Challenges in the Clinical Recognition of Acute Flaccid Myelitis and its Implications.

OBJECTIVES: To explore the challenges in diagnosing acute flaccid myelitis (AFM) and evaluate clinical features and treatment paradigms associated with under recognition. STUDY DESIGN: This was a retrospective multicenter study of pediatric patients (≤18 years) who were diagnosed with AFM from 2014 to 2018 using the Centers for Disease Control and Prevention's case definition. RESULTS: In 72% of the cases (126 of 175), AFM was not considered in the initial differential diagnosis (n = 108; 61.7%) and/or the patient was not referred for acute care (n = 90; 51.4%) at the initial clinical encounter, and this did not improve over time. Although many features of the presentation were similar in those initially diagnosed with AFM and those who were not; preceding illness, constipation, and reflexes differed significantly between the 2 groups. Patients with a non-AFM initial diagnosis more often required ventilatory support (26.2% vs 12.2%; OR, 0.4; 95% CI, 0.2-1.0; P = .05). These patients received immunomodulatory treatment later (3 days vs 2 days after neurologic symptom onset; 95% CI, -2 to 0; P = .05), particularly intravenous immunoglobulin (5 days vs 2 days; 95% CI, -4 to -2; P < .001). CONCLUSIONS: Delayed recognition of AFM is concerning because of the risk for respiratory decompensation and need for intensive care monitoring. A non-AFM initial diagnosis was associated with delayed treatment that could have a clinical impact, particularly as new treatment options emerge.

A Review of the Diagnosis and Management of Acute Flaccid Myelitis in the Emergency Department.

ABSTRACT: Since 2014, biennial rises in acute flaccid myelitis (AFM) have brought attention to this rare but debilitating condition. Children with AFM typically present with acute onset, flaccid weakness accompanied by longitudinally extensive gray matter injury demonstrated on magnetic resonance imaging. A clearer understanding of the epidemiology and suspected pathogenesis of AFM may result in increased recognition. The purpose of this review article is to guide emergency physicians in recognizing key clinical features, initiating diagnostic evaluation and providing appropriate interventions for children with suspected AFM.

A Nanobody-Mediated Virus-Targeting Drug Delivery Platform for the Central Nervous System Viral Disease Therapy.

Viral diseases of the central nervous system (CNS) represent a major global health concern. Difficulties in treating these diseases are caused mainly by the biological tissues and barriers, which hinder the transport of drugs into the CNS. To counter this, a nanobody-mediated virus-targeting drug delivery platform (SWCNTs-P-A-Nb) is constructed for CNS viral disease therapy. Viral encephalopathy and retinopathy (VER), caused by nervous necrosis virus (NNV), is employed as a disease model. SWCNTs-P-A-Nb is successfully constructed by employing single-walled carbon nanotubes, amantadine, and NNV-specific nanobody (NNV-Nb) as the nanocarrier, anti-NNV drug, and targeting ligand, respectively. Results showed that SWCNTs-P-A-Nb has a good NNV-targeting ability in vitro and in vivo, improving the specific distribution of amantadine in NNV-infected sites under the guidance of NNV-Nb. SWCNTs-P-F-A-Nb can pass through the muscle and gill and be excreted by the kidney. SWCNTs-P-A-Nb can transport amantadine in a fast manner and prolong the action time, improving the anti-NNV activity of amantadine. Results so far have indicated that the nanobody-mediated NNV-targeting drug delivery platform is an effective method for VER therapy, providing new ideas and technologies for control of the CNS viral diseases. IMPORTANCE CNS viral diseases have resulted in many deadly epidemics throughout history and continue to pose one of the greatest threats to public health. Drug therapy remains challenging due to the complex structure and relative impermeability of the biological tissues and barriers. Therefore, development in the intelligent drug delivery platform is highly desired for CNS viral disease therapy. In the study, a nanobody-mediated virus-targeting drug delivery platform is constructed to explore the potential application of targeted therapy in CNS viral diseases. Our findings hold great promise for the application of targeted drug delivery in CNS viral disease therapy.

Acute Flaccid Myelitis.

Acute flaccid myelitis (AFM) is an incompletely understood neurologic disorder occurring in epidemic fashion causing weakness ranging from mild paresis to devastating paralysis in children and some adults. This article reviews the case definition of AFM as well as its epidemiology and association with enteroviral infection. The clinical presentation, diagnostic investigation with particular attention to electrodiagnostics, acute management, and surgical options are described. Clinical outcomes and considerations for acute and long-term rehabilitation management are discussed extensively based on review of current literature, highlighting avenues for further study.

