Eye on ID

Acute flaccid myelitis: A mystery disease

Acute flaccid myelitis, or AFM, is not a new syndrome or disease. The classical cause of the syndrome is infection with the poliomyelitis virus. Of course, there has been no poliomyelitis originating in the United States since 1979. Sporadic cases of nonpolio AFM have been recognized in the U.S. for many years after the eradication of polio, but it was not until 2014, when there was a surge of cases in the U.S., that it reached the national consciousness and was given the name “acute flaccid myelitis” rather than “polio-like syndrome,” “acute flaccid paralysis” or other names that had been previously attached to the syndrome.

Donald Kaye

The CDC’s criteria for a confirmed diagnosis of AFM include acute onset of flaccid limb weakness in one or more limbs with confirmation by MRI of a spinal cord lesion largely restricted to gray matter and spanning one or more vertebral segments. If there is no MRI confirmation available, the case is considered probable, provided there is cerebrospinal fluid (CSF) showing pleocytosis (white blood cell count [WBC] > 5 cells/mm3). There was no official tracking of cases of AFM in the U.S. before 2014; however, from August through December of that year, there was a national outbreak of the disease that resulted in 120 cases. As of Feb. 15 — including those 120 cases from 2014 — there has been a total of 552 AFM cases confirmed after review by the CDC. The agency is attempting to collect retrospective MRI data to determine the annual number of yearly cases before 2014.

Epidemiology in the US

AFM causes disease primarily in children. More than 90% of cases have been aged younger than 18 years, and most of these have been aged 2 to 8 years. The majority of cases occur during August through October. The male-to-female ratio has been about 60:40. A very interesting observation is that larger outbreaks of AFM have occurred in alternate years from 2014 to 2018. For example, there were 120 cases in 2014, 22 cases in 2015, 149 cases in 2016, 35 cases in 2017 and 215 cases in 2018. This last number will probably increase because records are still under review.

The 2014 outbreak occurred against a backdrop of a large national outbreak of human enterovirus D68 (EV-D68) infection in children. EV-D68 (one of more than 100 nonpolio enteroviruses) was first described in 1962, but case clusters were not recognized until about 2008, when reports of respiratory infection, some severe, caused by EV-D68 came in from around the world. In 2014, EV-D68 was demonstrated in respiratory specimens of 20 of the 120 cases of AFM, and non-D68 enteroviruses were found in 21 of the cases. Cases of AFM associated with EV-D68 were also reported during the 2016 U.S. outbreak and from multiple other countries as well.

AFM has been linked to other viruses in addition to EV-D68. Three different viruses have been isolated from the spinal fluids in four of the 527 AFM cases in the U.S. — coxsackievirus A16, EV-A71, and EV-D68. Cases of AFM also have been linked to infection with West Nile virus and rhinoviruses. In 2018, 11 of 14 cases of AFM in Colorado were linked to EV-A71. Although AFM was temporally and geographically linked to EV-D68 in the 2014 U.S. outbreak, and EV-A71 has been linked to cases in the U.S. and elsewhere globally, close linkage with any one virus has not been demonstrated in the outbreaks in the U.S. after 2014.

As described later, almost all patients with AFM have a prodrome suggestive of a viral illness before onset of weakness. Therefore, by the time specimens were taken to search for viral etiologies, enough time may have passed in many cases to result in negative results for specimens that may have been positive previously. It is unclear at this point whether AFM is an active infectious or postinfectious inflammatory process. At present, EV-D68 seems to be the most likely candidate for the cause of many cases of AFM in the U.S.

Clinical syndrome

The syndrome of flaccid myelitis acutely affecting one or more limbs (most often upper limbs) typically follows a febrile respiratory or gastrointestinal illness. The illness usually has an onset with a median of 7 days and a usual range of 3 to 10 days before the onset of AFM. The onset of AFM has often been associated with a return of fever and headache, stiff neck, pain in the neck, back or affected limb and/or occasionally altered mental status. Some cases reported “numbness” in the affected limb. Of the 120 cases reported by the CDC in the 2014 outbreak, 51 reported pain and 28 had cranial nerve dysfunction. Interestingly, 35 of the 120 had brainstem lesions in addition to spinal cord lesions on MRI.

Diagnosis

CSF has generally shown a mild pleocytosis (WBCs < 100 cells/mm3), with mainly lymphocytes and mild elevations of protein; the glucose is usually normal. MRI imaging of the spinal cord usually shows gray matter lesions spanning multiple vertebral levels and sometimes brainstem lesions in the cranial nerve nuclei.

