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Acute Flaccid Myelitis

1.5 Contact Hours including 1.5 Pharmacology Hours
This peer reviewed course is applicable for the following professions:
Advanced Practice Registered Nurse (APRN), Certified Nurse Midwife, Certified Nurse Practitioner, Certified Registered Nurse Anesthetist (CRNA), Clinical Nurse Specialist (CNS), Licensed Practical Nurse (LPN), Licensed Vocational Nurses (LVN), Midwife (MW), Nursing Student, Occupational Therapist (OT), Occupational Therapist Assistant (OTA), Physical Therapist (PT), Physical Therapist Assistant (PTA), Registered Nurse (RN), Registered Nurse Practitioner, Respiratory Therapist (RT)
This course will be updated or discontinued on or before Sunday, April 30, 2023

Nationally Accredited

CEUFast, Inc. is accredited as a provider of nursing continuing professional development by the American Nurses Credentialing Center's Commission on Accreditation. ANCC Provider number #P0274.

CEUFast, Inc. is an AOTA Provider of professional development, Course approval ID#02060. This distant learning-independent format is offered at 0.15 CEUs Intermediate,Categories: OT Service Delivery and Foundational Knowledge. AOTA does not endorse specific course content, products, or clinical procedures. AOTA provider number 9575.

FPTA Approval: CE22-810698. Accreditation of this course does not necessarily imply the FPTA supports the views of the presenter or the sponsors.
Outcomes

Acute flaccid myelitis (AFM) refers to a polio-like neurologic disease first reported in 2012 in California in a child with evidence of enterovirus D68 in the respiratory tract specimens (Van Haren et al., 2015). It affects the nervous system, specifically the area of the spinal cord called gray matter, which causes the muscles and reflexes in the body to weaken (NIH, 2018). This condition is not new. However, an increase in reported cases was observed in the late summer and fall of subsequent years, including 2014 when surveillance first started, 2016, and 2018 (McKay et al., 2018).

The risk of getting AFM varies by age and year. It mainly occurs in children and very rarely in adults. AFM cases have increased every two years since 2014, mostly in young children. Still, the Centers for Disease Control and Prevention (CDC, 2019) estimates that less than one to two in a million children in the United States will get AFM every year. AFM is not contagious from person to person but may spread to humans from mosquitoes.

Objectives

After completing this course, the participant will be able to meet the following objectives:

  1. Define Acute Flaccid Myelitis (AFM).
  2. Identify four probable causative agents underlying the development of AFM.
  3. Describe the possible pathogenesis of AFM.
  4. Identify four clinical manifestations of AFM.
  5. Describe the clinical criteria for a probable AFM case versus a confirmed AFM case.
  6. Describe three strategies to prevent the spread of AFM.
  7. Discuss the prognosis/outcome for patients experiencing AFM.
CEUFast Inc. and the course planners for this educational activity do not have any relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.
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Author:    Pamela Downey (MSN, ARNP)

Epidemiology

AFM is rare, with an estimated incidence of less than one case per one million population in the United States (CDC, 2019). During the late summer and fall of 2014, 120 confirmed cases of AFM were reported to the CDC in the United States, and standardized surveillance was established in 2015. Since 2014, nearly 400 cases have been reported in the United States (CDC, 2020a). Similar cases have been reported from Europe, Canada, and Japan (Yea, 2017). The condition predominantly affects children and young adults.

The following graph shows the seasonal nature of the occurrence of AFM. Note the increases in the late summers of 2014, 2016, and 2018.

acute_flaccid_myelitis

The graph shows the number of AFM cases confirmed by the CDC as of February 1, 2019, with onset of the condition through January 31, 2019. The case counts are subject to change.
The data shown from August 2014 to July 2015 are based on the AFM investigation case definition: onset of acute limb weakness on or after August 1, 2014, and a magnetic resonance image (MRI) showing a spinal cord lesion largely restricted to gray matter in a patient age ≤ 21 years.
The data shown from August 2015 to present are based on the AFM case definition adopted by the Council of State and Territorial Epidemiologists (CSTE): acute onset of focal limb weakness and an MRI showing spinal cord lesion largely restricted to gray matter and spanning one or more spinal segments, regardless of age.

The CDC had confirmed 538 cases of Enterovirus 68 (also known as EV68, EVD68, EV-D68, HEV68) infection in 43 states. The CDC has determined and submitted to GenBank complete or nearly complete genomic sequences for three known strains of the virus, which are "genetically related to strains of Enterovirus 68 that were detected in previous years in the United States, Europe, and Asia (CDC, 2017, p 1)."

