Acute Flaccid Myelitis –

A needle in the haystackLeslie Benson, MD

Pediatric MS and Neuro-Immunology ProgramBoston Children’s Hospital

12/3/2020

Presenter Disclosure Information

• I, Leslie Benson, have been asked to disclose any significant relationships with commercial entities that are either providing financial support for this program or whose products or services are mentioned during our presentations.

• I will discuss the use of medications in a manner not approved by the U.S. Food and Drug Administration.

2

Disclosures• Department of Public Health - AFM Consultant • CDC AFM Task Force member

• Unrelated financial disclosures:o Site PI on an Alexion clinical trial in the past year (product not

related to AFM)o Vaccine injury compensation program

• All patient pictures are used with consent

Objectives• The participants will be able to recognize common

presentations and exam findings to help identify this diagnosis.

• The participants will be able to recognize clinical and radiographic features differentiating acute flaccid myelitis from Guillain Barre syndrome and inflammatory transverse myelitis.

• The participants will understand the current data supporting an association between enterovirus D68 and acute flaccid myelitis.

Luca

Case (2014)• 3 year-old healthy boy

• Right deltoid vaccinations 2 weeks prior

• 5 days febrile URI with wheeze requiring albuterol

• Day 1o Right arm &

bilateral neck weakness

o Headache, neck pain, right arm and leg pain

• Examo Fevero Confirmed

weako Hyporeflexico Hypotonic

neck and limbs

Presentation

Messacar K. 2016.

Presentation

Messacar K. 2016.

Spectrum of Disease

Respiratory failure &

death

Clear weaknessMinor limp

Mimics

Neurological Differential Diagnosis

• Guillain Barre Syndrome (peripheral demyelinating)• Acute Transverse Myelitis

o Clinically isolated syndrome (CIS), idiopathico Multiple sclerosis (MS)o Neuromyelitis Optica (NMO)

• Ischemia/strokeo Anterior or posterior spinal artery infarcto AV fistulao AV malformationo Fibrocartilaginous embolus

• Infection o bacterial, fungal, parasitic, viral

Work Up• No diagnostic biomarker• Imaging – MRI with and without

contrast o MRI cervical, thoracic and lumbar spine

• *Include lumbar spine if AFM or Guillain Barre are on the differential!

• Axial imaging

• MRI Braino *Early imaging may be normal, consider repeat

• Labs

Case

Anterior horn/gray matter predominant lesions

Radiculitis – anterior predominant

Characteristic MRI findings of AFM

*From Maloney JA et al. Am J Neuroradiol 2015;36(2):245-50 16

Anterior horn cell predominant injury

Weakness predominates

Level(s) and side affect localization

Secondary inflammation may contribute to sensory and other deficits

Diagnostic Findings

Messacar K. 2016.

Work Up• Labs – AS EARLY AS POSSIBLE• State Lab - NP swab (PCR), serum, stool, CSF • NP/OP – EV PCR vs panel w/ EV• Serum -

o EV PCRo MOG Abo Consider Coxsackie, Echovirus, West Nile serology, HSV, EBVo Lyme o Aquaporin 4 Ab (NMO)

• CSFo Cell count, protein, glucose, Gram stain, cultureo oligoclonal bandso Consider EV PCR, broad panel testing

• Stool – EV PCR

• Others guided by differential diagnosis, season

Specimens to collect and send to CDC for testing of cases of suspected AFM

20https://www.cdc.gov/acute-flaccid-myelitis/hcp/specimen-collection.html

Case – Lab evaluation • CSF:

o 102 WBC (20% neutrophils, 64% lymphocytes and 16% monocytes )

o 21 red blood cells, o glucose 63 o protein of 32.8.

History• Fall 2012 – CA surveillance and publications• Fall 2014 – recognized as following enterovirus D68

(EV D68) respiratory illness outbreak, starting in COo Acute flaccid myelitis (AFM) =

• A type of acute flaccid paralysis• “Polio-like myelitis”

• Fall 2016 • Fall 2018

CDC Monitoring

https://www.cdc.gov/acute-flaccid-myelitis/cases-in-us.html

Social distancing and enhanced infection precautions

Definitions• CDC definitions are for reporting and epidemiologic

studyo https://www.cdc.gov/acute-flaccid-myelitis/hcp/case-definitions.html

• Clinical and research criteria are needed

AFM Pathophysiology

Post-infectious autoimmune vs

Direct viral invasion

Pathophysiology

• Epidemiology• Mice• Viral Genes• Neurons• Humans

Hixon, et al. Viruses. 2019

AFM paralleled Enterovirus D68

• AFM

• EV D68

Sejvar J, et al. 2016

*Larger proportion of AFM cases +EVD68 than controls getting NP swabs

Lab Findings

Messacar K. 2016.

