Acute flaccid myelitis

INTRODUCTION — Acute flaccid myelitis (AFM) is an acquired spinal cord disorder that presents with the rapid onset of weakness in one or more limbs. This topic will review AFM. Related conditions are discussed elsewhere:

Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis
Acute disseminated encephalomyelitis (ADEM) in adults
Guillain-Barré syndrome in children: Epidemiology, clinical features, and diagnosis
Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis
Manifestations of multiple sclerosis in adults
Management of clinically and radiologically isolated syndromes suggestive of multiple sclerosis
Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis
Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis
Disorders affecting the spinal cord
Poliomyelitis and post-polio syndrome
Transverse myelitis: Etiology, clinical features, and diagnosis

HISTORY AND TERMINOLOGY — Historically, the term "acute flaccid paralysis" (AFP) has been used to describe any syndrome due to loss or dysfunction of anterior horn cells in the spinal cord caused by infectious or inflammatory conditions. AFP presents with the rapid onset of weakness in one or more limbs, occurs more often in children, and has both infectious and non-infectious causes. While numerous different pathologies can cause damage to anterior horn cells, the classic cause of AFP throughout history was the poliovirus, presenting as poliomyelitis. As polio has neared eradication via vaccination, there has been increasing recognition that other viruses may cause AFP, including enterovirus D68. (See "Poliomyelitis and post-polio syndrome".)

Since 2014, the similar term "acute flaccid myelitis" has been used to describe a specific condition recognized in outbreaks in the United States and Europe. These outbreaks have been associated with circulating enterovirus D68 and have caused significant public health concerns. The first reported cases of AFM were in 2012 from California in five children with onset of AFP, two of whom had evidence of enterovirus D68 in respiratory tract specimens [1,2]. Yet, some cases had been observed as early as 2009 [3]. Between 2014 and 2018, in the late summer/early fall, there were obvious clusters of patients presenting with AFM in dramatically increased numbers from background rates [4]. Most of these patients, if tested correctly, had evidence of systemic enterovirus D68 infection without evidence of the virus in the cerebrospinal fluid. (See 'Enterovirus D68' below and 'Epidemiology' below.)

PATHOGENESIS AND ETIOLOGY

Anterior horn cell injury — The clinical syndrome of acute motor neuron weakness (acute flaccid paralysis [AFP] or AFM) is caused by dysfunction or death of anterior horn cells within the gray matter of the spinal cord. Damage to these lower motor neurons leads to flaccid weakness of the innervated limb.

Acute motor weakness due to anterior horn cell involvement has been reported with many enterovirus serotypes (table 1) [5-8]. These include poliovirus and several nonpolio enteroviruses, such as enterovirus D68 and enterovirus A71, flaviviruses, and adenoviruses. Furthermore, immune-mediated causes of AFM have been identified (ie, myelin oligodendrocyte glycoprotein antibody-associated disease [MOGAD]) that can be indistinguishable from virally mediated AFM [9]. (See "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis".)

Of the viral causes, only a small number are associated with endemic and epidemic paralysis: poliovirus types 1, 2, and 3; enterovirus D68; and enterovirus A71. These viruses target motor neurons in the brainstem and spinal cord. (See "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention", section on 'Acute paralysis and brainstem encephalitis'.)

Poliovirus is one of four species within the Picornavirus family. These single-stranded RNA (ribonucleic acid) viruses include enteroviruses A, B, C, and D. Poliovirus is part of group C. Poliovirus, which has been responsible for large-scale outbreaks of paralysis throughout the world, is transmitted via the fecal oral route, and can be effectively prevented through vaccination campaigns. The most common neurologic manifestation, recognized early in the history of poliomyelitis, is flaccid weakness of one or more limbs (most commonly the lower extremities) [10]. (See "Poliomyelitis and post-polio syndrome", section on 'Clinical manifestations'.)

Enterovirus D68 — Enterovirus D68, the suspected cause of modern AFM, is a non-enveloped, single-stranded RNA virus belonging to the genus Enterovirus within the Picornaviridae family. It was first isolated in 1962 from the respiratory tract of four pediatric patients hospitalized in California [11]. The virus was rarely isolated from patients until the 2000s. In 2008 to 2009, there were a number of cases from pediatric patients with severe respiratory illness in the Philippines [12].

