Acute Flaccid Myelitis (FL INITIAL Autonomous Practice- Differential Diagnosis)

Acute Flaccid Myelitis (AFM) is a rare, but serious, neurologic disease, affecting the gray matter of the spinal cord causing muscle weakness and, in severe cases, permanent paralysis (Council of State and Territorial Epidemiologists, 2022). More than 90% of cases of AFM have been in young children. AFM is a newly recognized condition. Therefore, clinicians must be vigilant in reporting any patient that meets the clinical criteria.

Enteroviruses, specifically EV-D68, are prospective causative agents of AFM, likely leading to the increase in cases every two years since 2014 (Center for Disease Control and Prevention [CDC], 2020). During the late summer and fall of 2014, 120 confirmed cases of AFM were reported to the CDC in the United States with a cluster of cases in Colorado, and a standardized national surveillance program was initiated in 2015. Since August 2014, 729 confirmed cases have been reported in the United States, with noted increases mostly in young children in 2014, 2016, and 2018 (CDC, 2023; Bonwitt et al., 2017; Ruggieri et al., 2017). There was no observed outbreak in 2020, presumably related to protective measures in place against COVID-19.As of July 2023, there have been 5 confirmed cases out of 23 reported patients under investigation (CDC, 2023).

The following graph and data table demonstrate the seasonal nature of the occurrence of AFM by viewing cases by month. Note the increases in the late summers of 2014, 2016, and 2018. Most patients develop AFM between August and November when enteroviruses commonly circulate.

Image 1: Confirmed AFM Cases by CDC
(CDC, 2023)

The clinical presentation of AFM, acute motor neuron weakness, is caused by dysfunction and death of the anterior horn cells. These cells are found within the gray matter of the spinal cord. The damage in the lower motor neurons leads to flaccid weakness of the innervated limb. Cases of AFM with anterior horn cell damage are recorded with many viral families including Picornaviridae, Flaviviridae, and Adenoviridae, which include poliovirus and nonpolio enteroviruses (Greenberg, 2022).

Many of the AFM cases reported in 2014 were temporally associated with outbreaks of respiratory illness attributed to enterovirus D68 (EV-D68) (CDC, 2023). With subsequent increased circulation of EV-D68 in 2016 and 2018, there were repeated national outbreaks of severe respiratory illness. Furthermore, EV-D68 was the most common virus detected in specimens from patients with AFM (CDC, 2022). Additionally, detection of antibodies against enteroviruses in the spinal fluid of AFM patients more often than those without AFM adds to several factors suggest a possible association of AFM with EV-D68 infections (CDC, 2022).  The CDC emphasizes that the cause of AFM has not been established in most cases despite extensive pathogen-specific testing. The investigation is ongoing.

The cause of most cases of AFM remains unclear. Diagnosis may be supported by medical imaging of the spine, nerve conduction studies, and cerebral spinal fluid testing. Often, despite widespread testing of AFM patients, no pathogens are found in the spinal fluid. Suspected reasons for this may be that the pathogen has been cleared by the body, the pathogen is hiding in tissues that make it difficult to detect, or the pathogen triggers an immune response in the body that causes damage to the spinal cord. What triggers AFM in some children who have had a fever and/or a respiratory illness immediately prior to symptom presentation compared to most children who do not get AFM continues to be researched.

Sudden onset of arm or leg weakness, loss of muscle tone, and loss of reflexes are the most common symptoms of AFM (CDC, 2023; CDC, 2022; CDC, 2020).It is common for a febrile or respiratory illness to be present before the onset of neurologic symptoms.The evolution of flaccid weakness may progress over hours to days (Greenberg, 2022). Patients should be instructed to seek medical attention immediately if any of these symptoms are observed.

The CDC (2022) also notes that some patients reported:

• Difficulty moving the eyes
• Drooping eyelids
• Facial droop or weakness
• Difficulty swallowing
• Slurred speech
• Pain in arms or legs
• Pain the neck of back

There have also been uncommon cases with reports of numbness or tingling in the arms or legs (10-20% of the cases) (Murphy et al., 2021). The most severe and life-threatening symptoms include respiratory failure requiring ventilator support or serious neurologic complications with body temperature changes and hemodynamic instability (CDC, 2022).

Diagnostics for AFM include brain and spinal cord MRI, nasopharyngeal swab collection for enteroviral PCR tests, CSF studies, and serum antibody testing for anti-MOG antibody and anti-AQP4 antibody (CDC, 2023). It is important that the tests are done as soon as possible after the patient develops symptoms.

