Acute Flaccid Myelitis | Interim Considerations Clinical Management of Patients | CDC

Acute Flaccid Myelitis | Interim Considerations Clinical Management of Patients | CDC

Acute Flaccid Myelitis: Interim Considerations for Clinical Management

Please note: these considerations are intended to apply to acute flaccid myelitis (AFM) and are not intended to be generalized to all forms or etiologies of childhood acute flaccid paralysis, such as Guillain-Barré syndrome, transverse myelitis, or other immune-mediated etiologies. If an alternative diagnosis for the acute paralysis is under consideration, all efforts should be made to explore the alternative diagnosis, and if found, appropriate intervention should be rendered. The clinical considerations below reflect observations and input from individual subject matter experts and a review of available scientific literature. The clinical considerations do not represent consensus recommendations or official guidelines.

Summary of Interim Considerations

Based on the available evidence and input from individual experts:

• There is no indication and that any specific targeted therapy or intervention should be either preferred or avoided in the treatment of AFM. There are currently no targeted therapies/interventions with enough evidence to endorse or discourage their use for the treatment or management of AFM.
• Clinicians should expedite neurology and infectious disease consultations to discuss treatment and management considerations.
• Corticosteroids: There is no indication that corticosteroids should be either preferred or avoided in the treatment of AFM. There is no clear human evidence for efficacy of steroids in the treatment of AFM, and there is some evidence in a mouse model with EV-D68 that steroids may be harmful. The possible benefits of the use of corticosteroids to manage spinal cord edema or white matter involvement in AFM should be balanced with the possible harm due to immunosuppression in the setting of possible viral infection.
• Intravenous immunoglobulin (IVIG): There is no indication that IVIG should be either preferred or avoided in the treatment of AFM. There is no clear human evidence for efficacy of IVIG in the treatment of AFM; evidence for efficacy is based on early treatment in animal models and it has not been given in a systematic manner to AFM patients to allow for measurements of efficacy. There is no evidence that treatment with IVIG is likely to be harmful.
• Plasmapheresis: There is no indication that plasma exchange should be either preferred or avoided in the treatment of AFM. There is no clear human evidence for efficacy of plasma exchange in the treatment of AFM, and it has not been given in a systematic manner to AFM patients to allow for measurements of efficacy. Although there are inherent procedure-associated risks, there is no evidence that using plasma exchange for patients with AFM is likely to be harmful.
• Fluoxetine: There is no indication that fluoxetine should be used for the treatment of AFM. There is no clear human evidence for efficacy of fluoxetine in the treatment of AFM based on a single retrospective evaluation conducted in patients with AFM, and data from a mouse model also did not support efficacy.
• Antiviral medications: There is no indication that antivirals should be used for the treatment of AFM, unless there is suspicion of herpesvirus infection (e.g., concomitant supra-tentorial disease or other clinical or radiologic features of herpesvirus infection). Appropriate antiviral medications (i.e., acyclovir, ganciclovir) should be empirically administered until herpesvirus infection has been excluded.
• Interferon: There is no indication that interferon should be used for the treatment of AFM, and there is concern about the potential for harm from the use of interferon given the immunomodulatory effects in the setting of possible ongoing viral replication.
• Other immunosuppressive medications/biological modifiers: There is no indication that biologic modifiers and the use of other immunosuppressive agents should be used for the treatment of AFM, and there is a possibility of harm in their use.

Updated Interim Considerations for AFM Clinical Management

Since the recognition of AFM in 2014, CDC has received numerous requests from clinicians and public health officials for guidance on how to manage and treat patients with this condition. In October 2014, CDC consulted subject matter experts from a range of disciplines to assist CDC in developing considerations for management of children with this neurologic illness. These experts were from the fields of infectious diseases, neurology, pediatrics, critical care medicine, public health epidemiology, and virology. The opinions from these individual consultations formed the basis of the “Interim Considerations for Clinical Management of AFM” document drafted in 2014 (1). CDC updated this information following consultation with national experts and review of the peer-reviewed, published literature. There continues to remain a paucity of published evidence for treatment of AFM, limited to case reports and case-series of patients with AFM. Consultation with experts treating AFM patients remains essential. The clinical considerations below reflect the observations and input from individual experts and a review of available scientific literature. The clinical considerations do not represent consensus recommendations or official guidelines. Rather, they summarize these experts’ approaches to clinical treatment of AFM.