While rates of paralytic symptoms appear to be correlated with the number of respiratory infections, in initial anecdotal reports, the cases are not clustered within a family or school, suggesting that the paralysis per se is not directly contagious but arises as a very rare complication of the common respiratory infection.

Probable Causative Agents

Until AFM is confirmed, often similar neurologic conditions are termed acute flaccid paralysis which can have multiple causations.

As of October 2018, the CDC regarded the cause of AFM or similar neurologic conditions (Table 1 below) as having "a variety of possible causes” such as (CDC, 2019):

TABLE 1 Probable Causes of AFM are in bold text. Other causes of acute flaccid paralysis are in standard text.
INFECTIONS
Poliovirus
Adenoviruses
Herpes zoster: r/o*
Rabies: r/o
Nonpolio enteroviruses:
  • Coxsackievirus A16
  • EV-D68 (also known as EV68, EVD68, EV-D68, HEV68)
  • EV-A71 (also known as EV71, EVA71)
West Nile virus (WNV) and other family members:
  • Japanese encephalitis virus
  • Saint Louis encephalitis virus
Diphtheria: r/o
SPINAL CORD DISORDERS
Acute disseminated encephalomyelitis: r/o
Transverse myelitis: r/o
Cord infarction: r/o
Cord compression: r/o
PERIPHERAL NEUROPATHY
Guillain-Barré syndrome: r/o
Mononeuritis multiplex: r/o
Acute intermittent porphyria: r/o
Toxic: r/o
DISORDERS OF NEUROMUSCULAR TRANSMISSION
Myasthenia gravis: r/o
Botulism: r/o
Tick paralysis: r/o
DISORDERS OF MUSCLE
Inflammatory myopathy: r/o
Rhabdomyolysis: r/o

*Rule out (r/o)

Much research has focused on the non-polio enteroviruses 68 and 71, members of the enterovirus D and enterovirus A species, respectively, as suspected causes.

Most patients with AFM (more than 90%) had a mild respiratory illness or fever consistent with a viral infection before AFM developed. All the stool specimens received from AFM patients tested negative for poliovirus. Most patients had the onset of AFM between August and October.

It is difficult to establish causation by the virus is like the prolonged investigations that led to the confirmation of HIV as the cause of AIDS. Enterovirus 68 was far less virulent and spread much more slowly than polio. Unlike in polio, only a few cases of paralysis were seen per thousand children infected. He also suggested that adults with respiratory diseases should be evaluated for neurologic deficits. Infectious disease should be considered a cause when patients present with neurologic symptoms.

The cause of most cases of AFM remains unclear. The underlying mechanism involves damage to the spinal cord’s grey matter (CDC, 2019). Diagnosis may be supported by medical imaging of the spine, nerve conduction studies, and cerebral spinal fluid testing.

Often, despite extensive testing of AFM patients, no pathogens are found in the spinal fluid. Three 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.
  • 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 respiratory illness compared to most children who do not get AFM is being investigated.

Pathogenesis

Many of the AFM cases reported in 2014 were temporally associated with outbreaks of respiratory illness attributed to enterovirus D68. Testing has not identified enterovirus D68 or other viral pathogens in the cerebrospinal fluid in the vast majority of cases. Several factors suggest a possible association of AFM with enterovirus D68 infections (CDC, 2020b). Enterovirus D68 was the most common virus detected in respiratory samples from children with AFM. The CDC emphasizes that the cause of AFM has not been established in most cases despite extensive pathogen-specific testing. The investigation is ongoing.

Signs and Symptoms

Characteristic clinical features of AFM are:

  • A febrile or respiratory illness before the onset of neurologic symptoms
  • A clinical presentation similar to poliomyelitis with:
    • Limb weakness
      • Sudden onset begins with arm or leg weakness along with loss of muscle tone and decreased reflexes (CDC, 2019)
    • Variable cranial nerve involvement:
      • Facial droop/weakness
      • Ophthalmoplegia (i.e., paralysis or weakness of the eye muscles) which may result in:
        • Double or blurred vision
        • An inability to position the eyes in sync
        • Difficulty with moving both eyes in every direction
        • Drooping of the eyelids
      • Dysarthria (i.e., a motor speech disorder resulting from neurological injury of the motor component of the motor-speech system) may be characterized by:
        • Difficulty speaking
        • Slurred speech
      • Dysphagia (i.e., difficulty with swallowing)
    • MRI evidence of gray matter involvement in the spinal cord. The combination of hypotonic weakness and radiographic or electrophysiologic evidence of anterior horn cell involvement is the most specific finding in AFM.
  • Numbness or tingling is rare in people with AFM, although some individuals have pain in their arms or legs (CDC, 2019)
  • Some individuals with AFM may be unable to urinate
  • The most severe symptom of AFM is respiratory failure that occurs due to the weakness of the respiratory muscles. This can require urgent ventilator support (CDC, 2019)

