Clinical manifestations

Presentation and course

Acute flaccid myelitis predominantly affects the pediatric population. Acute flaccid myelitis is characterized clinically by acute development of unilateral or bilateral lower motor neuron type of limb weakness. Progression can be very rapid in some cases, evolving within a few hours. Limb weakness is usually proximal and asymmetrical. Upper limbs are more severely affected (48). Motor abnormality can range from mild weakness (4 out of 5 strength) to complete quadriplegia. Patients who are enterovirus positive are more likely to have quadriparesis, bulbar palsy, bowel or bladder dysfunction, and cardiovascular instability (21; 45).

The acute limb weakness may progress enough to affect respiratory muscles necessitating endotracheal intubation and mechanical ventilation. In a cohort of 238 patients (during 2018), 98% of patients needed hospitalization. Approximately half of the total patients required management in an intensive care unit. Twenty-three percent of patients required endotracheal intubation and mechanical ventilation (20).

A phase of prodromal illness often precedes the onset of weakness. In prodromal phase, patients experience upper respiratory tract manifestations such as cough, rhinorrhea, congestion, and gastrointestinal manifestations. The prodromal phase can extend from few days to few weeks, typically three to seven days, ending just before onset of weakness.

Certain clinical differences have been noted between patients reported in peak year versus patients seen in nonpeak years. McLaren and colleagues analyzed the clinical and laboratory data of acute flaccid myelitis that occurred during peak (2016 and 2018, n = 366) years and nonpeak (2015 and 2017, n = 50) years and noted that patients reported in peak years were younger (5.2 vs. 8.3 years) and had higher incidence of upper extremity involvement (33% vs. 16%) (29). Patients reported in peak years also had a higher incidence of preceding prodromal illness (90% vs, 62%). Evidence of enterovirus-D68 infection was observed only in patients seen during peak years.

Prognosis and complications

In a publication from Canada, Yea and colleagues noted that 88% (45/51) of patients with acute flaccid myelitis had significant improvement on the Kurtzke Expanded Disability Status Scale (EDSS) score (45). These authors compared follow-up disability status in enterovirus positive and enterovirus negative groups. They noted that patients who were enterovirus positive had more severe motor disability and were less likely to improve.

In a cohort of 12 children, Martin and colleagues described long-term outcomes (27). Complete follow-up data were available for eight patients. Six patients of the 12 had minimal to no improvement after one year. In addition, all had significant muscle atrophy of affected limb. Two patients had complete recovery. Matesanz and colleagues also had similar observations: a majority of patients after one year had only incomplete recovery (28). In a cohort of 14 patients, only two patients had recovered completely.

Extensive damage of anterior horn of the spinal cord can eventually result in atrophy of skeletal muscles months or years after acute illness (45).

Biological basis

Etiology and pathogenesis

A variety of viruses has been implicated in the causation of acute flaccid myelitis. These viruses include enteroviruses, coxsackie virus, many flavivirus, and adenovirus.

Enterovirus. In 2012, 2014, 2016, and 2018, the CDC reported outbreaks of acute flaccid myelitis, which coincided each time with peak in enterovirus-D68 transmission. Similar outbreak of acute flaccid myelitis and peak in enterovirus-D68 circulation were noted in many other parts of the world. Enterovirus-D68 is a predominant virus that is held responsible for the pathogenesis of acute flaccid myelitis. Enteroviruses-D68 is an RNA virus, and it belongs to the Picornaviridae family.

Another enterovirus, enterovirus-A71, was also implicated in the pathogenesis of acute flaccid myelitis. In 2018, a series of cases of acute flaccid myelitis, following enterovirus-A71 infection, have been reported from Colorado. Among 74 children with enterovirus neurologic disease, enterovirus-A71 was identified in 43 children. Ten (23%) children had acute flaccid myelitis. Enterovirus-A71 was identified either in stool, oropharyngeal, or nasopharyngeal specimens. In 20% of cases, virus was demonstrated in CSF (31).

In a cohort of 58 Canadian children with acute flaccid myelitis, 25 (43%) children had enterovirus demonstrated in at least one biological specimen: 16 cases with enterovirus-D68, two cases with enterovirus-A71, two with coxsackievirus, and 10 cases with untyped enterovirus (45).

Pathogenesis. Viral components are rarely recovered from the CSF. Animal studies have demonstrated presence of enterovirus-D68 VP2 protein within the anterior horn and subsequent damage of infected neurons (30). The precise mechanisms by which enterovirus enter in the spinal cord are not known. Experimental studies have demonstrated that enterovirus-D68 can spread anterior horn cells via their distal axons and spread by retrograde axonal transport to the neuronal cell bodies (18). Even via hematogenous route, virus can invade the spinal cord. The precise role of immune reaction against virus within the spinal cord is not known (26). An experimental study performed on human cell line demonstrated that EV-D68 infection causes the translocalization, cleavage, and aggregation of TDP-43, which is associated with enhanced degeneration of neurons. In human glioblastoma cells, the virus' protease 3C decreases the solubility of TDP-43, causing cell death. As a result, preventing 3C activity has potential to mitigate effects of EV-D68 infection (49).