Summary of Specific Interventions/Therapies

Corticosteroids

1. Steroids have been given in several published case-series of AFM patients, but most often in combination with other therapies such as IVIG and plasma exchange, making it difficult to assess their effects on the disease process (2-6).
2. There is a theoretical concern about the possible adverse effects of administration of corticosteroids in the setting of acute infection, which may compromise the innate immune response to the infection, thus propagating the infectious process and leading to further neuronal damage and worse clinical outcomes.
3. The use of corticosteroids has been associated with poorer outcome in observational studies of outbreaks of neuroinvasive disease due to enterovirus – 71 (EV-71) internationally and in mouse model (7,8). This observation following a 2012 outbreak in Cambodia led to the conclusion among a WHO-convened joint commission that corticosteroids were contraindicated in the management of EV-71 associated neuroinvasive disease (World Health Organization. Global alert and response (GAR): Severe complications of hand, foot and mouth disease (HFMD) caused by EV-71 in Cambodia — Conclusion of the joint investigation. Jul 13, 2012.). This is relevant, as an increase in EV-A71 associated neurologic disease has been reported in the United States in 2018.
4. In a mouse model of AFM using EV-D68 as the infectious virus, mice receiving dexamethasone at either early or late time points from infection had significantly higher mortality compared to infected controls. Individual dexamethasone treated mice that died had worse paralysis associated with their motor impairment score than in an infected control (9).
5. There may be theoretical benefit for steroids in the setting of severe cord swelling or long tract signs suggesting white matter involvement, where steroids may salvage tissue that may be harmed due to an ongoing immune/inflammatory response. While AFM is clinically and radiographically defined by the predominance of gray matter damage in the spinal cord, some patients may have some white matter involvement. It is not clear if these different patterns are important relative to therapeutic considerations.
6. The differential diagnosis for AFM includes conditions that would best be treated by early initiation of steroids (i.e., transverse myelitis, anti-MOG antibody related disease, acute disseminated encephalomyelitis).

Summary

There is no indication that corticosteroids should be either preferred or avoided in the treatment of AFM. There is no clear human evidence for efficacy of steroids in the treatment of AFM, and there is some evidence in a mouse model with EV-D68 that steroids may be harmful. The possible benefits of the use of corticosteroids to manage spinal cord edema or white matter involvement in AFM should be balanced with the possible harm due to immunosuppression in the setting of possible viral infection.

Intravenous Immune Globulin (IVIG)