The nature of AFM in the United States is illustrated by the following observations:

  • In 2012, the first cases of a polio-like illness of unknown etiology were reported in California (Van Haren et al., 2015)
    • In a summary of 59 cases from California identified through July 2015, the median age at onset was nine years. However, nine patients were older than 21 years
      • Common preceding or concurrent symptoms included respiratory or gastrointestinal illness, fever, and limb myalgia
      • At the onset of neurologic symptoms, fever, limb myalgia, headache, and neck stiffness were often present alone or in combination, and a minority experienced mental status changes
      • Weakness progressed rapidly, most often reaching maximum severity over a few hours to a few days
      • At disease nadir, the severity of neurologic impairments ranged from weakness in one limb (n = 5) to quadriparesis (n = 29)
      • Upper limb weakness was most common (n = 43)
      • Additional manifestations included:
        • Respiratory failure requiring mechanical ventilation (n = 20)
        • Cranial nerve palsies (n = 16)
        • Neurogenic bowel or bladder (n = 30)
        • Focal paresthesia (n = 21)
        • MRI of the spinal cord typically showed increased signal on T2-weighted sequences involving the central gray matter, particularly the anterior horns. The spinal cord lesions were longitudinally extensive (i.e., > 3 vertebral segments)
        • The cerebrospinal fluid analysis revealed pleocytosis (i.e., increased WBC count in the CSF) in 43 of 58 patients, with a median white count of 41 cells/microL. No viruses were isolated from the cerebrospinal fluid
        • Nonpolio enteroviruses were detected in other samples (i.e., nasopharynx swab, stool, or serum) in 15 of 45 patients, including enterovirus D68 in nine patients
        • Most patients were treated with intravenous glucocorticoids, intravenous immune globulin, or plasma exchange. Still, acute improvement with such treatment was rare
        • Two immunocompromised adult patients died within 60 days of symptom onset
        • Among 45 patients with follow-up data (median nine months), persistent weakness was noted in 38 (84%). In comparison, complete motor recovery was observed in only seven patients (16%)
  • Similar cases of children with acute limb weakness and abnormalities of spinal cord gray matter on MRI were reported from other regions of the United States (e.g., Colorado, Massachusetts, and Washington) (Bonwitt et al., 2016)
  • In a study of 12 children from Colorado with AFM:
    • The median age was 11.5 years
      • All had a preceding febrile illness followed at a median of seven days by the onset of neurologic symptoms
      • Flaccid limb weakness, mainly proximal, developed in 10 children and was asymmetric in 7
    • Additional deficits involved:
      • Bulbar weakness (n = 6)
      • Cranial nerve 6 dysfunction (n = 3)
      • Cranial nerve 7 dysfunction (n = 2)
    • MRI revealed extensive spinal cord lesions of the central gray matter with predominant anterior horn cell involvement in 10 children
      • These lesions spanned a median of 17 vertebral segments (range 4 to 20)
      • In nine children, brainstem lesions were present, mainly involving the dorsal pontine tegmentum
    • Cerebrospinal fluid pleocytosis (median 55 cells/microL) was observed in 10 children
    • Nasopharyngeal specimens were positive for rhinovirus or enterovirus in 8 of 11 children and were positive for enterovirus D68 in 5 of 11 children
    • Polymerase chain reaction (PCR) testing for enterovirus of cerebrospinal fluid, blood, and rectal swabs was negative
    • Testing for poliovirus, West Nile virus and other arboviruses was also negative
    • All children presented with limb weakness had an incomplete recovery with persistent motor deficits

Diagnoses

Criteria for a probable case of AFM (in patients without MRI) require:

  • Acute onset of focal limb weakness
  • Cerebrospinal fluid pleocytosis (i.e., a white count > 5 cells/microL after adjustment by subtraction of 1 white cell for every 500 red cells)