Enterovirus D68 has some genomic similarity and shares similar optimal growth profiles with rhinoviruses. This may explain why enterovirus D68 usually causes respiratory infections instead of gastrointestinal conditions (as typically seen in enteroviral infections) [13]. (See "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention", section on 'Respiratory disease'.)

●Association with AFM – Proving that enterovirus D68 is the cause of AFM has been hampered by the inability to isolate enterovirus D68 by polymerase chain reaction (PCR) or culture from the cerebrospinal fluid (CSF) of patients with AFM [14]. This obstacle is similar to the poliovirus in poliomyelitis, where PCR of spinal fluid is not a reliable diagnostic tool. Rather, poliovirus as a cause of AFM requires clinical phenotyping of a patient and isolation of the poliovirus from fecal samples [15]. Much of the data linking enterovirus D68 as the cause of AFM outbreaks in humans have come from epidemiologic studies. (See 'Epidemiology' below.)

The strongest indirect evidence to date is provided by a study of CSF from 42 AFM cases, in which intrathecal antiviral antibody synthesis was analyzed using a peptide phage display library derived from all known vertebrate and arboviruses [16]. Testing revealed elevated levels of anti-enterovirus antibodies in 29 of 42 cases (69 percent) versus 4 of 58 neurologic controls (7 percent). As in prior studies, enterovirus RNA could not be identified in the majority of case samples (19 of 20) analyzed by metagenomic next-generation sequencing; the one positive sample contained enterovirus A71 RNA, which was known to be present based on previous clinical PCR testing. In addition, enterovirus D68 was detected in the cerebrospinal fluid of a child who died of an AFM-like illness in 2008 [17]; examination of autopsy material using in situ hybridization and immunohistochemical techniques revealed enterovirus D68 RNA and protein in anterior horn motor neurons and their axons [18].

Other evidence and observations also implicate an enteroviral etiology of AFM. Enterovirus D68 has been the most commonly identified pathogen in respiratory samples of affected patients both in the United States and in other countries, and no other candidate pathogen has been detected consistently, even when using unbiased metagenomic next-generation sequencing approaches for pathogen detection [19]. AFM cases clustered during periods of enterovirus D68 circulation in 2014, 2016, and 2018, and were more sporadic when it was not circulating in alternate years.

During the biennial outbreaks of AFM in 2014, 2016, and 2018, enterovirus D68 was not isolated from CSF samples, but the majority of cases were PCR-positive for enterovirus D68 from nasopharyngeal swabs [4,14,19,20]. The percent positivity varied based upon the timing of collection relative to symptom onset. Samples obtained within seven days of onset had a higher rate of enterovirus D68 positivity than after seven days, and 0 percent of samples collected 14 days after onset were positive [20]. Due to the lack of a validated, specific anti-enterovirus D68 antibody, seroprevalence studies have been difficult to complete.

●Animal models – Animal models have confirmed the ability of recently circulating enterovirus D68 to cause flaccid paralysis in mice with symptoms similar to the human condition. Interestingly, enterovirus D68 isolated from patients in 1962 (the Fermon and Rhyne strains) were unable to cause paralysis in mice, but enterovirus D68 isolated from patient respiratory samples in 2014 were able to cause paralysis in Swiss Webster mice. Mice were injected intracerebrally and intramuscularly [20,21]. One hundred percent of mice injected in a limb muscle developed flaccid paralysis of that limb. Testing of the spinal cord identified viral RNA and viral antigen within the anterior horn cells. When administered intranasally, only 2.7 percent of mice developed motor symptoms, and the weakness was of a forelimb. To complete Koch's postulates relative to enterovirus D68 and flaccid paralysis, spinal cord tissue from paralyzed mice was cultured ex vivo and then injected into new mice who subsequently became ill. Viral RNA could be detected after passage of the previously infected tissue [21].

Pathology — While there have not been systematic pathologic descriptions of enterovirus D68-associated myelitis in humans, older literature from the polio era identified anterior horn cell death with an associated inflammatory response. This inflammatory response was evident with the anterior horns of the spinal cord and, in some cases, within the surrounding white matter. Thus, it was possible for patients with virally mediated anterior horn cell death to experience simultaneous inflammation-mediated white matter damage [22].