1. IVIG has been utilized for neurologic complications in enteroviral disease associated with neurologic involvement. Enteroviruses cause chronic, severe central nervous system (CNS) infections in agammaglobulinemic children, suggesting humoral immunity plays an important role in attenuating enteroviral infection (10). Similarly, infants who fail to acquire neutralizing antibody from their mothers have been described as having more severe disease when infected with enteroviruses (11).
2. IVIG has been shown to modulate cytokine production (i.e., IFN-γ, IL-6, IL-8, IL-10, IL-13) in the CNS and systemic inflammatory response. In addition, there is a theoretical risk of IVIG interfering with naturally acquired innate immunity, due to the immunomodulatory effects of the F(ab’) region of the immunoglobulin molecule, which may impact cell-mediated immunity.
3. For IVIG to modify disease in an active viral infectious process, early administration is likely required, and possibly prior to exposure. Pre-poliovirus vaccine era trials in the 1950s demonstrated potential efficacy of gamma globulin for prevention of poliomyelitis with mass gamma globulin administration to susceptible populations in an outbreak situation (12). However, a randomized, non-blinded trial of intramuscular (IM) gamma globulin treatment in 49 children (48 controls) with pre-paralytic poliomyelitis (i.e., CSF WBC>10 cells/mm without development of weakness) did not impact development or severity of paralysis during a poliovirus outbreak in New York City in 1944 (13).
4. There has been recent experience with the use of IVIG in the treatment of WNV and EV-D68 associated neuroinvasive disease. IVIG has been shown to have some efficacy in prevention of progression to neuroinvasive disease in rodent models (9,14,15). Paralysis in mice was prevented in a time-dependent fashion after administration of IVIG from time of infection. However, clear efficacy of IVIG has not been demonstrated in humans with WNV associated paralysis with most data limited to case reports or small case-series (16,17).
5. IVIG has been utilized for patients presenting with symptoms of AFM, but to date no systematic studies of IVIG have been conducted. In a 2014 – 2015 case-series, treatment of AFM using IVIG was done either alone or in combination with methylprednisolone and plasma exchange. All patients tolerated the treatment regimens well without major complications. Neurologic improvement was seen in all patients regardless of treatment, but in all except one patient, deficits persisted (3). Messacar, et al reported on a review of clinical cases from 2012 – 2015. All cohorts that were reviewed received various combinations of IVIG, steroids, plasma exchange, and antiviral medications. No significant improvement or deterioration was noted with these therapies, but a systematic assessment of response was not feasible with the retrospective review (4). Hopkins noted in her review piece on AFM diagnostic and management considerations that the current practice at Children’s Hospital Philadelphia is to initiate therapy with IVIG upon recognition of AFM in hopes of boosting humoral immunity (2).
6. IVIG is generally safe and well tolerated, though expensive. Common intra-infusion adverse effects of IVIG include fever, headache, myalgia, chills, nausea, and vomiting, which are typically infusion rate-dependent (18). Less commonly, hypersensitivity and anaphylactoid symptoms of flushing, tachycardia, and hypotension can be seen. Post-infusion adverse events include headaches and aseptic meningitis, fatigue, and arthralgias (19). IVIG is occasionally associated with severe adverse events such as acute renal failure, thromboembolic events, hemolytic anemia, and neutropenia.
7. IVIG preparations have been shown to contain antibody to circulating enteroviruses, including EV-D68 (20).

Summary

There is no indication that IVIG should be either preferred or avoided in the treatment of AFM. There is no clear human evidence for efficacy of IVIG in the treatment of AFM; evidence for efficacy is based on early treatment in animal models and it has not been given in a systematic manner to AFM patients to allow for measurements of efficacy. There is no evidence that treatment with IVIG is likely to be harmful.

Plasma Exchange (PLEX)

1. It is presumed that there are beneficial effects from the innate humoral immune response to an acute viral infection, in which the body produces neutralizing antibodies to the infectious pathogen (21). Removal of these antibodies induced in response to acute infection could cause potential harm. Additionally, plasmapheresis requires placement of invasive intravenous access and procedure-associated risks.
2. Plasmapheresis has been used in published case-series of AFM patients. From a case-series in Argentina, 4 children were given PLEX in combination with IVIG and steroids. Treatment did not lead to clinical improvement (22). Nelson et al referenced above also used PLEX in combination with steroids and IVIG (3). In a single AFM case published in 2017, Esposito et al treated a 4 y/o child with plasmapheresis in addition to corticosteroids and IVIG for 3 days. After 4 weeks of oral steroids and a 2-week taper, significant improvement was noted (5). No data was available to evaluate plasmapheresis in the absence of other therapies. No adverse events were noted for PLEX in the above publications.

Summary

There is no indication that plasma exchange should be either preferred or avoided in the treatment of AFM. There is no clear human evidence for efficacy of plasma exchange in the treatment of AFM, and it has not been given in a systematic manner to AFM patients to allow for measurements of efficacy. Although there are inherent procedure-associated risks, there is no evidence that using plasma exchange for patients with AFM is likely to be harmful.