Clinical criteria for a confirmed case of AFM require:

  • Acute onset of flaccid limb weakness
  • A spinal cord lesion on MRI is largely restricted to gray matter and spans one or more spinal segments

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

Evaluation of the Patient with Acute Flaccid Paralysis

Health History

Important factors to be taken in the health history include (UpToDate, 2020):

  • Time of onset, duration, and associated symptoms. Is the complaint chronic or acute?
    • It is important to understand the complaint thoroughly and understand its time course.
    • Most children reported a febrile respiratory illness in the two weeks preceding the development of neurologic symptoms.
  • Age, gender, and occupation of the patient:
    • Handedness (right- or left-handed).
      • Handedness is important in establishing the brain area important for language because almost all right-handed people have a left hemisphere responsible for language.
  • Past medical history.
  • Drug history.
  • Family and social history.

Physical Examination

A comprehensive neurological examination should be performed preferably by a neurologist to assess focal limb weakness, poor muscle tone, and decreased reflexes. None of the children experienced altered mental status or seizures.

CATEGORYTESTSEXAMPLE
Mental Status Examination
  • The assessment of consciousness, often using the Glasgow Coma Scale (GCS).
  • Global assessment of higher functions.
  • Intracranial pressure is roughly estimated by fundoscopy. This also enables assessment for microvascular disease.
"A&O x 3, short and long-term memory intact"
Cranial Nerve Examination
  • Cranial nerves (I-XII):
    • sense of smell (I)
    • visual fields and acuity (II)
    • eye movements (III, IV, VI) and pupils (III, sympathetic and parasympathetic)
    • sensory function of face (V)
    • strength of facial (VII) and shoulder girdle muscles (XI)
    • hearing (VII, VIII)
    • taste (VII, IX, X)
    • pharyngeal movement and reflex (IX, X)
    • tongue movements (XII).
These are tested by their individual purposes (e.g., visual acuity can be tested by a Snellen chart).		"CNI-XII grossly intact"
Motor System
  • Muscle strength, often graded on the Medical Research Council (MRC) scale 0 to 5 (i.e., 0 = Complete Paralysis to 5 = Normal Power).
  • Grades 4−, 4 and 4+ may be used to indicate movement against slight, moderate and strong resistance respectively.
  • Muscle tone and signs of rigidity.
  • Examination of posture:
    • Decerebrate
    • Decorticate
    • Hemiparetic
  • Resting tremors
  • Abnormal movements:
    • Seizure
    • Fasciculations
    • Tone
      • Spasticity:
        • Pronator drift
    • Rigidity:
      • Cogwheeling (abnormal tone suggestive of Parkinson's disease)
      • Gegenhalten – is resistance to passive change, where the strength of antagonist muscles increases with increasing examiner force. More common in dementia.
"Strength 5/5 throughout, tone WNL"
Deep Tendon Reflexes
  • Reflexes: masseter, biceps and triceps tendon, knee tendon, ankle jerk and plantar (i.e., Babinski sign).
  • Globally, brisk reflexes suggest an abnormality of the Upper Motor Neuron (UMN) or pyramidal tract, while decreased reflexes suggest abnormality in the anterior horn, lower motor neuron (LMN), nerve or motor end plate. A reflex hammer is used for this testing.
"2+ symmetric, downgoing plantar reflex"
Sensation
  • Sensory system testing involves provoking sensations of fine touch, pain and temperature. Fine touch can be evaluated with a monofilament test, touching various dermatomes with a nylon monofilament to detect any subjective absence of touch perception.
  • Sensory:
    • Light touch
    • Pain
    • Temperature
    • Vibration
    • Position sense
    • Graphesthesia
      • Stereognosis and Two-point discrimination (for discriminative sense)
  • Extinction
  • Romberg test :
    • 2 out of the following 3 must be intact to maintain balance:
      • vision
      • vestibulocochlear system
      • epicritic sensation
"Intact to sharp and dull throughout"
Cerebellum
  • Cerebellar testing
    • Dysmetria:
      • Finger-to-nose test
      • Ankle-over-tibia test
    • Dysdiadochokinesis:
      • Rapid pronation-supination
    • Ataxia:
      • Assessment of gait
    • Nystagmus
    • Intention tremor
    • Staccato speech
"Intact finger-to-nose, gait WNL"

The neurologic examination results are taken together to anatomically identify the lesion. This may be diffuse (e.g., neuromuscular diseases, encephalopathy) or highly specific (e.g., abnormal sensation in one dermatome due to compression of a specific spinal nerve by a tumor deposit).