One case of AFM reported in 2017 resulted in the death of a 21-year-old man who developed meningoencephalomyelitis and cerebral edema. Histopathology of the spinal cord revealed focal neuronal necrosis and inflammation with mononuclear cell infiltrates [14].

EPIDEMIOLOGY — AFM is rare, with an estimated incidence of less than one case per one million population in the United States [23]. In 2014, the Centers for Disease Control and Prevention (CDC) was alerted to a cluster of AFM cases in Colorado, and a national surveillance program was initiated [24]. An association with enterovirus D68 was recognized early, and subsequent outbreaks occurred in late summer/early fall on a biennial basis [25]. Since surveillance began, the number of confirmed AFM cases in the United States was 120 in 2014, 153 in 2016, and 236 in 2018; far fewer confirmed cases occurred in alternate years (figure 1) [26]. The expected outbreak was not observed in 2020; its absence was likely related to protective measures against coronavirus disease 2019 (COVID-19), including the use of masks in public, fewer children in school, and improved hygiene.

The previous outbreaks were not limited to the United States, but rather occurred as well in multiple European countries [4,27,28]. The majority of cases in the United States affected children with a median age of 6 years (range 3 months to 21 years) [14]. Note that the initial CDC case definition limited reported cases to patients age 21 years or younger [29]. Thus, the true rate of AFM among adults is not known, but it is thought to be extremely rare.

With standardized surveillance, the estimated incidence of AFM among children 1 to 18 years of age in northern California in 2016 was 1.43 cases per 100,000 person-years [30]. As of 2019, the definition used by the CDC to classify "confirmed" cases requires a clinically compatible case and a magnetic resonance imaging (MRI) showing a spinal lesion largely restricted to the gray matter. (See 'Case definitions' below.)

CLINICAL FEATURES — The majority of patients with AFM have upper respiratory symptoms or fever in the days or weeks preceding the onset of weakness. Once neurologic symptoms begin, the evolution of flaccid weakness can occur over hours to days [2,31]. Some have cranial nerve dysfunction, bowel or bladder dysfunction, and/or sensory alterations [31,32].

In a report of 193 confirmed AFM cases from 2015 through 2017, fever, cough, rhinorrhea, vomiting, and/or diarrhea occurred in over 80 percent of patients, and preceded neurologic symptoms by a median of five days (range 0 to 28 days) [14]. Weakness involved one or two limbs in 55 percent, three or four limbs in 45 percent, and at least one upper limb in approximately 80 percent. At the time of limb weakness onset, quadriparesis was present in 36 percent. Patients also presented with cranial nerve dysfunction in 33 percent and altered mental status in 28 percent. Ventilator support was required in 33 percent.

While most AFM cases identified during the biennial outbreaks since 2014 have had cervical spine involvement, a significant minority had quadriparesis, apparently from white matter changes within the cervical spinal cord. Thus, these children presented with flaccid weakness in one or more arms from anterior horn cell death, and leg weakness from involvement of the white matter-based corticospinal tracts with the cervical cord [33].

DIAGNOSTIC APPROACH

When to suspect AFM — Suspicion for AFM arises when children present with acute onset of muscle weakness and hyporeflexia involving one or more limbs, particularly if preceded by respiratory symptoms or fever. The weakness can evolve over an acute or hyperacute time period.

Evaluation — Standard testing of patients suspected of AFM includes magnetic resonance imaging (MRI) of the cervical and thoracic spine with and without contrast, MRI of the brain with and without contrast, cerebrospinal fluid (CSF) analysis, nasopharyngeal swabs for viral testing (eg, enterovirus polymerase chain reaction [PCR]), fecal samples for viral testing (eg, enterovirus PCR), and serum testing (eg, enterovirus PCR, aquaporin-4 [AQP4] antibodies, anti-myelin oligodendrocyte glycoprotein [MOG] antibodies, and arbovirus panel including West Nile virus antibodies) [34]. Given the emergence of polio cases in the US among unvaccinated individuals, it is important to include fecal testing for the poliovirus among patients with suspected AFM.