Fluoxetine

1. Fluoxetine is a selective serotonin reuptake inhibitor that demonstrates activity in vitro against enteroviruses including EV-D68. Its concentration in the brain far exceeds that of the serum, which suggested a possible option for treating CNS infection due to enteroviruses.
2. In a mouse model of EV-D68 induced paralysis, fluoxetine injections had no effect on paralysis compared to infected controls, regardless of dose. In addition, mortality was higher in mice who received fluoxetine compared to controls (9).
3. In a comparison of patients who received treatment with fluoxetine, and those who did not, using a summative limb strength score between their initial examination and most recent follow-up as an outcome, fluoxetine was not associated with improved neurologic outcomes (6). The patients treated with fluoxetine were more likely to have severe paralysis and to have EV-D68 isolated from respiratory specimens.

Summary

There is no indication that fluoxetine should be used for the treatment of AFM. There is no clear human evidence for efficacy of fluoxetine in the treatment of AFM based on a single retrospective evaluation conducted in patients with AFM, and data from a mouse model also did not support efficacy.

Antiviral medications

1. It is important to point out that, while symptoms of a viral illness precede limb weakness onset, and clinical data supporting pathogenesis point to an acute infectious process, a specific pathogen isolated from a sterile site in the majority of AFM patients has yet to be identified.
2. Any guidance regarding antiviral medications should be interpreted with great caution, given the unknowns about the pathogenesis of this illness at present. Heath departments, CDC, and other academic entities are working to try to identify all causative agents for AFM, which will help provide further guidance regarding the use of anti-microbial therapies for this illness.
3. Testing has been conducted at CDC for antiviral activity of compounds pleconaril, pocapavir, and vapendavir and none have significant activity against currently circulating strains of EV-D68 at clinically relevant concentrations (23).

Summary

There is no indication that antivirals should be used for the treatment of AFM, unless there is suspicion of herpesvirus infection (e.g., concomitant supra-tentorial disease or other clinical or radiologic features of herpesvirus infection). Appropriate antiviral medications (i.e., acyclovir, ganciclovir) should be empirically administered until herpesvirus infection has been excluded.

Interferon

1. Anecdotal accounts of improvement with interferon α-2b in the treatment of West Nile poliomyelitis-like illness were reviewed in 2014. In addition, a case-series assessing the efficacy of IFN-α in the treatment of Saint Louis encephalitis, including AFP presentations, suggested some improvement in a non-randomized pilot trial (24); however, subsequent non-controlled assessments failed to replicate this improvement in cases of Saint Louis encephalitis and West Nile Virus.
2. A randomized trial performed in Vietnam from 1996–1999 evaluated 117 children with Japanese encephalitis randomized to receive interferon (10 million units/m2 daily for 7 days) or placebo. Outcome at discharge and 3 months did not differ between the two treatment groups; 20 (33%) of 61 children in the interferon group had a poor outcome (e.g., death, severe sequelae), compared with 18 (32%) of 56 in the placebo group (p=0.85, difference 0.1%, 95% CI –17.5 to 17.6% (25).
3. Although there are limited in vitro, animal, and anecdotal human data suggesting activity of some interferons against viral infections, sufficient data are lacking in the setting of AFM.

Summary

There is no indication that interferon should be used for the treatment of AFM, and there is concern about the potential for harm from the use of interferon given the immunomodulatory effects in the setting of possible ongoing viral replication.

Other immunosuppressive medications / biological modifiers

1. In the setting of AFM, biologic modifiers may have an adverse impact on patients, presuming infectious etiology. The combination of immunosuppressive agents directly impairing T-cell function (and B-cell function indirectly), or therapy directed against primary humoral immunity (e.g., rituximab) may further worsen the ability to clear infection.

Summary

There is no indication that biologic modifiers and the use of other immunosuppressive agents should be used for the treatment of AFM, and there is a possibility of harm in their use.