Acute Flaccid Myelitis: A Multidisciplinary Protocol to Optimize Diagnosis and Evaluation.

Acute flaccid myelitis is an emerging neurologic disease, first described in 2014 and predominantly affecting young children. Acute flaccid myelitis cases tend to spike every 2 years, in the late summer to fall, and the next peak is expected in 2020. The diagnosis of acute flaccid myelitis is often delayed, leading to suboptimal evaluation, including incomplete laboratory assessment. Acute and chronic morbidity are high, and a standardized, multidisciplinary approach to evaluation and treatment is essential to optimizing outcomes. In a review of acute flaccid myelitis patients treated in 2018 at our institution, we noted considerable variability in days to presentation, evaluation, and treatment. In response, the authors developed a protocol for the evaluation and management of pediatric patients suspected of having acute flaccid myelitis. The protocol was developed using local experience/case review, expert consensus, and the relevant literature. The protocol spans the spectrum of care, from initial evaluation in a primary care or emergency setting, to acute hospital management and evaluation and long-term inpatient and rehabilitation settings. The purpose of this report is both to share the findings from our 2018 case review and to disseminate our acute flaccid myelitis protocol. Our hope is that publication of our protocol will both inform the development of a standardized approach to acute flaccid myelitis and to encourage other centers to form a multidisciplinary acute flaccid myelitis team to provide expert care throughout the disease process, from presentation to recovery.

Central Nervous System Infections in the Immunocompromised Adult Presenting to the Emergency Department.

Over the past 2 decades, the population of immunocompromised patients has increased dramatically in the United States. These patients are at elevated risk for both community-acquired and opportunistic central nervous system infections. We review the most common and serious central nervous system pathogens affecting these patients and outline a diagnostic and therapeutic approach to their management in the emergency department. We recommend a broad diagnostic evaluation, including neuroimaging and cerebrospinal fluid studies where appropriate, empiric antimicrobial therapy, and early involvement of subspecialists to provide comprehensive care for these complex patients.

Characteristics of Upper Extremity Recovery in Acute Flaccid Myelitis: A Case Series.

BACKGROUND: Clinical characteristics and timing associated with nonsurgical recovery of upper extremity function in acute flaccid myelitis are unknown. METHODS: A single-institution retrospective case series was analyzed to describe clinical features of acute flaccid myelitis diagnosed between October of 2013 and December of 2016. Patients were consecutively sampled children with a diagnosis of acute flaccid myelitis who were referred to a hand surgeon. Patient factors and initial severity of paralysis were compared with upper extremity muscle strength outcomes using the Medical Research Council scale every 3 months up to 18 months after onset. RESULTS: Twenty-two patients with acute flaccid myelitis (aged 2 to 16 years) were studied. Proximal upper extremity musculature was more frequently and severely affected, with 56 percent of patients affected bilaterally. Functional recovery of all muscle groups (≥M3) in an individual limb was observed in 43 percent of upper extremities within 3 months. Additional complete limb recovery to greater than or equal to M3 after 3 months was rarely observed. Extraplexal paralysis, including spinal accessory (72 percent), glossopharyngeal/hypoglossal (28 percent), lower extremity (28 percent), facial (22 percent), and phrenic nerves (17 percent), was correlated with greater severity of upper extremity paralysis and decreased spontaneous recovery. There was no correlation between severity of paralysis or recovery and patient characteristics, including age, sex, comorbidities, prodromal symptoms, or time to paralysis. CONCLUSIONS: Spontaneous functional limb recovery, if present, occurred early, within 3 months of the onset of paralysis. The authors recommend that patients without signs of early recovery warrant consideration for early surgical intervention and referral to a hand surgeon or other specialist in peripheral nerve injury. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Association of outcomes in acute flaccid myelitis with identification of enterovirus at presentation: a Canadian, nationwide, longitudinal study.