Criteria for a probable case of AFM requires (CDC, 2023): 

1. Acute onset of focal limb weakness
2. Cerebrospinal fluid pleocytosis with mild to moderate elevation in white blood cell count (<100 per μL with lymphocytic predominance)

Clinical criteria for a confirmed case of AFM requires (CDC, 2023; Murphy et al., 2021):

1. Acute onset of flaccid limb weakness
2. A spinal cord lesion on MRI is largely restricted to gray matter and spans one or more spinal segments. This is demonstrated by hyperintensity of the spinal cord grey matter. This is the hallmark of AFM

The following information includes CDC requested confirmatory testing (CDC, 2023):

Case reporting, for public health tracking purposes, follows the CDC case definition of presenting illness with onset of acute flaccid limb weakness. Confirmatory evidence of MRI with spinal cord lesion largely restricted to gray matter, while supportive evidence requires a CSF with pleocytosis (Greenberg, 2022).

The CDC also requests that healthcare professionals collect and submit specimens to the CDC for testing as early as possible in the illness. These requested specimens include cerebrospinal fluid, blood, and stool (CDC, 2023). The CDC requests submission of nasal (mid-turbinate) or nasopharyngeal plus oropharyngeal swab specimens only if the patient tests positive for enterovirus or rhinovirus at an external lab (CDC, 2023). Specimens that are submitted to the CDC are not intended for clinical diagnosis. Pathogen-specific testing should be performed at a hospital or state public health laboratories (CDC, 2023).

The differential diagnosis of AFM includes infectious and noninfectious causes of acute flaccid paralysis. Other conditions that present with flaccid weakness, mimicking AFM, as well as other potential causes of acute anterior horn cell death include the following that should be considered in your differentials (Greenberg, 2022):

• Myopathic issues:
  • Inflammatory myopathy
  • Periodic paralysis
  • Rhabdomyolysis
  • Carnitine deficiency
• Neuropathic issues:
  • Guillain-Barré Syndrome
  • Multifocal motor neuropathy
  • Acute intermittent porphyria
  • Acquired motor axonal neuropathy
  • Acquired motor sensory axonal neuropathy
• Myelopathic issues:
  • Compression from spinal abscess, hemorrhage, or tumor
  • Arterial or venous spinal cord infarction
  • Postinfectious transverse myelitis
• Other disorders of neuromuscular transmission:
  • Botulism
  • Tick paralysis
  • Myasthenia gravis

An excellent resource was created by the Children’s Hospital of Philadelphia (Hopkins et al., 2022). This resource is an emergency department and inpatient clinical pathway that can be utilized with suspected AFM (Hopkins et al., 2022). This clinical pathway includes additional information to be considered when considering differential diagnoses. Because this clinical pathway is updated by The CHOP Clinical Pathways Program team regularly, the document is “living”. As a “living” document, a stagnant screenshot would do this pathway and the user a true injustice in not getting the full picture. Therefore, please feel free to take an in-depth look at this clinical pathway by directly visiting: here. 

For more information about this clinical pathway and its authors, take a look at this reference included in the list at the end of the course.

Since the cause of most AFM cases is unknown, there is no specific action to take to prevent AFM. However, most children had a respiratory illness or fever consistent with a viral infection before developing AFM. Recommendations to decrease the risk of catching or spreading viral infections include:

• Washing hands often with soap and water
• Avoiding touching the face with unwashed hands
• Avoiding close contact with people who are sick
• Staying home if you are ill
• Cleaning and disinfecting touched surfaces

Poliovirus and West Nile virus may sometimes lead to AFM. Recommendations to prevent AFM possibly associated with poliovirus include immunization for polio.Avoiding mosquito bites which can carry West Nile virus, is a recommended prevention tactics. This is done by:

• Using mosquito repellent
• Saying indoors at dusk and dawn (when bites are more common)
• Removing standing or stagnant water near your home (where mosquitoes can breed)

There is no current specific treatment for AFM, but a neurologist may recommend certain interventions on a case-by-case basis. There have been no prospective, controlled trials of specific medical therapies in AFM thus far.

Treatment aims to provide supportive care, limit damage to the spinal cord, and provide early and intensive rehabilitation (Greenberg, 2022). Hospital admission is recommended for close monitoring of symptoms and in the event of rapid deterioration. In the case of respiratory failure, respiratory support with mechanical ventilation may be required. Rehabilitation therapies are essential to maximize recovery. These techniques include electrical stimulation, functional electrical stimulation, physical therapy, and activity-based therapy.