Pathology. Detailed neuropathological studies of the brain or spinal cord from cases of acute flaccid myelitis have not been published. Haddad and colleagues performed a detailed pathological examination of musculocutaneous nerve obtained from a 5-year-old female patient who underwent nerve transfer for the treatment of weakness associated with residual acute flaccid myelitis (14). A redundant segment of the affected musculocutaneous nerve was subjected to pathologic analysis. Pathologic findings were consistent with axonal loss and demyelination. There was no evidence of regeneration.

Other viruses. In isolated reports, several other viruses have been implicated in the causation of an acute flaccid myelitis-like illness.

SARS-COV-2. Spinal cord involvement is rare in patients with COVID-19. Abdelhady and colleagues described a case of acute flaccid myelitis in the setting of COVID-19 (01).

Japanese encephalitis virus. Dev and colleagues described an isolated case from India; in this case a 13-year-old girl presented with acute flaccid myelitis and in CSF Japanese encephalitis virus was isolated (10).

Rabies. Pannu and colleagues described an unusual case resembling acute flaccid myelitis in which myelitis was a manifestation of paralytic rabies (35). MR T2/FLAIR hyperintensity was also noted in brainstem and basal ganglion.

Coxsackie virus. Coxsackie virus has also been implicated in the pathogenesis of acute flaccid myelitis. Kim and Cho described acute flaccid myelitis caused by coxsackie virus B1 where neuroimaging changes affected whole of the spinal cord (23). In another report, a 36-year-old man who presented with acute encephalopathy and flaccid paraplegia had neuroimaging that revealed a central cord lesion extending from C6-T12 (06).

Human echovirus 11. Human echovirus, a type of enterovirus, has been reported to cause acute flaccid myelitis (33).

Epidemiology

United States. In the U.S. cases of acute flaccid myelitis have been recorded since 2014. The number of acute flaccid myelitis cases peaks biannually in the late summer to early fall (43).

In 2014, nine children with acute flaccid myelitis were reported from Colorado. In the same year 23 similar cases were noted in California. Subsequently, the Centers for Disease Control and Prevention actively searched similar cases and tracked down 120 more children with acute flaccid myelitis.

The United States witnessed other outbreaks in 2016 and 2018 as well. The majority of cases were recorded between August to October. In the last epidemic of 2018, 238 cases were reported (20).

Since August 2014, the CDC has tracked down records of 729 confirmed cases. In 2019, there were 47 total confirmed cases in 18 states. In 2020, there were 33 confirmed cases in 18 states and the District of Columbia. In 2021, there were 28 total confirmed cases in 15 states. In 2022, there were 45 confirmed cases in 25 states. CDC also provided preliminary data for 2023. As of July 5, 2023, there have been a total of five confirmed cases reported across five different states (05).

Many viruses were circulating in the community at this same time of year. These viruses, particularly enterovirus, were held responsible for the increase in cases of acute flaccid myelitis in peak years (43).

Kidd and colleagues observed significant changes in the epidemiology of acute flaccid paralysis during 2019 and 2020 (22). There were 238 confirmed acute flaccid myelitis cases in 2018, 47 reported cases in 2019, and only 32 reported cases in 2020. Enterovirus D68 was demonstrated in 37 cases in 2018, in one case in 2019, and in none in 2020. Cases reported during 2019 and 2020 were more frequent in older children, and upper limb involvement was less frequent. Preceding febrile or respiratory illness and CSF pleocytosis were also less frequent.

Outbreaks outside the United States. Cases of acute flaccid myelitis have also been reported from Canada and several European and Asian countries. A similar link between enterovirus-D68 and acute flaccid myelitis has also been noted.

Canada. In Canada, between 2014 and 2018, 58 children with acute flaccid myelitis were identified. In 25 children, enterovirus virus was detected in at least one biological specimen from nonsterile sites. Yea and colleagues recorded presence of enterovirus-D68 in 16 cases (45). In two cases each, enterovirus-A71 and coxsackievirus were identified. In another 10 cases an untyped enterovirus was recognized.

In 2018 or 2019, 10 confirmed cases were reported in Canada along with 30 possible cases. The majority of cases were younger than 5-years-old. Enteroviruses were detected in 50% of confirmed cases (11).

Argentina. A cluster of six cases of acute flaccid myelitis were reported in Argentina in 2016 (03). In four patients, evidence of enterovirus-D68 infection was found.

