Acute flaccid myelitis patients : researchers found direct evidence of enterovirus infection in the cerebrospinal fluid (CSF)


A new study analyzing samples from patients with and without acute flaccid myelitis (AFM) provides additional evidence for an association between the rare but often serious condition that causes muscle weakness and paralysis, and infection with non-polio enteroviruses.

The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, funded the research, which was conducted by investigators at Columbia University’s Center for Infection and Immunity and investigators from the Centers for Disease Control and Prevention. The findings are reported in the online journal mBio.

There have been 570 confirmed cases since CDC began tracking AFM in August 2014. AFM outbreaks were reported to the CDC in 2014, 2016 and 2018.

AFM affects the spinal cord and is characterized by the sudden onset of muscle weakness in one or more limbs.

Spikes in AFM cases, primarily in children, have coincided in time and location with outbreaks of EV-D68 and a related enterovirus, EV-A71.

Both of these viruses typically cause mild respiratory illness from which most people recover fully.

Despite the epidemiological link between enterovirus circulation and AFM cases, evidence of direct causality has not been found.

The researchers first looked for direct evidence of enterovirus infection in the cerebrospinal fluid (CSF) of 13 children and one adult diagnosed with AFM in 2018.

They also examined five CSF samples taken from people with other central nervous system diseases.

The team used a new tool they developed called VirCapSeq-VERT, which can detect any viral genetic material that is at least 60% like that of any known vertebrate virus.

They found enteroviral genetic material (EV-A71) in only the one adult AFM case and genetic material from another enterovirus (echovirus 25) in one of the non-AFM cases.

The investigators also sought indirect evidence of enterovirus infection by looking for antibodies to enteroviruses made by the immune system in response to an infection.

The team developed a microchip assay, AFM-SeroChip-1, that detects the presence of antibodies generated in response to any human enterovirus (EV-A, EV-B, EV-C or EV-D) infection.

Using this assay, the team tested the same 14 CSF samples from the AFM patients.

They also tested CSF samples taken from 11 adults with central nervous system conditions, such as multiple sclerosis, and from 10 children with Kawasaki disease, none of whom had AFM.

EV-specific antibodies were detected in the CSF of 79% (11 of 14) of the AFM cases.

Of those, six samples were positive for EV-D68, strongly indicating that enterovirus had been in the central nervous system, even though it had not been detected by VirCapSeq-VERT.

None of the CSF samples from children with Kawasaki disease had antibodies that reacted with any enterovirus.

While other etiologies of AFM continue to be investigated, this study provides further evidence that enterovirus infection may be a factor in AFM.

In the absence of direct detection of a pathogen, antibody evidence of pathogen exposure within the central nervous system can be an important indicator of the underlying cause of disease, the researchers note.

Enterovirus (EV) D68 was first isolated in 1962 in Berkeley, California, the United States.[1]

Four children had severe respiratory tract infection and pneumonia associated with EV D68. In 2014, there was an outbreak of EV D68 infection occurred in the United States.[2] 

Another outbreak of EV D68, B3 lineage, occurred in Sweden in 2016.[3] Most of them suffered from respiratory tract symptoms, whereas some patients had severe respiratory infection that required endotracheal intubation and intensive unit care.

Among them, a few polio-like acute flaccid myelitis (AFM) cases presenting as acute flaccid paralysis (AFP) have also been reported in the literature.[13] 

Mortality due to AFM caused by EV D68 is very low[3]; however, the prognosis was guarded. Many patients continued to experience sequelae of flaccid paralysis, or even bowel or bladder dysfunction.

In Taiwan, the Centers of Disease Control had 32 specimens that tested positive for EV D68 during the period 2014 to 2015. All patients had respiratory symptoms without paralysis. The patient group consisted of 19 male and 13 female patients.

The age ranged from 0 to 49 years. More than half (59.4%) patients were aged younger than 5 years.

Herein, we present the first case of AFM caused by EV D68 infection in Taiwan in 2016.

Case report

A 5-year-old boy, who was previously healthy, experienced fever (up to 38.8°C) on August 13, 2016. He also experienced headache, dizziness, vomiting, productive cough, nasal obstruction, and rhinorrhea. Azithromycin was prescribed at another hospital. On August 15, 2016, left arm weakness was noted in the patient. Transient right lower leg pain was noted on the next day. On August 17, 2016, he experienced right leg weakness (grade 4). Urination and defecation were normal. Therefore, he was admitted.

