation for consulting for MedImmune and Quest Diagnostics. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by the authors.
References and Recommended Reading 1.
2.
3. 4.
5.
Gelfand JM. Multiple sclerosis: diagnosis, differential diagnosis, and clinical presentation. Handb Clin Neurol. 2014;122:269–90. Weinshenker BG et al. The natural history of multiple sclerosis: a geographically based study. 2. Predictive value of the early clinical course. Brain. 1989;112(Pt 6):1419–28. Polman CH et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292–302. Scalfari A et al. The natural history of multiple sclerosis: a geographically based study 10: relapses and long-term disability. Brain. 2010;133(Pt 7):1914–29. Confavreux C, Vukusic S, Adeleine P. Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain. 2003;126(Pt 4):770–82.
6.
7.
8. 9. 10. 11.
Balashov KE, Lindzen E. Acute demyelinating lesions with restricted diffusion in multiple sclerosis. Mult Scler. 2012;18(12):1745–53. Gaitan MI et al. Evolution of the blood-brain barrier in newly forming multiple sclerosis lesions. Ann Neurol. 2011;70(1):22–9. Horsfield MA et al. Diffusion magnetic resonance imaging in multiple sclerosis. J Neurol Neurosurg Psychiatry. 1998;64 Suppl 1:S80–4. Simon JH. MRI outcomes in the diagnosis and disease course of multiple sclerosis. Handb Clin Neurol. 2014;122:405–25. Isaac C et al. Multiple sclerosis: a serial study using MRI in relapsing patients. Neurology. 1988;38(10):1511–5. Green AJ. Understanding pseudo: the symptoms are real, the cause is unclear. Neurology. 2009;72(19):1626–7.
17 12. 13. 14. 15. 16. 17. 18.
19. 20. 21. 22. 23.
24. 25. 26.
27. 28.
29.
30. 31. 32.
Curr Treat Options Neurol (2015) 17:17
Page 12 of 14 Thrower BW. Relapse management in multiple sclerosis. Neurologist. 2009;15(1):1–5. Panitch HS. Influence of infection on exacerbations of multiple sclerosis. Ann Neurol. 1994;36(Suppl):S25–8. Trapp BD et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998;338(5):278–85. Ramo-Tello C et al. A randomized clinical trial of oral versus intravenous methylprednisolone for relapse of MS. Mult Scler. 2014;20(6):717–25. Filippini G et al. Corticosteroids or ACTH for acute exacerbations in multiple sclerosis. Cochrane Database Syst Rev. 2000;4, CD001331. Berkovich R. Treatment of acute relapses in multiple sclerosis. Neurotherapeutics. 2013;10(1):97–105. Ross AP, Halper J, Harris CJ. Assessing relapses and response to relapse treatment in patients with multiple sclerosis: a nursing perspective. Int J MS Care. 2012;14(3):148–59. Thompson AJ et al. Relative efficacy of intravenous methylprednisolone and ACTH in the treatment of acute relapse in MS. Neurology. 1989;39(7):969–71. Glaser GH, Merritt HH. Effects of ACTH and cortisone in multiple sclerosis. Trans Am Neurol Assoc. 1951;56:130–3. Magana SM et al. Beneficial plasma exchange response in central nervous system inflammatory demyelination. Arch Neurol. 2011;68(7):870–8. Weinshenker BG et al. A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease. Ann Neurol. 1999;46(6):878–86. Weiner HL et al. Double-blind study of true vs. sham plasma exchange in patients treated with immunosuppression for acute attacks of multiple sclerosis. Neurology. 1989;39(9):1143–9. O’Connor PW et al. Randomized multicenter trial of natalizumab in acute MS relapses: clinical and MRI effects. Neurology. 2004;62(11):2038–43. Weiner HL. Immunosuppressive treatment in multiple sclerosis. J Neurol Sci. 2004;223(1):1–11. Edan G et al. Mitoxantrone prior to interferon beta-1b in aggressive relapsing multiple sclerosis: a 3-year randomised trial. J Neurol Neurosurg Psychiatry. 2011;82(12):1344–50. Coles AJ. Alemtuzumab treatment of multiple sclerosis. Semin Neurol. 2013;33(1):66–73. Pfender N, Saccardi R, Martin R. Autologous hematopoietic stem cell transplantation as a treatment option for aggressive multiple sclerosis. Curr Treat Options Neurol. 2013;15(3):270–80. Burman J et al. Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: the Swedish experience. J Neurol Neurosurg Psychiatry. 2014;85(10):1116–21. Freedman MS. ‘Time is brain’ also in multiple sclerosis. Mult Scler. 2009;15(10):1133–4. Sorensen PS. New management algorithms in multiple sclerosis. Curr Opin Neurol. 2014;27(3):246–59. Okuda DT. Immunosuppressive treatments in multiple sclerosis. Handb Clin Neurol. 2014;122:503–11.
33. 34.
35.
36. 37. 38. 39. 40.
41.
42.
43. 44. 45. 46. 47.
48.
49.
O’Connor PW, Oh J. Disease-modifying agents in multiple sclerosis. Handb Clin Neurol. 2014;122:465–501. Beck RW et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritis Study Group. N Engl J Med. 1992;326(9):581–8. Goodin DS. Perils and pitfalls in the interpretation of clinical trials: a reflection on the recent experience in multiple sclerosis. Neuroepidemiology. 1999;18(2):53–63. Miller H, Newell DJ, Ridley A. Multiple sclerosis. Treatment of acute exacerbations with corticotrophin (A.C.T.H.). Lancet. 1961;2(7212):1120–2. Rose AS et al. Cooperative study in the evaluation of therapy in multiple sclerosis. ACTH vs. placebo—final report. Neurology. 1970;20(5):1–59. Sellebjerg F et al. Randomized controlled trial of highdose peroral methylprednisolone in attacks of multiple sclerosis. Ugeskr Laeger. 1999;161(48):6625–9. Sellebjerg F et al. Double-blind, randomized, placebocontrolled study of oral, high-dose methylprednisolone in attacks of MS. Neurology. 1998;51(2):529–34. Filipovic SR et al. The effects of high-dose intravenous methylprednisolone on event-related potentials in patients with multiple sclerosis. J Neurol Sci. 1997;152(2):147–53. Milligan NM, Newcombe R, Compston DA. A doubleblind controlled trial of high dose methylprednisolone in patients with multiple sclerosis: 1. Clinical effects. J Neurol Neurosurg Psychiatry. 1987;50(5):511–6. Durelli L et al. High-dose intravenous methylprednisolone in the treatment of multiple sclerosis: clinicalimmunologic correlations. Neurology. 1986;36(2):238–43. Morrow SA et al. The bioavailability of IV methylprednisolone and oral prednisone in multiple sclerosis. Neurology. 2004;63(6):1079–80. Martinelli V et al. A short-term randomized MRI study of high-dose oral vs intravenous methylprednisolone in MS. Neurology. 2009;73(22):1842–8. Barnes D et al. Randomised trial of oral and intravenous methylprednisolone in acute relapses of multiple sclerosis. Lancet. 1997;349(9056):902–6. Piper JM et al. Corticosteroid use and peptic ulcer disease: role of nonsteroidal anti-inflammatory drugs. Ann Intern Med. 1991;114(9):735–40. Arvin AM et al. Varicella-zoster virus infections in patients treated with fingolimod: risk assessment and consensus recommendations for management. JAMA Neurol. 2015;72(1):31–9. Arnason BG et al. Mechanisms of action of adrenocorticotropic hormone and other melanocortins relevant to the clinical management of patients with multiple sclerosis. Mult Scler. 2013;19(2):130–6. U.S. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 022432Orig1s000 Risk Assessment and Risk Mitigation Review(s). 2010. http://www.accessdata.fda.gov/
Curr Treat Options Neurol (2015) 17:17
50.
