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Acute flaccid myelitis: cause, diagnosis, and management
Abstract
on behalf of the AFM working group* Acute flaccid myelitis (AFM) is a disabling, polio-like illness mainly affecting children. Outbreaks of AFM have occurred across multiple global regions since 2012, and the disease appears to be caused by non-polio enterovirus infection, posing a major public health challenge. The clinical presentation of flaccid and often profound muscle weakness (which can invoke respiratory failure and other critical complications) can mimic several other acute neurological illnesses. There is no single sensitive and specific test for AFM, and the diagnosis relies on identification of several important clinical, neuroimaging, and cerebrospinal fluid characteristics. Following the acute phase of AFM, patients typically have substantial residual disability and unique long-term rehabilitation needs. In this Review we describe the epidemiology, clinical features, course, and outcomes of AFM to help to guide diagnosis, management, and rehabilitation. Future research directions include further studies evaluating host and pathogen factors, including investigations into genetic, viral, and immunological features of affected patients, host-virus interactions, and investigations of targeted therapeutic approaches to improve the long-term outcomes in this population.
Supplementary resources (3)
Data
December 2020
Data
December 2020
... 3,4 The recent outbreaks of viral disorders such as enterovirus D68, flavivirus infections such as West Nile virus (WNV) and Zika virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have highlighted the susceptibility of the spinal cord to disease processes leading to myelitis and myelopathies. [5][6][7][8] Expanding the diagnostic spectrum of inflammatory and noninflammatory myelopathies underlies the need to establish precise etiologic diagnosis and treatment approaches. The escalating use of precision medicine methods, neuroimaging techniques, and immunologic biomarkers has contributed to better evaluation of patients with spinal cord disorders, and the spectrum of etiologies associated with myelopathies is expanding rapidly. ...
... 6,7 During the season of enterovirus circulation, frequently in the summer and fall, outbreaks of acute flaccid myelitis may be observed in children. 5,23 In the case of acute vascular myelopathy, such as a spinal cord stroke, triggering factors may include intense exercising, weightlifting, extreme flexion, or hyperextension of the neck during exercise activities or neck and spine trauma. 10,24 Similarly, worsening symptoms during and after active exercise or steroid treatment are frequently observed in chronic evolving vascular myelopathies such as those associated with dural AVF 17 as illustrated in CASE 1-1. ...
... A spinal cord MRI demonstrated a longitudinally extensive T2 hyperintense lesion in the thoracic and lumbar spinal cord with subtle marginal contrast enhancement. The axial images showed expanded symmetric central cord signal abnormalities (FIGURE [1][2][3][4][5]. CSF analysis showed no pleocytosis but an elevated protein concentration (75 mg/dL). ...
OBJECTIVE
This article describes an integrative strategy to evaluate patients with suspected myelopathy, provides advice on diagnostic approach, and outlines the framework for the etiologic diagnosis of myelopathies.
LATEST DEVELOPMENTS
Advances in diagnostic neuroimaging techniques of the spinal cord and improved understanding of the immune pathogenic mechanisms associated with spinal cord disorders have expanded the knowledge of inflammatory and noninflammatory myelopathies. The discovery of biomarkers of disease, such as anti–aquaporin 4 and anti–myelin oligodendrocyte glycoprotein antibodies involved in myelitis and other immune-related mechanisms, the emergence and identification of infectious disorders that target the spinal cord, and better recognition of myelopathies associated with vascular pathologies have expanded our knowledge about the broad clinical spectrum of myelopathies.
ESSENTIAL POINTS
Myelopathies include a group of inflammatory and noninflammatory disorders of the spinal cord that exhibit a wide variety of motor, sensory, gait, and sensory disturbances and produce major neurologic disability. Both inflammatory and noninflammatory myelopathies comprise a broad spectrum of pathophysiologic mechanisms and etiologic factors that lead to specific clinical features and presentations. Knowledge of the clinical variety of myelopathies and understanding of strategies for the precise diagnosis, identification of etiologic factors, and implementation of therapies can help improve outcomes.
... Мышечный тонус в пораженной конечности резко снижается, сухожильные рефлексы отсутствуют. При проведении МРТ выявляются очаги поражения серого вещества спинного мозга [14]. Один из наиболее грозных симптомов ОВM -дыхательная недостаточность, требующая искусственной вентиляции легких, поэтому пациенты с подозрением на ОВМ должны быть немедленно госпитализированы [14]. ...
... При проведении МРТ выявляются очаги поражения серого вещества спинного мозга [14]. Один из наиболее грозных симптомов ОВM -дыхательная недостаточность, требующая искусственной вентиляции легких, поэтому пациенты с подозрением на ОВМ должны быть немедленно госпитализированы [14]. ...
... Электромиография (ЭМГ) игольчатым электродом в ряде случаев выявляет признаки поражения мотонейронов передних рогов спинного мозга. В связи со сходной клинической картиной ОВМ следует дифференцировать от иных патологий, включая инфекционные полинейропатии, острый диссеминированный энцефаломиелит, заболевания спектра оптикомиелита Дейвика и инфекционные миелиты [14]. ...
Acute flaccid myelitis is a syndrome characterized as the development of acute flaccid paralysis of one or more limbs due to lesions of the anterior horns of the spinal cord, which occurs against the background of a viral infection. More than 300 acute flaccid paralysis cases are registered in the Russian Federation annually, most of them are of a non-infectious etiology. In some cases, patients develop a complex of symptoms similar to poliomyelitis, but without isolation of polioviruses from stool samples. Clinical characteristics of such cases include acute onset, fever, persistent peripheral asymmetric paresis/paralysis of predominantly proximal parts of the limbs, and absence of pathological reflexes, pelvic disturbances, or pyramidal symptoms. In literature, such complex of symptoms is referred as acute flaccid myelitis. We provide an analysis of 18 cases of acute flaccid myelitis detected in the Russian Federation in the period from 2015 to 2019. A clear seasonality of the disease from July to November was noted. Studies of faecal samples, cerebrospinal fluid and blood samples did not reveal the pathogen. In all patients, regardless of therapy, there was a positive trend, but complete recovery was not achieved: paresis of varying severity persisted, mainly in the proximal extremities Therefore, acute flaccid myelitis cases as acute flaccid paralysis cases of unknown etiology require an additional observation and an expanded algorithm of laboratory investigation aimed to finding a possible pathogen.
... Before the acute neurologic injury phase, the viral prodromal tends to resolve and comprises flaccid weakness in the limbs along with the lower motor neuron disorder. The neurologic manifestations persist rapidly (within hours to days), and fever, muscular pain (in one or more muscles), as well as flaccid weakness of either of the limbs, can reoccur [33]. The exact pathophysiology of AFM is not fully understood, but it is believed to involve an inflammatory response that affects the gray matter of the spinal cord, specifically the anterior horn cells. ...
... It mainly affects the neuraxial part of the trunk, respiratory muscles, neck, and face muscle paralysis (leading to difficulty in swallowing), and eye muscles. The lack of tone and firmness of muscles means deep muscle hypertonicity, excessive physical sensitivity of the skin (hyperesthesia), and abnormal sensitivity towards pain (hyperalgesia) [33]. In 1934, a work published by Sabin and Wright had shown a case of primary acute infectious myelitis with clinical manifestations like the absence of the Babinski sign, no knee jerks, and meningeal irritation [34]. ...