4

AFM Pathophysiology• Mouse models suggests direct viral invasion

AFM Pathophysiology• 4/5 strains from 2014 →

paralyzed neonatal mice• Age dependent paralysis• Loss of motor neurons• Infectious virus, viron particles

and viral genome in spinal cords

• Immune sera protective against paralysis

Hixon, et al. PLOS Pathogens. 2017

EV68 Neuronal Transport• Like polio, EV-D68 can be transported from distal to

proximal nerveo Mouseo In vitro motor neurons

• Newer EV D68 strains (but not older) are neuro-invasive in vitro

• BUT Mice aren’t humans

Hixon et al. J Virology. 2019; Hixon, et al. PLOS Pathogens. 2017

CSF Anti-EV Antibodies

CSF Anti-EV Antibodies

Polio-like myelitis• Similar mechanism• Different virus an presentation:

o Arm predominant vs lego Case numbers

EVD68 is NOT the only culprit

Kincaid O, Lipton H. 2006.

CDC Monitoring

https://www.cdc.gov/acute-flaccid-myelitis/cases-in-us.html

?

Case – Hospital Course• 2-3 week hospitalization• Remained febrile• IVIG 2g/kg days 2 and 3• Progressive weakness – 4 limbs, neck• Respiratory decompensation day 3 requiring BiPAP,

intermediate care unit transfer• Plasma exchange with IVIG dosed after

Case – Hospital Course• Day 4

o Steroids + Pocapavir (anti-viral under a compassionate use emergency IND)

• Day 5 – started to improve

• Symptomatic/supportive managemento Gabapentin for paino NGTo Hypertension management

Treatment Approach• Acute & Chronic Rehab• Acute & Chronic supportive care• Acute anti-viral?• Acute anti-inflammatory?• IVIG?• Surgery?• New?

Treatment Approach

Messacar K. 2016.

Acute Treatment• Preliminary Mouse Data

o IVIG – GOOD o Steroids - BADo Fluoxetine – EQUIVOCALo More on the horizon

Tyler K. AAN 2017.

Acute Treatment• Preliminary Mouse Data

o IVIG – GOOD o Steroids – BAD - lethalo Fluoxetine – EQUIVOCALo More on the horizon?

Tyler K. AAN 2017.

as much and as early as possible?

Monoclonal antibody therapy

• BUT Mice aren’t humans

Case - Rehabilitation• 1 month rehabilitation

o Non-ambulatory, breathing unassisted -> walked out

• Years of outpatient therapy• Ongoing right shoulder weakness• Neck weakness requiring brace

Rehabilitation and Chronic Treatment

• Symptomatic• Supportive• Respiratory• Physical Therapy• Occupational Therapy• Speech therapy• Feeding therapy• Pool therapy• Bladder/Bowel• E-stim

Rehabiliation

E-Stim• Theory: Electrical stimulation

of the motor nerves to “exercise” the muscle while the nerves branch and reinnervate

Nerve Transfer Surgeries• Take fascicles from a strong nerve (donor) and

move to a weak nerve• Increasing publications• Promise with lots of uncertainty

Prognosis

Messacar K. 2016.

Prognosis• Joint

subluxations/dislocations• Limb length

discrepancies• Scoliosis• Contractures• Reduced protective

reflexes• Osteopenia• Fractures• Chest wall deformities• Ventilator dependence• Dysphagia• Constipation• Psychological struggles• Cosmetic concerns

Restorative surgeries• Muscle transfer• Tendon transfer• Scoliosis interventions

Prognosis- further theories

• Post Polio Syndrome?

• Early degenerative joint disease?

• Restrictive lung disease?

• Sleep disordered breathing/ hypoventilation?

What can you do?• Diagnose ->Refer• Hospitalize• Provide acute support• Report and send specimens• Be aware of acute treatment

options as evolves• Refer to centers doing research

https://www.cdc.gov/acute-flaccid-myelitis/hcp/clinicians-health-departments.html

TipsFindings Check

Fever History

Limb, back, neck pain History

Bulbar dysfunction Listen to speechHistory- swallow/cough

Cranial neuropathy Smile/cryEye tracking toy

Weakness (often proximal)

Jump, leg raise forward and backward, march, get up from floorLift arms over head

Gait/limp

Hyporeflexia CHECK REFLEXES

Flaccid tone Feel limb, resting posture

Why is Diagnosis Urgent• Avoid complications

o Unsupported respiratory decompensationo Aspiration

• Sample collection → understanding etiology• Optimize treatment response• Virus may prognosticate

Dominguez C et al. Canadian

Future Directions

• CDC AFM Task Force• National AFM Working Group• NIH “Natural History Study”• Biomarker, therapeutic and

vaccine discovery research• CSF EV-D68 Ab test• Long term follow up studies

• Collaboration!

Summary• AFM is caused by viral injury of the motor neurons

of the spinal cord similar to polio and linked to EV-D68

• A viral prodrome followed by neck or back pain, progressive weakness

• NP/OP, blood, stool and CSF labs along with MRI are indicated

• Early work up for higher yield• Cases should be reported to CDC

o https://www.cdc.gov/acute-flaccid-myelitis/hcp/index.html

• Early IVIG may help

Summary (cont)• Phone a friend –

• Page me• Visit www.cdc.gov/afm• Contact CDC AFM program at

AFMinfo@cdc.gov• Contact other AFM specialists

via the AFM Physician Consult and Support Portal: https://wearesrna.org/living-with-myelitis/resources/afm-physician-support-portal/