Europe. During 2018, the United Kingdom reported 40 cases of acute flaccid myelitis (42). Detection of an enterovirus was recorded in 15 cases, mainly from specimens obtained from the upper respiratory tract. In nine cases, enterovirus-D68 was identified.

In a survey Knoester and colleagues collected data of 29 cases of acute flaccid myelitis from 12 different European countries (France = 5, Scotland = 5, Sweden = 3, Norway = 3, and Spain = 3) (24). In 27 cases, enterovirus-D68 infection was identified in respiratory samples. The current European data on the incidence of acute flaccid myelitis in children in the Netherlands indicated that, among 143 patients with limb weakness and/or CNS infection, 11 were diagnosed with acute flaccid myelitis between 2014 to 2019, with a mean incidence rate of 0.06 per 100,000 children/year. Increased acute flaccid myelitis cases coincided with periods of EV-D68 and EV-A71 circulation (16).

In Turkey, between 2016 and 2018, 34 cases of acute flaccid myelitis were observed (44). A preceding prodromal illness was present in all cases. Eighteen cases showed cerebrospinal fluid pleocytosis. In five cases, presence of enterovirus/rhinovirus was noted in respiratory specimens.

Australia. Between 2007 and 2017, the Australian Paediatric Active Enhanced Disease Surveillance Network (PAEDS) identified 97 cases of acute flaccid paralysis (02). In this cohort, 24 cases presented with acute transverse myelitis. Of these 24 acute transverse myelitis cases, 10 cases fulfilled the imaging criteria of acute flaccid myelitis. One of each case biological sample tested positive for enterovirus-D68 and enterovirus-A71 (02). Walker and colleagues estimated the annual Australian incidence of acute flaccid myelitis to be 0.07 cases per 100,000 person-years in children younger than 15 years of age (47). The authors reviewed all 915 acute flaccid paralysis cases that were reported during 2000 to 2018 and used the U.S. Council of State and Territorial Epidemiologists case definition to identify the subset of acute flaccid myelitis cases. The authors were able to identify 37 confirmed cases using magnetic resonance imaging findings and four probable cases on the basis of cerebrospinal fluid pleocytosis.

Asia. In 2015 in Japan, 59 cases of acute flaccid myelitis were identified (07). The acute flaccid myelitis epidemic coincided with the EV-D68 epidemic. Enterovirus-D68 virus was identified in nine patients.

In 2017 and 2018, an outbreak of acute flaccid myelitis was recorded in the Zhejiang province of China (13). Eighteen cases met the definition of acute flaccid myelitis. Biological samples tested positive for enterovirus-D68 infection in eight patients. Cerebrospinal fluid pleocytosis was noted in a majority of patients.

Nine children who met the case definition of acute flaccid myelitis were reported from India (39). All these patients presented with a febrile illness followed by limb weakness. Cerebrospinal fluid demonstrated pleocytosis and neuroimaging revealed characteristic central spinal cord signal abnormalities.

Prevention

There is currently no effective preventing strategy against acute flaccid myelitis. Awareness about epidemiological characteristics of enteroviruses circulation in the community can help in predicting and preparing against the outbreaks of acute flaccid myelitis. In the future, a vaccine that help in protecting children with enteroviruses may protect children from acute flaccid myelitis as well (34).

Differential diagnosis

Confusing conditions

There are three main differential diagnoses of acute flaccid myelitis: Guillain-Barré syndrome, spinal cord infarction, and transverse myelitis. There several other acute demyelinating myelopathies and neuromuscular disorders can present with acute flaccid weakness of limbs. Acute myelopathies like neuromyelitis optica spectrum disorder, myelin oligodendrocyte glycoprotein-antibody associated myelitis, multiple sclerosis, and acute disseminated encephalomyelitis can pose formidable diagnostic challenges. Lower motor neuron disorders like periodic paralysis and acute myasthenia gravis also come in the differential diagnosis of acute flaccid myelitis. In countries where poliomyelitis is still reported, poliovirus needs to be considered as a diagnostic possibility. A close watch of anti-SARS-COV-2 vaccine is also warranted, as this vaccine will be administered to billions of people in the future.

Differential diagnosis is generally difficult. Weakness in acute flaccid myelitis peaks more rapidly in comparison to weakness in Guillain-Barré syndrome (17). Weakness in acute flaccid myelitis is often asymmetric, and sensory manifestations are less common. CSF in Guillain-Barré syndrome is generally characterized by cyto-albuminic dissociation, with a disproportionate rise of proteins; in acute flaccid myelitis, protein concentrations are lower. Spinal cord magnetic resonance imaging signal abnormalities are noted only in patients with acute flaccid myelitis. Among children with acute flaccid myelitis, an investigation found that in 72% of cases of acute paralysis, acute flaccid myelitis was not considered in the initial differential diagnosis (15). These patients were not referred to acute care at the initial clinical encounter. Delayed recognition of acute flaccid myelitis was associated with delayed treatment and an increased risk of respiratory involvement.

