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Acute Flaccid Myelitis

1.50 Contact Hours
BOC
To earn of certificate of completion you have one of two options:
  1. Take test and pass with a score of at least 80%
  2. Reflect on practice impact by completing self-reflection, self-assessment and course evaluation.
    (NOTE: Some approval agencies and organizations require you to take a test and self reflection is NOT an option.)
Author:    Pamela Downey (MSN, ARNP)

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.1 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.2,3 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 2018.4,5

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) estimates that less than one to two in a million children in the United States will get AFM every year. AFM is not contagious 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 case of AFM verses a confirmed case of AFM.
  6. Describe three strategies to prevent the spread of AFM.
  7. Discuss the prognosis/outcome for patients experiencing AFM.

Epidemiology

AFM is rare, with an estimated incidence of less than one case per one million population in the United States.6 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.4,7 Similar cases have been reported from Europe, Canada, and Japan.8-14 The condition predominantly affects children and young adults.1,15

The following graph shows the seasonal nature of the occurrence of AFM. Note the increases that occurred 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."16,17

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.18

History

Acute flaccid myelitis is not a new condition, but the incidence has spiked in recent years.

In 2013 a group in Texas reported having observed a pattern of one to four cases per year with similar polio-like characteristics.18

In 2014 the CDC Morbidity and Mortality Weekly Report19 and a CDC Clinician Outreach and Communication Activity (COCA) conference call,20 noted that many cases had neck, back, or extremity pain, but otherwise those affected generally had normal sensation in their limbs.21 A few participants in the conference call discussed whether pain, later abating, might precede the onset of paralysis.20,22

  • An October 2014 report described outbreaks in California and Colorado, suggesting that the number of cases might be 100 or more nationwide.23 Diagnosis included a detailed medical history, MRI imaging, and the elimination of transverse myelitis or Guillain–Barré syndrome as potential causes. Physicians were using an online mailing list to communicate about similar cases in Alabama and Kansas. The largest known cluster of cases was in Colorado, with 29 total, 12 of which were reported since August 2014.23
  • Three out of four cases treated in Alabama in 2014 involved a complete inability to move one arm, reminiscent of peripheral nerve injury:
    • The three cases since August resembled each other. They had severe arm flaccidity and no mental status changes. All of them had similar spine MRIs showing gray matter involvement. If all three MRIs were laid on top of each other, they would look almost the same. On physical examination, if the arm was lifted up, it literally dropped. The sensation was usually intact. There might have been slightly decreased sensation in the opposite arm, but since these were younger kids, they were not always so cooperative in giving a good sensory exam.23
  • Children's Mercy Hospital in Kansas City Missouri, which had three or four cases in 2014, reported that the MRI images and symptoms closely mimicked polio. They reported: "The sudden onset of flaccid paralysis in single or multiple limbs with absolutely no sensory findings, the MRIs all showing uniformly a signal increase in the ventral horns of the spinal cord - this is exactly the same region of the spinal cord affected in polio. Almost all of the patients have an increase in their white blood cells in the cerebrospinal fluid (CSF). Some of the patients have brainstem findings and cranial-nerve findings."23
  • Of 64 patients meeting the CDC criteria before October 29, 2014, 80% had had a preceding respiratory illness, and 75% reported fever in the days leading up to limb weakness, the onset of which was generally abrupt.24 By November 20, the number of confirmed cases stood at 88 from 29 states.25

The CDC requested that physicians provide information about cases meeting the following criteria:23,26

  • Patients diagnosed after August 1, 2014
  • Patients who are no older than 21 years of age
  • Patients showing acute onset of focal limb weakness
  • Patients with a spinal cord lesion largely restricted to grey matter visualized by MRI.

In November 2018, the CDC reported that they were investigating 286 cases, with at least 116 confirmed cases in 31 states.27 The CDC is setting up a task force to investigate the causes and to find treatments.28

AFM Cases in the United States

It is important to remember the following:

  • Due to a decline in reports of patients under investigation (PUIs) for AFM, the CDC will be updating the case counts bi-weekly starting January 21, 2019.
  • The case counts represent only those cases for which information has been sent to and confirmed by the CDC.
  • It is currently difficult to interpret trends of the AFM data. Collecting information about PUIs for AFM is relatively new. There may initially be more variability in the AFM data from year to year making it difficult to interpret or compare case counts between years.

Confirmed Cases:

  • So far in 2019, there have been 7 reports of PUIs, one of which has been confirmed (from North Carolina).
  • In 2018, the CDC received information for 210 confirmed cases of AFM in 40 states across the U.S.
  • These 210 confirmed cases are among the total of 367 reports of PUIs. CDC and state and local health departments are still investigating some of the PUIs.
  • In 2017, the CDC received information for 35 confirmed cases of AFM in 16 states across the U.S.
  • In 2016, the CDC received information for 149 confirmed cases of AFM in 39 states and DC.
  • In 2015, the CDC received information for 22 confirmed cases of AFM in 17 states.
  • From August to December 2014, the CDC received information for 120 confirmed cases of AFM in 34 states.

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:2

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. As of 2018, the exact cause of AFM is not widely agreed upon.26,29-31

Since 2014, 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, with increases in AFM cases every two years since 2014. At this same time of year, many viruses commonly circulate, including enteroviruses, and will be temporally associated with AFM.

A 2014 MMWR report noted the difficulty of establishing causation by the virus.19 Avindra Nath, clinical director of the National Institute of Neurological Disorders and Stroke and president of the International Society for NeuroVirology, compared the situation to the prolonged investigations that led to the confirmation of HIV as the cause of AIDS. In response to the suggestion that the enterovirus might be taking over the role of polio, Nath said that enterovirus 68 was far less virulent and spread much more slowly than polio, and that, unlike in polio, only a few cases of paralysis were seen per thousand children infected. He also suggested that adults with respiratory diseases should also be evaluated for neurologic deficits and that infectious disease should be considered as a cause when patients presented with neurologic symptoms.32

A subsequent report described 29 cases of enterovirus D68-associated AFM in Europe in 2016, noting that "these probably represent only the tip of the iceberg."14

As of 2018, the cause of most cases of AFM remains unclear.33 More than 90% of recent cases have followed a mild viral infection such as from enteroviruses.33 While polio can cause AFM, since 2014, it has not been involved in cases in the United States.2,34 The underlying mechanism involves damage to the spinal cord’s grey matter.2 Diagnosis may be supported by medical imaging of the spine, nerve conduction studies, and cerebral spinal fluid testing.2,3

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. For all other patients, no pathogen has been detected in their spinal fluid to confirm a cause. When a pathogen is found in the spinal fluid, it is good evidence that it was the cause of a patient’s illness.

Oftentimes, however, 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 currently 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.35 Several factors suggest a possible association of AFM with enterovirus D68 infections:36,37

  • Enterovirus D68 was the most common virus detected in respiratory samples from children with AFM.
  • AFM cases clustered during periods of enterovirus D68 circulation from 2014 to 2016 and were more sporadic when enterovirus D68 was not circulating in 2015.
  • Enterovirus D68 was detected in the blood of one child with AFM.
  • Metagenomic next-generation sequencing of cerebrospinal fluid from 14 children with AFM did not find evidence of an alternative infectious cause.
  • Experimentally, contemporary enterovirus D68 strains cause paralytic myelitis in a mouse model.38
  • The CDC emphasizes that the cause of AFM has not been established in the majority of cases despite extensive pathogen-specific testing. The investigation is ongoing.39

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 which begins with arm or leg weakness40 along with loss of muscle tone and decreased reflexes2
    • 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) which 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 are the most specific findings in AFM.15
  • Numbness or tingling is rare in people with AFM, although some individuals have pain in their arms or legs.2
  • 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.2

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.1,41,42
    • In a summary of 59 cases from California identified through July 2015, the median age at onset was nine years, though nine patients were older than 21 years.1
      • 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 the course of 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. In most cases, 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, but 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%), while 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).43-46
  • 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.44
      • 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 longitudinally 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).
      • Brainstem lesions were present in nine children, 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 who 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 largely restricted to gray matter and spanning one or more spinal segments.39

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 course of the illness, to include 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:47,48

  • Time of onset, duration and associated symptoms. Is the complaint chronic or acute?
    • It is important to gain an idea of 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 area of the brain important for language because almost all right-handed people have a left hemisphere, which is 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.

CATEGORY TESTS EXAMPLE
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 549 (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 results of the neurologic examination 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:50

  • 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 whether it is multifocal.

A differential diagnosis may then be constructed that takes into account 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.51

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.40 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, the CDC recommends that individuals:19

  • 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:3
    • 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:2,3

  • 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 how to manage and treat patients with this condition. In October 2014, the CDC consulted subject matter experts from a range of disciplines to assist the CDC in developing considerations for management of children with AFM. These experts were from the fields of infectious diseases, neurology, pediatrics, critical care medicine, public health epidemiology, and virology. The opinions from these individual consultations formed the basis of the “Interim Considerations for Clinical Management of AFM” document drafted in 2014.52 The CDC updated this information following consultation with national experts and review of the peer-reviewed, published literature. There continues to remain a paucity of published evidence for treatment of AFM, limited to case reports and case-series of patients with AFM. Consultation with experts treating AFM patients remains essential. The clinical considerations below reflect the observations and input from individual experts and a review of available scientific literature. The clinical considerations do not represent consensus recommendations or official guidelines. Rather, they summarize these experts’ approaches to clinical treatment of AFM.

Summary of 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.53-56
  • 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 outcome in observational studies of outbreaks of neuroinvasive disease due to enterovirus-71 (EV-71) internationally and in mouse models.57,58
    • This observation following a 2012 outbreak in Cambodia led to the conclusion among a WHO-convened joint commission that corticosteroids were contraindicated in the management of EV-71 associated neuroinvasive disease.59
    • This is relevant, as an increase in EV-A71 associated neurologic disease was reported in the United States in 2018.
  • In a mouse model of AFM using EV-D68 as the infectious virus, mice receiving dexamethasone at either early or late time points from infection had significantly higher mortality compared to infected controls. Individual dexamethasone-treated mice that died had worse paralysis associated with their motor impairment score than in an infected control.60
  • 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 some white matter involvement. It is not clear if 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 the treatment of AFM.
  • 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 the use of corticosteroids to manage spinal cord edema or white matter involvement in AFM should be balanced with the possible harm due to immunosuppression in the setting of possible viral infection.

Intravenous Immunoglobulin (IVIG)

  • IVIG has been utilized for neurologic complications in enteroviral disease associated with neurologic involvement.
    • Enteroviruses cause chronic, severe CNS infections in agammaglobulinemic children, suggesting humoral immunity plays an important role in attenuating enteroviral infection.61
    • Similarly, infants who fail to acquire neutralizing antibody from their mothers have been described as having more severe disease when infected with enteroviruses.62
  • 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 prior to exposure.
    • Pre-poliovirus vaccine era trials in the 1950s demonstrated potential efficacy of gamma globulin for prevention of poliomyelitis with mass gamma globulin administration to susceptible populations in an outbreak situation.63
    • 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 development or severity of paralysis during a poliovirus outbreak in New York City in 1944.64
  • 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 the prevention of progression to neuroinvasive disease in rodent models.60,65,66 Paralysis in mice was prevented in a time-dependent fashion after administration of IVIG from time of infection.
    • Clear efficacy of IVIG has not been demonstrated in humans with WNV associated paralysis with most data limited to case reports or small case-series.67,68
  • IVIG has been utilized for patients presenting with symptoms of AFM, but to date, no systematic studies of IVIG have been conducted.
    • In a 2014 – 2015 case-series, treatment of AFM using IVIG was done either alone or in combination with methylprednisolone and plasma exchange. All patients tolerated the treatment regimens well without major complications. Neurologic improvement was seen in all patients regardless of treatment, but in all except one patient, deficits persisted.54
    • Messacar, et al. reported on a review of clinical cases from 2012 – 2015. All cohorts that were reviewed received various combinations of IVIG, steroids, plasma exchange, and antiviral medications. No significant improvement or deterioration was noted with these therapies, but a systematic assessment of response was not feasible with the retrospective review.55
    • Hopkins noted in her review piece on AFM diagnostic and management considerations that the current practice at Children’s Hospital Philadelphia is to initiate therapy with IVIG upon recognition of AFM in hopes of boosting humoral immunity.53
  • IVIG is generally safe and well tolerated, though expensive.
    • Common intra-infusion adverse effects of IVIG include fever, headache, myalgia, chills, nausea, and vomiting, which are typically infusion rate-dependent.69
    • 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.70
    • 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-D68.71

Summary:

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

Plasma Exchange (PLEX)

  • It is presumed that there are beneficial effects from the innate humoral immune response to an acute viral infection, in which the body produces neutralizing antibodies to the infectious pathogen.72 Removal of these antibodies induced in response to acute infection could cause potential harm.
    • Additionally, plasmapheresis requires placement of invasive intravenous access and procedure-associated risks.
  • Plasmapheresis has been used in published case-series of AFM patients.
    • From a case-series in Argentina, 4 children were given PLEX in combination with IVIG and steroids. Treatment did not lead to clinical improvement.73
    • Nelson et al. also used PLEX in combination with steroids and IVIG.54
    • 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.56
    • No data was available to evaluate plasmapheresis in the absence of other therapies. No adverse events were noted for PLEX in the above publications.

Summary:

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

Fluoxetine

  • 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 compared to controls.60
  • In a comparison of patients who received treatment with fluoxetine, and those who did not, using a summative limb strength score between their initial examination and most recent follow-up as an outcome, fluoxetine was not associated with improved neurologic outcomes.74 The patients treated with fluoxetine were more likely to have severe paralysis and to have EV-D68 isolated from respiratory specimens.

Summary:

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

Antiviral medications

  • It is important to point out that, while symptoms of a viral illness precede limb weakness onset and clinical data supporting pathogenesis point to an acute infectious process, a specific pathogen isolated from a sterile site in the majority of AFM patients has yet to be identified.
  • 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 working on 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 and none have significant activity against currently circulating strains of EV-D68 at clinically relevant concentrations.75

Summary:

  • There is no indication that antivirals should be used for the treatment of 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.76
    • Subsequent non-controlled assessments, however, failed to replicate this improvement in cases of Saint Louis encephalitis and West Nile Virus.
  • A randomized trial performed in Vietnam from 1996 – 1999 evaluated 117 children with Japanese encephalitis randomized to receive interferon (10 million units/m2 daily for 7 days) or placebo. Outcome at discharge and 3 months did not differ between the two treatment groups. 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.77
  • 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 for the treatment of 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 the setting of AFM, biologic modifiers may have an adverse impact on patients, presuming infectious etiology. The combination of immunosuppressive agents directly impairing T-cell function (and B-cell function indirectly), or therapy directed against primary humoral immunity (e.g., rituximab) may further worsen the ability to clear the infection.

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 evidence of effectiveness, including glucocorticoids, intravenous immune globulin, plasma exchange, interferon, antivirals, or other immunomodulatory agents.1,35,44 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.15 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.3 Studies from 2014 to 2017 indicated a poor outcome for many cases. In 7 of 61 cases with EVD68 detected and eight long-term follow-ups, few had a full recovery. Two deaths were described in severely immunocompromised people (one with EVD68 and one with both EVD68, and coxsackievirus A16 detected).78

Six of 10 children in Denver were sent home for outpatient treatment. Some children with mild symptoms have recovered from temporary limb weakness, while the fate of those more severely affected remains unclear. Intensive physical therapy and occupational therapy may be beneficial for recovery.18,79,80

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 is unable to speak clearly and cannot lift her right arm. The previous evening she had been playing 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 go to school, he had difficulty understanding her and noticed that her right arm just hung down by her side.

Emily lives with her biologic 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 younger than five. She has no surgical history.

Emily had a “chest cold” with fever seven days ago but recovered after three days with children’s Tylenol given every 4-6 hours when her temperature went above 100o 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 trying to talk.
  • Posture normal.
  • Muscle strength 5/5 throughout except for right upper extremity: 0/5.
  • No resting tremors, fasciculations or seizure activity 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 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. Report was called by both the physician and nurse to University Children’s Hospital with accompanying notes faxed. Results of the stat brain and spinal cord MRI are pending and will be faxed to the University Children’s Hospital upon receipt in the Emergency Department.

Strengths and Weaknesses

Childs health history and physical assessment performed quickly with appropriate orders written. Transfer to 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 from 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. For all other patients, no pathogen has been detected in their spinal fluid to confirm a cause.
  • Most patients had the onset of AFM between August and October, with increases in AFM cases every two years since 2014. At this same time of year, many viruses commonly circulate, 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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This course is applicable for the following professions:

Advanced Registered Nurse Practitioner (ARNP), Athletic Trainer (AT/AL), 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), Respiratory Therapist (RT)

Topics:

CPD: Practice Effectively, Infection Control/Disease, Pediatrics, Pharmacology (All Nursing Professions)


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