After admission, a physical examination revealed that the muscle power of the left arm was grade 1 and that of the left forearm was grade 3. The muscle power of the right arm and left leg was normal. The muscle power of the right thigh was grade 4. The left scapula showed a winging sign. The deep tendon reflexes (DTRs) of the left biceps, brachioradialis, and triceps were 1+. The left deltoid DTR was 2+. The cremasteric reflex and anal reflex were normal. Sensory dermatomes were also normal.

He had neck pain with nuchal rigidity. Brudzinski sign and Kernig sign were positive. He had no ankle clonus or spasticity. The Babinski sign was negative. Other physical examinations indicated lymphadenopathy over the neck.

There was no infected throat, vesicles, or ulcers in the oral cavity. The breathing sound was slightly coarse. No rales, rhonchi, or wheezing was heard.

The abdomen was soft, tympanic, and without tenderness. The abdominal bowel sound indicated hypoactivity.

Blood laboratory data revealed a normal leukocyte count and normal C-reactive protein level. A chest x-ray showed increased infiltration of both lungs. A neck x-ray showed no bone or mass lesion. Cerebral spinal fluid (CSF) data showed pleocytosis (270/μL) with a predominance of polymorphonuclear (PMN) leukocytes (PMNL: 69%; lymphocytes: 31%). The CSF glucose level was normal (48 mg/dL), and the CSF protein level was slightly elevated (83 mg/dL). The observed opening pressure was 20 cm H2O. The serum IgG level was 2300 mg/dL, and the CSF IgG level was 33.9 mg/dL.

The IgG index was 0.682, which was within normal range. We also obtained virus cultures from the blood, CSF, throat, and stools of the patient. Vancomycin and cefotaxime were added to the treatment regimen.

A brain and neck computed tomography (CT) on August 17, 2016 revealed no mass lesions. The patient complained of neck and back pain on the next day. Brudzinski sign and Kernig sign remained positive. Increased intracranial pressure was suspected and glycerin was administered.

The pain was relieved gradually after glycerin infusion. Brudzinski sign and Kernig sign were negative after treatment. T2-weighted magnetic resonance imaging (MRI) of the brain and neck on August 19, 2016 revealed a swelling change over C1–T5 of the spinal cord (Figs. ​(Figs.1 and ​and2).2). The patient was diagnosed with meningomyelitis. Moreover, the muscle power of the left leg decreased. Intravenous immunoglobulin (IVIG) 1 g/kg was started on the same day. We also changed vancomycin to ciprofloxacin due to suspected mycoplasmal infection.

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Figure 1
Sagittal T2WI MRI of the spinal cord showing enhanced signal over C1–T5 (arrow). MRI = magnetic resonance imaging, T2WI = T2-weighted image.
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Figure 2
Transverse T2WI MRI of the sixth segment of the cervical spinal cord showing the involvement of gray matter (arrow). MRI = magnetic resonance imaging, T2WI = T2-weighted image.

After IVIG 1 g/kg administration, the muscle power of his hand improved to normal. Pulse steroid therapy was delivered from August 20, 2016, for 3 days. Rehabilitation was started then.

The muscle power of the distal upper extremity improved to grade 4. Then, IVIG 1 g/kg was administered again on August 23, 2016. Bacterial cultures from the blood, CSF, and throat of the patient showed no growth.

No fever was noted after admission. The muscle power improved after medical treatment and rehabilitation. On discharge (August 25, 2016), the muscle power levels of the left hand, left forearm, and left arm were grades 5, 4, and 2, respectively.

The winging of the left scapula improved. The DTR over the left upper extremity decreased slightly.

The muscle power in both lower extremities was grade 5. The patient could ascend and descend stairs unassisted with alternate feet.

Finally, the Centers for Disease Control in Taiwan reported that the throat viral culture was identified as EV D68 (B3 lineage). After discharge, the patient again experienced myalgia in both legs and weakness of left leg 2 days later. Subsequently, pulse steroid therapy was used for 3 days. Then, oral prednisolone (1 mg/kg/d) was prescribed and tapered weekly for approximately 4 weeks.

The muscle power of the left proximal upper extremity improved to grade 4. He had sequel of mild left arm weakness (grade 4+) after following up for 1 year (Fig. ​(Fig.3).

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Figure 3
Timeline of clinical course of the case.

This study was approved by ethic committee of Cathay General Hospital and with the informed consent from the parent for publication.

More information: Nischay Mishra et al, Antibodies to Enteroviruses in Cerebrospinal Fluid of Patients with Acute Flaccid Myelitis, mBio (2019).DOI: 10.1128/mBio.01903-19

Journal information: mBio
Provided by NIH/National Institute of Allergy and Infectious Diseases


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