Q: How is a clinical MS relapse defined?

A: In the context of an established MS diagnosis, a clinical relapse is defined as a “monophasic clinical episode with patient-reported symptoms and objective findings typical of MS, reflecting a focal or multifocal inflammatory demyelinating event in the CNS, developing acutely or subacutely, with a duration of at least 24 hours in the absence of fever or infection.”1 Other synonyms that have been used for MS relapse include exacerbation, flare, attack, and bout. Common relapse syndromes include unilateral optic neuritis, focal brainstem or cerebellar syndromes, or partial myelitis.1 Atypical symptoms that would warrant further evaluation include encephalopathy, complete ophthalmoplegia, headache, or isolated fatigue.1 A typical MS relapse evolves over 24-48 hours and reaches a nadir in several days. More sudden or gradual symptoms should prompt evaluation of alternative diagnoses. Most patients experience some spontaneous recovery though it is variable and affected by other factors such as comorbidities, functional status prior to the relapse, and age. 

Q: What is the differential diagnosis for a MS relapse?

A: MS can manifest with a wide array of new or worsening symptoms and they do not all constitute a relapse. A pseudorelapse is a temporary recrudescence of prior neurological deficits usually in the setting of certain stressors such as an infection, heat exposure (including fever or exercise), or adverse psychosocial event. 2

Common paroxysmal syndromes include trigeminal neuralgia, Lhermitte sign which is an electrical sensation elicited with neck flexion or Pulfrich phenomenon which is an illusionary, binocular disturbance where object moving across the visual field is perceived as travelling along a curved trajectory. Uhthoff phenomenon specifically refers to transient visual blurring with exercise in patients with a history of optic neuritis though other motor or sensory symptoms can exhibit the same phenomenon.

Disability accrual in MS can also occur independent of relapses (ie progression). The most common phenotypic presentation is gradual worsening myelopathy. This can be a challenging diagnosis because this qualifier is made retrospectively over time and patients can have overlying relapses.

Progressive multifocal leukoencephalopathy (PML) can be very difficult to distinguish from a MS relapse especially early in PML. Clinicians should be vigilant in MS patients treated with certain therapies associated with PML infection, particularly natalizumab. In patients being treated with highly effective therapies, there is usually a low risk of breakthrough disease so PML as the cause of new symptoms should be considered, especially if they include seizures, behavioral changes or cognitive abnormalities; if they evolve subacutely or do not respond to corticosteroids. MRI can assist in differentiating a PML lesion from a MS relapse.3,4

Q: What work-up should be pursued for a relapse?

A: The evaluation of a relapse should be tailored to the clinical scenario. In the setting of an established diagnosis of MS, new neurologic symptoms compatible with those caused by MS, and no symptoms or history suggesting an intercurrent condition, no further ancillary testing may be needed. When symptoms are atypical of a relapse, a targeted work-up should be pursued to identify the cause. For example, if a patient presents with reemergence of remote neurological deficits concerning for a pseudorelapse they should undergo basic laboratory testing before consider pharmacological treatment for a relapse. This includes a urinalysis with culture since occult urinary tract infections are common in MS, along with a complete cell count and comprehensive metabolic panel. Based on the clinical history, further investigative measures can be ordered if symptoms suggest an intercurrent condition or alternative medical condition. An infection or other derangement does not exclude a concomitant relapse, but identification and correction of the possible trigger should be managed before the relapse is treated.

Q: Is MRI necessary to diagnosis a MS relapse?

A: In general, neuroimaging is not necessary to diagnose a relapse, which is a clinical diagnosis. MRI can be a useful adjuvant to screen for other mimics such as PML or stroke. MRI can also be helpful if there is diagnostic uncertainty as radiographic activity in the context of new neurological symptoms would support the diagnosis of a MS relapse. The prototypical MRI finding in a relapse is gadolinium enhancement reflecting blood brain barrier breakdown. Gadolinium enhancement is observed in most but not all new lesions and resolves over the course of several weeks.5 Clinicians should be aware that potential treatment such as corticosteroids can alter these radiographic findings. Enhancing lesions can also occur without obvious clinical signs or symptoms.6

Q: When is pharmacological treatment indicated?