51. 52. 53. 54.
55. 56. 57.
58.
59.
60.
61.
62. 63. 64.
drugsatfda_docs/nda/2010/022432Orig1s000RiskR. pdf Accessed 3 March 2015. Pollack A. Questcor finds profits at $28,000 a vial. The New York Times. Published December 29, 2012. http://www.nytimes.com/2012/12/30/business/ questcor-finds-profit-for-acthar-drug-at-28000-a-vial. html Accessed 3 March 2015. Keegan M et al. Plasma exchange for severe attacks of CNS demyelination: predictors of response. Neurology. 2002;58(1):143–6. Llufriu S et al. Plasma exchange for acute attacks of CNS demyelination: predictors of improvement at 6 months. Neurology. 2009;73(12):949–53. Sorensen PS et al. IV immunoglobulins as add-on treatment to methylprednisolone for acute relapses in MS. Neurology. 2004;63(11):2028–33. Visser LH et al. A randomized, double-blind, placebocontrolled pilot study of i.v. immune globulins in combination with i.v. methylprednisolone in the treatment of relapses in patients with MS. Mult Scler. 2004;10(1):89–91. Roed HG et al. A double-blind, randomized trial of IV immunoglobulin treatment in acute optic neuritis. Neurology. 2005;64(5):804–10. Haas J, Hommes OR. A dose comparison study of IVIG in postpartum relapsing-remitting multiple sclerosis. Mult Scler. 2007;13(7):900–8. Achiron A et al. Effect of intravenous immunoglobulin treatment on pregnancy and postpartum-related relapses in multiple sclerosis. J Neurol. 2004;251(9):1133–7. Achiron A et al. Intravenous immunoglobulin treatment in multiple sclerosis and experimental autoimmune encephalomyelitis—the Israeli experience. MS Study Group. Mult Scler. 1997;3(2):142–4. Fazekas F et al. Randomised placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Austrian Immunoglobulin in Multiple Sclerosis Study Group. Lancet. 1997;349(9052):589–93. Elovaara I et al. EFNS guidelines for the use of intravenous immunoglobulin in treatment of neurological diseases: EFNS task force on the use of intravenous immunoglobulin in treatment of neurological diseases. Eur J Neurol. 2008;15(9):893–908. Goodin DS et al. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology. 2002;58(2):169–78. Fazekas F et al. Intravenous immunoglobulin in relapsing-remitting multiple sclerosis: a dose-finding trial. Neurology. 2008;71(4):265–71. Siffrin V et al. How to treat tumefactive demyelinating disease? Mult Scler. 2014;20(5):631–3. Sempere AP et al. Neurological picture. Rituximab for tumefactive demyelination refractory to corticosteroids and plasma exchange. J Neurol Neurosurg Psychiatry. 2013;84(12):1338–9.
Page 13 of 14 17 65. 66. 67.
68.
69. 70.
71.
72. 73. 74.
75.
76. 77. 78. 79. 80. 81.
Fan X et al. Rituximab for tumefactive inflammatory demyelination: a case report. Clin Neurol Neurosurg. 2012;114(10):1326–8. Hardy TA, Chataway J. Tumefactive demyelination: an approach to diagnosis and management. J Neurol Neurosurg Psychiatry. 2013;84(9):1047–53. Harrison DM et al. Treatment of relapsing-remitting multiple sclerosis with high-dose cyclophosphamide induction followed by glatiramer acetate maintenance. Mult Scler. 2012;18(2):202–9. Krishnan C et al. Reduction of disease activity and disability with high-dose cyclophosphamide in patients with aggressive multiple sclerosis. Arch Neurol. 2008;65(8):1044–51. Makhani N et al. Cyclophosphamide therapy in pediatric multiple sclerosis. Neurology. 2009;72(24):2076–82. Smith DR et al. A randomized blinded trial of combination therapy with cyclophosphamide in patientswith active multiple sclerosis on interferon beta. Mult Scler. 2005;11(5):573–82. Le Page E et al. Long-term safety profile of mitoxantrone in a French cohort of 802 multiple sclerosis patients: a 5-year prospective study. Mult Scler. 2011;17(7):867–75. Azzopardi L et al. Predicting autoimmunity after alemtuzumab treatment of multiple sclerosis. J Neurol Neurosurg Psychiatry. 2014;85(7):795–8. Bevan CJ, Cree BA. Disease activity free status: a new end point for a new era in multiple sclerosis clinical research? JAMA Neurol. 2014;71(3):269–70. Havrdova E et al. Disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with daclizumab high-yield process in the SELECT study. Mult Scler. 2014;20(4):464–70. Giovannoni G et al. Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis. Lancet Neurol. 2011;10(4):329–37. Vercellino M et al. Multiple sclerosis relapses: a multivariable analysis of residual disability determinants. Acta Neurol Scand. 2009;119(2):126–30. Noseworthy JH et al. Multiple sclerosis. N Engl J Med. 2000;343(13):938–52. van Winsen LM et al. Outcome measurement in multiple sclerosis: detection of clinically relevant improvement. Mult Scler. 2010;16(5):604–10. Solaro C, Uccelli MM. Management of pain in multiple sclerosis: a pharmacological approach. Nat Rev Neurol. 2011;7(9):519–27. Hadjimichael O et al. Persistent pain and uncomfortable sensations in persons with multiple sclerosis. Pain. 2007;127(1–2):35–41. Tang DH et al. Impact of urinary incontinence on health-related quality of life, daily activities, and healthcare resource utilization in patients with neurogenic detrusor overactivity. BMC Neurol. 2014;14:74.
17 82. 83. 84. 85.
Curr Treat Options Neurol (2015) 17:17
Page 14 of 14 Rizzo MA et al. Prevalence and treatment of spasticity reported by multiple sclerosis patients. Mult Scler. 2004;10(5):589–95. Zwibel HL, Smrtka J. Improving quality of life in multiple sclerosis: an unmet need. Am J Manag Care. 2011;17(Suppl 5 Improving):S139–45. Frohman TC et al. Symptomatic therapy in multiple sclerosis. Ther Adv Neurol Disord. 2011;4(2):83–98. Courtney AM et al. Functional treatments in multiple sclerosis. Curr Opin Neurol. 2011;24(3):250–4.
86.
87. 88.