BACKGROUND: Acute flaccid myelitis (AFM) is characterised by rapid onset of limb weakness with spinal cord grey-matter abnormalities on MRI scan. We aimed to assess whether detection of enterovirus in respiratory or other specimens can help predict prognosis in children with AFM. METHODS: In this nationwide, longitudinal study, we evaluated the significance of detection of enterovirus in any sample in predicting outcomes in a cohort of Canadian children younger than 18 years presenting with AFM to tertiary paediatric hospitals in Canada in 2014 and 2018. All patients fulfilled the 2015 US Centers for Disease Control and Prevention case definition for definite AFM or probable AFM. Clinical data, laboratory findings, treatment, and neuroimaging results were collected (follow up period up to 5 years). We assessed neurological function and motor outcomes using Kurtzke's Expanded Disability Status Scale (EDSS) and a Weakest Limb Score. FINDINGS: 58 children with AFM (median age 5·1 years, IQR 3·8-8·3) were identified across five of Canada's ten provinces and three territories. 25 (43%) children had enterovirus detected in at least one specimen: 16 (64%) with EV-D68, two (8%) with EV-A71, two (8%) with coxsackievirus, 10 (40%) with untyped enterovirus. Children who were enterovirus positive were more likely than those that were negative to have had quadriparesis (12 [48%] of 25 vs four [13%] of 30; p=0·028), bulbar weakness (11 [44%] of 25 vs two [7%] of 30; p=0·028), bowel or bladder dysfunction (14 [56%] of 25 vs seven [23%] of 30; p=0·040), cardiovascular instability (nine [36%] of 25 vs one [3%] of 30; p=0·028), and were more likely to require intensive care unit admission (13 [52%] of 25 vs 5 [17%] of 30; p=0·028). On MRI, most children who were enterovirus positive showed brainstem pontine lesions (14 [61%] of 23), while other MRI parameters did not correlate with enterovirus status. Median EDSS of enterovirus positive (EV+) and enterovirus negative (EV-) groups was significantly different at all timepoints: baseline (EDSS 8·5, IQR 4·1-9·5 vs EDSS 4·0, IQR 3·0-6·0; p=0·0067), 3 months (EDSS 4·0, IQR 3·0-7·4 vs EDSS 3·0, IQR 1·5-4·3; p=0·0067), 6 months (EDSS 3·5, IQR 3·0-7·0 vs EDSS 3·0, IQR 1·0-4·0; p=0·029), and 12 months (EDSS 3·0, IQR 3·0-6·9 vs EDSS 2·5 IQR 0·3-3·0; p=0·0067). Kaplan-Meier survival analysis of a subgroup of patients showed significantly poorer motor recovery among children who tested positive for enterovirus than for those who tested negative (p=0·037). INTERPRETATION: Detection of enterovirus in specimens from non-sterile sites at presentation correlated with more severe acute motor weakness, worse overall outcomes and poorer trajectory for motor recovery. These results have implications for rehabilitation planning as well as counselling of families of children with these disorders. The findings of this study support the need for early testing for enterovirus in non-CNS sites in all cases of AFM. FUNDING: None.

A ten-year retrospective evaluation of acute flaccid myelitis at 5 pediatric centers in the United States, 2005-2014.

BACKGROUND: Acute flaccid myelitis (AFM) is a severe illness similar to paralytic poliomyelitis. It is unclear how frequently AFM occurred in U.S. children after poliovirus elimination. In 2014, an AFM cluster was identified in Colorado, prompting passive US surveillance that yielded 120 AFM cases of unconfirmed etiology. Subsequently, increased reports were received in 2016 and 2018. To help inform investigations on causality of the recent AFM outbreaks, our objective was to determine how frequently AFM had occurred before 2014, and if 2014 cases had different characteristics. METHODS: We conducted a retrospective study covering 2005-2014 at 5 pediatric centers in 3 U.S. regions. Possible AFM cases aged ≤18 years were identified by searching discharge ICD-9 codes and spinal cord MRI reports (>37,000). Neuroradiologists assessed MR images, and medical charts were reviewed; possible cases were classified as AFM, not AFM, or indeterminate. RESULTS: At 5 sites combined, 26 AFM cases were identified from 2005-2013 (average annual number, 3 [2.4 cases/100,000 pediatric hospitalizations]) and 18 from 2014 (12.6 cases/100,000 hospitalizations; Poisson exact p<0.0001). A cluster of 13 cases was identified in September-October 2014 (temporal scan p = 0.0001). No other temporal or seasonal trend was observed. Compared with cases from January 2005-July 2014 (n = 29), cases from August-December 2014 (n = 15) were younger (p = 0.002), more frequently had a preceding respiratory/febrile illness (p = 0.03), had only upper extremities involved (p = 0.008), and had upper extremity monoplegia (p = 0.03). The cases had higher WBC counts in cerebrospinal fluid (p = 0.013). CONCLUSION: Our data support emergence of AFM in 2014 in the United States, and those cases demonstrated distinctive features compared with preceding sporadic cases.

