Acute Flaccid Myelitis

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.

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.

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.

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

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

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

*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.

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

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.

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.

• 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)

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)

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.

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

• 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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