... Many cases of permanent disability have been noted. Physical disability is common after 1 year of diagnosis [33]. ...
Acute Flaccid Myelitis (AFM) is a neurological condition in the anterior portion of the spinal cord and can be characterised as paraplegia (paralysis of the lower limbs), and cranial nerve dysfunction. These lesions are caused by the infection due to Enterovirus 68 (EV-D68); a member of the Enterovirus (EV) family belongs to the Enterovirus species within the Picornavirus family and a Polio-like virus. In many cases, the facial, axial, bulbar, respiratory, and extraocular muscles were affected, hence reducing the overall quality of the patient's life. Moreover, severe pathological conditions demand hospitalisation and can cause mortality in a few cases. The data from previous case studies and literature suggest that the prevalence is high in paediatric patients, but careful clinical assessment and management can decrease the risk of mortality and paraplegia. Moreover, the clinical and laboratory diagnosis can be performed by Magnetic resonance imaging (MRI) of the spinal cord followed by Reverse transcription polymerase chain reaction (rRT-PCR) and VP1 seminested PCR assay of the cerebrospinal fluid (CSF), stool, and serum samples can reveal the disease condition to an extent. The primary measure to control the outbreak is social distancing as advised by public health administrations, but more effective ways are yet to discover. Nonetheless, vaccines in the form of the whole virus, live attenuated, sub-viral particles, and DNA vaccines can be an excellent choice to treat these conditions. The review discusses a variety of topics, such as epidemiology, pathophysiology, diagnosis/clinical features, hospitalisation/mortality, management/treatment, and potential future developments.
... For the sake of completeness, we included in Table 2 the most frequent lower motor neuron diseases, underlining the typical clinical features to consider in the differential diagnosis [1,[32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49]. ...
... This could suggest that the final outcome after surgery is determined by the presence of a precise dural defect in myelography imaging. Amyotrophic lateral sclerosis (ALS) [1] Rapid progression in 3-5 years Older age of onset (in median 65 years) Upper motor neuron involvement Hirayama syndrome [32] Younger age of onset Prominent distal involvement Worsening with cervical flexion Progressive muscular atrophy (PMA) [33] Older age Slower disease progression than ALS Spinal muscular atrophy (SMA) type IV [34] Genetic inheritance X-linked bulbospinal muscular atrophy (Kennedy's disease) [35] Bulbar involvement Sensory neuropathy Chin fasciculations Sexual/endocrinological dysfunctions and gynecomastia Multifocal motor neuropathy (MMN) [36] Single nerves distribution Less prominence of atrophy, cramps, and fasciculation Multifocal demyelinating motor neuropathy with or without conduction block Anti-GM1 antibodies (20%) Cervical spondylotic myelopathy [37] Upper motor neuron signs Neck or radicular pain Possible sensory disturbance Sphincter disturbance (e.g., urgency incontinence) Spinal dural arteriovenous fistula [38] Upper motor neuron signs Sensory sacral deficits Most frequently involvement of lower limbs Variable disease course (stepwise or acutely), worsen by physical activity Cord hyperintense signal on T2-weighted images (cord edema) Transthyretin amyloidosis (ATTR) [39] Sensory signs Dysautonomia Multisystemic (cardiac, ocular, and renal) involvement Progressive sensory or sensory-motor axonal polyneuropathy Positive genetic tests Inclusion body myositis (IBM) [40] Dysphagia Early and asymmetric involvement of proximal lower limbs Anti-NT5C1a antibodies (30-60%) West Nile virus and poliomyelitis [41] Early onset (< 21 years) Rapid progression (over days) Preceded by viral prodromes of fever, malaise, myalgia, nausea, vomiting, or diarrhea Encephalopathy Bowel and bladder dysfunction Post-polio syndrome [42] Preceded by acute paralysis and a following period of partial or complete functional recovery Myasthenia gravis with MuSK antibody [43] Rapid progression (over days) Extraocular muscle weakness Anti-MuSK antibody Response to immunotherapy Facial onset sensory and motor neuronopathy (FOSMN) [44] Sensory loss (facial, scalp, neck, trunk, and upper limbs) Cranial-to-caudal spreading Post-radiation syndrome [45] Absence of long-term progression Myokymia Peripheral nerve hyperexcitability [46] Rapid progression (over days) Rarely weakness and muscle wasting Autonomic features Myokymia Voltage-gated potassium channel antibody (note: may be present in up to 50% of patients who have neuromyotonia) ...
Intraspinal cerebrospinal fluid (CSF) collection has been reported as a rare cause of lower motor neuron (LMN) disorder. We report a case of bibrachial diplegia associated with intraspinal CSF collection and perform a systematic literature review.
A 52-year-old man developed a bibrachial amyotrophy over 6 years, confirmed by the presence of cervical subacute neurogenic changes at electromyography (EMG). Brain magnetic resonance imaging (MRI) revealed cerebral siderosis, while spine MRI showed a ventral longitudinal intraspinal fluid collection (VLISFC) from C2 to L2. No CSF leakage was localized at myelography; a conservative treatment was chosen. We searched for all published cases until 30th April 2023 and extrapolated data of 44 patients reported in 27 publications.
We observed a male predominance, a younger disease onset compared to amyotrophic lateral sclerosis, and a quite long disease duration, highlighting a slow disease progression. LMN signs were more frequently bilateral, mostly involving C5-C6 myotomes. Around 61% of patients presented additional symptoms, but only three referred to a history of headache. Accordingly, CSF opening pressure was mostly normal. Spinal MRI revealed the presence of VLISFC and in some cases myelomalacia. EMG patterns displayed both chronic and subacute neurogenic change in the cervical region. The disease course mainly depended on the treatment choice, which was mostly represented by a surgical approach when a specific dural defect was detected by imaging.
Bibrachial diplegia due to VLISFC can be a treatable cause of focal amyotrophy and presents some clinical and radiological “red flags” which cannot be missed by a clinical neurologist.
... There have also been reports of cases of acute perivascular myelinoclasis, acute disseminated encephalomyelitis (ADEM), stroke, Guillain-Barré syndrome, transverse myelitis, concurrent optic neuritis, and neuropathic pain in Mpox infection [2,48,[55][56][57]. ...
... CSF testing could provide useful information if there are concerns about involvement of the CNS [48]. CSF can be characterized by elevated opening pressure, elevated white blood cell counts, mild lymphocytic pleocytosis, possibly neutrophilic early on, normal to low glucose level, and normal to mildly increased protein level [48,55]. Furthermore, anti-orthopoxvirus IgM detection in CSF may be useful in diagnosing Mpox-induced encephalitis and may persist for a long time. ...
This review is attempted in view of World Health Organization (WHO) warning on Monkeypox virus (Mpox) to summarize the available data regarding the potential effect on central nervous system (CNS), its complications, and diagnostic methods. We combed various international databases (including Scopus, PubMed, Web of Science, and Google Scholar) for articles mentioning Mpox infection, orthopox infection, and the central nervous system that were published between the years 2000 and 2022. Further evidence was evaluated from relevant studies published in the literature. There is emerging evidence of central nervous system neurological involvement. In addition to encephalopathy, which is one of the most serious neurologi-cal complications of Mpox, the most common complications of Mpox infection are headache, weakness, myalgia, anorexia, and altered consciousness. Anxiety and depression have also been identified as the most common psychiatric symptoms in these patients.