A: In general, we treat relapses, as they cause significant morbidity and symptoms typically interfere patients’ ability to function. Mild relapses such as non-disabling sensory symptoms or those already exhibiting spontaneous improvement may not require intervention as the risk of therapy may outweighs potential benefit of treatment. Ultimately, treatment decisions are made jointly between the patient and provider using a shared decision-making model.7

Mild, asymptomatic MRI lesion activity does not require treatment as the rationale for pharmacological treatment is to decrease the duration and intensity of neurological symptoms. We often treat in the setting of multiple asymptomatic active lesion as those patients are at increased risk for clinical worsening.8,9 New clinical or radiographic disease activity may warrant a change in disease modifying therapy. Please refer to the Mellen Center Approach (MCA) on switching disease modifying therapies for more information on that topic.

Q: How are relapses treated?

A: Corticosteroids are the mainstay treatment option for MS relapses. High dose corticosteroids offer rapid symptom relief and hasten neurologic recovery. While there has been much debate about intravenous vs oral administration, it has been demonstrated that dose rather than the route of administration is the most important factor in terms of efficacy.10 We typically use intravenous methylprednisolone (IVMP 1000mg daily) or an equivalent dose of intravenous of high dose oral prednisone (1250mg daily which equates to twenty-five 50mg tablets) for 3-5 days for relapses. Multiple studies have shown that high-dose, oral corticosteroid and high-dose, IV methylprednisolone are bioequivalent with a similar side effect profile and equivalent MRI /clinical outcomes.11,12 If the oral regimen is selected, we advise patients that they do not need to take all the pills at one time but they take the pills earlier in the day to prevent potential sleep disturbance. 

To lessen side effects, we typically prescribe a proton pump inhibitor or H2 antagonists along with a sleep aid (typically melatonin or diphenhydramine) to proactively manage the impact of the high dose corticosteroids. In addition, steroids are associated with rare yet serious complications including aseptic necrosis of the shoulder or hip and hepatic failure.13 If patients experience severe psychiatric manifestations including mania, depression or psychosis we have a higher threshold for prescribing corticosteroids as those symptoms are difficult to mitigate and could be life threatening. Corticosteroid-induced psychosis usually self-resolves once the medication is stopped but discontinuation is not always possible. Symptoms can be managed with short courses of atypical antipsychotic or mood stabilizing medications though we would encourage treatment coordination with a mental health professional.14 Hypersensitivity reactions to corticosteroids are rare yet serious adverse reaction that providers should also be aware of. Reactions seem to be attributable to the specific formulation (i.e. the salt or preservative agent) rather than the steroid itself. A different corticosteroid preparation can be tried again in a controlled setting where emergency medications and personnel are present.15

A steroid taper can be considered based on relapse severity and clinical context (i.e. comorbidities) but is not required.16 There is no clear evidence that a taper contributes to recovery17 or that a short course of high dose corticosteroids significantly suppresses the hypothalamic-pituitary-adrenal axis which would necessitate a taper in most patients. 18 

Q: What treatments options are available for relapses with incomplete recovery?

A: We will consider a second course of corticosteroids if a patient has an incomplete response to the initial treatment though we have a low threshold to escalate therapy as incomplete symptom resolution is a major cause of early disability in MS.19 We typically use plasmapheresis for treatment of severe or refractory relapses with an incomplete response to the corticosteroids. The length of treatment can vary between 3-7 sessions depending on the treatment response and tolerance. The most common treatment period is 5 sessions over 7-10 days. Plasmapheresis is usually well tolerated but there are a number of potential side effects clinicians should be aware of including infection (specifically related to the venous catheter), deep venous thrombosis, anemia, hypotension, and hypoalbuminemia. Most of these side effects are easily managed and do not require plasmapheresis discontinuation, though close coordination with the plasmapheresis administration team is essential.