Craig J et al. A randomised controlled trial comparing rehabilitation against standard therapy in multiple sclerosis patients receiving intravenous steroid treatment. J Neurol Neurosurg Psychiatry. 2003;74(9):1225–30. Hauser SL, Chan JR, Oksenberg JR. Multiple sclerosis: prospects and promise. Ann Neurol. 2013;74(3):317–27. Suhs KW et al. A randomized, double-blind, phase 2 study of erythropoietin in optic neuritis. Ann Neurol. 2012;72(2):199–210.
Multiple Sclerosis and Related Disorders (P Villoslada, Section Editor)
Therapeutic Management of Severe Relapses in Multiple Sclerosis Carolyn Bevan, MD, MS Jeffrey M. Gelfand, MD, MAS* Address * MS Center, Department of Neurology, University of California, 675 Nelson Rising Lane, Box 3206, San Francisco, CA 94158-3206, USA Email: [email protected]
* Springer Science+Business Media New York 2015
This article is part of the Topical Collection on Multiple Sclerosis and Related Disorders Keywords Multiple sclerosis (MS) I MS relapses I Pseudo-relapse I Glucocorticoids I Adrenocorticotropic hormone (ACTH) I Neuroprotection I Neuroreparation I Therapeutic management
Opinion statement While not all multiple sclerosis (MS) relapses require treatment, relapses that are bothersome or that impair function should prompt consideration of timely treatment to restore function and minimize disability. Patients with suspected MS relapses should be evaluated to confirm the diagnosis, exclude other causes of neurological dysfunction, and identify potential triggers for relapse or pseudo-relapse, such as urinary tract infections, fever, or metabolic derangements. The diagnosis of an MS relapse is clinical, but MRI may be useful for confirmation and to evaluate for multifocal disease activity. High-dose oral or intravenous glucocorticoids, with or without an oral taper, are first-line therapy for MS relapses. Adrenocorticotropic hormone (ACTH) provides an alternative to glucocorticoid treatment but is currently much more expensive and does not have proven superiority. If the acute neurological deficits remain severe after steroid treatment, and particularly if there is persistent abnormal contrast-enhancement of the symptomatic lesion on repeat MRI, plasma exchange (PLEX) should be considered as an acute rescue therapy for relapse. In exceptional cases, particularly fulminant or tumefactive disease that fails to improve following treatment with steroids and PLEX, cytoxic agents such as cyclophosphamide or B cell-depleting regimens such as rituximab may be considered, although risk must be carefully weighed and the kinetics of such regimens indicate that they probably serve more to accelerate remission of disease activity than as an immediate relapse remedy. A single dose of natalizumab given as acute therapy for MS relapse was shown not to improve clinical outcomes in a randomized controlled trial. Attention to symptom management and promotion of neurorehabilitation are important aspects of MS relapse care. Neuroprotective and neuroreparative therapies remain under investigation, but are likely to become important complementary elements of relapse therapy in the future. Relapses
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serve as important indicators of MS disease activity. In the context of the emerging treatment paradigm of targeting freedom from evidence of MS disease activity, relapses should prompt consideration of transitioning to a disease-modifying treatment that may offer better efficacy.
Introduction The majority of patients diagnosed with multiple sclerosis (MS) experience a relapsing disease course [1, 2]. A relapse is defined by International Panel (McDonald) criteria as a patient reported or objectively observed attack with characteristics consistent with a demyelinating event lasting greater than 24 h in the absence of fever or infection [3]. Relapses serve as important markers of MS disease activity [2, 4, 5], and all currently available MS immunomodulatory and immunosuppressive diseasemodifying treatments were approved in part due to efficacy in reducing relapse activity as preventive therapy. The diagnosis of MS relapse is clinical, but MRI can be helpful if there is diagnostic uncertainty or to define the extent of new disease activity, which can be multifocal. The radiological correlate of an MS relapse is an active demyelinating lesion on MRI. Active MS lesions on MRI are characterized by abnormal contrast enhancement on post-gadolinium T1 sequences and/or restricted diffusion [6–8]. However, not all active MS lesions on MRI cause symptoms [9]. While subclinical MRI disease activity is a marker of disease progression and may prompt initiation or escalation of preventive diseasemodifying therapy, radiological findings alone are not an indication to initiate acute relapse therapy. On the other hand, MRI activity in MS correlates imperfectly with clinical attacks [10], so treatment decisions must b e b a s ed o n c l i n i c a l j u d g m e n t a nd c l i n i c a l symptomatology. Fever and infection may cause worsening of MS symptoms in the absence of new MS disease activity, a phenomenon referred to as pseudo-relapse. Pseudorelapses are typically characterized by fatigue or malaise or by the reemergence or worsening of neurological deficits that were at one time present [11]. While classically associated with fever or infection, and particularly urinary tract infections that may be otherwise subclinical, pseudo-exacerbations can also be caused by metabolic derangements, especially in patients with other medical comorbidities [12]. Screening for potential causes of pseudo-relapse is an important part of the initial evaluation of suspected relapse to ensure appropriate treatment, to avoid unnecessary steroid exposure,
and to avert mislabeling such patients as nonresponders to immunomodulatory therapy. The presence of a possible trigger of pseudo-relapse does not necessarily exclude concomitant relapse, and in some cases infections may even trigger MS attacks [13], but identification of a possible cause of pseudo-relapse should at least lead to targeted treatment of the likely trigger followed by neurological reassessment. While MS relapses are, by definition, self-limited, some relapses can cause significant morbidity and recovery can be incomplete. On neuropathology, acute MS lesions are also associated with early axonal injury that can be irreversible [14]. An ideal acute treatment for MS relapse would promote rapid recovery of neurological function and prevent permanent injury from the offending lesion. Not all relapses necessarily need to be treated, but relapses that are bothersome or substantially impair function should prompt consideration of timely treatment to restore function and minimize disability. There is no established scale to grade the severity of MS relapses, but a recent trial of oral glucocorticoids for MS attacks used a 1- to 2.5-point increase in the Expanded Disability Status Scale (EDSS) to define a moderate relapse and a greater than or equal to 3-point increase in EDSS to define a severe relapse [15]. While there are numerous high quality, low risk of bias clinical trials of disease-modifying treatments in MS, there are many fewer trials examining MS relapse management. When treatment for relapse is indicated, high dose glucocorticoids are the first-line treatment [16]. While IV administration of high-dose glucocorticoids was favored historically, oral glucocorticoids at bioequivalent high doses are increasingly used in clinical practice due to ease of administration and cost effectiveness. Intravenous methylprednisolone 1000 mg daily for 3 days or oral methylprednisolone 1250 mg daily for 3 days both lowered the EDSS score in patients experiencing moderate to severe relapse in a head-tohead randomized controlled comparison that demonstrated statistical non-inferiority of oral compared to IV administration at bioequivalent doses for the treatment of MS relapses [15].