... Current rehabilitation and surgical interventions address restoring respiration function and upper and lower extremity function. There is no information published on the recovery of head control (4)(5)(6). For children who are ventilator-dependent and do not have head control, a common practice in rehabilitation is passive positioning for head support. ...
... The training protocol was developed using current trunk and head control literature available on SCI, Cerebral Palsy, and an iterative approach to addressing head control deficits (6,9,11,12,19) (Figure 3). ...
Background
Acute flaccid myelitis (AFM) occurs rarely in children and adolescents when damage to spinal motor neurons rapidly causes flaccid paralysis of limb, trunk, and neck muscles and potentially respiratory failure. When neck muscles are weakened or paralyzed, a child loses head control, severely compromising engagement with their environment. Compensation for lack of head control is achieved with external support devices attached to a wheelchair, but there is no indication in the AFM literature of therapeutic efforts to restore head control. In this case series, we explore the possibility of the recovery of head control when children with AFM received activity-based restorative therapies (ABRTs) guided by principles targeting motor control.
Case description
Three children, two male and one female, aged 6, 9, and 7, with a history of AFM-onset at 5, 7, and 4 years respectively, enrolled in an activity-based restorative therapies outpatient program targeting activation of the neuromuscular system below the lesion. Each of them lacked head control, was either ventilator-dependent or had a tracheostomy, and was a power wheelchair user via hand/foot control.
Methods
Activity-based restorative therapies were provided 5 days/week: 1.5 h of activity-based locomotor training and 1.5 h of activity-based neuromuscular electrical stimulation.
Results
An approach to addressing head/neck control developed iteratively across disciplines, from complete compensation with passive external head support to emerging head control during diverse tasks, e.g., sitting, reaching, driving a power chair, sit-to-stand, standing, stepping on a treadmill, and walking. Key principles identified and employed were (a) passive facilitation, (b) external head support, (c) posterior head support, (d) graded manual facilitation, and (e) independent head control.
Discussion
The recovery of head control in children with paralysis due to AFM may be accelerated when executing a step-wise progression to effectively target and challenge head control in parallel with activity-based restorative therapies. In treating three children with a chronic lack of head control, a therapeutic strategy was iteratively developed guided by scientific principles, e.g., segmental assessment of control, to promote recovery of head control. While this strategy is encouraging, gaps in sensitive and responsive measurement instruments and treatment technologies persist in guiding assistance, challenging, and promoting independent head control.
... Conversely, steroid treatment elevated spinal cord viral titers and worsened outcomes. 37 The incidence and mortality from EVA71 in Taiwan declined dramatically between 1998 and 2020 when proactive EV surveillance and preventative measures were put in place. 38 ...
Background and Aims
Disease X represents the possibility that an unidentified infection may spread globally and start a pandemic. This study explored various aspects of emerging non‐polio enteroviruses (NPEVs) as a possible source of “Disease X,” an enigmatic agent declared by the World Health Organization, and discussed the potential impact of NPEVs on global public health.
Methods
In this perspective article, we collected information from publicly available sources such as Google Scholar, PubMed, and Scopus. We used NPEVs, viral diseases, pandemics, and zoonotic diseases as keywords. We extracted information from the most relevant articles.
Results
Notable outbreaks caused by NPEVs include enterovirus D68 (EV‐D68) and enterovirus A71 (EV‐A71), among many others. With a focus on therapeutic and preventative components, alternate modes of therapy, and the development of broad‐spectrum antivirals, this analysis looks at the origin, epidemiology, genetic alterations, transmission dynamics, and disease pathophysiology of NPEVs. The information presented in the review indicates the current risk assessment of NPEVs, taking into account the following factors: the need for research and therapeutic interventions, the diversity of clinical manifestations, the impact of genetic variability on virulence, the persistence of emergence despite vaccination efforts, recurrent outbreaks, and the global impact of these viruses.
Conclusion
There is a possibility that NPEVs could trigger global pandemics based on their zoonotic origins and urges for complete readiness, continuous research, cooperation, and a comprehensive strategy to combat emerging infectious diseases in a constantly changing global environment. It is peak time to acknowledge how important it is to abide by safety and health laws to prevent these illnesses.
... Thirty-nine patients, 35 with confirmed and 4 with probable AFM (see Appendix Supplemental Table 1) [1][2][3] , were referred to our clinic for surgical reconstruction from 2011 to 2019 after initial care by their pediatricians. Patient demographics are presented in Table I. ...
Background
Acute flaccid myelitis (AFM) is a disabling, poliomyelitis-like illness that mainly affects children. Although various surgical interventions are performed for intractable paralysis due to AFM, the timing of surgery and its long-term outcomes have yet to be established, especially for shoulder reconstruction. This study aimed to analyze the midterm outcomes of nonsurgically and surgically treated upper-extremity AFM and the factors influencing shoulder functional outcomes after surgical reconstruction.
Methods
We retrospectively examined 39 patients with AFM in 50 upper extremities between 2011 and 2019. The degree of spontaneous recovery of completely paralyzed muscles was evaluated at a median of 3, 6, and 37 months after the onset of paralysis. Twenty-seven patients with 29 extremities underwent surgery involving nerve transfer, muscle-tendon transfer, or free muscle transfer for shoulder, elbow, and hand reconstruction.
Results
Patients with complete paralysis of shoulder abduction at 6 months did not show later recovery. Twenty-two patients with 24 extremities underwent shoulder surgery, and all but 1 were followed for at least 24 months after surgery. Although postoperative shoulder abduction recovery was similar between transfer of the spinal accessory nerve and of the contralateral C7 nerve root to the suprascapular nerve, the outcomes obtained with spinal accessory nerve transfer had more variability, likely related to latent spinal accessory nerve paralysis, shoulder instability related to pectoralis major paralysis, and the type of paralysis. Shoulder abduction recovery was also greatly affected by scapulothoracic joint movement. In contrast, the outcomes of the elbow flexion and hand reconstructions were more consistent and acceptable.
Conclusions
All patients had loss of shoulder abduction, and restoration of shoulder function was less predictable and depended on the quality of the donor nerves and recovery of the synergistic muscles. Strict donor nerve selection and additional nerve transfer for shoulder reconstruction are imperative for satisfactory outcomes.
Level of Evidence
Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.
... По мнению O.C. Murphy и соавт. (2021), через 3 мес от начала болезни при плохой динамике восстановления больным показано выполнение транспозиции нервов [42]. P.A. Pino и соавт. ...
The term “acute flaccid myelitis” is used to describe a condition characterized by acute flaccid paralysis of the limb, as well as damage to the motor neurons of the spinal cord. The absence of specific treatment, severe neurological deficit that persists in 75–95 % of patients in the long term indicates its severity.
The aim of the work is to describe acute flaccid myelitis in children, modern methods of treatment, and estimate the effectiveness of nerve transfers for restoration of the upper limb function.