General principles include (Nelson et al., 2016):

  • Looking for side to side symmetry: one side of the body serves as a control for the other. Determine if there is focal asymmetry.
  • Determining whether the process involves the peripheral nervous system (PNS), central nervous system (CNS), or both. Considering if the finding (or findings) can be explained by a single lesion or whether it requires a multifocal process.
  • Establishing the lesion's location. If the process involves the CNS, clarifying if it is cortical, subcortical, or multifocal. If subcortical, clarify whether it is white matter, basal ganglia, brainstem, or spinal cord. If the process involves the PNS, then determining whether it localizes to the nerve root, plexus, peripheral nerve, neuromuscular junction, muscle, or multifocal.

A differential diagnosis may then be constructed that considers the patient's past health history and present findings to include the most likely causes. Examinations are aimed at ruling out the most clinically significant causes.

Laboratory/Diagnostic Tests

It is important that the tests are done as soon as possible after the patient develops symptoms.

Blood testing may include:

  • Sedimentation rate
  • Autoimmune serology for vasculitis
  • Lyme titers
  • HIV-1 titers
  • HTLV-1 titers (Human T-cell lymphotropic virus type 1)
  • CK level (Creatine kinase)

Other laboratory tests may include:

  • Stool samples for polio and nonpolio enteroviruses
  • Nasopharyngeal and oropharyngeal swabs for polio and nonpolio enteroviruses
  • Respiratory tract culture and toxin testing for diphtheria
  • Toxin testing in serum, stool, and wounds for botulism
  • Urinary porphobilinogen for porphyria
  • Acetylcholine receptor antibodies for myasthenia gravis
  • Cerebrospinal fluid analysis, including genetic amplification for polio and non-polio enteroviruses, West Nile virus, varicella-zoster virus, and rabies as indicated.
    • In most cases, CSF analyses demonstrated mild-moderate pleocytosis (increased cell count in the CSF) consistent with an inflammatory or infectious process.

Diagnostic tests may include:

  • Electrodiagnostic testing (electromyography, nerve conduction studies, and repetitive stimulation studies)
  • MRI of the spine
    • An MRI of the spinal cord shows nonenhancing lesions largely restricted to the grey matter. In most cases, these lesions spanned more than one level of the spinal cord. Some also had acute cranial nerve dysfunction with correlating nonenhancing brainstem lesions on MRI. None had any cortical, subcortical, basal ganglia, or thalamic lesions on MRI.

acute_flaccid_myelitis_2

Magnetic resonance imaging of the spinal cord in a case of AFM showing cord swelling in (d) which has resolved three weeks later in (e).

  • MRI of the brain if bulbar involvement
  • Nerve and muscle biopsy if mononeuritis multiplex and/or vasculitis is suspected

Diagnosis of AFM requires acute onset limb paralysis and at least one gray-matter spinal-cord lesion. CSF should show pleocytosis.

Differential Diagnoses

  • Viruses
    • Poliovirus
      • Polioviruses are part of the human enterovirus species C group.
      • Poliovirus is transmitted by fecal-hand-oral contamination. During epidemics, it also may be transmitted by pharyngeal spread. Entry is via the oral route, during which the virus infects cells of the mouth, nose, and throat.
    • Non-polio enteroviruses:
      • Coxsackievirus A16
      • Enterovirus 68 (also known as EV68, EVD68, EV-D68, HEV68)
      • Enterovirus 71 (also known as EV71, EVA71)
    • Adenoviruses
    • West Nile virus (WNV) and viruses in the same family as WNV, specifically:
      • Japanese encephalitis virus
      • Saint Louis encephalitis virus
  • Rule out (r/o) all other causes of acute flaccid paralysis (see Table 1 above)

Prevention

Since the cause of most of these AFM cases or what triggers AFM 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

To prevent infections in general:

  • Should stay home if they are ill
  • Cover coughs and sneezes with a tissue or upper shirt sleeve, not hands
  • Frequently washing hands with soap and water
  • Avoid close contact (such as touching and shaking hands) with those who are ill
  • Clean and disinfect frequently touched surfaces, including toys and doorknobs

Poliovirus and West Nile virus may sometimes lead to AFM. Recommendations include:

Adults and children should receive the polio vaccination

Avoiding mosquitoes bites which can carry West Nile virus, by:

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

Treatment

There is no specific treatment for AFM, but a neurologist may recommend certain interventions on a case-by-case basis. Treatment primarily involves:

  • Supportive care
  • Physical or occupational therapy may be recommended to help with arm or leg weakness
  • Occasionally mechanical ventilation is required to support breathing

Summary of Specific Interventions/Therapies

Since the recognition of AFM in 2014, the CDC has received numerous requests from clinicians and public health officials for guidance on managing and treating patients with this condition. In October 2014, the CDC consulted subject matter experts from various disciplines to assist the CDC in developing considerations for managing children with AFM. These experts were from 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. The CDC updated this information following consultation with national experts and reviewing the peer-reviewed, published literature. There remains 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 Interim Considerations of Clinical Management of AFM

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

  • 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 (Hixon, 2017).
  • Theoretically, there exists 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.
  • The use of corticosteroids has been associated with poorer outcomes in observational studies of outbreaks of neuroinvasive disease due to enterovirus-71 (EV-71) internationally and in mouse models.
    • This observation following an outbreak in Cambodia led to a WHO-convened joint commission that corticosteroids were contraindicated in the management of EV-71 associated neuroinvasive disease.
    • This is relevant, as an increase in EV-A71 associated neurologic disease was reported in the United States.
  • 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 than infected controls. Individual dexamethasone-treated mice that died had worse paralysis associated with their motor impairment score than in an infected control.
  • There may be a 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 white matter involvement. It is unclear whether these different patterns are important relative to therapeutic considerations.
  • 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 AFM treatment.
  • There is no clear human evidence for the 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 using 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)

  • IVIG has been utilized for neurologic complications associated with neurologic involvement in enteroviral disease.
    • Enteroviruses cause chronic, severe CNS infections in agammaglobulinemic children, suggesting humoral immunity plays an important role in attenuating enteroviral infection (Hurst, 2018).
    • Similarly, infants who fail to acquire neutralizing antibodies from their mothers have been described as having the more severe disease when infected with enteroviruses.
  • 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.
  • For IVIG to modify disease in an active viral infectious process, early administration is likely required, and if possible, before exposure.
    • Pre-poliovirus vaccine era trials in the 1950s demonstrated the potential efficacy of gamma globulin to prevent poliomyelitis with mass gamma globulin administration to susceptible populations in an outbreak situation.
    • 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 the development of weakness) did not impact the development or severity of paralysis during a poliovirus outbreak in New York City in 1944.
  • 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 preventing progression to neuroinvasive disease in rodent models (Hurst, 2017). Paralysis in mice was prevented in a time-dependent fashion after administration of IVIG from the time of infection.
    • IVIG's clear efficacy has not been demonstrated in humans with WNV associated paralysis, with most data limited to case reports or small case series.
  • IVIG has been utilized for patients presenting with symptoms of AFM. Still, 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 deficits persisted in all except one patient.
    • Messacar et al. (2018) reported on a review of clinical cases from 2012 – 2015. All reviewed cohorts received various combinations of IVIG, steroids, plasma exchange, and antiviral medications. No significant improvement or deterioration was noted with these therapies. Still, a systematic response assessment was not feasible with the retrospective review.
  • IVIG is generally safe and well-tolerated, though expensive.
    • IVIG's common intra-infusion adverse effects include fever, headache, myalgia, chills, nausea, and vomiting, which are typically infusion rate-dependent (Ruggieri et al., 2017).
    • 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 (Messacar et al., 2018).
    • IVIG is occasionally associated with severe adverse events such as acute renal failure, thromboembolic events, hemolytic anemia, and neutropenia.
  • IVIG preparations have been shown to contain antibodies to circulating enteroviruses, including EV-D68.

Summary:

  • There is no indication that IVIG should be either preferred or avoided in AFM treatment.
  • There is no clear human evidence for the efficacy of IVIG in the treatment of AFM. Evidence for efficacy is based on early treatment in animal models. It has not been given systematically to AFM patients to allow efficacy measurements.
  • There is no evidence that treatment with IVIG is likely to be harmful.