Specimens for testing should be collected as early as possible in the course of the illness. In addition to local diagnostic laboratory testing, clinicians In the United States should send all specimens to their state or local health department. (See 'Case reporting' below.)

In some cases, electrophysiology may be useful if there is suspicion for an acquired demyelinating peripheral neuropathy (ie, Guillain-Barré syndrome) or a neuromuscular junction disorder causing flaccid weakness (eg, botulism). A detailed list of studies for the evaluation of acute flaccid paralysis is provided in the table (table 2).

●Spinal cord MRI – MRI of the spinal cord typically identifies T2-hyperintense lesions restricted to the gray matter or predominantly involving the gray matter and some of the white matter (image 1). In a series of 34 cases of strictly defined AFM diagnosed between 2012 and 2016 in the United States, all patients had gray matter predominant, T2-hyperintense spinal cord signal abnormality on MRI, which was fully restricted to gray matter in approximately half of patients [35]. In most cases, the spinal cord gray matter lesions are longitudinally extensive [31,36]. Note that MRI abnormalities may be subtle in the first 72 hours after onset of limb weakness [29,31].

●Brain MRI – MRI of the brain may reveal brainstem lesions, most often T2 hyperintensity of the dorsal pons [31,37-39]. In a retrospective report of 66 patients with AFM, brain MRI abnormalities were present in 34 patients (52 percent) [39]. Among patients with brain abnormalities, most were infratentorial, involving the dorsal pons (88 percent), medulla (74 percent), cerebellum (41 percent), and midbrain (38 percent). A minority had both supratentorial and infratentorial abnormalities (26 percent); isolated supratentorial abnormalities affected only 3 percent. Contrast enhancement or meningeal involvement were uncommon.

●Nasopharyngeal swab – For enteroviral PCR tests.

●CSF studies – CSF should be sent for analysis including cell count and differential, glucose, protein, culture, oligoclonal bands, AQP4 antibody, enterovirus PCR, cytomegalovirus PCR, Epstein-Barr virus PCR, herpes virus PCR, varicella-zoster virus PCR, and IgG index [34]. CSF studies typically identify a lymphocytic pleocytosis and mildly elevated protein [14]. In the series of 34 cases of AFM just cited, the mean CSF white cell count was 211 cells/microL, and mean CSF protein was 54 g/dL [35].

●Serum antibody testing – Anti-MOG antibody and anti-AQP4 antibody.

Case reporting — In the United States, suspected AFM cases should be reported to state and local health departments using the patient summary form available from the Centers for Disease Control and Prevention (CDC) Acute Flaccid Myelitis Data Collection site. The CDC also requests that clinicians collect and submit specimens to their state or local health department, which coordinates with the CDC for testing. This should be done as early as possible in the course of the illness, preferably on the day of onset of limb weakness, and should include CSF, blood, stool, and respiratory-nasopharyngeal or oropharyngeal swab specimens. Note that specimens submitted to the CDC are not intended for clinical diagnosis; pathogen-specific testing should be performed at hospital or state public health laboratories.

An overview of CDC information and resources for AFM in the United States is available from the CDC Acute Flaccid Myelitis site.

Diagnosis — The diagnosis of AFM requires a clinical phenotype that includes acute flaccid weakness and MRI of the spinal cord that reveals predominantly gray matter involvement. The diagnosis does not require the identification of enterovirus D68, but testing for the virus is recommended for public health purposes.

Recognizing and ruling out the potential mimics of AFM is an essential part of the diagnostic evaluation. (See 'Differential diagnosis' below.)

Case definitions — For public health purposes, the CDC has established and revised a case definition for AFM. The CDC case definition requires an illness with the onset of acute flaccid limb weakness; confirmatory evidence requires an MRI showing a spinal cord lesion largely restricted to gray matter, while supportive evidence requires a CSF with pleocytosis (white blood cell count >5 cells/mm³) [40]. Of note, this case definition is intended for case reporting and tracking purposes. It is not meant to supersede clinical diagnoses from practitioners caring for patients, and should not be used to guide clinical decision-making.