The search for publications was carried out in the PubMed/MEDLINE, Google Scholar databases from 2003 to 2022, and data from the US Centers for Disease Control and Prevention (https://www.cdc.gov) were used. There were analyzed surgical treatments of 57 children with paresis of the upper extremities due to AFM (105 nerve transfers). Restoration of shoulder function (neurotization of n. axillaris, n. suprascapularis ) was performed in 57 (54.3 %) patients, elbow flexion (neurotization of n. musculocutaneus ) in 37 (35.2 %), elbow extension in 9 (8.5 %) (neurotization of the branch of n. radialis to m. triceps brachii ), fingers flexion in 1 (1 %) (neurotization of the n. interosseus anterior branch), fingers extension in 1 (1 %) (neurotization of n. interosseus posterior ).
The review demonstrated the effectiveness of nerve transfers in children with paresis of the upper extremities due to acute flaccid myelitis who were operated up to 1 year from the onset of the disease.
... Generally, MS affects white matter and spares grey matter, while selective gray matter involvement, resembling an H-shape, is seen in MOGAD [7,11]. Yet, conditions like spinal cord infarction or viral myelitis may present similarly [13][14][15]. Anterior horn "polio-like" involvement may suggest pathologies such as anterior spinal artery infarct, chronic compressive myelopathy, or viral myelitis [16][17][18]. The level of spinal cord involvement is a less reliable indicator since both tumors and pseudotumors may involve either cervical or thoracic segments. ...
Simple Summary
This review delineates the diagnostic challenges in distinguishing neoplastic from non-neoplastic spinal cord pathologies, highlighting the importance of a comprehensive radiological evaluation. An integral component of this evaluation is the detailed analysis of MRI findings to accurately diagnose lesions that mimic spinal cord tumors. It emphasizes the need for careful consideration of common non-surgical myelopathies in differential diagnoses due to their higher prevalence. Additionally, the review discusses the principal etiologies of spinal pseudotumors, including inflammatory, vascular, and infectious neurological diseases. This approach aims to refine diagnostic accuracy and enhance clinical decision-making by providing a nuanced understanding of the varied manifestations of spinal cord pathologies.
Abstract
Differentiating neoplastic from non-neoplastic spinal cord pathologies may be challenging due to overlapping clinical and radiological features. Spinal cord tumors, which comprise only 2–4% of central nervous system tumors, are rarer than non-tumoral myelopathies of inflammatory, vascular, or infectious origins. The risk of neurological deterioration and the high rate of false negatives or misdiagnoses associated with spinal cord biopsies require a cautious approach. Facing a spinal cord lesion, prioritizing more common non-surgical myelopathies in differential diagnoses is essential. A comprehensive radiological diagnostic approach is mandatory to identify spinal cord tumor mimics. The diagnostic process involves a multi-step approach: detecting lesions primarily using MRI techniques, precise localization of lesions, assessing lesion signal intensity characteristics, and searching for potentially associated anomalies at spinal cord and cerebral MRI. This review aims to delineate the radiological diagnostic approach for spinal cord lesions that may mimic tumors and briefly highlight the primary pathologies behind these lesions.
... We have long known that numerous viruses have the potential to cause various neuropathology in both children and adults. Neurological diseases such as encephalitis, meningitis, acute cerebellar ataxia, vasculopathy, and acute flaccid myelitis have all been directly related to viral etiologies (Costa & Sato, 2020;Grose et al., 2023;McGill et al., 2017;Murphy et al., 2021;Parvez & Ohtsuki, 2022). Thus, it is not surprising that SARS-CoV-2 infection also has the potential to affect the nervous system. ...
While COVID-19 is no longer the “hot-topic” it was 2 years ago, its prevalence and impact are still significant. In 2022, the CDC estimated that over 90% of children from 6 months to 17 years old have had COVID-19 infection. While most children have limited and mild symptoms, a substantial subset experiences significant neurological manifestations and/or complications which may lead to long-lasting morbidity or even mortality. Such neurological manifestations of SARS-CoV-2 include acute encephalitis, seizures, central demyelinating disease, cerebrovascular events, peripheral neurological disorders, and chronic symptoms in the setting of long COVID, which may affect up to 25% of infected children and adolescents. Given the high prevalence of COVID-19 in the general and pediatric population, it is essential for clinicians to understand the full breadth of its potential effects. In this article, we review common neurological manifestations and sequelae of SARS-CoV-2 in the pediatric population and describe their prevalence, timing, and associated neuroimaging findings.
Background
Acute flaccid myelitis (AFM) is a rare debilitating poliomyelitis-like illness characterized by the sudden onset of flaccid palsy in the extremities. The purpose of this study was to report the mid-term clinical course of knee extension in AFM and the effect of contralateral obturator nerve-to-femoral nerve transfer (CONFNT) for restoration of knee extension in AFM.
Methods
Twenty-six patients with lower extremity palsy due to AFM were referred to our clinic for possible surgical reconstruction. Their median age was 4.0 years, and the first evaluation of the palsy was done at a mean of 6 months after paralysis onset. The paralysis ranged from lower limb monoplegia to quadriplegia. The clinical course of knee extension was assessed using the British Medical Research Council (MRC) grading scale and surface electromyography (EMG). Five patients with unilateral paralysis of knee extension underwent CONFNT.
Results
The mean follow-up period for 19 limbs with complete paralysis of knee extension (MRC grade M0) in 13 patients who were evaluated for spontaneous recovery was 43 months. No patient who had complete paralysis of knee extension at >6 months and paralysis of the hip adductor muscle had improvement of knee extension to better than M2. Five of the original 26 patients were treated with CONFNT and followed for a mean of 61 months. Two of 5 patients had the CONFNT ≤8 months after paralysis onset and obtained M4 knee extension. Only 1 of the 3 patients with CONFNT performed approximately 12 months after paralysis onset obtained M3 knee extension; the other 2 obtained only M1 or M2 knee extension.
Conclusions
The paralysis of the lower extremity in our patients with AFM was similar to that in poliomyelitis. However, in AFM, spontaneous recovery of knee extension was possible if there were signs of recovery from hip adductor paralysis up to 6 months after paralysis onset. CONFNT may enhance the recovery of knee extension and seems to be a reliable reconstruction for restoring knee extension if performed no more than 8 months after paralysis onset.
Level of Evidence
Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.
Currently nearly one-quarter of admissions to pediatric intensive care units (PICUs) worldwide are for neurocritical care diagnoses that are associated with significant morbidity and mortality. Pediatric neurocritical care is a rapidly evolving field with unique challenges due to not only age-related responses to primary neurologic insults and their treatments but also the rarity of pediatric neurocritical care conditions at any given institution. The structure of pediatric neurocritical care services therefore is most commonly a collaborative model where critical care medicine physicians coordinate care and are supported by a multidisciplinary team of pediatric subspecialists, including neurologists. While pediatric neurocritical care lies at the intersection between critical care and the neurosciences, this narrative review focuses on the most common clinical scenarios encountered by pediatric neurologists as consultants in the PICU and synthesizes the recent evidence, best practices, and ongoing research in these cases. We provide an in-depth review of (1) the evaluation and management of abnormal movements (seizures/status epilepticus and status dystonicus); (2) acute weakness and paralysis (focusing on pediatric stroke and select pediatric neuroimmune conditions); (3) neuromonitoring modalities using a pathophysiology-driven approach; (4) neuroprotective strategies for which there is evidence (e.g., pediatric severe traumatic brain injury, post–cardiac arrest care, and ischemic stroke and hemorrhagic stroke); and (5) best practices for neuroprognostication in pediatric traumatic brain injury, cardiac arrest, and disorders of consciousness, with highlights of the 2023 updates on Brain Death/Death by Neurological Criteria. Our review of the current state of pediatric neurocritical care from the viewpoint of what a pediatric neurologist in the PICU needs to know is intended to improve knowledge for providers at the bedside with the goal of better patient care and outcomes.