Update on acute flaccid myelitis: recognition, reporting, aetiology and outcomes.

Acute flaccid myelitis, defined by acute flaccid limb weakness in the setting of grey matter lesions of the spinal cord, became increasingly recognised in 2014 following outbreaks in Colorado and California, temporally associated with an outbreak of enterovirus D68 respiratory disease. Since then, there have been biennial increases in late summer/early fall. A viral infectious aetiology, most likely enteroviral, is strongly suspected, but a definitive connection has yet to be established. Patients typically present with asymmetric weakness, maximal proximally, in the setting of a febrile illness. MRI demonstrates T2/FLAIR abnormalities in the central grey matter of the spinal cord, and cerebrospinal fluid typically shows a lymphocytic pleocytosis with variable elevation in protein. The weakness may be progressive over several days and involve respiratory muscles, making early recognition and close monitoring essential. Other complications in the acute period may include autonomic instability and bowel/bladder involvement. There is no clear recommended treatment at this time, although intravenous immunoglobulin, steroids and plasma exchange have been used. Intensive therapies and rehab services have shown benefit in maximising function, and surgical interventions may be considered in cases without optimal response to therapies. Close attention should also be paid to psychosocial factors. Prognosis is generally guarded, and additional factors that predict final outcome, including host factors and treatment effects, have yet to be elucidated. Multicentre collaborative efforts will be required to provide answers about this rare but serious disorder.

Enterovirus D68 in a 6-year-old acute flaccid myelitis case in China, 2018: a case report.

BACKGROUND: Acute flaccid myelitis (AFM) are reported to be associated with enterovirus D68 infection. Though an increasing number of AFM cases were reported with EV-D68 infection in the US, few such cases have been found in China. CASE PRESENTATION: A 6-year-old boy presented with acute flaccid myelitis (AFM) involving left arm after fever and respiratory symptoms for 6 days. Computed Tomography (CT) revealed inflammation in both lungs and magnetic resonance imaging (MRI) of the brain and spine showed swelling in the left frontal lobe and brain stem. The patient was diagnosed with meningomyelitis. EV-D68 was detected from pharyngeal samples 36 days after the onset of the disease. CONCLUSION: We report the first EV-D68 infection in case of AFM in mainland China. AFM surveillance systems is recommended to be established in China to guide diagnosis, case reporting, and specimen collection and testing for better understanding its etiologies.

Unmet Needs in the Evaluation, Treatment, and Recovery for 167 Children Affected by Acute Flaccid Myelitis Reported by Parents Through Social Media.

BACKGROUND: We aimed to characterize the outcomes of 167 children affected by acute flaccid myelitis by leveraging the power of social media. METHODS: Members of a closed social media (Facebook) group were invited to participate in an anonymous online survey. Descriptive statistics were applied to quantitative responses, and free-text responses were grouped into themes using a grounded theory approach. RESULTS: Caregivers provided information about 167 affected children; 77% were at least 6 months since onset. Clinical features matched those of larger published case series (e.g., walking impairment in 76.7%, intravenous immunoglobulin treatment in 80.8%; 28.2% tested positive for Enterovirus D68; 17% children had asthma before acute flaccid myelitis onset). Mean duration of initial hospitalization was 49.1 (S.D., 74.0) days, and of initial inpatient rehabilitation was 42.3 (S.D., 67.6) days. Among challenges, parents frequently reported delays in diagnosis, including lack of neurological examination at initial medical evaluation for weakness. Other challenges included familial and professional impact of protracted hospitalizations, uncertainty about cause or prognosis of acute flaccid myelitis, and the dynamic nature of care needs in growing children. The social media group played a critical role not only for social support but also for dissemination of rehabilitation approaches and of networks of expert clinicians. CONCLUSIONS: Children with acute flaccid myelitis have persistent and dynamic deficits, but many continue to show ongoing functional improvements beyond the initial expected window of recovery. In an emerging disease paralyzing young children, social media can strengthen knowledge networks and focus on rehabilitation.