Curr Treat Options Neurol (2015) 17:17 Adrenocorticotropic hormone (ACTH) is included in some MS relapse treatment algorithms [17, 18]. Various trials and meta-analyses show that ACTH exhibits similar efficacy in relapse recovery in comparison to highdose glucocorticoids [16, 19, 20]. Because of a marked difference in cost without proven superiority, however, the current role of ACTH in the management of MS relapses remains unclear. Plasma exchange (PLEX) provides additional benefit in recovery from severe MS and acute inflammatorydemyelinating disease attacks in patients with insufficient improvement following treatment with steroids [21–23]. In a classic trial of PLEX in the treatment of refractory inflammatory-demyelinating relapses, patients were treated with seven exchanges, every other day, for a total of 14 days [22]. More recently, partly in an attempt to minimize length of hospital stay, some clinicians offer daily exchanges with close monitoring of hematologic markers and careful monitoring for other complications. If significant acute disability persists after treatment with glucocorticoids and plasma exchange, careful analysis of risk-benefit should be undertaken before further acute therapy is offered. In a randomized, double-blind multicenter trial, a single dose of natalizumab administered soon after the onset of MS relapse did not speed up clinical recovery, although there was a reduction in
Page 3 of 14 17 gadolinium enhancement lesion volume on MRI [24]. Cytotoxic agents like cyclophosphamide [25] or B celldepleting agents like rituximab may have some role as rescue therapy in particularly aggressive, fulminant, or tumefactive disease, but are only used exceptionally in this context and may serve more to accelerate induction of disease activity than as a truly acute treatment. Induction strategies with mitoxantrone [26] or alemtuzumab [27] have also been proposed for the treatment of aggressive MS, but their possible role as a rapid rescue therapy for acute relapse remains unclear, and these treatments are not currently used in this context. Hematopoetic stem cell transplant (HSCT) is an experimental treatment that may have some role in the management of severe MS as a preventive therapy [28, 29] but does not have an established role for treatment of acute relapse. Any evidence of new disease activity, and particularly a clinical relapse, should prompt a review of the patient’s current disease-modifying treatment strategy. Better control of relapse activity earlier in the disease course has been shown to correlate with lower long-term disability status [4, 30]. In addition to pharmacological treatment, care should be taken to address symptom management and promote neuro-rehabilitation with the goal of improving function, comfort, and quality of life.
Treatment Pharmacologic treatment This review focuses on the acute treatment of severe MS relapses (Fig. 1). For a discussion of preventive disease modifying therapy in MS, we refer the reader to a number of excellent summaries [31–33].
Glucocorticoids Glucocorticoids are the first-line acute pharmacological therapy for MS relapses. Glucocorticoids exert a rapid immunosuppressant effect and also reduce CNS swelling. Glucocorticoids appear to promote clinical recovery after MS relapses but do not appear to alter the longer-term course of the disease. The Optic Neuritis Treatment Trial (ONTT), first reported in 1992, demonstrated that intravenous methylprednisolone 1 g per day for 3 days (administered in the trial as 250 mg every 6 h) followed by an 11-day oral taper promoted faster recovery of visual function as assessed by visual field metrics at 6 months compared to placebo and to lower-dose oral prednisone [34]. In the ONTT, oral prednisone at a lower dose of 1 mg/kg/day for 14 days was associated with an increased risk of subsequent episodes of optic neuritis, although the biological plausibility of that observation remains dubious and controversial [35]. While the ONTT is one of the most familiar and frequently
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Clinical concern for MS relapse
Clinical evaluaon Labs including urinalysis and urine culture Further studies as indicated by history and exam
Relapse
Pseudorelapse
Disabling or parcularly bothersome to paent
Not disabling to paent
Treat with pulse glucocorcoids: Oral or IV
Symptom management
+/- oral taper
No improvement
Treat underlying cause Monitor for improvement and reevaluate
Monitor Re-evaluate DMT Rehabilitaon as indicated
Improvement
Consider plasma exchange if severe acute disability. May also consider extending course of glucocorcoid pulse.
No improvement
Improvement
Recovery aer PLEX may be delayed. May consider repeat steroids. For fulminant disease consider cytotoxic or B-cell depleng therapy.
Fig. 1. An algorithmic approach to treating severe MS relapses.
cited studies in support of the efficacy of steroid treatment for MS exacerbations, it is by no means the only one. Building upon favorable clinical observations published in case series from as early as 1951, Miller et al. in 1961 published a controlled trial of corticotropin (ACTH) in comparison to placebo for MS relapse [36]. Several other trials for MS relapse followed suit examining ACTH [37] and methylprednisolone [38–42] utilizing a range of clinical endpoints,
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and the vast majority showed benefit for shorter-term clinical outcomes. A 2000 Cochrane review concluded that there was evidence of moderate quality to support the efficacy of methylprednisolone in comparison to placebo for the treatment of MS relapses [16]. A number of studies have since demonstrated the non-inferiority of bioequivalent high doses of oral compared to IV steroids for the treatment of MS relapse, and oral treatment is increasingly substituting for IV treatment in many clinical contexts because of ease of administration and lower cost. In a pharmacokinetic study in MS patients, the bioavailability of 1250 mg oral prednisone had a similar area under the curve of drug concentration over 24 h as 1000 mg IV methylprednisolone, although there was a higher and earlier peak concentration with IV administration [43]. The OMEGA trial, a phase IV multicenter randomized controlled trial that enrolled 49 patients with MS, showed that oral methylprednisolone 1250 mg daily was non-inferior to a bioequivalent dose of 1000 mg IV methylprednisolone per day for 3 days on both clinical (EDSS) and radiological (gadolinium-enhanced lesions) endpoints and had a similar safety and tolerability profile [15]. A single-blind randomized controlled trial of oral versus IV methylprednisolone administered 500 mg twice daily for 5 days showed non-inferiority of oral administration for the radiological endpoint of reducing the number of gadolinium-enhanced lesions [44]. An earlier double-blind placebo-controlled trial in 80 patients with MS of 1000 mg IV methylprednisolone versus a lower dose of 48 mg prednisone a day for 7 days followed by a 14-day taper showed no significant difference in clinical disability (EDSS) as an outcome, but this trial was neither designed nor powered as a non-inferiority analysis [45] (see Table 1).
ACTH ACTH gel (repository corticotropin injection) is a purified preparation of porcine adrenocorticotropic hormone (ACTH) in a gelatin suspension administered by IM or SQ injection. ACTH influences both the corticotropic and melanocortin pathways [48]. ACTH first received new drug application approval from the US Food and Drug Administration (FDA) in 1952. MS was added as an indication for ACTH in 1972. When the FDA approved ACTH gel in 2010 under an orphan drug designation for infantile spasms, the FDA permitted the new label to include MS in addition to 17 other “legacy” indications [49]. The relative efficacy of IVMP compared to ACTH for the treatment of MS relapse was compared in a double-blind randomized controlled study in 1989 [19]. The study included 61 patients randomized to either IV methylprednisolone 1 g daily for 3 days or IM ACTH dosed at 80 units for 7 days, 40 units for 4 days, and 20 units for 3 days. Both groups improved over the course of the study without a significant difference in rate of recovery or final outcome at 3 months. A 2000 Cochrane Collaboration review concluded that both IV methylprednisolone and ACTH result in acceleration of recovery and improvement in relapse-related disability [16]. For many years, the cost of ACTH was nominal relative to glucocorticoids. However, in 2007, the cost of ACTH increased to more than $23,000 a vial, and by 2012, the price had reached more than $28,000 a vial [50]. Due to such dramatic cost differentials, the role of ACTH in the routine management of MS relapse remains unclear, and ACTH is not currently part of the standard relapse treatment algorithm in our clinical practice (see Table 2).