Plasma Exchange (PLEX)

  • It is presumed that there are beneficial effects from the innate humoral immune response to an acute viral infection. The body produces neutralizing antibodies to the infectious pathogen. Removal of these antibodies induced in response to acute infection could cause potential harm.
    • Additionally, plasmapheresis requires the placement of invasive intravenous access and procedure-associated risks.
  • Plasmapheresis has been used in published case series of AFM patients.
    • From a case series in Argentina, 4 children were given PLEX combined with IVIG and steroids. Treatment did not lead to clinical improvement.
    • Nelson et al. also used PLEX in combination with steroids and IVIG.
    • 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.
    • No data were 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 AFM treatment.
  • There is no clear human evidence for the efficacy of plasma exchange in AFM treatment. It has not been given systematically to AFM patients to allow for efficacy measurements.
  • Although there are inherent procedure-associated risks, there is no evidence that using plasma exchange for patients with AFM is harmful.

Fluoxetine

  • 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.
  • 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 than controls.
  • In comparing 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. The patients treated with fluoxetine were more likely to have severe paralysis and EV-D68 isolated from respiratory specimens.

Summary:

  • There is no indication that fluoxetine should be used for AFM treatment.
  • There is no clear human evidence for the 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

  • 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 most AFM patients has yet to be identified.
  • Any guidance regarding antiviral medications should be interpreted with great caution, given the unknowns about the pathogenesis of this illness at present. Heath departments, the CDC, and other academic entities are trying to identify all causative agents for AFM, which will help provide further guidance regarding the use of anti-microbial therapies for this illness.
  • Testing has been conducted at the CDC for antiviral activity of compounds pleconaril, pocapavir, and vapendavir. None have significant activity against currently circulating strains of EV-D68 at clinically relevant concentrations.

Summary:

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

Interferon

  • 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.
    • However, subsequent non-controlled assessments failed to replicate this improvement in cases of Saint Louis encephalitis and West Nile Virus.
  • A randomized trial 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. Twenty (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.
  • Although there are limited in vitro, animal, and anecdotal human data suggesting the 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 to treat AFM.
  • Concern exists 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

  • In AFM, biologic modifiers may harm patients, presuming infectious etiology. The combination of immunosuppressive agents directly impairs T-cell function (and B-cell function indirectly), or therapy directed against primary humoral immunity (e.g., rituximab) may further worsen the infection's ability to clear.

Summary:

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

Although evidence is limited to clinical experience, immunomodulatory therapies or interventions used to treat AFM have shown no effectiveness, including glucocorticoids, intravenous immune globulin, plasma exchange, interferon, antivirals, or other immunomodulatory agents (Van Haren et al., 2015) Thus, management is supportive.

Prognosis/Outcome

The long-term prognosis for individuals with AFM is unknown.,

Approximately 20 to 35% of patients have respiratory failure requiring ventilatory support due to respiratory muscle and/or bulbar muscle weakness, including some with prolonged ventilator dependence. Neurologic recovery is variable and often incomplete. Most children have persistent motor deficits and significant muscle atrophy in the affected limbs a year or more after disease onset.

Outcomes are variable. Studies from 2014 to 2017 indicated a poor outcome for many cases. Few had a full recovery in 7 of 61 cases with EVD68 detected and eight long-term follow-ups (NIH, 2018). Two deaths were described in severely immunocompromised people (one with EVD68 and one with both EVD68 and coxsackievirus A16 detected).

Six of 10 children in Denver were sent home for outpatient treatment. Some children with mild symptoms have recovered from temporary limb weakness. At the same time, the fate of those more severely affected remains unclear. Intensive physical therapy and occupational therapy may be beneficial for recovery.

Case Study

Scenario/Situation/Patient Description

Mr. Williams runs into the Emergency Room triage area on August 5, 2019, at 0700, carrying his 9-year-old daughter, Emily, in his arms. He states she cannot speak clearly and cannot lift her right arm. The previous evening, she played with his other two children (2 and 5-year-olds) after finishing her homework. She had taken a shower, kissed everyone goodnight, and went off to bed. Upon waking her up to school, he had difficulty understanding her and noticed that her right arm just hung down by her side.

Emily lives with her biological parents and two younger siblings in a one-story house. Both parents and siblings are in good health. Emily is an elementary school student in third grade at Wilber elementary school and is right-handed. Past medical history is remarkable for only “colds” and “ear infections” when she was five. She has no surgical history.

Emily had a “chest cold” with fever seven days ago. Still, she recovered after three days with children’s Tylenol given every 4-6 hours when her temperature went above 100? F. Otherwise, she is on no medications.