Management

Virtually all patients with AFM have required hospitalization. The mortality rate has been very low, with few deaths occurring in 2014 among patients who were immunocompromised. Management of the disease has been mainly supportive, with physical therapy and occupational therapy playing an important role. Some patients require ventilatory support. Many cases have been treated with antiviral agents, along with one or more of the following: corticosteroids, IV immunoglobulins, interferon, fluoxetine and plasmapheresis. However, these agents have had no reported impact on the illness. As of November 2018, the CDC stated, “There is no indication that any specific targeted therapy or intervention should be either preferred or avoided in the treatment of AFM.”

Prevention

The CDC suggests taking precautions to avoid viral illnesses because AFM seems to follow or be caused by a viral illness. The suggestions are frequent hand-washing for children, avoiding touching the face with unwashed hands and avoiding close contact with people who are sick. Also recommended is cleaning and disinfecting frequently touched surfaces, including toys and doorknobs, having the child cover coughs and sneezes with a tissue or upper shirt sleeve — not hands — and keeping sick children at home.

EV-A71 genotype C4 is a major cause of large epidemics of hand-foot-and-mouth disease and herpangina in young children in the Far East, causing significant mortality. An effective inactivated vaccine has been developed against EV-A71 and tested in China. Vaccine development against other enteroviruses is also reportedly underway, but pending further elucidation of the etiology of cases of AFM and considering the rarity of the disease, commercial development of vaccines to prevent AFM is unlikely to proceed in the U.S. at present. For comparison, before the availability of poliomyelitis vaccine, there were over 15,000 cases of paralytic poliomyelitis yearly in the U.S.

Course

Recovery from AFM has generally been very slow, taking months or longer, with muscle atrophy in the affected limb(s) in many cases. There is usually functional improvement, but often residual weakness is reported. The more severely affected patients have had more delayed or incomplete recoveries.

Conclusions

It seems highly likely that AFM is a syndrome that can follow infection with a number of different viruses (especially enteroviruses), some perhaps still unidentified. It is unknown if it is an active infectious or postinfectious inflammatory process. It is unclear why the incidence of the syndrome seems to be increasing and why it seems to peak in alternating years, at least in the U.S. Improved surveillance may explain some of the apparent increase in the numbers of reported cases. AFM is a syndrome searching for a cause(s), possible prevention and treatment — truly a mystery disease.

Disclosure: Kaye reports no relevant financial disclosures.

Acute flaccid myelitis, or AFM, is not a new syndrome or disease. The classical cause of the syndrome is infection with the poliomyelitis virus. Of course, there has been no poliomyelitis originating in the United States since 1979. Sporadic cases of nonpolio AFM have been recognized in the U.S. for many years after the eradication of polio, but it was not until 2014, when there was a surge of cases in the U.S., that it reached the national consciousness and was given the name “acute flaccid myelitis” rather than “polio-like syndrome,” “acute flaccid paralysis” or other names that had been previously attached to the syndrome.

Donald Kaye

The CDC’s criteria for a confirmed diagnosis of AFM include acute onset of flaccid limb weakness in one or more limbs with confirmation by MRI of a spinal cord lesion largely restricted to gray matter and spanning one or more vertebral segments. If there is no MRI confirmation available, the case is considered probable, provided there is cerebrospinal fluid (CSF) showing pleocytosis (white blood cell count [WBC] > 5 cells/mm3). There was no official tracking of cases of AFM in the U.S. before 2014; however, from August through December of that year, there was a national outbreak of the disease that resulted in 120 cases. As of Feb. 15 — including those 120 cases from 2014 — there has been a total of 552 AFM cases confirmed after review by the CDC. The agency is attempting to collect retrospective MRI data to determine the annual number of yearly cases before 2014.

Epidemiology in the US

AFM causes disease primarily in children. More than 90% of cases have been aged younger than 18 years, and most of these have been aged 2 to 8 years. The majority of cases occur during August through October. The male-to-female ratio has been about 60:40. A very interesting observation is that larger outbreaks of AFM have occurred in alternate years from 2014 to 2018. For example, there were 120 cases in 2014, 22 cases in 2015, 149 cases in 2016, 35 cases in 2017 and 215 cases in 2018. This last number will probably increase because records are still under review.

The 2014 outbreak occurred against a backdrop of a large national outbreak of human enterovirus D68 (EV-D68) infection in children. EV-D68 (one of more than 100 nonpolio enteroviruses) was first described in 1962, but case clusters were not recognized until about 2008, when reports of respiratory infection, some severe, caused by EV-D68 came in from around the world. In 2014, EV-D68 was demonstrated in respiratory specimens of 20 of the 120 cases of AFM, and non-D68 enteroviruses were found in 21 of the cases. Cases of AFM associated with EV-D68 were also reported during the 2016 U.S. outbreak and from multiple other countries as well.