Adrenocorticotropic hormone (ACTH) treatment has been approved for use in MS relapses since the 1960s20 though it was supplanted in clinical practice by corticosteroids in the 1980s. There has been some recent, renewed interest in ACTH given its effects on melanocortin receptors on circulating lymphocytes.21 There is no conclusive evidence that ACTH has any additional benefits when compared to corticosteroids or improves the recovery of patients with incomplete response to corticosteroids. Clinical trials are currently underway to further investigate.

Current evidence does not support intravenous immunoglobulin (IVIG) as a treatment for acute MS relapse.22,23 IVIG could be considered if a patient was intolerant to both IVMP and PLEX but we do not typical prescribe it at the Mellen Center. Please refer to the MCA on IVIG for more information regarding that specific therapy.

Q: Where should a relapse be treated?

A: Relapses are typically managed in the outpatient setting unless circumstances necessitate inpatient treatment such as an inability for the patient to perform self-care, loss of ability to ambulate, or comorbidities that increase the risk of corticosteroid-related complications. Given the challenges of arranging out-patient plasmapheresis, we usually admit these patients to the hospital for expedited central venous line placement and treatment, though sometimes outpatient therapy can be arranged. Acute treatment in the inpatient setting also is considered if subsequent inpatient rehabilitation is anticipated.

Q: What adjunctive methods can be used to manage a relapse?

A: We believe rehabilitation is an integral part of relapse management. Our patients engage with a multidisciplinary team to focus on their physical and emotional wellbeing when being treated for a relapse or pseudorelapse. This team encompasses physiatrists, psychologists, physical therapists, occupational therapists, and speech therapists. Rehabilitation can focus on motor impairment, gait instability or cognitive dysfunction. These services can also focus on a broader range of functions including an ability to perform activities of daily living, improve mobility, or a return to work. Management of the relapse symptoms can also lead to improved quality of life for patients. For example, treating painful sensory disturbances with a neuropathic pain medications or addressing disabling fatigue with pharmacological and non- pharmacological methods.

Q: How are relapses managed during pregnancy or breastfeeding?

A: Typically, disease modifying therapy is discontinued during pregnancy and while breast feeding, which increases the risk of disease activity. Fortunately, MS disease activity decreases during this time though women with highly active disease before pregnancy are at higher risk for a relapse, especially for three to four months postpartum.24 Women undergoing an assisted reproductive technique may also have a higher relapse risk due to the hormone changes induced by gonadotropin-releasing hormone agonists. We typically use the standard treatment strategy for relapses during pregnancy or while breastfeeding. We do have a higher threshold for treatment in the first trimester as there is some evidence for adverse fetal outcomes with corticosteroids, including cleft palate and low birth weight. Generally, relapses during the second and third trimesters can be treated safely with corticosteroids. Ultimately, a joint decision is made between the patient, provider and obstetrician (OBGYN). Corticosteroids can cross into the breast milk so we recommend patients to avoid breast feeding for several hours after their treatment. 25 For disabling, corticosteroids-refractory relapses, plasmapheresis can be considered. For more information regarding MRIs during pregnancy and breast feeding please refer to the MCA on MRI Activity.