With the thought that AFM may be from neuroinvasive enteroviral disease, intravenous immunoglobulin (IVIG) may be used in hopes that it provides some benefit. As far as dosing, a 2g/kg single dose administered over one full day with attention to total volume of fluid administered may be considered (Hopkins, et al., 2022). Second line treatment of steroids or plasma exchange are not indicated or supported by evidence in the treatment of AFM. However, neurology may evaluate on a case-by-case basis the use of steroids or plasma exchange to treat malignant spinal cord swelling (Hopkins et al., 2022).

The long-term prognosis for individuals with AFM is unknown.Persistent neurologic deficits in the majority of children affected with AFM have been reported in short-term outcome studies. It is known that more than half of children affected by AFM continue to experience motor deficit and muscle atrophy more than a year after disease onset (Greenberg, 2022). It is noted that children continue to slowly improve overtime with continued rehabilitation interventions.  However, the extent of recovery remains highly variable. Deaths associated with AFM are rare and are limited to immunocompromised adults and children with early or late complications of respiratory failure (Murphy et al., 2021).

Most patients with AFM, more than 90% of them, have had a mild respiratory illness or fever consistent with a viral infection before they developed AFM (CDC, 2023). AFM cases are not caused by poliovirus since all the stool specimens received from AFM patients tested negative for poliovirus (CDC, 2023). Viral infections such as enteroviruses are common, especially in children, and most recover. It is unknown why a small number of individuals develop AFM while most others recover. This is currently under investigation.

Most patients have had the onset of AFM occur between August and November, with increases in AFM cases every two years since 2014 (CDC, 2023). Many viruses circulate at this same time of year, including enteroviruses, and will be temporally associated with AFM. It is also essential to note and remember that most AFM cases are children (over 90%) (CDC, 2023). Clinicians must be vigilant in reporting any patient that meets the aforementioned clinical criteria.

• Bonwitt, J., Poel, A., DeBolt, C., Gonzales, E., Lopez, A., Routh, J., Rietberg, K., Linton, N., Reggin, J., Sejvar, J., Lindquist, S., & Otten, C. (2017). Acute flaccid myelitis among children - Washington, September-November 2016. MMWR Morb Mortal Wkly Rep 2017, 66:826. Visit Source.
• Centers for Disease Control and Prevention. (CDC). (2023, April 4). AFM cases and outbreaks. Centers for Disease Control and Prevention (CDC). Visit Source.
• Centers for Disease Control and Prevention. (CDC). (2022). Centers for Disease Control and Prevention (CDC). About acute flaccid myelitis. Centers for Disease Control and Prevention (CDC). Visit Source.
• Centers for Disease Control and Prevention (CDC). (2020, August 11). Acute flaccid myelitis (AFM) VitalSigns. Centers for Disease Control and Prevention (CDC). Visit Source.
• Council of State and Territorial Epidemiologists. (2022, July 1). Revision to the standardized case definition, case classification, and public health reporting for acute flaccid myelitis. National Center for Immunization and Respiratory Diseases, Division of Viral Diseases. Visit Source.
• Greenberg, B. (2022, June 28). Acute flaccid myelitis. UpToDate. Visit Source.
• Hopkins, S., Kirschen, M., Topjian, A., Tsarouhas, N., Katz, E., McGuire, J., Vossough, A., Swami, S., & Kunzelman, E. (2022, September). Emergency department and inpatient clinical pathway for evaluation of suspected acute flaccid myelitis. Last Revised: September 2022. Children’s Hospital of Philadelphia (CHOP) Clinical Pathways Program. Center for Healthcare Quality and Analytics, Children’s Hospital of Philadelphia. Visit Source.
• Murphy, O., Messacar, K., Benson, L., Bove, R., Carpenter, J., Crawford, T., Dean, J., DeBiasi, R., Desai, J., Elrick, M., Farias-Moeller, R., Gombolay, G., Greenberg, B., Harmelink, M., Hong, S., Hopkins, S., Oleszek, J., Otten, C., Sadowsky, C.,… Pardo, C. (2021). Acute flaccid myelitis: Cause, diagnosis, and management. The Lancet, 397(10271), 334-346. Visit Source.
• Nelson, GR., Bonkowsky, JL., Doll, E., Green, M., Hedlund, G., Moore, K., & Bale, J. (2016). Recognition and management of acute flaccid myelitis in children. Pediatric Neurology, 55,17-21. Visit Source.
• Ruggieri, V., Paz, MI., Peretti, MG., Rugilo, C., Bologna, R., Freire, C., Vergel, S., & Savransky, A. (2017). Enterovirus d68 infection in a cluster of children with acute flaccid myelitis. European Journal of Pediatric Neurology, 21, 884-890. Visit Source.