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Table 1. Glucocorticoid drug information - Standard dosage IV: methylprednisolone 1000 mg IV daily for 3–7 days (most typically 3–5 days) Oral: methylprednisolone 1250 mg by mouth daily; or prednisone 1000 to 1250 mg by mouth daily; or dexamethasone 160– 200 mg by mouth daily; all for 3–7 days (most typically 3–5 days)—note that special instructions to the pharmacist are often required given the number of pills prescribed per day, as the most concentrated dose per pill of common oral glucocorticoid formulations that pharmacies routinely carry is usually relatively low in this context. For example, the most potent formulations are likely to be prednisone 60 mg pills or dexamethasone 4 mg pills An oral taper may be considered based on relapse severity and clinical context but is not always necessary nor required - Contraindications and cautions Active infection Poorly controlled diabetes (as steroids aggravate hyperglycemia) Recent GI bleed (though the major risk appears to be concomitant use of steroids and NSAIDs, so counsel to avoid NSAID use during the acute steroid course) [46] History of mania, psychosis, severe depression, or suicidality Thromboembolic disorders Major cardiovascular disease Goal of minimizing use in pregnancy when possible and using lowest effective dose when needed - Main drug interactions NSAIDS (may increase risk of GI bleeding) [46] May increase risk of opportunistic infection in combination with other immune suppressive therapies; consider suppressive antiviral therapy with acyclovir or valacyclovir in patients taking fingolimod for MS [47] Avoid live vaccines for at least 1 month post high-dose exposure (although the biggest concern in this context is when the steroid dose is 920 mg/day prednisone equivalent for more than 2 weeks) May cause an increase in INR in patients on warfarin - Main side effects Acute/chronic: insomnia (very common, sleep-promoting medication can be helpful) Acute/chronic: mood disturbance: anxiety, depression, euphoria, mania, psychosis Acute/chronic: avascular necrosis of bone Acute/chronic: osteopenia/osteoporosis risk, fracture risk Acute/chronic: hyperglycemia Acute/chronic: gastritis/GI upset, GI ulcer (especially in combination with NSAIDS) Chronic: skin thinning, easy bruising (purpura), impaired wound healing Chronic: increased risk of infections (consider PCP prophylaxis for long-term use especially if on another form of immunosuppression) Chronic: weight gain Chronic: fluid retention Chronic: cushingoid features, fat redistribution Chronic: menstrual irregularities Chronic: steroid myopathy Chronic: cardiovascular disease Chronic: cataracts Chronic: glaucoma - Cost Oral: relatively inexpensive IV: more expensive when accounting for procedural and facility costs for nursing and infusions (note that IV steroids can be administered to an inpatient or outpatient)
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Table 2. HP Acthar drug information - Standard dosage HP Acthar 80 units administered intramuscularly or subcutaneously daily for 5–15 days - Contraindications Do not administer intravenously Avoid in systemic fungal infections, ocular herpes simplex, or other active infections Avoid live or live-attenuated vaccines Per labeling, medical conditions including scleroderma, osteoporosis, congestive heart failure, uncontrolled hypertension, primary adrenocortical insufficiency, adrenocortical hyperfunction, sensitivity to proteins of porcine origin Recent surgery GI bleeding, ulcer — avoid concomitant NSAID use - Caution: patients with hypertension, CHF, renal insufficiency - Precautions: increased risk of infection, chronic use may cause Cushing’s syndrome and adrenal insufficiency upon withdrawal. May require taper to discontinue safely. Risk related to mineralocorticoid effects includes elevated blood pressure, salt and water retention, and hypokalemia due to increased excretion of potassium and calcium Hyperglycemia - Main drug interactions May accentuate electrolyte losses associated with diuretic therapy - Main side effects GI bleeding and gastric ulceration Behavioral and mood disturbances including euphoria, insomnia, irritability, mood swings, personality changes, severe depression, psychosis Ophthalmic: cataracts, glaucoma, ocular infections Osteopenia/osteoporosis Fluid retention Alteration in glucose tolerance Elevation of blood pressure Increased appetite and weight gain May cause development of antibodies, risk of hypersensitivity Use in pregnancy: class C. Potentially embryocidal. Excretion in human milk unknown Extremely high cost currently - Special points Enhanced effect in patients with hypothyroidism, hepatic cirrhosis - Cost: very expensive
Interventional procedures Plasma exchange Therapeutic plasma exchange (PLEX) is generally reserved for patients who have severe neurologic deficits caused by inflammatory-demyelinating disease and who fail to recover sufficient neurological function following first-line highdose glucocorticoid treatment. The exchange procedure involves placement of central or peripheral venous access, filtration of the plasma compartment of blood, and substitution of plasma volume with a replacement fluid. PLEX is thought to be beneficial for the treatment of inflammatory disease by removing
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Curr Treat Options Neurol (2015) 17:17 antibodies and other immunologically active products such as immune complexes from the plasma compartment, but PLEX is not thought to directly prevent production of new antibodies or new immunological activity. For indications like MS that are not monophasic, PLEX is best conceived of as an adjunctive or rescue therapy in combination with steroids and not as a substitute for steroids. In 1999, Weinshenker et al. [22] published a randomized controlled trial of PLEX in 22 patients with acute inflammatory-demyelinating attacks, 12 of whom had definitive MS by 1983 criteria and 12 of whom had other demyelinating diseases. Participants enrolled in the study were treated with IV high-dose methylprednisolone for a minimum of 5 days with minimal or no improvement. At the time of treatment with plasma exchange, patients were at least 21 days from the onset of symptoms and 14 days from initiation of corticosteroid treatment. Meaningful improvement in disability was observed in 42 % of treated patients versus 5.9 % of controls (p=0.011). The improvement was sustained on follow-up on days 58 and 208 [22]. While earlier treatment is probably preferable, benefit from PLEX has been observed in some cases in observational analyses even when initiation of plasma exchange occurred 60 days or more after symptom onset [51]. In a series of 153 patients with inflammatorydemyelinating conditions treated with PLEX at the Mayo Clinic, the median time to neurological improvement was 4 days (range, 1 to 100 days) and the odds of improvement were four times greater if there was ring enhancement of the offending lesion on post-gadolinium T1 MRI [21]. Continued improvement has been documented as late as 6 months after completion of plasma exchange in other studies [21, 52]. The major risks of PLEX include those related to securing central venous access, hypotension from volume loss, bleeding secondary to coagulopathy, and infection (particularly related to lines). There is also increased risk of anaphylaxis and infusion-related reactions if donor plasma is needed as a replacement fluid (as opposed to albumin, which is more typical in this context), such as for concomitant treatment of coagulopathy (see Table 3).