As more information becomes available, the disease definition may evolve. A more restrictive and specific set of criteria for AFM has been proposed to include the following [35]:

●Prodromal fever or viral syndrome

●Weakness in a lower motor neuron pattern involving limbs, neck, face, and/or bulbar muscles; limb weakness should be accompanied by decreased tone and decreased or absent tendon reflexes

●Supportive evidence to include at least one of the following:

•Gray matter predominant, T2-hyperintense lesion on spine MRI, spanning multiple levels, with or without ventral nerve root enhancement

•Electromyography (EMG) and nerve conduction study evidence of a motor neuronopathy with intact sensory nerve conductions

•CSF studies showing pleocytosis (white count >5 cells/microL)

●Absence of:

•Objective sensory deficits on neurologic examination

•Supratentorial white matter or cortical lesions >1 cm

•Encephalopathy that cannot be explained by fever, illness, respiratory distress, or metabolic abnormalities

•Elevation of CSF protein greater than two times the upper limit of normal in the absence of CSF pleocytosis

•Definable alternative diagnosis

Of note, these criteria would be used to quantify "definite" AFM cases and have some limitations. For example, in several case series, patients with AFM can experience sensory symptoms and as such should not be excluded.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of AFM includes a range of infectious and noninfectious causes of acute flaccid paralysis (AFP) (table 3), and can be divided into two main categories. First, clinicians must consider the multiple conditions that can present with flaccid weakness, mimicking AFM. Second, clinicians and scientists must be aware of the many potential causes of acute anterior horn cell death other than AFM.

Conditions mimicking AFM — A number of spinal cord, peripheral nerve, and neuromuscular junction-based conditions can present with acute flaccid weakness that resembles AFM, as outlined in the table (table 3).

●Myelopathic – Spinal cord disorders that may mimic AFM include white matter predominant myelitis, syringomyelia, spinal cord tumors, spinal cord infarcts, and conditions that cause compressive myelopathies (hemorrhages, tumors, and abscesses).

The pattern of weakness caused by upper motor neuron (corticospinal tract) damage in classic myelitis usually includes increased muscle tone and increased reflexes. By contrast, patients with AFM present with decreased tone, reduced reflexes, and (eventually) rapid atrophy of affected limb muscles.

While most spinal cord disorders are associated with upper motor neuron patterns of weakness, acute myelopathies can present with flaccid weakness, making a clinical differentiation difficult in the early course of a spinal cord pathology. Given the potential for patients with AFM to experience hyperacute onset of weakness (ie, weakness reaching nadir in under six hours), vascular myelopathies should be considered in the differential diagnosis. These conditions, however, are extremely rare in pediatric patients.

●Neuropathic – Peripheral nerve disorders that can present with flaccid weakness include the demyelinating and axonal variants of Guillain-Barré syndrome (GBS). In most cases, GBS can be distinguished from AFM by the absence of a cerebrospinal fluid (CSF) pleocytosis and the presence of multifocal demyelination on electrodiagnostic testing. The electrodiagnostic findings are less helpful early in the course of GBS, when demyelinating findings may not yet have developed, or in the case of axonal forms of GBS.

In a retrospective study that compared 26 children with AFM and 156 children with GBS, early clinical features and diagnostic results associated with AFM included the following [41]:

•A shorter median interval from onset of weakness to nadir (3 versus 8 days)

•Asymmetric limb weakness (58 versus 0 percent)

•Less frequent sensory deficits (0 versus 40 percent)

•Higher median CSF leukocyte count (79/microL versus 4/microL)

•Lower median CSF protein concentration (44 mg/dL [0.44 g/L] versus 76 mg/dL [0.76 g/L])

•Spinal cord lesions on MRI (found only in patients with AFM)

GBS is reviewed in detail separately. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis" and "Guillain-Barré syndrome in children: Epidemiology, clinical features, and diagnosis".)

●Disorders of neuromuscular transmission – Neuromuscular junction disorders such as myasthenia gravis and botulism can present with acute flaccid weakness and should be considered in patients with suspected AFM. (See "Clinical manifestations of myasthenia gravis" and "Botulism".)