Neuroinfections rank among the top ten leading causes of child mortality globally, even in high-income countries. The crucial determinants for successful treatment lie in the timing and swiftness of diagnosis. Although viruses constitute the majority of infectious neuropathologies, diagnosing and treating viral neuroinfections remains challenging. Despite technological advancements, the etiology of the disease remains undetermined in over half of cases. The identification of the pathogen becomes more difficult when the infection is caused by atypical pathogens or multiple pathogens simultaneously. Furthermore, the modern surge in global passenger traffic has led to an increase in cases of infections caused by pathogens not endemic to local areas. This review aims to systematize and summarize information on neuroinvasive viral pathogens, encompassing their geographic distribution and transmission routes. Emphasis is placed on rare pathogens and cases involving atypical pathogens, aiming to offer a comprehensive and structured catalog of viral agents with neurovirulence potential.
Human enteroviruses are the most common human pathogen with over 300 distinct genotypes. Previous work with poliovirus has suggested that it is possible to generate antibody responses in humans and animals that can recognize members of multiple enterovirus species. However, cross protective immunity across multiple enteroviruses is not observed epidemiologically in humans. Here we investigated whether immunization of mice or baboons with inactivated poliovirus or enterovirus virus-like-particles (VLPs) vaccines generates antibody responses that can recognize enterovirus D68 or A71. We found that mice only generated antibodies specific for the antigen they were immunized with, and repeated immunization failed to generate cross-reactive antibody responses as measured by both ELISA and neutralization assay. Immunization of baboons with IPV failed to generate neutralizing antibody responses against enterovirus D68 or A71. These results suggest that a multivalent approach to enterovirus vaccination is necessary to protect against enterovirus disease in vulnerable populations.
A 44-year-old woman with a subacute onset of an altered mental status, urinary retention, and fluctuating blood pressure was initially diagnosed with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis, meeting the criteria of Graus et al. Cardiac arrest occurred, which required pacemaker placement. She subsequently showed profound flaccid limb paralysis, with magnetic resonance imaging demonstrating focal necrotic lesions localized in the anterior horn of the longitudinal segments of the spinal cord and in the pontine tegmentum. Enteroviruses or autoimmune encephalitis-associated autoantibodies were not detected. We herein report a case of acute flaccid myelitis with profound psychiatric symptoms and dysautonomia, resembling NMDAR encephalitis.
Acute neuromuscular disorders are a group of neurological emergencies characterized by rapid onset of motor weakness commonly involving the respiratory and bulbar muscles. These can be acute or an exacerbation of the chronic neuromuscular disease. An accurate and timely diagnosis allows for the timely institution of specific therapies, improving long-term functional outcomes. Landry–Guillain–Barre syndrome (LGBS), acute transverse myelitis, compressive myelopathy, traumatic spinal lesions, and anterior horn cell myelitis (due to viral infections) are some of the common causes of acute motor weakness in children. LGBS is the most common among all. The diagnosis relies on clinical presentation, signs, cerebrospinal fluid analysis, electrophysiological studies, and neuroimaging of the spine. Once compressive or traumatic spinal lesions are suspected, immediate neuroimaging of the spine is essential to plan early neurosurgical intervention. Pediatric intensive care unit (PICU) admission is often required for supportive management and immunomodulation. Supportive management typically includes endotracheal intubation to protect the airway, mechanical ventilation (MV) to support breathing, monitoring, management of autonomic dysfunction, control of pain, physiotherapy, adequate nutrition, prevention of pressure sores, bladder–bowel care, psychological support, and planning of long-term care. Autonomic dysfunction can cause hemodynamic instability, arrhythmias, sudden cardiac arrest, and death, requiring close monitoring and management in PICU. Tracheostomy is often needed in children who continue to have respiratory paralysis and are predicted to require long-term term mechanical ventilation. The outcome generally depends on the primary disease and long-term care.
Human rhinovirus (HRV) has been sporadically detected in patients with acute flaccid myelitis (AFM). We report a case of AFM in a 2-year-old boy with severe neurologic sequelae, whose nasopharyngeal and stool samples tested positive for HRV-A19. Clinical information related to AFM with HRV is limited. Further study of the association of AFM with HRV is warranted.
Surveillance for emerging pathogens is critical for developing early warning systems to guide preparedness efforts for future outbreaks of associated disease. To better define the epidemiology and burden of associated respiratory disease and acute flaccid myelitis (AFM), as well as to provide actionable data for public health interventions, we developed a multimodal surveillance program in Colorado, USA, for enterovirus D68 (EV-D68). Timely local, state, and national public health outreach was possible because prospective syndromic surveillance for AFM and asthma-like respiratory illness, prospective clinical laboratory surveillance for EV-D68 among children hospitalized with respiratory illness, and retrospective wastewater surveillance led to early detection of the 2022 outbreak of EV-D68 among Colorado children. The lessons learned from developing the individual layers of this multimodal surveillance program and how they complemented and informed the other layers of surveillance for EV-D68 and AFM could be applied to other emerging pathogens and their associated diseases.
Background . Acute flaccid paralysis is a clinical syndrome characterized by a sudden onset of weakness in one or more limbs with decreased or absent tendon reflexes in the affected limbs. This condition may be a manifestation of such pathologies as Guillain-Barré syndrome and neuromyelitis optica spectrum disorder. Clinical cases description . We describe two clinical cases of Guillain-Barré syndrome in patient M., 7 years old, and neuromyelitis optica spectrum disorder in patient D., 3 years old. In both children, the main clinical manifestation was acute flaccid paralysis. Patient M. was admitted to the Neurological Department of the Moscow Regional Center for Maternity and Childhood Protection with complaints of sharp pronounced weakness in the limbs, inability to walk. According to the disease history, the patient had an acute respiratory viral infection in October 2022. The conducted neurologic examination revealed decreased muscle tone and muscle strength in all limbs, absence of reflexes from the lower limbs. A liquor test was conducted, which revealed increased protein contents. Electroneuromyography detected a pronounced axonal lesion of all motor fibers in the arms and legs. The formulated diagnosis was “Guillain-Barré syndrome, variant of acute motor axonal neuropathy.” The treatment with plasmapheresis and intravenous immunoglobulins showed positive dynamics. In the second case, patient D. was admitted to the Pediatric Infectious Disease Department of Naro-Fominsk Hospital with similar complaints of sharp weakness in the limbs. Neurological examination showed a diffuse decrease in muscle tone, absence of reflexes from all limbs. Elevated protein contents were determined in the liquor. MRI of the cervical spinal cord showed myelitis of segments C3–C7. Negative antibodies to aquaporin-4 were found. The patient was treated with ceftriaxone, methylprednisolone, and plasmapheresis. Then he was transferred to the Neurological Department of the Moscow Regional Center for Maternity and Childhood Protection, where a repeated MRI of the cervicothoracic spinal cord revealed, in addition to myelitis at the level of C3–C7, a lesion of segments from the level of C2 to the medulla oblongata. The formulated diagnosis was “Neuromyelitis optica spectrum disease, seronegative form. Flaccid tetraparesis.” The continued treatment with prednisolone and intravenous immunoglobulin produced positive effect. Conclusion . The presented clinical cases will help neurologists to improve timely diagnosis and treatment of causes of acute flaccid paralysis in children, thereby reducing possible complications, disability, and mortality.