Severe relapses: the role of intravenous immunoglobulin (IVIg) in MS Available evidence does not support IVIg as a treatment for acute MS relapse. Two separate trials evaluating the addition of IVIg to IV methylprednisolone showed no evidence of added benefit of IVIg for treatment of MS relapse [53, 54]. A separate randomized trial evaluating the efficacy of IVIg versus placebo for the treatment of acute optic neuritis showed no benefit [55]. IVIg has been explored as an alternative to steroid treatment in women at risk for increased disease activity in the post-partum period [56, 57], but it should be emphasized that these studies evaluated the use of IVIg as a preventive disease-modifying therapy and did not assess IVIg for acute treatment of relapses. Other investigations of IVIg as a diseasemodifying therapy in MS have been conducted, some of which showed positive results [58, 59]; however, the evidence supporting the utility of IVIg has been questioned in large meta-analyses, [60, 61] and a 2008 randomized placebo-controlled trial of 0.2 and 0.4 mg/kg monthly IVIg showed no benefit as a preventive disease-modifying MS therapy for clinical or radiological endpoints at 1 year [62].
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Table 3. Plasma Exchange (PLEX) treatment - Standard procedure The traditional PLEX treatment protocol for CNS inflammatory-demyelinating disease [22] consists of seven exchange treatments, every other day, for 14 days. In the interest of reducing hospital length of stay and cost, some centers will consider administering five to seven exchanges as frequently as every day with close monitoring for coagulopathy - Complications Hypotension Anemia potentially requiring transfusion Thromboembolic events, including those related to heparin-induced thrombocytopenia Bleeding secondary to coagulopathy (fibrinogen levels are helpful to monitor in advance of reinfusion, especially with accelerated regimens; albumin replacement fluid does not contain fibrinogen) Infection, including line-related sepsis Central venous access-related complications It is advisable to hold ACE inhibitors for at least 24 h due to concern for flushing, GI symptoms, and hypotension, possibly related to the kinin pathway Infusion reactions/anaphylaxis, particularly if the replacement fluid involves donor plasma as opposed to albumin Hypocalcemia and arrhythmia (induced by citrate which is typically used as an anticoagulant in the filtration system or replacement fluid) - Cost/cost effectiveness High cost due to procedural costs, equipment, replacement fluids, blood products, inpatient admission (at some centers), use of central access (at some centers)
Severe relapses: third line and investigational therapies Despite treatment with pulse dose steroids and PLEX, some patients fail to recover fully from relapse symptoms. If residual symptoms remain but the patient has stabilized or begun to recover, it is advisable to defer further acute treatment and monitor for continued improvement over time. If the patient remains significantly disabled or continues to worsen from persistent acute inflammatory activity, however, the evidence becomes less clear regarding further management strategies. Some clinicians will offer another round of steroid treatment in this context, perhaps with a prolonged oral steroid taper. For fulminant or tumefactive demyelinating lesions, which account for a very small subset of MS-related relapses, there may be a role for cytotoxic therapy with agents like cyclophosphamide or B cell depletion with agents such as rituximab [63–66]. Given the kinetics of such therapies, however, their primary effect is probably more of accelerating induction of immunosuppression to prevent subsequent relapse disease activity than acting as true acute rescue treatments for relapse. Myeloablative induction dosing of cyclophosphamide (i.e., 50 mg/kg/day for 4 days) has been shown in small studies in MS to lead to remission of disease activity and improvement in disability [67, 68], and there are reports of the use of such strategies in children [69], although the risks of such therapy in this context require better characterization and such treatment is typically reserved for use in exceptional cases involving fulminant or tumefactive syndromes. Cyclophosphamide can also be given as an intravenous pulse of 500–800 mg/m2 of body surface area every 3–4 weeks without inducing severe myeloablation, but this treatment strategy functions more as a relatively aggressive preventive immunosuppressive therapy and not as an acute
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Curr Treat Options Neurol (2015) 17:17 treatment option [69, 70]. Mitoxantrone has shown benefit for inducing remission of MS disease activity as an aggressive preventive immunosuppressive therapy, but such benefit is usually outweighed by dose-related lifetime cardiac and hematologic toxicity and is now only rarely used given the availability of other proven disease-modifying treatment options [26, 71]. Rituximab has been reported to be beneficial for tumefactive demyelination in case reports [64, 65]. Alemtuzumab can bring about sustained remission of relapse disease activity as an aggressive preventive disease-modifying therapy, but carries a significant risk of secondary autoimmunity and has not been demonstrated as an acute relapse therapy [27, 72]. Autologous hematopoetic stem cell transplantation (HSCT) remains investigational and has also not been established to promote recovery from acute relapse [28, 29]. While these approaches may prove to be highly efficacious as preventive therapies, their role in promoting rapid recovery from severe relapses has not been established and exposing patients to these treatments during the acute phase of a severe relapse may increase risk of adverse events.
Severe relapses: impact on choice of disease-modifying therapy There are various algorithms for escalating disease-modifying therapies in MS after relapse. As more effective MS treatments become available, the paradigm of disease activity free status (DAFS) or no evidence of disease activity (NEDA) has become an important consideration in MS management [73–75]. If a patient experiences a relapse while off treatment, initiation of a diseasemodifying therapy should be discussed. If a patient experiences a relapse while on an established treatment, transition to a more efficacious disease-modifying agent should be explored.
Severe relapses: symptom management and rehabilitation Though most MS relapses tend to resolve over time with complete or substantial recovery, time to recovery is variable and full recovery to pre-attack baseline may not be achieved [76, 77]. Furthermore, patients and their physicians do not always define recovery in the same way [78]. Care must be taken to identify and manage relapse-related symptoms during both the acute and recovery phases. Management of symptoms like pain, spasticity, or urinary symptoms can greatly increase a patient’s quality of life and allow the patient to participate in physical therapy and regain functional independence more quickly [79–82]. A number of detailed reviews of symptom management strategies in patients with MS have been published and are worthy of study [83–85]. Physical and occupational therapy serve as important tools in expediting a patient’s recovery after an attack and maintaining optimal functional status [86].
Severe relapses: remyelination, neuroprotection, and future directions In spite of aggressive treatment, some patients do not fully recover from severe MS attacks. Emerging therapeutic approaches that promote myelin repair may one day allow for acute or post-acute treatment strategies to reverse damage inflicted by MS attacks. Neuroprotective agents may also prevent or attenuate relapse-related damage [87]. One potentially promising observation and proof of principle for neuroprotective therapy was a 2012 double-blind placebocontrolled trial of recombinant human erythropoietin dosed at 33,000 IU
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intravenously ×3 days given in addition to usual pulse methylprednisolone for the treatment of acute demyelinating optic neuritis, which showed less loss of retinal nerve fiber layer and improved visual-evoked potential latencies at 16 weeks in the erythropoietin-treated group compared to methylprednisolone alone [88]. We envision and hope for a future in which treatment for acute MS relapses will come to consist of combination immunosuppressive, neuroprotective, and reparative strategies.
Acknowledgments Funding was provided through the National MS Society Institutional Clinician Training Award and NIH KL2TR000143.
Compliance with Ethics Guidelines Conflict of Interest Carolyn Bevan declares no conflict of interest. Jeffrey M. Gelfand declares that he has received compensation for medical legal consulting relating to CNS inflammatory disease. Dr. Gelfand has also received compensation for consulting for MedImmune and Quest Diagnostics. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by the authors.
References and Recommended Reading 1.
2.
3. 4.
5.