Other causes of anterior horn cell injury — A number of infectious and noninfectious etiologies can cause acute dysfunction or death of anterior horn cells, as noted in the table (table 1). There are reports of immune-mediated episodes of AFM associated with the anti-myelin oligodendroglial glycoprotein (MOG) antibody [9].

Poliovirus remains a consideration, although it has been eradicated from most parts of the world. AFM associated with enterovirus D68, which is related to the poliovirus, differs from it in several ways. First, enterovirus D68 commonly causes a respiratory illness while poliovirus most commonly causes a gastrointestinal illness. Secondly, enterovirus D68-associated AFM most commonly causes flaccid paralysis in the upper extremities, while the poliovirus most commonly causes flaccid paralysis in the lower extremities. Whether the locations of paralysis are related to the primary site of infection (respiratory versus gastrointestinal) remains unknown. (See "Poliomyelitis and post-polio syndrome".)

Enteroviruses other than wild-type polio are also potential etiologies and as such must also be tested for, particularly in the current era in which polio has been eradicated in most countries. (See "Poliomyelitis and post-polio syndrome", section on 'Transmission and pathogenesis'.)

West Nile virus, a mosquito-borne flavivirus, can also produce AFP. (See "Clinical manifestations and diagnosis of West Nile virus infection".)

An autoimmune condition, caused by the anti-MOG antibody can cause an AFM syndrome [9]. (See "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis".)

TREATMENT — There are no specific therapies for AFM and/or enterovirus D68 that have been proven in prospective trials. Therapy is based on supportive care, agents that may limit damage to the spinal cord, and early/intensive rehabilitation.

Supportive care — Immediate treatment of AFM is primarily supportive, and hospital admission is recommended to monitor for rapid deterioration of weakness and respiratory failure [42]. Approximately 20 to 35 percent of patients have respiratory failure requiring ventilatory support due to respiratory muscle and/or bulbar muscle weakness, including some with prolonged ventilator dependence [43].

Acute-phase immune modulating therapies

●Our approach – There is no established or proven therapy for acute AFM. For patients with only flaccid weakness (ie, only lower motor neuron involvement) and T2-hyperintense lesions restricted to the gray matter on spinal cord magnetic resonance imaging (MRI), we generally treat during the acute phase with intravenous immunoglobulin (IVIG) for a total dose of 2 g/kg given over four to five days. For patients with mixed upper and lower motor neuron involvement and/or gray and white matter lesions on spinal cord MRI, we generally treat using high-dose glucocorticoids (eg, methylprednisolone 30 mg/kg per day, maximum daily dose 1000 mg, given for four to five days) combined with plasma exchange, typically five to seven exchanges given over 8 to 14 days. In both cases, rehabilitation therapy is essential. (See 'Rehabilitation' below.)

Recommendations from the Centers for Disease Control and Prevention (CDC) leave it up to the treating clinician to determine the best therapeutic approach. Guidance is available from the CDC online publication Acute Flaccid Myelitis: Interim Considerations for Clinical Management.

●Efficacy data – Our approach is based upon clinical experience, observational studies, and animal data, but is unproven [33]. Immune modulating treatments for AFM have shown no clear signal of effectiveness, although the published clinical evidence is limited mainly to retrospective reports [2,19,44]. Patients have been treated with glucocorticoids, intravenous immunoglobulin (IVIG), and plasma exchange (similar to treatment for transverse myelitis), without prospective studies to document outcomes. Empiric treatments have also included interferon, antivirals, and other immunomodulatory agents.

Some experience suggests that deficits related to white matter pathology may benefit from anti-inflammatory approaches, but this has not been proven in prospective, randomized trials [33].

There is no antiviral treatment or vaccine for enterovirus D68. In vitro data suggested a possible role for fluoxetine as an anti-enterovirus D68 molecule [45]. However, an open label, uncontrolled, multicenter study examining the outcome in children treated with fluoxetine found no benefit [46].

Rehabilitation — Early and regular rehabilitation therapies are essential to maximal recovery [31,47]. The techniques used include activity-based therapy, electrical stimulation, and functional electrical stimulation. Rehabilitation may be required for years after the initial event.