Current status of enterovirus D68 worldwide and in Taiwan.

Enterovirus D68 was first identified in 1962 and caused a worldwide outbreak starting from the North America in 2014. Enterovirus D68 has been in continuous circulation among many countries recently, including Taiwan. Reports also reveal high seroprevalence, which indicates that the disease burden of enterovirus D68 may be underestimated via viral culture or polymerase chain reaction results. Although most infected cases have mild respiratory illness, severe complications including acute flaccid myelitis and acute respiratory distress syndrome have also been reported. In the position of an emerging pathogen, enterovirus D68 poses a threat to public health and may cause devastating diseases. Diverse severity of neurological sequelae remains inevitable among acute flaccid myelitis patients, but no curable treatment is available currently. According to the management suggestions of the American Centers of Disease Control, uses of corticosteroids and plasmapheresis are either preferred or avoided and intravenous immunoglobulin also has no clear indication in the treatment for acute flaccid myelitis. In this review article, we provide information about the epidemiology, clinical recognition and treatment strategy of enterovirus D68. Better understanding of this disease is the foothold for advanced investigation and monitoring in the future.

Acute Flaccid Myelitis: Characteristics and Outcomes of 2014 and 2016 Cases at a Single Center.

Acute flaccid myelitis (AFM) is a rare condition associated with spinal cord gray matter abnormalities and frequent persistent motor deficits in the limbs. We present our experience with the diagnosis, management, and outcomes of affected children in 2014 and 2016, emphasizing features that should trigger early consideration of AFM. Early viral testing may increase the rate of detecting associated viruses.

Acute flaccid myelitis and enterovirus D68: lessons from the past and present.

Acute flaccid myelitis is characterized by the combination of acute flaccid paralysis and a spinal cord lesion largely restricted to the gray matter on magnetic resonance imaging. The term acute flaccid myelitis was introduced in 2014 after the upsurge of pediatric cases in the USA with enterovirus D68 infection. Since then, an increasing number of cases have been reported worldwide. Whereas the terminology is new, the clinical syndrome has been recognized in the past in association with several other neurotropic viruses such as poliovirus.Conclusion: This review presents the current knowledge on acute flaccid myelitis with respect to the clinical presentation and its differential diagnosis with Guillain-Barré syndrome and acute transverse myelitis. We also discuss the association with enterovirus D68 and the presumed pathophysiological mechanism of this infection causing anterior horn cell damage. Sharing clinical knowledge and insights from basic research is needed to make progress in diagnosis, treatment, and prevention of this new polio-like disease. What is Known: • Acute flaccid myelitis (AFM) is a polio-like condition characterized by rapid progressive asymmetric weakness, together with specific findings on MRI • AFM has been related to different viral agents, but recent outbreaks are predominantly associated with enterovirus D68. What is New: • Improving knowledge on AFM must increase early recognition and adequate diagnostic procedures by clinicians. • The increasing incidence of AFM urges cooperation between pediatricians, neurologists, and microbiologists for the development of treatment and preventive options.

Acute Flaccid Myelitis: Something Old and Something New.

Since 2014, acute flaccid myelitis (AFM), a long-recognized condition associated with polioviruses, nonpolio enteroviruses, and various other viral and nonviral causes, has been reemerging globally in epidemic form. This unanticipated reemergence is ironic, given that polioviruses, once the major causes of AFM, are now at the very threshold of global eradication and cannot therefore explain any aspect of AFM reemergence. Instead, the new AFM epidemic has been temporally associated with reemergences of nonpolio enteroviruses such as EV-D68, until recently thought to be an obscure virus of extremely low endemicity. This perspective reviews the enigmatic epidemiologic, virologic, and diagnostic aspects of epidemic AFM reemergence; examines current options for clinical management; discusses future research needs; and suggests that the AFM epidemic offers important clues to mechanisms of viral disease emergence.

Acute Flaccid Myelitis Associated With Enterovirus D68: A Review.

Acute flaccid myelitis is a disease that affects the anterior horn cells of the spinal cord, leading to rapid onset of flaccid paralysis. Recent biennial epidemics, beginning in the summer of 2014, have been associated with enterovirus D68, although the underlying pathophysiology is unknown. Patients present with asymmetric flaccid weakness of the extremities, with cranial neuropathy and without encephalopathy, and often have residual disability. Here we review the current literature on this disabling disease and discuss treatment modalities and ongoing research.