 References:
  1. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17(2):162-173.
  2. Rae-Grant AD. Unusual symptoms and syndromes in multiple sclerosis. Continuum (Minneap Minn). 2013;19(4 Multiple Sclerosis):992-1006.
  3. Bag AK, Cure JK, Chapman PR, Roberson GH, Shah R. JC virus infection of the brain. AJNR Am J Neuroradiol. 2010;31(9):1564-1576.
  4. Yousry TA, Major EO, Ryschkewitsch C, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med. 2006;354(9):924-933.
  5. Absinta M, Sati P, Gaitan MI, et al. Seven-tesla phase imaging of acute multiple sclerosis lesions: a new window into the inflammatory process. Ann Neurol. 2013;74(5):669-678.
  6. Willoughby EW, Grochowski E, Li DK, Oger J, Kastrukoff LF, Paty DW. Serial magnetic resonance scanning in multiple sclerosis: a second prospective study in relapsing patients. Ann Neurol. 1989;25(1):43-49.
  7. Kopke S, Kasper J, Muhlhauser I, Nubling M, Heesen C. Patient education program to enhance decision autonomy in multiple sclerosis relapse management: a randomized-controlled trial. Mult Scler. 2009;15(1):96-104.
  8. Gasperini C, Pozzilli C, Bastianello S, et al. The influence of clinical relapses and steroid therapy on the development of Gd-enhancing lesions: a longitudinal MRI study in relapsing-remitting multiple sclerosis patients. Acta Neurol Scand. 1997;95(4):201-207.
  9. Smith ME, Stone LA, Albert PS, et al. Clinical worsening in multiple sclerosis is associated with increased frequency and area of gadopentetate dimeglumine-enhancing magnetic resonance imaging lesions. Ann Neurol. 1993;33(5):480-489.
  10. Le Page E, Veillard D, Laplaud DA, et al. Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP): a randomised, controlled, double-blind, non-inferiority trial. Lancet. 2015;386(9997):974-981.
  11. Ramo-Tello C, Grau-Lopez L, Tintore M, et al. A randomized clinical trial of oral versus intravenous methylprednisolone for relapse of MS. Mult Scler. 2014;20(6):717-725.
  12. Martinelli V, Rocca MA, Annovazzi P, et al. A short-term randomized MRI study of high-dose oral vs intravenous methylprednisolone in MS. Neurology. 2009;73(22):1842-1848.
  13. Nociti V, Biolato M, De Fino C, et al. Liver injury after pulsed methylprednisolone therapy in multiple sclerosis patients. Brain Behav. 2018;8(6):e00968.
  14. Kenna HA, Poon AW, de los Angeles CP, Koran LM. Psychiatric complications of treatment with corticosteroids: review with case report. Psychiatry Clin Neurosci. 2011;65(6):549-560.
  15. Butani L. Corticosteroid-induced hypersensitivity reactions. Ann Allergy Asthma Immunol. 2002;89(5):439-445; quiz 445-436, 502.
  16. Bevan C, Gelfand JM. Therapeutic management of severe relapses in multiple sclerosis. Curr Treat Options Neurol. 2015;17(4):345.
  17. Perumal JS, Caon C, Hreha S, et al. Oral prednisone taper following intravenous steroids fails to improve disability or recovery from relapses in multiple sclerosis. Eur J Neurol. 2008;15(7):677-680.
  18. Levic Z, Micic D, Nikolic J, et al. Short-term high dose steroid therapy does not affect the hypothalamic-pituitary-adrenal axis in relapsing multiple sclerosis patients. Clinical assessment by the insulin tolerance test. J Endocrinol Invest. 1996;19(1):30-34.
  19. Stoppe M, Busch M, Krizek L, Then Bergh F. Outcome of MS relapses in the era of disease-modifying therapy. BMC Neurol. 2017;17(1):151.
  20. Miller H, Newell DJ, Ridley A. Multiple sclerosis. Treatment of acute exacerbations with corticotrophin (A.C.T.H.). Lancet. 1961;2(7212):1120-1122.
  21. Arnason BG, Berkovich R, Catania A, Lisak RP, Zaidi M. Mechanisms of action of adrenocorticotropic hormone and other melanocortins relevant to the clinical management of patients with multiple sclerosis. Mult Scler. 2013;19(2):130-136.
  22. Visser LH, Beekman R, Tijssen CC, et al. A randomized, double-blind, placebo-controlled 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.
  23. Roed HG, Langkilde A, Sellebjerg F, et al. A double-blind, randomized trial of IV immunoglobulin treatment in acute optic neuritis. Neurology. 2005;64(5):804-810.
  24. Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N Engl J Med. 1998;339(5):285-291.
  25. Ost L, Wettrell G, Bjorkhem I, Rane A. Prednisolone excretion in human milk. J Pediatr. 1985;106(6):1008-1011.