Nerve transfer — A novel approach to treating the lower motor neuron deficits has been the use of nerve transfer procedures. These surgeries involve the identification of "donor" nerves in proximity to a denervated muscle, followed by the surgical transfer of the healthy nerve to a recipient target. These procedures have produced positive results in a subset of patients with AFM [48-51]. The optimal timing of the surgery has not been firmly established and not every patient is a candidate for these procedures.

PROGNOSIS — The long-term outcomes of modern-day AFM have not been systematically collected. Short-term outcome studies have documented persistent neurologic deficits in the majority of children affected by AFM [2,27,30,52-54]. Neurologic recovery is variable and often incomplete. More than half of all children have persistent motor deficits and significant muscle atrophy in the affected limbs a year or more after disease onset.

Clinical experience, however, has noted that children will continue to improve very slowly over time with ongoing rehabilitation. A multicenter retrospective review from the United States identified 109 children (median age five years) hospitalized with AFM between January 2014 and October 2019 [55]. Of these, 67 were discharged to inpatient rehabilitation and 42 were discharged directly to home. While all children had some improvements in strength, proximal arm muscles remained weaker than distal arm muscles. Compared with children discharged to home, children who went to inpatient rehabilitation had higher rates of respiratory support at follow-up, likely due to the location of anterior horn cell involvement or more severe spinal cord damage. In an earlier study of 21 patients who were diagnosed with AFM in Texas during 2016, recovery of the ability to perform activities of daily living with only mild deficits or complete independence was achieved by 16 patients (71 percent), including complete recovery by five patients (24 percent) [56]. Deficits related to white matter corticospinal tract damage appear to recover faster and more completely than lower motor neuron deficits.

ADDITIONAL INFORMATION — More information about AFM for clinicians, families, and caregivers is available from the Centers for Disease Control and Prevention and the Siegel Rare Neuroimmune Association.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Acute flaccid myelitis (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Historically, the term "acute flaccid paralysis" (AFP) has been used to describe any syndrome of acute motor weakness due to loss of anterior horn cells in the spinal cord caused by infectious or inflammatory conditions. The classic cause throughout history was poliomyelitis. Since 2014, the similar term "acute flaccid myelitis" (AFM) has been used to describe a specific condition recognized in biennial outbreaks in the United States and Europe associated with circulating enterovirus D68. (See 'History and terminology' above.)

●Proving that enterovirus D68 is the cause of AFM has been hampered by the inability to isolate the virus in the cerebrospinal fluid (CSF) of affected individuals. However, clustering of AFM cases with periods of enterovirus D68 circulation, and detection of enterovirus D68 from nasopharyngeal swabs in most cases, supports the association. (See 'Pathogenesis and etiology' above.)

●AFM is rare; most cases have occurred in young children. (See 'Epidemiology' above.)

●Characteristic features of AFM include a febrile or respiratory illness before the onset of neurologic symptoms, acute flaccid limb weakness with evolution of weakness over hours to days, and magnetic resonance imaging (MRI) evidence of predominantly gray matter involvement in the spinal cord. (See 'Clinical features' above.)

●The diagnosis of AFM requires a clinical phenotype that includes acute flaccid weakness and MRI of the spinal cord that reveals predominantly gray matter involvement. Standard testing of patients suspected of AFM includes MRI of the cervical and thoracic spine with and without contrast, MRI of the brain with and without contrast, CSF analysis, nasopharyngeal swabs for viral testing, fecal samples for viral testing, serum testing for potential mimics, and, in some cases, electrophysiology. (See 'Diagnostic approach' above.)

●All suspected AFM cases should be reported to local and state health department officials. (See 'Case reporting' above.)

●The differential diagnosis of AFM includes a range of infectious and noninfectious causes of AFP (table 3). (See 'Differential diagnosis' above.)

●Treatment of AFM includes supportive care. Immune modulating treatments for AFM have shown no clear signal of effectiveness, although evidence is limited to clinical experience and retrospective reports. Long-term treatment includes intensive rehabilitation and potentially nerve transfer procedures in select patients. (See 'Treatment' above.)

●Short-term outcome studies have documented persistent neurologic deficits in most children affected by AFM. Function may recover in patients over time, but a consistent approach and commitment to rehabilitation is required. (See 'Prognosis' above.)