Diagnostic workup

Diagnosis of acute flaccid myelitis is based on criteria given by the Centers for Disease Control and Prevention. The case ascertainment of acute flaccid paralysis is done in three categories: confirmed, probable, and suspect. The confirmed cases fulfil clinical criteria with confirmatory laboratory/imaging criteria. Probable cases fulfil clinical criteria; however, laboratory/imaging evidence remains presumptive. Diagnosis remains in “suspect” category if case fulfills clinical criteria along with supportive laboratory/imaging evidence. In a suspect case MRI evidence may not be conclusive (04; 09).

Table 1. Diagnostic Criteria of Acute Flaccid Myelitis

Magnetic resonance imaging. MRI of the spinal cord is the most valuable test in the diagnosis of acute flaccid myelitis. MRI typically demonstrates T2/FLAIR hyperintensity in the gray matter. Usually, gray matter hyperintensity is localized to cervical spinal segments. In many patients, gray matter hyperintensity is restricted to the thoracic region. Spinal cord grey matter hyperintensity may not be apparent on initial MRI. A normal MRI, if performed within the first 72 hours of weakness, does not rule out possibility of acute flaccid paralysis. Brainstem pontine lesions are noted in 44% of cases. In some cases, brachial plexus hyperintensity has also been noted (08; 45).

CSF. CSF examination characteristically demonstrates pleocytosis. The CSF protein may also be marginally elevated. CSF glucose level is always normal. Oligoclonal bands and antieaquaporin-4 antibodies are classically absent in CSF. CSF pleocytosis helps in differentiating acute flaccid myelitis from its close differential diagnosis, Guillain Barré syndrome. In Guillain Barré syndrome, CSF examination classically reveals cyto-albuminic dissociation (34).

Electrophysiology. In the majority of patients with acute flaccid myelitis, motor nerve conduction studies of the affected limbs demonstrate an absent or markedly reduced response to electrical stimulation (37). Nerve conduction and electromyographic studies are, generally, not mandatory in patients with acute flaccid myelitis.

Virology. Virologic studies, by reverse transcription polymerase chain reaction (RT-PCR) method in nasopharyngeal, oropharyngeal, and stool or rectal swab specimen, may detect enterovirus RNA (34). A metagenomic next-generation sequencing technique is now being used to identify enterovirus-specific antibodies in CSF. In a study, high levels of enterovirus-specific antibodies in CSF of patients with acute flaccid myelitis have been found (40).

Management

No satisfactory treatment option for acute flaccid myelitis is currently available. Treatment options that are frequently used include intravenous immunoglobulin, high-dose methylprednisolone, or plasmapheresis. Response to treatment is generally poor.

In mice enterovirus-D68-reactive human monoclonal antibodies have been demonstrated to protect mice from respiratory and neurologic disease when given either before or after enterovirus-D68 intraperitoneal inoculation (46). An experimental treatment model for acute flaccid myelitis associated with enterovirus D68 (EV-D68) was developed using a human-mouse chimeric monoclonal antibody. Treatment slowed the progression of paralysis and reduced viral titer in EV-D68-infected mice. The therapeutic effect was greatest in EV-D68 isolates that were neutralized by low concentrations of antibody, highlighting the potential of virus-specific immunotherapy for acute flaccid myelitis (38).

Fluoxetine, an antidepressant, has antiviral activities but its use in the treatment of acute flaccid myelitis failed to provide any benefit (32).

Nerve transfer. Nerve transfer surgery may help in restoring the function of shoulder girdle muscles. For example, spinal accessory nerve can be transferred to suprascapular nerve and the intercostal nerves to the axillary nerve (36). In a systematic review, Texakalidis and colleagues analyzed data from 44 patients (93 upper extremity nerve transfer) in five studies and noted that upper extremity nerve transfers appear to be effective and safe for patients with acute flaccid myelitis (41). In 38 patients, nerve transfer procedures were done with the aim of recovery of shoulder abduction or external rotation with a transfer to the axillary or suprascapular nerve. Shoulder abduction and external rotation functions were achieved in 40.7% (n = 11/27) and 60% (n = 6/10) of patients, respectively.

Outcomes

Long-term outcome in patients with acute flaccid myelitis is generally poor. An analysis of data of 238 patients revealed that 98% of patients required hospitalization (20). Approximately half of hospitalized patients needed an intensive care. Approximately 23% of patients had to be mechanically ventilated. The majority of long-term survivors are left with significant residual weakness requiring life-long rehabilitation. Isolated cases do recover completely (12). Patients who tested positive for enterovirus had poorer motor outcome (45).