References

1. Prevention CfDCa. Interim Considerations for Clinical Management of Patients 2014. Available at: https://www.cdc.gov/acute-flaccid-myelitis/hcp/clinical-management.html. Accessed November 8, 2018.
2. Hopkins SE. Acute Flaccid Myelitis: Etiologic Challenges, Diagnostic and Management Considerations. Current treatment options in neurology. 2017;19:48.
3. Nelson GR, Bonkowsky JL, Doll E, et al. Recognition and Management of Acute Flaccid Myelitis in Children. Pediatric neurology. 2016;55:17-21.
4. Messacar K, Schreiner TL, Van Haren K, et al. Acute flaccid myelitis: A clinical review of US cases 2012-2015. Annals of neurology. 2016;80:326-338.
5. Esposito S, Chidini G, Cinnante C, et al. Acute flaccid myelitis associated with enterovirus-D68 infection in an otherwise healthy child. Virology journal. 2017;14:4.
6. Messacar K SS, Hopkins S, et al. Safety, Tolerability, and Efficacy of Fluoxetine as an Anti-viral for Acute Flaccid Myelitis. Neurology. 2018; Nov 9.
7. He Y, Yang J, Zeng G, et al. Risk factors for critical disease and death from hand, foot and mouth disease. The Pediatric infectious disease journal. 2014;33:966-970.
8. Shen FH, Shen TJ, Chang TM, Su IJ, Chen SH. Early dexamethasone treatment exacerbates enterovirus 71 infection in mice. Virology. 2014;464-465:218-227.
9. Hixon AM, Clarke P, Tyler KL. Evaluating Treatment Efficacy in a Mouse Model of Enterovirus D68-Associated Paralytic Myelitis. The Journal of infectious diseases. 2017;216:1245-1253.
10. Wilfert CM, Buckley RH, Mohanakumar T, et al. Persistent and fatal central-nervous-system ECHOvirus infections in patients with agammaglobulinemia. The New England journal of medicine. 1977;296:1485-1489.
11. Modlin JF, Kinney JS. Perinatal enterovirus infections. Advances in pediatric infectious diseases. 1987;2:57-78.
12. Ward R, Logrippo GA, Graef I, Earle DP, Jr. Quantitative studies on excretion of poliomyelitis virus: a comparison of virus concentration in the stools of paralytic and non-paralytic patients. The Journal of clinical investigation. 1954;33:354-357.
13. Bahlke AM, Perkins JE. Treatment of preparalytic poliomyelitis with gamma globulin. Journal of the American Medical Association. 1945;129:1146-1150.
14. Hurst BL, Evans WJ, Smee DF, et al. Evaluation of antiviral therapies in respiratory and neurological disease models of Enterovirus D68 infection in mice. Virology. 2018; Oct 31; 526:146-154.
15. Srivastava R, Ramakrishna C, Cantin E. et.al. Anti-inflammatory activity of IVIG protects against West Nile virus encephalitis. J Gen Viro. 2015; Jun; 96 (Pt 6): 1347-57.
16. Shimoni Z, Bin H, Bulvik S. The clinical response of West Nile virus neuroinvasive disease to intravenous immunoglobulin therapy. Clin Pract. 2012; Jan 27; 2 (1):e18.
17. Hebert J, Armstrong D, Daneman, N. et al. Adult-onset opsoclonus-myoclonus syndrome due to West Nile virus treated with IVIG. J Neurovirol. 2017; Feb; 23(1):158-159.
18. Pediatrics AAo. Passive Immunization. In: Pickering LK B, CJ, Kimberlin DW, Long SS, eds., ed. Red Book: 2012 Report of the Committee on Infectious Diseases Elk Grove Village, IL: American Academy of Pediatrics; 2012:59-62.
19. Singh-Grewal D, Kemp A, Wong M. A prospective study of the immediate and delayed adverse events following intravenous immunoglobulin infusions. Archives of disease in childhood. 2006;91:651-654.
20. Zhang Y, Moore DD, Nix WA, Oberste MS, Weldon WC. Neutralization of Enterovirus D68 isolated from the 2014 US outbreak by commercial intravenous immune globulin products. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology. 2015;69:172-175.
21. Schwartz J. Evidence-based guideline update: plasmapheresis in neurologic disorders. Neurology. 2011;77:e105-106; author reply e106.
22. Ruggieri V, Paz MI, Peretti MG, et al. Enterovirus D68 infection in a cluster of children with acute flaccid myelitis, Buenos Aires, Argentina, 2016. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 2017;21:884-890.
23. Rhoden E, Zhang M, Nix WA, Oberste MS. In Vitro Efficacy of Antiviral Compounds against Enterovirus D68. Antimicrobial agents and chemotherapy. 2015;59:7779-7781.
24. Rahal JJ, Anderson j, Rosenberg C. et al. Effect of interferon-alpha2b therapy on St. Louis viral meningoencephalitis: clinical and laboratory results of a pilot study. JID. 2004; Sept 15; 190 (6):1084-7.
25. Solomon T, Dung NM, Wills B, et al. Interferon alfa-2a in Japanese encephalitis: a randomised double-blind placebo-controlled trial. Lancet (London, England). 2003;361:821-826.