Objective
Infectious myelopathy of any stage and etiology carries the potential for significant morbidity and mortality. This article details the clinical presentation, risk factors, and key diagnostic components of infectious myelopathies with the goal of improving the recognition of these disorders and guiding subsequent management.
Latest Developments
Despite our era of advanced multimodal imaging and laboratory diagnostic technology, a causative organism often remains unidentified in suspected infectious and parainfectious myelopathy cases. To improve diagnostic capability, newer technologies such as metagenomics are being harnessed to develop diagnostic assays with a greater breadth of data from each specimen and improvements in infection identification. Conventional assays have been optimized for improved sensitivity and specificity.
Essential Points
Prompt recognition and treatment of infectious myelopathy decreases morbidity and mortality. The key diagnostic tools include serologies, CSF analysis, and imaging; however clinical presentation, epidemiologic risk factors, and history of recent illness are all vital to making the proper diagnosis because current laboratory and imaging modalities are often inconclusive. The cornerstone of recommended treatment is targeted antimicrobials with appropriate immune modulation, surgical intervention, supportive care, and interdisciplinary involvement, all of which further improve outcomes for patients with infectious myelopathy.
Pathogens are continually evolving, driven by the environmental pressures we create and amplify as medical advances endeavor to keep pace. As new pathogens emerge and old foes adapt, our approaches to management of infections must also evolve. We discuss advances in the field of pediatric infectious disease for select topics and provide updates on: (i) management of febrile infants; (ii) shortened antibiotic courses for the treatment of community-acquired pneumonia and urinary tract infections; (iii) impact of the Covid-19 pandemic on infection control strategies and respiratory viruses circulation in primary care settings; (iv) recognition and management of acute flaccid myelitis; and (v) the threat of vaccine hesitancy. These diverse topics share a goal to inform primary care practitioners seeking useful information on recent developments to advance the pediatrician’s approach to managing and preventing infectious illnesses in a child.
Introduction
We describe the first case of acute flaccid myelitis (AFM) related to enterovirus D68 (EV-D68) infection in Belgium. The clinical and radiological presentation of AFM associated with EV-D68 although well described currently remains a challenging diagnosis. Through this interesting clinical case, we aimed to review the differential diagnosis of acute flaccid palsy in a child and discuss the specific point of interest related to AFM.
Case Presentation
We present the case of a 4-year-old girl with a torticollis associated with an acute palsy of the right upper limb. The magnetic resonance imaging revealed an increased T2 signal intensity of the entire central gray matter of the cervical cord with involvement of the posterior brainstem. A polymerase chain reaction (PCR) conducted on a nasopharyngeal swab was found positive for EV-D68. The definition of AFM proposed by the Center for Disease Control and Prevention (CDC) is an acute-onset flaccid weakness of one or more limbs in the absence of a clear alternative diagnosis and the radiological evidence of gray matter involvement on an MRI picture, and our case fits these two criteria. A prompt and detailed workup is required to distinguish this emergent disease from other forms of acute flaccid palsy. The functional prognosis of AFM is poor, and there are no evidence-based treatment guidelines so far.
Conclusion
AFM is an emerging pathology that requires the attention of pediatricians to quickly rule out differential diagnoses and adequately manage the patient. Further research is needed to optimize treatments, improve outcomes, and provide scientifically based guidelines.
Acute Flaccid Myelitis is a paralytic illness with significant similarities to poliomyelitis, and which affects predominantly children. It was first fully delineated only in 2014 in the USA, occurring in epidemic clusters with a likely overall increasing incidence. It has subsequently rapidly been identified in Europe, the UK, and Australasia and the Far East, confirming it to be an emerging, global, infectious neurological disease. It has, however, been very little studied in low- and middle-income countries—reflecting partly of the global imbalance in science and medical research, and partly the extremely low provision of neurological care in most low- and middle-income countries: Uganda currently has no specialized neurology services outside the capital Kampala. During extended visits over a 2-year period with involvement in acute adult and paediatric internal medicine, one of us (NS) encountered at least six new patients with acute flaccid myelitis, suggesting that both the geographical reach and the frequency of the disorder may be significantly greater than previously thought. Here, these cases are described together with their clinical features and, where available, course and (limited) investigation results. These observations have significant implications concerning the current, and potentially the future geographical spread of the disease, and its clinical phenomenology. In addition, they highlight serious problems concerning the global applicability of the current Acute Flaccid Myelitis diagnostic criteria.
Enterovirus D68 (EV-D68) causes cyclical outbreaks of respiratory disease and acute flaccid myelitis. EV-D68 is primarily transmitted through the respiratory route, but the duration of shedding in the respiratory tract is unknown. We prospectively enrolled 9 hospitalized children with EV-D68 respiratory infection and 16 household contacts to determine EV-D68 RNA shedding dynamics in the upper respiratory tract through serial midturbinate specimen collections and daily symptom diaries. Five (31.3%) household contacts, including 3 adults, were EV-D68-positive. The median duration of EV-D68 RNA shedding in the upper respiratory tract was 12 (range 7-15) days from symptom onset. The most common symptoms were nasal congestion (100%), cough (92.9%), difficulty breathing (78.6%), and wheezing (57.1%). The median illness duration was 20 (range 11-24) days. Understanding the duration of RNA shedding can inform the expected rate and timing of EV-D68 detection in associated acute flaccid myelitis cases and help guide public health measures.
Enteroviruses are a vast genus of positive-sense RNA viruses that cause diseases ranging from common cold to poliomyelitis and viral myocarditis. They encode a membrane-bound AAA+ ATPase, 2C, that has been suggested to serve several roles in virus replication, e.g. as an RNA helicase and capsid assembly factor. As an oligomeric peripheral membrane protein, the low solubility of 2C has hitherto impaired biochemical studies of the full-length protein. Here, we report a biochemical reconstitution poliovirus 2C association with membranes. We show that a conserved glycine divides the N-terminal membrane-binding domain of 2C into two amphipathic helix regions, AH1 and AH2. AH2 is the main mediator of 2C oligomerization, and is sufficient for its membrane binding. AH1 is the main mediator of a novel function of 2C: clustering of membranes. Cryo-electron tomography reveal that several 2C copies mediate this function by localizing to vesicle-vesicle interfaces. 2C-mediated clustering is partially outcompeted by nucleic acids, suggesting a way by which 2C can switch from an early role in coalescing replication organelles, and recruiting lipid droplets to them, to a later role where 2C assists RNA replication and particle assembly. 2C is sufficient to recruit RNA to membranes, with a preference for double-stranded RNA, thus being a candidate for the factor that localizes viral RNA replication to membranes. Finally, the in vitro reconstitution revealed that full-length 2C localized to a membrane has weak RNA chaperoning activity, dependent on having a free N terminus, but does not possess ATP-dependent helicase activity. Together, this study suggests two novel roles for 2C in membrane clustering and double-stranded RNA recruitment to membranes, and calls into question a role of 2C as an RNA helicase. The reconstitution of functional, 2C-decorated vesicles provides a platform for further experimental studies into this protein and its roles in enterovirus replication.
Acute flaccid myelitis (AFM) is a polio-like condition predominantly affecting children that is characterized by acute-onset, asymmetric flaccid paralysis, often preceded by a prodromal fever or viral illness. With prompt diagnosis and early surgical referral, nerve transfers may be performed to improve function. Highly selective nerve transfers are ideal to preserve existing functions while targeting specific deficits. In this report, we present a case of a double fascicular nerve transfer of median and ulnar nerve fascicles to the axillary nerve, combined with selective transfer of the spinal accessory nerve to the supraspinatus branch of the suprascapular nerve, performed for a 5-year-old girl who developed AFM after an upper respiratory infection. Six months after the onset of the patient's symptoms, the patient had continued weakness of shoulder flexion and abduction, atrophy of the deltoid, and supraspinatus muscles, though needle electromyography revealed a functioning infraspinatus muscle. The patient had no post-operative complications and at 2 years of postoperative follow up achieved shoulder abduction and flexion Active Movement Scale scores of 7/7 compared to preoperative scores of 2/7, with no loss of function in the donor nerve domains. The patient showed active shoulder abduction against gravity to 90° from 30° preoperatively and shoulder flexion to 180° from 15° preoperatively. This case report shows that highly selective nerve transfers may preserve existing functions while targeting specific deficits. A double fascicular transfer from the median and ulnar nerves to axillary nerve may provide abundant axons for functional recovery.
Accurate diagnosis of multiple sclerosis requires careful attention to its differential diagnosis-many disorders can mimic the clinical manifestations and paraclinical findings of this disease. A collaborative effort, organised by The International Advisory Committee on Clinical Trials in Multiple Sclerosis in 2008, provided diagnostic approaches to multiple sclerosis and identified clinical and paraclinical findings (so-called red flags) suggestive of alternative diagnoses. Since then, knowledge of disorders in the differential diagnosis of multiple sclerosis has expanded substantially. For example, CNS inflammatory disorders that present with syndromes overlapping with multiple sclerosis can increasingly be distinguished from multiple sclerosis with the aid of specific clinical, MRI, and laboratory findings; studies of people misdiagnosed with multiple sclerosis have also provided insights into clinical presentations for which extra caution is warranted. Considering these data, an update to the recommended diagnostic approaches to common clinical presentations and key clinical and paraclinical red flags is warranted to inform the contemporary clinical evaluation of patients with suspected multiple sclerosis.
Background
Enterovirus A71 is one of the causative agents of hand, foot, and mouth disease, which is usually a self-limiting disease. Complications of enterovirus infection are also very rare. However, when such complications occur, they can lead to serious neurological diseases or even death.
Case presentation
In this report, we describe a case of enterovirus A71-associated acute flaccid paralysis in a 13-month-old Caucasian girl that was managed in our hospital. The patient presented with sudden onset of left arm paresis that could not be attributed to any other cause. Establishing a diagnosis was furthermore complicated by negative virological investigations of cerebrospinal fluid and non-pathological radiological findings. A polymerase chain reaction test of the child’s stool sample however tested positive for enterovirus and sequencing results revealed the presence of enterovirus A71. A previous history of febrile gastroenteritis just before the paresis started also supported the suspected diagnosis of enterovirus-associated acute flaccid paralysis. Following this, the child was treated with intravenous immunoglobulin over 5 days and a remarkable improvement was observed in the child’s paresis.
Conclusion
This case report describes a possible complication of enterovirus A71 infection in a child. It also highlights the prolonged detection of enterovirus in the child’s stool sample as compared with cerebrospinal fluid weeks after the primary infection occurred. Finally, it shows the need for increased clinical and diagnostic awareness especially in the management of sudden and unknown causes of paresis or paralysis in children.
Audience:
Emergency medicine residents and medical students on emergency medicine rotation.
Introduction:
Although a somewhat rare disease, acute flaccid myelitis (AFM) can cause death, and for those pediatric patients that survive, less than 10% have full recovery.1 A cluster of cases that resembled polio was first described in California in 2012.2 After 120 cases of the disease were confirmed in 2014 in a 5-month period, the Centers for Disease Control and Prevention (CDC) began surveillance of the disease. Since surveillance began, clusters of cases have occurred in a biennial pattern, usually late summer and early fall. There were 218 cases between 2015 to 2017, 238 cases in 2018, 47 cases in 2019, and 32 in 2020.3,4,5 AFM has become recognized as a global disease with cases reported across many countries.1 The CDC has noted that the most common location of the first medical encounter of pediatric patients presenting with AFM is the emergency department in every year that surveillance occurred.5 Most of the children that are diagnosed with AFM are admitted to the hospital and of those admitted, 30% require intubation.5 Deaths related to AFM are due to respiratory involvement and complications. With appropriate recognition and supportive care, mortality can be avoided.
Educational objectives:
At the end of this oral board session, examinees will: 1) demonstrate the ability to obtain a complete pediatric medical history, 2) demonstrate an appropriate exam on a pediatric patient including a neurological exam, 3) investigate the broad differential diagnoses for neuromuscular weakness in a pediatric patient, 4) order the appropriate evaluation studies including an MRI, 5) interpret the use of a negative inspiratory force in determining the need for intubation and level of care upon admission, and 6) demonstrate effective communication with parents and caregivers.
Educational methods:
Oral board case following a standard American Board of Emergency Medicine-style case in a tertiary care hospital with access to all specialists and resources needed. This case was tested using 5 resident volunteers ranging from PGY 1 - 3 in an ACGME (Accreditation Council for Graduate Medical Education)-accredited emergency medicine program. Also, approximately 3 - 5 observers (other residents and medical students) were present during the presentation. Learners were immediately able to provide feedback during the debriefing of the case.
Research methods:
Immediate Feedback was solicited from the learners and observers participating in the case both by verbal discussion and completion of a rating for the case following the debriefing. The efficacy of the educational content was assessed by comparing scoring measures across residents based on the training year. Scoring measures of the ACGME core competencies were performed using a scale from 1-8, 1-4 being unacceptable performance and 5 - 8 being acceptable. Efficacy was assumed based on full completion of the case by the residents who acted as practice oral board candidates, and a debriefing session followed to discuss the key components of the case.
Results:
Practice candidates were 1 PGY1 level, 2 PGY2 Level and 2 PGY3 level residents. All residents that were practice candidates anchored on the diagnosis of Guillain-Barré Syndrome (GBS) but despite the anchoring were able to manage the patient appropriately and safely. The average score for practice candidates per level was: PGY1: 5.1, PGY2: 5.8, and PGY3: 6.5. The critical action missed by the PGY1 resident was ordering a negative inspiratory force and one PGY2 did not completely order all of the spinal MRI. All learners, both practice candidates and observers rated the case as 4.2 (1 - 5 Likert scale, 5 being excellent).