Gelfand JM. Multiple sclerosis: diagnosis, differential diagnosis, and clinical presentation. Handb Clin Neurol. 2014;122:269–90. Weinshenker BG et al. The natural history of multiple sclerosis: a geographically based study. 2. Predictive value of the early clinical course. Brain. 1989;112(Pt 6):1419–28. Polman CH et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292–302. Scalfari A et al. The natural history of multiple sclerosis: a geographically based study 10: relapses and long-term disability. Brain. 2010;133(Pt 7):1914–29. Confavreux C, Vukusic S, Adeleine P. Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain. 2003;126(Pt 4):770–82.
6.
7.
8. 9. 10. 11.
Balashov KE, Lindzen E. Acute demyelinating lesions with restricted diffusion in multiple sclerosis. Mult Scler. 2012;18(12):1745–53. Gaitan MI et al. Evolution of the blood-brain barrier in newly forming multiple sclerosis lesions. Ann Neurol. 2011;70(1):22–9. Horsfield MA et al. Diffusion magnetic resonance imaging in multiple sclerosis. J Neurol Neurosurg Psychiatry. 1998;64 Suppl 1:S80–4. Simon JH. MRI outcomes in the diagnosis and disease course of multiple sclerosis. Handb Clin Neurol. 2014;122:405–25. Isaac C et al. Multiple sclerosis: a serial study using MRI in relapsing patients. Neurology. 1988;38(10):1511–5. Green AJ. Understanding pseudo: the symptoms are real, the cause is unclear. Neurology. 2009;72(19):1626–7.
17 12. 13. 14. 15. 16. 17. 18.
19. 20. 21. 22. 23.
24. 25. 26.
27. 28.
29.
30. 31. 32.
Curr Treat Options Neurol (2015) 17:17
Page 12 of 14 Thrower BW. Relapse management in multiple sclerosis. Neurologist. 2009;15(1):1–5. Panitch HS. Influence of infection on exacerbations of multiple sclerosis. Ann Neurol. 1994;36(Suppl):S25–8. Trapp BD et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998;338(5):278–85. Ramo-Tello C et al. A randomized clinical trial of oral versus intravenous methylprednisolone for relapse of MS. Mult Scler. 2014;20(6):717–25. Filippini G et al. Corticosteroids or ACTH for acute exacerbations in multiple sclerosis. Cochrane Database Syst Rev. 2000;4, CD001331. Berkovich R. Treatment of acute relapses in multiple sclerosis. Neurotherapeutics. 2013;10(1):97–105. Ross AP, Halper J, Harris CJ. Assessing relapses and response to relapse treatment in patients with multiple sclerosis: a nursing perspective. Int J MS Care. 2012;14(3):148–59. Thompson AJ et al. Relative efficacy of intravenous methylprednisolone and ACTH in the treatment of acute relapse in MS. Neurology. 1989;39(7):969–71. Glaser GH, Merritt HH. Effects of ACTH and cortisone in multiple sclerosis. Trans Am Neurol Assoc. 1951;56:130–3. Magana SM et al. Beneficial plasma exchange response in central nervous system inflammatory demyelination. Arch Neurol. 2011;68(7):870–8. Weinshenker BG et al. A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease. Ann Neurol. 1999;46(6):878–86. Weiner HL et al. Double-blind study of true vs. sham plasma exchange in patients treated with immunosuppression for acute attacks of multiple sclerosis. Neurology. 1989;39(9):1143–9. O’Connor PW et al. Randomized multicenter trial of natalizumab in acute MS relapses: clinical and MRI effects. Neurology. 2004;62(11):2038–43. Weiner HL. Immunosuppressive treatment in multiple sclerosis. J Neurol Sci. 2004;223(1):1–11. Edan G et al. Mitoxantrone prior to interferon beta-1b in aggressive relapsing multiple sclerosis: a 3-year randomised trial. J Neurol Neurosurg Psychiatry. 2011;82(12):1344–50. Coles AJ. Alemtuzumab treatment of multiple sclerosis. Semin Neurol. 2013;33(1):66–73. Pfender N, Saccardi R, Martin R. Autologous hematopoietic stem cell transplantation as a treatment option for aggressive multiple sclerosis. Curr Treat Options Neurol. 2013;15(3):270–80. Burman J et al. Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: the Swedish experience. J Neurol Neurosurg Psychiatry. 2014;85(10):1116–21. Freedman MS. ‘Time is brain’ also in multiple sclerosis. Mult Scler. 2009;15(10):1133–4. Sorensen PS. New management algorithms in multiple sclerosis. Curr Opin Neurol. 2014;27(3):246–59. Okuda DT. Immunosuppressive treatments in multiple sclerosis. Handb Clin Neurol. 2014;122:503–11.
33. 34.
35.
36. 37. 38. 39. 40.
41.
42.
43. 44. 45. 46. 47.
48.
49.
O’Connor PW, Oh J. Disease-modifying agents in multiple sclerosis. Handb Clin Neurol. 2014;122:465–501. Beck RW et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritis Study Group. N Engl J Med. 1992;326(9):581–8. Goodin DS. Perils and pitfalls in the interpretation of clinical trials: a reflection on the recent experience in multiple sclerosis. Neuroepidemiology. 1999;18(2):53–63. Miller H, Newell DJ, Ridley A. Multiple sclerosis. Treatment of acute exacerbations with corticotrophin (A.C.T.H.). Lancet. 1961;2(7212):1120–2. Rose AS et al. Cooperative study in the evaluation of therapy in multiple sclerosis. ACTH vs. placebo—final report. Neurology. 1970;20(5):1–59. Sellebjerg F et al. Randomized controlled trial of highdose peroral methylprednisolone in attacks of multiple sclerosis. Ugeskr Laeger. 1999;161(48):6625–9. Sellebjerg F et al. Double-blind, randomized, placebocontrolled study of oral, high-dose methylprednisolone in attacks of MS. Neurology. 1998;51(2):529–34. Filipovic SR et al. The effects of high-dose intravenous methylprednisolone on event-related potentials in patients with multiple sclerosis. J Neurol Sci. 1997;152(2):147–53. Milligan NM, Newcombe R, Compston DA. A doubleblind controlled trial of high dose methylprednisolone in patients with multiple sclerosis: 1. Clinical effects. J Neurol Neurosurg Psychiatry. 1987;50(5):511–6. Durelli L et al. High-dose intravenous methylprednisolone in the treatment of multiple sclerosis: clinicalimmunologic correlations. Neurology. 1986;36(2):238–43. Morrow SA et al. The bioavailability of IV methylprednisolone and oral prednisone in multiple sclerosis. Neurology. 2004;63(6):1079–80. Martinelli V et al. A short-term randomized MRI study of high-dose oral vs intravenous methylprednisolone in MS. Neurology. 2009;73(22):1842–8. Barnes D et al. Randomised trial of oral and intravenous methylprednisolone in acute relapses of multiple sclerosis. Lancet. 1997;349(9056):902–6. Piper JM et al. Corticosteroid use and peptic ulcer disease: role of nonsteroidal anti-inflammatory drugs. Ann Intern Med. 1991;114(9):735–40. Arvin AM et al. Varicella-zoster virus infections in patients treated with fingolimod: risk assessment and consensus recommendations for management. JAMA Neurol. 2015;72(1):31–9. Arnason BG et al. Mechanisms of action of adrenocorticotropic hormone and other melanocortins relevant to the clinical management of patients with multiple sclerosis. Mult Scler. 2013;19(2):130–6. U.S. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 022432Orig1s000 Risk Assessment and Risk Mitigation Review(s). 2010. http://www.accessdata.fda.gov/
Curr Treat Options Neurol (2015) 17:17
50.
51. 52. 53. 54.
55. 56. 57.
58.
59.
60.
61.
62. 63. 64.
drugsatfda_docs/nda/2010/022432Orig1s000RiskR. pdf Accessed 3 March 2015. Pollack A. Questcor finds profits at $28,000 a vial. The New York Times. Published December 29, 2012. http://www.nytimes.com/2012/12/30/business/ questcor-finds-profit-for-acthar-drug-at-28000-a-vial. html Accessed 3 March 2015. Keegan M et al. Plasma exchange for severe attacks of CNS demyelination: predictors of response. Neurology. 2002;58(1):143–6. Llufriu S et al. Plasma exchange for acute attacks of CNS demyelination: predictors of improvement at 6 months. Neurology. 2009;73(12):949–53. Sorensen PS et al. IV immunoglobulins as add-on treatment to methylprednisolone for acute relapses in MS. Neurology. 2004;63(11):2028–33. Visser LH et al. A randomized, double-blind, placebocontrolled pilot study of i.v. immune globulins in combination with i.v. methylprednisolone in the treatment of relapses in patients with MS. Mult Scler. 2004;10(1):89–91. Roed HG et al. A double-blind, randomized trial of IV immunoglobulin treatment in acute optic neuritis. Neurology. 2005;64(5):804–10. Haas J, Hommes OR. A dose comparison study of IVIG in postpartum relapsing-remitting multiple sclerosis. Mult Scler. 2007;13(7):900–8. Achiron A et al. Effect of intravenous immunoglobulin treatment on pregnancy and postpartum-related relapses in multiple sclerosis. J Neurol. 2004;251(9):1133–7. Achiron A et al. Intravenous immunoglobulin treatment in multiple sclerosis and experimental autoimmune encephalomyelitis—the Israeli experience. MS Study Group. Mult Scler. 1997;3(2):142–4. Fazekas F et al. Randomised placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Austrian Immunoglobulin in Multiple Sclerosis Study Group. Lancet. 1997;349(9052):589–93. Elovaara I et al. EFNS guidelines for the use of intravenous immunoglobulin in treatment of neurological diseases: EFNS task force on the use of intravenous immunoglobulin in treatment of neurological diseases. Eur J Neurol. 2008;15(9):893–908. Goodin DS et al. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology. 2002;58(2):169–78. Fazekas F et al. Intravenous immunoglobulin in relapsing-remitting multiple sclerosis: a dose-finding trial. Neurology. 2008;71(4):265–71. Siffrin V et al. How to treat tumefactive demyelinating disease? Mult Scler. 2014;20(5):631–3. Sempere AP et al. Neurological picture. Rituximab for tumefactive demyelination refractory to corticosteroids and plasma exchange. J Neurol Neurosurg Psychiatry. 2013;84(12):1338–9.
Page 13 of 14 17 65. 66. 67.
68.
69. 70.
71.
72. 73. 74.
75.
76. 77. 78. 79. 80. 81.
Fan X et al. Rituximab for tumefactive inflammatory demyelination: a case report. Clin Neurol Neurosurg. 2012;114(10):1326–8. Hardy TA, Chataway J. Tumefactive demyelination: an approach to diagnosis and management. J Neurol Neurosurg Psychiatry. 2013;84(9):1047–53. Harrison DM et al. Treatment of relapsing-remitting multiple sclerosis with high-dose cyclophosphamide induction followed by glatiramer acetate maintenance. Mult Scler. 2012;18(2):202–9. Krishnan C et al. Reduction of disease activity and disability with high-dose cyclophosphamide in patients with aggressive multiple sclerosis. Arch Neurol. 2008;65(8):1044–51. Makhani N et al. Cyclophosphamide therapy in pediatric multiple sclerosis. Neurology. 2009;72(24):2076–82. Smith DR et al. A randomized blinded trial of combination therapy with cyclophosphamide in patientswith active multiple sclerosis on interferon beta. Mult Scler. 2005;11(5):573–82. Le Page E et al. Long-term safety profile of mitoxantrone in a French cohort of 802 multiple sclerosis patients: a 5-year prospective study. Mult Scler. 2011;17(7):867–75. Azzopardi L et al. Predicting autoimmunity after alemtuzumab treatment of multiple sclerosis. J Neurol Neurosurg Psychiatry. 2014;85(7):795–8. Bevan CJ, Cree BA. Disease activity free status: a new end point for a new era in multiple sclerosis clinical research? JAMA Neurol. 2014;71(3):269–70. Havrdova E et al. Disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with daclizumab high-yield process in the SELECT study. Mult Scler. 2014;20(4):464–70. Giovannoni G et al. Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis. Lancet Neurol. 2011;10(4):329–37. Vercellino M et al. Multiple sclerosis relapses: a multivariable analysis of residual disability determinants. Acta Neurol Scand. 2009;119(2):126–30. Noseworthy JH et al. Multiple sclerosis. N Engl J Med. 2000;343(13):938–52. van Winsen LM et al. Outcome measurement in multiple sclerosis: detection of clinically relevant improvement. Mult Scler. 2010;16(5):604–10. Solaro C, Uccelli MM. Management of pain in multiple sclerosis: a pharmacological approach. Nat Rev Neurol. 2011;7(9):519–27. Hadjimichael O et al. Persistent pain and uncomfortable sensations in persons with multiple sclerosis. Pain. 2007;127(1–2):35–41. Tang DH et al. Impact of urinary incontinence on health-related quality of life, daily activities, and healthcare resource utilization in patients with neurogenic detrusor overactivity. BMC Neurol. 2014;14:74.
17 82. 83. 84. 85.
Curr Treat Options Neurol (2015) 17:17
Page 14 of 14 Rizzo MA et al. Prevalence and treatment of spasticity reported by multiple sclerosis patients. Mult Scler. 2004;10(5):589–95. Zwibel HL, Smrtka J. Improving quality of life in multiple sclerosis: an unmet need. Am J Manag Care. 2011;17(Suppl 5 Improving):S139–45. Frohman TC et al. Symptomatic therapy in multiple sclerosis. Ther Adv Neurol Disord. 2011;4(2):83–98. Courtney AM et al. Functional treatments in multiple sclerosis. Curr Opin Neurol. 2011;24(3):250–4.
86.
87. 88.
Craig J et al. A randomised controlled trial comparing rehabilitation against standard therapy in multiple sclerosis patients receiving intravenous steroid treatment. J Neurol Neurosurg Psychiatry. 2003;74(9):1225–30. Hauser SL, Chan JR, Oksenberg JR. Multiple sclerosis: prospects and promise. Ann Neurol. 2013;74(3):317–27. Suhs KW et al. A randomized, double-blind, phase 2 study of erythropoietin in optic neuritis. Ann Neurol. 2012;72(2):199–210.