For further information / questions regarding AFM, please visit https://www.cdc.gov/acute-flaccid-myelitis/index.html or send inquiry to AFMinfo@cdc.gov.

The following external experts provided input for this document:

2018

Mark J. Abzug, MD
Professor of Pediatrics (Infectious Diseases)
University of Colorado School of Medicine and Children’s Hospital Colorado

Leslie Benson, MD
Assistant Director, Pediatric Neuro-Immunology and Pediatric MS and Related Disorders, Department of Neurology
Boston Children’s Hospital

Samuel R. Dominguez, MD, PhD
Associate Professor, Pediatric Infectious Diseases
University of Colorado School of Medicine
Medical Directory, Clinical Microbiology Laboratory, Children’s Hospital Colorado

Benjamin Greenberg, MD, MHS
Associate Professor, Department of Neurology and Neurotherapeutics
University of Texas Southwestern Medical Center

Sarah Hopkins, MD, MSPH
Pediatric Neurologist and Section Head for Multiple Sclerosis and Neuroinflammatory Disorders, Division of Neurology
Children’s Hospital of Philadelphia

Matthew Kirschen, MD, PhD
Departments of Anesthesiology and Critical Care Medicine, Neurology, and Pediatrics
Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania

Kevin Messacar, MD
Assistant Professor, Department of Pediatrics, Sections of Hospital Medicine and Infectious Diseases
University of Colorado School of Medicine and Children’s Hospital Colorado

Sean T. O’Leary, MD, MPH
Associate Professor of Pediatrics
Sections of Pediatric Infectious Diseases and General Academic Pediatrics
University of Colorado Denver Anschutz Medical Campus

Catherine E. Otten, MD
Pediatric Neurologist, Department of Pediatric Neurology
Seattle Children’s Hospital

Daniel M. Pastula, MD, MHS
Assistant Professor and Director, Neuro Infectious Diseases Fellowship, Department of Neurology
University of Colorado School of Medicine
Affiliate Neurologist and Medical Epidemiologist, Division of Viral Diseases, Centers for Disease Control and Prevention

Amanda L. Piquet, MD
Assistant Professor of Neurology
University of Colorado School of Medicine

Kenneth L. Tyler, MD
Louise Baum Endowed Chair and Chairman of Neurology
University of Colorado School of Medicine

Keith Van Haren, MD
Assistant Professor, Department of Neurology
Stanford University

Ann Yeh, MD, FRCPC
Director, Pediatric Neuroinflammatory Disorders Program
Hospital for Sick Children
University of Toronto

The following staff from the Centers for Disease Control and Prevention contributed to this document:

2018

Janell Routh, MD MHS, Measles Mumps Rubella Poliovirus and Herpesviruses Team, Division of Viral Diseases, National Center for Immunization and Respiratory Diseases

Adriana Lopez, MPH, Measles Mumps Rubella Poliovirus and Herpesviruses Team, Division of Viral Diseases, National Center for Immunization and Respiratory Diseases

Manisha Patel, MD MS, Team Lead, Measles Mumps Rubella Poliovirus and Herpesviruses Team, Division of Viral Diseases, National Center for Immunization and Respiratory Diseases

James J. Sejvar, MD, Neuroepidemiologist, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases