Acute Flaccid Myelitis

Disease/ Disorder

Definition

Acute Flaccid Myelitis (AFM) is a rapidly progressive immune and infectious mediated disease process that causes flaccid weakness of one or more limbs.^1,2 It is further characterized by specific gray-matter abnormalities on MRI and probable pleocytosis (WBC >5 cells/mm3) in CSF.³

Etiology

No exact cause has been specifically identified; however, it has temporally and geographically been noted to be associated with Enterovirus 68 (EVD68) and, to a lesser extent, Enterovirus A71 and coxsackie A16. ^1,2,4,5 AFM is not caused by polio. Enterovirus/Rhinovirus (EV/RV) were only present in 37% of cases in 2019 and 26% of cases in 2020.²⁴

Epidemiology including risk factors and primary prevention

• AFM outbreaks occur every 2 years (since 2014) and primarily between the months of August and October.⁴ There were 120 cases reported in 2014, 149 cases in 2016, 223 cases in 2018, ² 47 cases in 2019 and 32 cases in 2020.²⁴
• Children represent over 90% of the reported AFM cases.²
• There are no specific actions that have been identified to prevent AFM apart from decreasing risk of acquiring and spreading viral infections.^4,6
• 2019 and 2020 case numbers are more consistent with non-peak years, and it is possible that non-pharmacologic measures instituted against COVID 19 (ex. Masks, hand hygiene, physical distancing and virtual schooling) have helped decrease the spread of respiratory viruses including the Enterovirus class.²⁴
• There are no cases reported of recurrence after initial diagnosis.²

Patho-anatomy/physiology

• While exact cause and pathology has yet to be identified, pathogenesis is likely initially infectious and immune-mediated.^1,2
• A possible viral cause is enterovirus which is a respiratory virus closely related to rhinovirus infrequently occurring in US until late 2000s.¹ Hixon et al. inoculated mice with a strain of EVD68 from 2014 that caused similar clinical picture of paralysis.²
• A majority of insult appears to be in spinal column. There is a predilection for involvement of the anterior horn cells.^1,2,5,8
• Three general phases of pathogenic process have been proposed:¹
• Inflammatory: largely reversible
• Demyelination: moderately reversible
• Axon transection: marginally reversible
• Two pathophysiological subtypes have been identified on imaging including gray-matter restricted and mixed gray-white matter.¹ It has been proposed that the initial inflammation that occurs in the anterior horn cells may “spill” into adjacent white matter. This may explain presentation of mixed upper motor neuron and lower motor neuron signs. ¹
• Some patients may present with MRI brain abnormalities such as dorsal pons, medulla, cerebellum, or varied supratentorial lesions. ^9,10,11

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

New onset/acute: Home to Acute Hospital Setting

• Prodromal illness of fever, respiratory, or gastrointestinal symptoms lasting a median of 7 days in one study.¹²
• Clinical presentation includes rapidly progressive flaccid limb weakness which is preceded by symptoms of viral illness.^1,2,4,6,8 Weakness often occurs over a few hours to a few days.¹³ Upper extremities are involved more often than lower extremities, and weakness is usually asymmetric.¹² However, lower limb involvement was more common among AFM patients in 2019 and 2020, 74% and 81% respectively compared to 44% in 2018.²⁴ There is variable cranial nerve involvement resulting in dysphagia, dysarthria, facial weakness, dysphonia, and ophthalmoplegia. There can be absent deep tendon reflexes. Bowel and bladder dysfunction may be present. A mix of upper motor neuron signs and lower motor neuron signs may be present.¹
• Evidence of CSF pleocytosis and diffuse spinal cord gray matter lesions.
• CSF pleocytosis resolution occurs at 2 weeks.¹²

Subacute: Inpatient rehabilitation

• Functional and respiratory optimization (details discussed in Rehabilitation Management and Treatments).

Chronic/stable: Outpatient setting

• Improvement and resolution of spinal cord changes in weeks to months.
• Persistent motor weakness common 1 year out from diagnosis.¹⁴
• Functional improvement with intermittent plateaus anecdotally common.
• Slower motor gains, especially when compared to transverse myelitis.²
• Muscle atrophy will occur.¹⁰
• Weakness may present with head tilt.

Specific secondary or associated conditions and complications

• Some studies have indicated that 25-40% require ventilation.²
• A preceding viral illness was reported in 90% of patients in 2018 and prior. Proceeding viral illness was present in 57% and 63% in 2019 and 2020 respectively.²⁴
• Autonomic dysfunction is often present.⁸

Essentials of Assessment

History

• Acute Flaccid Myelitis presents with history of a viral infection with either respiratory or gastrointestinal symptoms.⁴
• After prodromal viral symptoms of 7 days, patients report sudden onset of arm or leg weakness and loss of muscle tone.^12,18
• Other symptoms reported include headaches, neck pain, facial droop, double vision, difficulty swallowing, pain in affected limbs, difficulty moving eyes, drooping eyelids, numbness and tingling, change in voice, and/or inability to urinate.¹⁸
• In severe cases, patients can have respiratory failure needing ventilation or neurological complication leading to death.¹⁸

Physical examination

• Examination of these patients reveal findings similarly seen in patients with spinal cord injury; this includes spinal shock.¹⁹
• Weakness is evaluated as asymmetric paralysis in arms or legs. Often, patients are weaker proximally and stronger distally. Sometimes, this results in children “finger crawling” where their fingers will direct movement of the extremity across tables or their torso without elbow flexion to complete a functional task like scratching the nose. In some patients with cervical involvement, they may present with flaccid upper extremities and hypertonic lower extremities with; however, this is not always the case.
• Patients will also present with diplopia, ophthalmoplegia, dysphagia, dysphonia, dysarthria, impaired sensation (allodynia, dysesthesias, paresthesias), decreased tone, hyporeflexia, autonomic instability, facial weakness, and decreased trunk/cervical tone.^8,19

Clinical functional assessment: mobility, self-care cognition/behavior/affective state

• Mobility: inability to sit, stand, walk, or transfer
• Self care: deficits in dressing, eating, drinking, bathing, toileting, bowel and bladder function affected
• Cognition/Behavior/Affect: abnormal coping strategies. With associated hypoxic events, there may be cognitive issues like memory, executive function being affected.
• Respiratory status may be affected

Laboratory studies

Source 8	Test
Nasopharynx	Respiratory PCR panel, enterovirus PCR
Serum- for differential diagnosis
Infectious	West Nile IgG, IgM, EBV antibodies, Lyme serology, Enterovirus PCR
Inflammatory/metabolic	CBC, CMP, Vitamin B12, D-25-OH,IgA, NMO-IgG, ANA, Oligo clonal bands
CSF-
Infectious	CSF HSV, EBV PCR, enterovirus PCR
Inflammatory	Oligoclonal bands, ?NMO IgG
Urine	Enterovirus PCR
Stool	Enterovirus PCR (CDC per polio testing guidelines)

Imaging

• MRI spinal cord may show increased T2 signal, non-enhancing, throughout central gray matter of spinal cord, mainly the anterior horn cells.^1,2,5,8
• By current definition, these spinal cord lesions span one or more spinal segment.⁴
• Cord lesions have a predilection for the cervical area, but lesions can extend below this region.²⁰
• MRI brain may show prominent increased T2 changes in pons and medulla and occasional involvement of dentate nucleus of cerebellum, substantia nigra with enhancement of facial nerves, and supratentorial changes.¹⁰ Lesions may be seen primarily affecting cortical and subcortical gray matter, including caudate nucleus and thalamus is seen.¹¹

Supplemental assessment tools

• Electrodiagnostic studies may be normal acutely.¹² Electromyography (EMG) changes are usually observed in C5 to C7 levels, but changes are also noted in muscle groups and limbs that were clinically unaffected.¹²
• At 1-3 weeks following neurologic injury, EMG may variably show fibrillations and reduced recruitment of motor unit action potentials; nerve conductions studies (NCS) may show low amplitudes of compound unit action potentials (CMAPs).^12,14
• After 3 weeks, most patients with AFM will definitively show fibrillations, reduced recruitment of MUAPs, and CMAPs with low amplitude.¹² Similar results can be seen at months to 1 year, or even over a year in some cases.¹²

Early prediction of outcomes

• Highest frequency of residual abnormalities on neuroimaging seen in lumbar spinal cord, is associated with higher frequency of disability in lower extremities.²¹
• Atlas-based measures of proportion of GM T2 signal abnormality measured on a single axial MR imaging section and across the full lesion segment correlate with motor impairment and outcome in patients with acute flaccid myelitis.²²
• Anecdotally, patients who present with mixed gray-white matter lesions may respond to treatment better than restricted gray-matter lesions.
• There seems to be a better prognosis for vent weaning when chest and shoulder musculature returns, but this is speculative.

Environmental

As discussed previously, no exact cause has been specifically identified; but due to its possible association with EVD68, Enterovirus A71, and coxsackie A16, assessing recent illness or travel is warranted.^1,2,4,5

Social role and social support system

Families face social isolation while caring for their loved ones. It is important to help families be connected with other families in similar situations. The patients and families may also require counseling for coping strategies.

Professional issues

• Suspected cases should be reported to CDC
• Difficulty in performing placebo controlled trials limits the ability to definitively identify treatment options.
• Families should be encouraged to pursue options for recreation for their loved ones, thus enhancing their quality of life.
• Families should be provided with appropriate equipment, splinting to maintain mobility, ROM. It is possible that some of the recommended equipment may not be covered by insurance.

Rehabilitation Management and Treatments

Available or current treatment guidelines

• Acute treatment consists of intravenous immunoglobulin (IVIG), steroids, and/or plasmapheresis (PLEX). However, there is no evidence to suggest one over the other.
• There is limited research that provides specific guidelines and recommendations for rehabilitation management of AFM.
• Early initiation of therapies while in acute phases of illness is preferred to address functional needs.⁸

At different disease stages

New onset/acute: Hospital setting

• Early initiation of therapies includes physical therapy, occupational therapy, and speech therapy.
• Orthotics for positioning, support, and function.
• Pressure Relief Ankle Orthotics (PRAFO) to prevent ankle contractures and skin breakdown at the heel for leg weakness.
• Neuromuscular electrical stimulation.
• Monitor for spastic neurogenic bladder. There is no specific duration as to when a spastic bladder emerges from flaccidity. This is complicated in the setting of mixed gray-white matter involvement.
• Monitor for constipation.
• Address sleep/wake cycle as indicated.
• May require turns every 2 hours to prevent skin breakdown with limited mobility and/or a specialized mattress.
• Pain management for neuropathic pain but not common.
• Neurology treatment plan during acute hospital stay.
• Monitoring medical stability for potential transfer to inpatient rehabilitation.
• Addressing role as PM&R physician in their child’s care

Subacute: Inpatient Rehabilitation

In addition to above, address the following:

• Neuromuscular electrical stimulation has been shown to be one of the current best effective practices in treatment.
• Robotic-assisted technologies.
• Vent optimization.
• Shoulder subluxation prevention with sling and/or kinesiotaping.
• Addressing adjustment and mood disorders.
• Neck bracing for weak cervical musculature in the setting of tracheostomy status and ventilation.
• Dysphagia diet management as indicated.
• Assessing cervical and truncal stability.

Chronic/stable: Outpatient Management

• Continues outpatient therapies.
• Episodic inpatient rehabilitation admissions.
• Osteopenia management.
• Consideration for nerve transfer surgeries at 6 months after diagnosis.
• Consider pool therapy or hippotherapy.
• Continues neuromuscular electrical stimulation home exercise program.

Coordination of care

• Throughout each setting, adequate handoff is crucial across the continuum of care. A multi-disciplinary team-based approach is optimal for management.
• Medical teams may also include pulmonology (vent support or sleep study), ENT, primary pediatrician, endocrinology (osteopenia assessment), gastroenterology/surgery (possible gastrostomy tube placement)
• Therapy teams include physical therapy, occupational therapy, or speech therapy. Other therapies to consider are pet therapy, music therapy, or art therapy.
• Other team members include child life, social work, care coordinators, nursing, nutrition/dietician, psychology/counseling, and respiratory therapy.
• Alternative treatments may include massage, osteopathic manipulation, and acupuncture.
• After inpatient stay, follow up in an outpatient clinic may include pediatric physiatry, neurology, neuropsychology, physical therapy, social worker, and nursing coordinator.

Patient & family education

• Centers for Disease Control and Protection (CDC) and AFM Task Force website has resources for clinicians and family members.⁴
• Some families find social media outlets helpful such as the Facebook group for AFM families.
• Podcasts about AFM are available.²³

Measurement of Treatment Outcomes including those that are impairment-based, activity participation-based and environmentally-based

• Functional Independent Measures for Children (WeeFIM).
• AFM Task Force Rehab Subgroup is currently discussing a variety of possible functional measures for research

Translation into Practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

• Incorporate neuromuscular electrical stimulation as early as possible in the course of their disease process. Encourage family to obtain NMES units for home use with guidance from PM&R or therapist for use. Settings and frequency should be based on what the child can tolerate with guidance from therapists. It is common to initiate at lower amplitudes, but enough to generate a motor response. The range for use can be 30-90 minutes daily, but psychosocial factors must be taken into consideration such as timing for therapies, school, etc.
• Patients often require multiple stays at an inpatient rehabilitation facility to address new goals towards function. If possible, consider increasing daily therapy time from 3 hours up to 6 hours; this patient population can generally tolerate this intensity of therapy and functionally benefit from this intense “burst” of therapies. These can include therapy co-treatments.
• There have been functional gains noted in patients post-nerve transplants and could be considered for inpatient rehabilitation.^9,16
• There is a likely risk of osteopenia in this patient population; be aware of risk with aggressive ROM and electrical stimulation as this could cause fracture.
• Consider use of fluoxetine for depression/anxiety due to its anti-viral properties, however, this is not officially recommended by the CDC.^2,17

Cutting Edge/ Emerging and Unique Concepts and Practice

• Early mobility programs that include activity based rehabilitative therapies including weight bearing activities, bed mobility, NMES, and transfers may be advantageous.
• NMES and functional electrical stimulation (FES) with and without muscle contraction is beneficial.
• Utilization of aquatic therapy
• Massed practice with repetition and increased level of activity is tolerated by children up to 5 hours per day.
• Vibration therapy may help activate denervated muscles.
• Nerve transfers need validated studies to guide timing for maximum benefit.
• Use of robotic therapies may be useful to obtain functional goals.

Gaps in the Evidence-Based Knowledge

• There is no specific definite cause of AFM.
• It is also unclear why some patients are affected more than others.
• Though it is considered a condition affecting the gray matter, there is some extension to white matter as well.
• Recovery is also variable.
• Difficulty in performing placebo-controlled trials.

References

1. Greenberg B. Acute Flaccid Myelitis: A Modern Day Polio? Presentation at New Frontiers in Pediatric Neurology. 31 May 2019.
2. Wang C and B Greenberg. Clinical Approach to Pediatric Transverse Myelitis, Neuromyelitis Optica Spectrum Disorder, and Acute Flaccid Myelitis. Children (Basel). 2019 May; 6(5): 70.
3. Standardized Case Definition for Acute Flaccid Myelitis. https://c.ymcdn.com/sites/www.cste.org/resource/resmgr/2017PS/2017PSFinal/17-ID-01.pdf
4. Centers for Disease Control and Prevention AFM Investigation 2019. [(accessed on 15 May 2019)]; Available online:https://www.cdc.gov/acute-flaccid-myelitis/afm-surveillance.html.
5. Fernandez-Garcia MD, Kebe O, Fall AD, Dia H, Diop OM, Delpeyroux F, Ndiaye K. Enterovirus A71 Genogroups C and E in Children with Acute Flaccid Paralysis, West Africa. Emerg Infect Dis. 2016 Apr; 22(4):753-5.
6. Centers for Disease Control and Protection. Causes and Preventions of AFM. https://www.cdc.gov/acute-flaccid-myelitis/causes-prevention.html
7. Hixon AM, Yu G, Leser JS, Yagi S, Clarke P, Chiu CY, et al. A mouse model of paralytic myelitis caused by enterovirus D68. PLoS Pathog. 2017:13.
8. Hopkins S. Acute Flaccid Myelitis: Etiologic Challenges, Diagnostic and Management Considerations. Curr Treat Options Neurol (2017) 19: 48 DOI 10.1007/s11940-017-0480-3
9. Maloney JA, Mirsky DM, Messacar K, Dominguez SR, Schreiner T, Stence NV. MRI findings in children with acute flaccid paralysis and cranial nerve dysfunction occurring during the 2014 enterovirus D68 outbreak. Am J Neuroradiol. 2015;36:245–50.
10. Sejvar JJ, Lopez AS, Cortese MM, Leshem E, Pastula DM, Miller L, et al. Acute flaccid myelitis in the United States, August-December 2014: results of nationwide surveillance. Clin Infect Dis. 2016;63:737–45.
11. Van Haren K, Ayscue P, Waubant E, Clayton A, Sheriff H, Yagi S, et al. Acute flaccid myelitis of unknown etiology in California, 2012-2015. JAMA. 2015;314:2663–71.
12. Messacar K, Schreiner TL, Van Haren K, Yang M, Glaser CA, Tyler KL, Dominguez SR. Acute flaccid myelitis: A clinical review of US cases 2012-2015.Ann Neurol. 2016;80(3):326. Epub 2016 Aug 4.
13. Van Haren K, Ayscue P, Waubant E, Clayton A, Sheriff H, Yagi S, Glenn-Finer R, Padilla T, Strober JB, Aldrovandi G, Wadford DA, Chiu CY, Xia D, Harriman K, Watt JP, Glaser CA Acute Flaccid Myelitis of Unknown Etiology in California, 2012-2015. JAMA. 2015;314(24):2663.
14. Martin JA, Messacar K, Yang ML, Maloney JA, Lindwall J, Carry T, Kenyon P, Sillau SH, Oleszek J, Tyler KL, Dominguez SR, Schreiner TL. Outcomes of Colorado children with acute flaccid myelitis at 1 year. Neurology. 2017 Jul 11; 89(2):129-137.
15. Nath RK and C Somasundaram. Functional Improvement of Upper and Lower Extremity After Decompression and Neurolysis and Nerve Transfer in a Pediatric Patient with Acute Flaccid Myelitis.” Am J Case Rep. 2019; 20: 668–673.
16. Hopkins SE, Elrick MJ, Messacar K. Acute Flaccid Myelitis-Keys to Diagnosis, Questions About Treatment, and Future Directions. JAMA Pediatr. 2018 Nov 30.
17. Messacar K et al. 1901. Tolerability, and Efficacy of Fluoxetine as an Antiviral for Enterovirus D68 Associated Acute Flaccid Myelitis: A Retrospective Multicenter Cohort Study. Open Forum Infect Dis. 2018 Nov; 5(Suppl 1): S546.
18. Centers for Disease Control. Symptoms of AFM. [Accessed 11 August 2019]; Available online: https://www.cdc.gov/acute-flaccid-myelitis/symptoms.html
19. Transverse Myelitis Association. Acute Flaccid Myelitis. [10 August 2019]; Available online: https://myelitis.org/living-with-myelitis/disease-information/afm/
20. Maloney JA et al. MRI findings in children with acute flaccid paralysis and cranial nerve dysfunction occurring during the 2014 entervorus D68 outbreak. Am J Neuroradiol. 2015;36:245-50.
21. Gordon-Lipkin E et al. Comparative quantitative clinical, neuroimaging, and functional profiles in children with acute flaccid myelitis at acute and convalescent stages of disease. Dev Med Child Neurol. 2019 Mar;61(3):366-375.
22. McCoy DB et al. MRI Atlas-Based Measurement of Spinal Cord Injury Predicts Outcome in Acute Flaccid Myelitis. AJNR Am J Neuroradiol. 2017 Feb;38(2):410-417.
23. Transverse Myelitis Association. Resource library. [Accessed on 10 August 2019]; Available online: https://myelitis.org/living-with-myelitis/resources/resource-library/
24. Kidd S, Yee E, English R, et al. National Surveillance for acute flaccid myelitis — United States, 2018–2020. MMWR Morbidity and Mortality Weekly Report. 2021;70(44):1534-1538. doi:10.15585/mmwr.mm7044a2

Original Version of the Topic

Rajashree Srinivasan, MD, MBBS, Kelli Chaviano, DO. Acute Flaccid Myelitis. 10/8/2019

Author Disclosure

Sarah Matthews, MD
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Kelli Chaviano, DO
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Rajashree Srinivasan, MD, MBBS
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