Acute flaccid myelitis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Synonyms and Keywords: ; Acute flaccid paralysis, acute flaccid paralysis with anterior myelitis, paralysis with anterior myelitis, AFM, Enterovirus D68-Associated Anterior Myelitis

Overview

Acute flaccid myelitis (AFM) is a rare but serious neurological condition characterized by sudden onset of paralysis and weakness in extremities (lower > upper). AFM affects the area of the spinal cord called gray matter, which causes the muscles and reflexes in the body to become weak. It is typically a lower motor neuron lesion but cases have been identified where there was reported involvement of the midbrain and medulla oblongata. The risk of getting AFM varies by age and year. There has been an increased number of AFM cases every two years since 2014 and mostly in young children. Still, CDC estimates that less than one to two in a million children in the United States will get AFM every year. AFM should be differentiated from other diseases which present with muscle weakness, hypotonia and flaccid paralysis. AFM has been known to be associated with viral infections such as West Nile virus, coxsackie virus, Adenovirus, Poliovirus, Enterovirus D71 and Enterovirus D68 as well as environmental toxins. The clinical course of the disease is characterized by a prodormal phase, progressive neurological injury phase and a convalescent phase. There is no specific treatment for AFM and prevention is aimed at measures which curtail the rate of infection by viruses known to be associated with AFM.

Historical Perspective

  • In 2014, physicians in California and Colorado (USA) noted an increase in the number of patients presenting with the acute onset of flaccid paralysis and MRI findings consistent with lesions in the gray matter of the spinal cord.
  • In 2014, a total of 120 cases were identified in the US and 22 were identified in 2015
  • In 2016, 145 cases of AFM were diagnosed across the USA.

Causes

Acute flaccid myelitis (AFM) may be caused by viral infections or environmental toxins. The following viruses are known to be associated with AFM:[1][2][3][4][5]

  • West Nile Virus
  • Coxsackievirus (A24)
  • Adenovirus
  • Enterovirus 71 (EV 71) and Entervirus D68 (EV 68)

Differentiating Acute Flaccid Myelitis From Other Diseases

The following table differentiates acute flaccid myelitis from other diseases that cause muscle weakness, hypotonia, and flaccid paralysis:[6][6][7][8][1][9][10][11][12][13][14][15][16][17][18][19][20]

Diseases History and Physical Diagnostic tests Other Findings
Motor Deficit Sensory deficit Cranial nerve Involvement Autonomic dysfunction Proximal/Distal/Generalized Ascending/Descending/Systemic Unilateral (UL)

or Bilateral (BL)

or

No Lateralization (NL)

Onset Lab or Imaging Findings Specific test
Acute Flaccid Myelitis + + + - Proximal > Distal Ascending UL/BL Sudden MRI (Longitudinal hyperintense lesions) MRI and CSF PCR for viral etiology Drooping eyelids

Difficulty swallowing

Respiratory failure

Adult Botulism + - + + Generalized Descending BL Sudden Toxin test Blood, Wound, or Stool culture Diplopia, Hyporeflexia, Hypotonia, possible respiratory paralysis
Infant Botulism + - + + Generalized Descending BL Sudden Toxin test Blood, Wound, or Stool culture Flaccid paralysis (Floppy baby syndrome), possible respiratory paralysis
Guillian-Barre syndrome + - - - Generalized Ascending BL Insidious CSF: ↑Protein

↓Cells

Clinical & Lumbar Puncture Progressive ascending paralysis following infection, possible respiratory paralysis
Eaton Lambert syndrome + - + + Generalized Systemic BL Intermittent EMG, repetitive nerve stimulation test (RNS) Voltage gated calcium channel (VGCC) antibody Diplopia, ptosis, improves with movement (as the day progresses)
Myasthenia gravis + - + + Generalized Systemic BL Intermittent EMG, Edrophonium test Ach receptor antibody Diplopia, ptosis, worsening with movement (as the day progresses)
Electrolyte disturbance + + - - Generalized Systemic BL Insidious Electrolyte panel ↓Ca++, ↓Mg++, ↓K+ Possible arrhythmia
Organophosphate toxicity + + - + Generalized Ascending BL Sudden Clinical diagnosis: physical exam & history Clinical suspicion confirmed with RBC AchE activity History of exposure to insecticide or living in farming environment. with : Diarrhea, Urination, Miosis, Bradycardia, Lacrimation, Emesis, Salivation, Sweating
Tick paralysis (Dermacentor tick) + - - - Generalized Ascending BL Insidious Clinical diagnosis: physical exam & history - History of outdoor activity in Northeastern United States. The tick is often still latched to the patient at presentation (often in head and neck area)
Tetrodotoxin poisoning + - + + Generalized Systemic BL Sudden Clinical diagnosis: physical exam & dietary history - History of consumption of puffer fish species.
Stroke +/- +/- +/- +/- Generalized Systemic UL Sudden MRI +ve for ischemia or hemorrhage MRI Sudden unilateral motor and sensory deficit in a patient with a history of atherosclerotic risk factors (diabetes, hypertension, smoking) or atrial fibrillation.
Poliomyelitis + + + +/- Proximal > Distal Systemic BL or UL Sudden PCR of CSF Asymmetric paralysis following a flu-like syndrome.
Transverse myelitis + + + + Proximal > Distal Systemic BL or UL Sudden MRI & Lumbar puncture MRI History of chronic viral or autoimmune disease (e.g. HIV)
Neurosyphilis + + - +/- Generalized Systemic BL Insidious MRI & Lumbar puncture CSF VDRL-specifc

CSF FTA-Ab -sensitive

History of unprotected sex or multiple sexual partners.

History of genital ulcer (chancre), diffuse maculopapular rash.

Muscular dystrophy + - - - Proximal > Distal Systemic BL Insidious Genetic testing Muscle biopsy Progressive proximal lower limb weakness with calf pseudohypertrophy in early childhood. Gower sign positive.
Multiple sclerosis exacerbation + + + + Generalized Systemic NL Sudden CSF IgG levels

(monoclonal)

Clinical assessment and MRI Blurry vision, urinary incontinence, fatigue
Amyotrophic lateral sclerosis + - - - Generalized Systemic BL Insidious Normal LP (to rule out DDx) MRI & LP Patient initially presents with upper motor neuron deficit (spasticity) followed by lower motor neuron deficit (flaccidity).
Inflammatory myopathy + - - - Proximal > Distal Systemic UL or BL Insidious Elevated CK & Aldolase Muscle biopsy Progressive proximal muscle weakness in 3rd to 5th decade of life. With or without skin manifestations.

Epidemiology and Demographics

Incidence and Prevalence

USA

  • From June 1, 2012 to July 31, 2015, 59 reported cases met the California Department of Public Health (CDPH) case definition of acute flaccid myelitis (AFM), which defines AFM as acute onset of flaccid limb paralysis along with a lesion in the gray matter of the spinal cord.[8]
  • Between August and December of 2014, 120 children from 34 US states met the criteria of AFM as outlined by the CDC.[21]
  • From August 2014 through October 2018, CDC has received information on a total of 404 confirmed cases of acute flaccid myelitis (AFM) across the US; most of the cases have occurred in children[22]
  • In 2015, 22 people were confirmed to have AFM. (Note: The cases occurred in 17 states across the U.S.)
  • In 2016, 149 people were confirmed to have AFM. (Note: The cases occurred in 39 states across the U.S. and DC)
  • In 2017, CDC received information for 33 confirmed cases of AFM. (Note: The cases occurred in 16 states across the U.S.)
  • In October 2018, the New York State Department of Health (NYSDOH) confirmed 39 cases of the enterovirus EV-D68 in children across the state which was associated with an increase in number of cases of AFM.[23]
Acute Flaccid Myelitis number of confirmed cases from August 2014 to October 2018 based on AFM case definition: Onset of acute limb weakness and an MRI showing a spinal cord lesion largely restricted to gray matter


Age

  • AFM affects older children. Median age at presentation is 9 years.[24]

Gender

  • Male children are affected more frequently than females.

Risk Factors

The following risk factors increase the risk of development of AFM:

  • Pulmonary comorbities (Asthma, COPD)
  • Immunocompromised states (Immunosuppressants, organ transplantation, diabetes, systemic autoimmune diseases, hematologic malignancies)

Natural History, Complications and Prognosis

Natural History

  • The clinical course of AFM typically consists of three phases:
    • Prodormal phase
    • Progressive neurological injury phase
    • Convalescent phase

Prodormal phase

  • A prodromal, often febrile, illness often precedes the onset of neurological deficits in most patients by a median of 5 days.
  • The prodormal period consists of respiratory symptoms such as rhinorrhea, cough, or pharyngitis and/or gastrotestinal symptoms such as nausea, vomiting or diarrhea.
  • Some patients report clinical improvement in their preceding illness before return of fever accompanied by headaches, stiff neck, or pain in the neck, back, or affected limb around the time of neurological deficit onset

Progressive neurological injury

  • The pattern of limb weakness in AFM corresponds to a lower motor neuron lesion and upper extremities are more commonly affected.
  • Involvement of cranial nerves points towards lesions in the cranial nerve motor nuclei of the brainstem
  • On CSF examination, mild pleocytosis with mildly elevated protein may be seen
  • On MRI, confluent, longitudinally extensive gray matter lesions may be seen in spinal cord. This may progress to nerve root enhancement on MRI in 2-3 weeks.
  • On electromyography (EMG), reduced recruitment of motor unit potentials (MUPs) and low amplitude of compound muscle action potentials may be seen.

Convalescent phase

  • Months after the initial acute neurological illness, patients suffering from AFM may smild improvements with rehabilitation therapies.
  • On CSF examination, pleocytosis may resolve and protein remains elevated
  • On EMG, fibrillations may be seen

Complications

AFM may lead to the development of following complications:

  • Respiratory failure
  • Urinary tract infections
  • Skin ulcers and traumatic injury (specially in the affected extremity)
  • Progressive muscular atrophy

Prognosis

  • Physical and occupational therapy are especially important during recovery from AFM
  • The extent of recovery varies. Although some people may make a full recovery, most have continued muscle weakness even after a year.
  • Long term outcomes for patients suffering from AFM are not known.

Diagnosis

Diagnostic Criteria

The following table describes the case definition of AFM as outlined by the CDC:[25]

Diagnosis Criteria
Confirmed
  • Acute onset of flaccid limb weakness

AND

  • An MRI showing a spinal cord lesion largely restricted to gray matter and spanning one or more spinal segments
Probable
  • Acute onset of flaccid limb weakness

AND

  • Cerebrospinal fluid (CSF) with pleocytosis (white blood cell count 9 5 cells/mm3

Symptoms

The following are the symptoms of acute flaccid myelitis:[26][27][1]

  • Acute onset of flaccid limb paralysis (asymmetric)
  • Fever
  • Pain in the paralytic limb
  • Eyelid drooping
  • Difficulty with swallowing or slurred speech
  • Cranial nerve abnormalities
  • Headache
  • Neck pain
  • Bowel/bladder changes

Physical Examination

Temperature

Extremities

  • Weakness of the extremities, predominantly of the proximal muscles, is characteristic of this form of the disease. Lower extremities are more often involved.
  • Asymmetrical flaccid paralysis, predominantly of the proximal muscles, is characteristic of this form of the disease. Lower extremities are more often involved.

Neurologic

  • Initially hyperactive deep tendon reflexes, that later become absent.
  • Common combinations of limb involvement include:
  • One lower limb, followed by one upper limb
  • Both lower limbs, followed by both upper limbs

Laboratory Findings

Non specific tests

Blood tests

It is performed routinely to any suspected meningitis patients. It includes the following:

Virus detection

Virus may be detected through two ways:

  • Samples can be taken by different ways from the suspected meningitis patients to detect the virus causing the disease.They may be collected for testing by:

Specific tests

Specific diagnostic tests include lumbar puncture with CSF examination. CSF examination findings in viral meningitis are as follows:

Cerebrospinal fluid level Normal level Viral meningitis
Cells/ul < 5 >100
Cells Lymphos:Monos 7:3 Lymphocytes>granulocytes
Total protein (mg/dl) 45-60 Normal or slightly elevated
Glucose ratio (CSF/plasma) > 0.5 >0.6
Lactate (mmols/l) < 2.1 < 2.1
Others ICP:6-12 (cm H2O) Throat swap

Video explaining the lumbar puncture procedure:

Imaging Findings

Magnetic resonance imaging (MRI) may reveal the following findings in patients suffering from AFM:

Treatment

Medical Therapy

  • There is no specific treatment for AFM.
  • Treatments that have been tried include:

Corticosteroids

  • There is no indication that corticosteroids should be either preferred or avoided in the treatment of AFM.
  • There is no clear human evidence for 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)

  • 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.

Plasmapheresis

  • 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

  • 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

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

Interferon

  • There is no indication that interferon should be used for the treatment of AFM, and there is concern 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

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

Prevention

  • There is no specific action to take to prevent AFM.
  • Certain viruses are known to cause AFM including enteroviruses, such as poliovirus and enterovirus A71 (EV-A71), and West Nile virus.
    • Poliovirus infection can be prevented by getting vaccinated. Polio vaccine contains inactivated (not live) virus, and protects against poliovirus. This vaccine does not protect against other viruses that may cause AFM.
    • Protection from mosquito bites, which can carry West Nile virus, can be achieved by using mosquito repellent, staying indoors at dusk and dawn (when bites are more common), and removing standing or stagnant water (where mosquitoes can breed).
    • Protection from enteroviruses by washing hands often with soap and water, avoiding close contact with people who are sick, and cleaning and disinfecting frequently touched surfaces, including toys.

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