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AFM has been linked to other viruses in addition to EV-D68. Three different viruses have been isolated from the spinal fluids in four of the 527 AFM cases in the U.S. — coxsackievirus A16, EV-A71, and EV-D68. Cases of AFM also have been linked to infection with West Nile virus and rhinoviruses. In 2018, 11 of 14 cases of AFM in Colorado were linked to EV-A71. Although AFM was temporally and geographically linked to EV-D68 in the 2014 U.S. outbreak, and EV-A71 has been linked to cases in the U.S. and elsewhere globally, close linkage with any one virus has not been demonstrated in the outbreaks in the U.S. after 2014.

As described later, almost all patients with AFM have a prodrome suggestive of a viral illness before onset of weakness. Therefore, by the time specimens were taken to search for viral etiologies, enough time may have passed in many cases to result in negative results for specimens that may have been positive previously. It is unclear at this point whether AFM is an active infectious or postinfectious inflammatory process. At present, EV-D68 seems to be the most likely candidate for the cause of many cases of AFM in the U.S.

Clinical syndrome

The syndrome of flaccid myelitis acutely affecting one or more limbs (most often upper limbs) typically follows a febrile respiratory or gastrointestinal illness. The illness usually has an onset with a median of 7 days and a usual range of 3 to 10 days before the onset of AFM. The onset of AFM has often been associated with a return of fever and headache, stiff neck, pain in the neck, back or affected limb and/or occasionally altered mental status. Some cases reported “numbness” in the affected limb. Of the 120 cases reported by the CDC in the 2014 outbreak, 51 reported pain and 28 had cranial nerve dysfunction. Interestingly, 35 of the 120 had brainstem lesions in addition to spinal cord lesions on MRI.

Diagnosis

CSF has generally shown a mild pleocytosis (WBCs < 100 cells/mm3), with mainly lymphocytes and mild elevations of protein; the glucose is usually normal. MRI imaging of the spinal cord usually shows gray matter lesions spanning multiple vertebral levels and sometimes brainstem lesions in the cranial nerve nuclei.

Management

Virtually all patients with AFM have required hospitalization. The mortality rate has been very low, with few deaths occurring in 2014 among patients who were immunocompromised. Management of the disease has been mainly supportive, with physical therapy and occupational therapy playing an important role. Some patients require ventilatory support. Many cases have been treated with antiviral agents, along with one or more of the following: corticosteroids, IV immunoglobulins, interferon, fluoxetine and plasmapheresis. However, these agents have had no reported impact on the illness. As of November 2018, the CDC stated, “There is no indication that any specific targeted therapy or intervention should be either preferred or avoided in the treatment of AFM.”

PAGE BREAK

Prevention

The CDC suggests taking precautions to avoid viral illnesses because AFM seems to follow or be caused by a viral illness. The suggestions are frequent hand-washing for children, avoiding touching the face with unwashed hands and avoiding close contact with people who are sick. Also recommended is cleaning and disinfecting frequently touched surfaces, including toys and doorknobs, having the child cover coughs and sneezes with a tissue or upper shirt sleeve — not hands — and keeping sick children at home.

EV-A71 genotype C4 is a major cause of large epidemics of hand-foot-and-mouth disease and herpangina in young children in the Far East, causing significant mortality. An effective inactivated vaccine has been developed against EV-A71 and tested in China. Vaccine development against other enteroviruses is also reportedly underway, but pending further elucidation of the etiology of cases of AFM and considering the rarity of the disease, commercial development of vaccines to prevent AFM is unlikely to proceed in the U.S. at present. For comparison, before the availability of poliomyelitis vaccine, there were over 15,000 cases of paralytic poliomyelitis yearly in the U.S.

Course

Recovery from AFM has generally been very slow, taking months or longer, with muscle atrophy in the affected limb(s) in many cases. There is usually functional improvement, but often residual weakness is reported. The more severely affected patients have had more delayed or incomplete recoveries.

Conclusions

It seems highly likely that AFM is a syndrome that can follow infection with a number of different viruses (especially enteroviruses), some perhaps still unidentified. It is unknown if it is an active infectious or postinfectious inflammatory process. It is unclear why the incidence of the syndrome seems to be increasing and why it seems to peak in alternating years, at least in the U.S. Improved surveillance may explain some of the apparent increase in the numbers of reported cases. AFM is a syndrome searching for a cause(s), possible prevention and treatment — truly a mystery disease.

PAGE BREAK

Disclosure: Kaye reports no relevant financial disclosures.