Interventions/Strategies

The registered nurse immediately brought Emily and her father into the back of the Emergency Department and notified the emergency room physician of Emily’s symptoms. A cardiac monitor and O2 saturation monitor were attached to Emily. Emily’s vital signs were taken with initial readings of: 99.7, 110, 24. O2 sat obtained was 97%. IV access was obtained with blood drawn and 0.9 Normal Saline hung at 40 cc/hr.

Emergency physician obtained an initial neurologic examination:

  • GCS was 15. A&O x 3, short and long-term memory intact.
  • No facial droop or weakness. No ophthalmoplegia. No dysphagia.
  • Dysarthria is present, manifested by slurred speech and frustration when talking.
  • Posture normal.
  • Muscle strength 5/5 throughout except for right upper extremity: 0/5.
  • No resting tremors, fasciculations, or seizure activity was noted.
  • 2+ symmetric reflexes except for 0 in biceps and triceps reflex in the right upper extremity, downgoing plantar reflex bilaterally.
  • Unable to test sensation due to child’s distress.
  • Cerebellar testing is deferred at present.
  • Cardiac, Respiratory, GI/GU systems: all WNL.
  • MRI of the brain and spinal cord ordered stat.

Discussion of Outcomes

Emily was transferred by a children’s EMS team to a University Children’s Hospital for further evaluation by a pediatric neurologist. The report was called by both the physician and nurse to University Children’s Hospital with accompanying notes faxed. The stat brain and spinal cord MRI are pending. They will be faxed to the University Children’s Hospital upon receipt in the Emergency Department.

Strengths and Weaknesses

The Childs health history and physical assessment were performed quickly with appropriate orders written. Transfer to an appropriate level of care at a University Children's Hospital arranged and accomplished safely.

Summary

  • Most of the patients with AFM (more than 90%) had a mild respiratory illness or fever consistent with a viral infection before they developed AFM.
    • 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.
  • AFM cases are not caused by poliovirus since all the stool specimens received from AFM patients tested negative for poliovirus.
  • Coxsackievirus A16, EV-A71, and EV-D68 were detected in the spinal fluid of four of 537 confirmed cases of AFM since 2014, which points to the cause of their AFM. No pathogen has been detected in their spinal fluid to confirm a cause for all other patients.
  • Most patients had the onset of AFM between August and October, with increases in AFM cases every two years since 2014. Many viruses circulate at this same time of year, including enteroviruses, and will be temporally associated with AFM.
  • Most AFM cases are children (over 90%) and have occurred in 48 states and DC.

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References and Resources

  • Bonwitt J, Poel A, DeBolt C, et al. Acute Flaccid Myelitis Among Children - Washington, September-November 2016. MMWR Morb Mortal Wkly Rep 2017; 66:826.
  • CDC (2019) Centers for Disease Control and Prevention (CDC). About Acute Flaccid Myelitis. Retrieved 02-10-2019.
  • CDC (2020a) Transcript for CDC Telebriefing: Update on Acute Flaccid Myelitis (AFM) in the US. l Accessed on March 3, 2020. Visit Source.
  • CDC (2020b) AFM in the United States. Accessed on March 3, 2020. Visit Source.
  • CDC (2017) Centers for Disease Control and Prevention (CDC). Enterovirus D68 in the United States, 2014. 2014-10-24. Archived from the original on 2017-09-08. March 3, 2020.
  • 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.
  • 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.
  • McKay SL, Lee AD, Lopez AS, et al. Increase in Acute Flaccid Myelitis - United States, 2018. MMWR Morb Mortal Wkly Rep 2018; 67:1273.
  • Messacar K, Hopkins S, et al. Safety, Tolerability, and Efficacy of Fluoxetine as an Anti-viral for Acute Flaccid Myelitis. Neurology. 2018; November 9.
  • Nelson GR, Bonkowsky JL, Doll E, et al. Recognition and Management of Acute Flaccid Myelitis in Children. Pediatric neurology. 2016; 55:17-21.
  • 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 pediatric neurology: EJPN: Official Journal of the European Pediatric Neurology Society. 2017; 21:884-890.
  • "UpToDate". www.uptodate.com. Retrieved March 3, 2020.
  • Van Haren K, Ayscue P, Waubant E, et al. Acute Flaccid Myelitis of Unknown Etiology in California, 2012-2015. JAMA 2015; 314:2663.
  • Yea C, Bitnun A, Robinson J, et al. Longitudinal Outcomes in the 2014 Acute Flaccid Paralysis Cluster in Canada. J Child Neurol 2017; 32:301.