Discussion:
The educational content effectiveness was two-fold. The content was effective for teaching the presentation and appropriate evaluation to diagnose AFM. AFM is significantly like the presentation of poliomyelitis which originally occurred in sporadic cluster outbreaks and then the number of cases in the United States doubled every 4 - 5 years from 1940 - 1952.6 AFM is a disease that occurs in a biennial pattern and needs to be recognized and reported appropriately. The case also encouraged the cognizance of other etiologies for acute neuromuscular weakness in a pediatric patient which may require different diagnostic evaluation and medical management. AFM'ster clinical presentation generally involves asymmetric weakness and may occur in either an ascending or descending pattern with the nadir to maximum weakness attained in a few days. Although there are variants of GBS, the neuromuscular weakness is usually symmetrical and occurs in an ascending pattern with the nadir being reached in 1 - 2 weeks.7 AFM requires an MRI with specific abnormalities to meet the case definition while an MRI can be performed when GBS is suspected, but it is not necessary. AFM MRI abnormalities demonstrate brainstem and spinal cord lesions with a predominance of gray matter affected while a GBS MRI demonstrates ventral root abnormalities without any spinal cord or brainstem lesions. Without the MRI results, a patient may be assigned the incorrect diagnosis upon admission. A lumbar puncture and electromyography are required for the diagnosis of GBS. The cerebrospinal fluid (CSF) of GBS demonstrates high protein levels and white blood cell count (WBC) < 10 cells/mm3 while the CSF of AFM demonstrates pleocytosis although usually < 100 cells/mm3.1,8 Electromyography will be abnormal in both GBS and AFM, but the test is not necessary for the diagnosis of AFM as it is with GBS. Both intravenous immunoglobulin (IVIG) and plasma exchange shorten the recovery time of GBS while there is no recommendation for treatment of AFM at this time. IVIG, plasmapheresis, and steroids have been utilized with unclear benefits.1,8 Physical therapy and occupational therapy appear to be significantly important in AFM with nerve transfer surgery as a possibility of cure to areas of muscles that have not recovered significant function in AFM.9 Reaching the appropriate diagnosis allows the emergency medicine physician to communicate more accurately with worried parents, providing them with correct information on treatment and progression of the disease.
Topics:
Pediatric weakness, pediatric neurologic disorders, acute flaccid myelitis, Gullian-Barré Syndrome, neuromuscular weakness.
To ensure proper specimen handling for detecting pathogens, like Enterovirus D68 (EV-D68), from home- and self-collection, alternative techniques are needed to ensure safe transport and reliable testing. PrimeStore® Molecular Transport Medium (MTM) may be an option since it does not require cold storage and inactivates virus while preserving RNA for detection. The purpose of this validation study was to demonstrate the ability to detect EV-D68 via rRT-PCR in MTM. Using a quantified EV-D68 positive control standard, MTM limit of detection for EV-D68 RNA is 104 cp/mL and RNA remains stable up to 30 days unfrozen. Positive and negative residual respiratory specimens from the 2018 EV-D68 outbreak were used for clinical testing. There was an 80% positive and 100% negative agreement with samples in MTM compared to reference. This study demonstrates the feasibility of EV-D68 detection from respiratory specimens collected and stored in PrimeStore® MTM, with implications for home- and self-collection.
Background:
Myelopathies require prompt etiologic diagnosis. We aimed to identify a specific myelopathy diagnosis in cases of suspected myelitis to highlight clinicoradiologic differences.
Methods:
In this retrospective, single-centre cohort of subjects with suspected myelitis referred to London Multiple Sclerosis (MS) Clinic between 2006 and 2021, we identified those with MS and reviewed the remaining charts for etiologic diagnosis based on clinical, serologic, and imaging details.
Results:
Of 333 included subjects, 318/333 (95.5%) received an etiologic diagnosis. Most (274/333, 82%) had MS or clinically isolated syndrome. Spinal cord infarction (n = 10) was the commonest non-inflammatory myelitis mimic characterized by hyperacute decline (n = 10/10, 100%), antecedent claudication (n = 2/10, 20%), axial owl/snake eye (n = 7/9, 77%) and sagittal pencillike (n = 8/9, 89%) MRI patterns, vertebral artery occlusion/stenosis (n = 4/10, 40%), and concurrent acute cerebral infarct (n = 3/9, 33%). Longitudinal lesions were frequent in aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD) (n = 7/7, 100%) and myelin oligodendrocyte glycoprotein-IgG-associated disorder (MOGAD) (n = 6/7, 86%), accompanied by bright spotty (n = 5/7, 71%) and central-grey-restricted (n = 4/7, 57%) T2-lesions on axial sequences, respectively. Leptomeningeal (n = 4/4, 100%), dorsal subpial (n = 4/4, 100%) enhancement, and positive body PET/CT (n = 4/4, 100%) aided the diagnosis of sarcoidosis. Spondylotic myelopathies had chronic sensorimotor presentations (n = 4/6, 67%) with relative bladder sparing (n = 5/6, 83%), localizable to sites of disc herniation (n = 6/6, 100%). Metabolic myelopathies showed dorsal column or inverted 'V' sign (n = 2/3, 67%) MRI T2-abnormality with B12 deficiency.
Conclusions:
Although no single feature reliably confirms or refutes a specific myelopathy diagnosis, this study highlights patterns that narrow the differential diagnosis of myelitis and facilitate early recognition of mimics.
Background:
Acute flaccid myelitis (AFM) and transverse myelitis (TM) are serious conditions that may be difficult to differentiate, especially at onset of disease. In this study we compared clinical features of pediatric AFM and TM and evaluated current diagnostic criteria, aiming to improve early and accurate diagnosis.
Methods:
Two cohorts of children with enterovirus D68-associated AFM and clinically diagnosed TM were compared regarding presenting clinical features, additional investigations and outcome. Current diagnostic criteria for AFM and TM were applied to evaluate their specificity.
Results:
Children with AFM (n=21) compared to those with TM (n=36) were younger (median 3 vs. 10 years), more often had a prodromal illness (100% vs. 39%), predominant proximal weakness (69% vs. 17%) and hyporeflexia (100% vs. 44%), and less often had sensory deficits (0% vs. 81%), bowel and/or bladder dysfunction (12% vs. 69%) and hyperreflexia (0% vs. 44%). On MRI, brainstem involvement was more common in AFM (74% vs. 21%), while supratentorial abnormalities were only seen in TM (0% vs. 40%). When omitting the criterion of a sensory level, 11/15 (73%) children with AFM fulfilled the diagnostic criteria for TM. Of children with TM, 4/33 (12%) fulfilled the diagnostic criteria for probable/definite AFM.
Conclusion:
While there is considerable overlap between AFM and TM in children, we found important early differentiating clinical and diagnostic features. Meeting diagnostic criteria for AFM in children with TM and vice versa, underlines the importance of thorough clinical examination and early and accurate diagnostic studies.
Objectives
Acute inflammatory demyelinating polyneuropathy (AIDP) is the leading cause of acute flaccid paralysis in children and hypothesized to be triggered by antecedent infection. We sought to determine the association between AIDP and commonly acquired community infections in children. We utilized the reduction in these infections due to measures during coronavirus disease 2019 (COVID‐19) to serve as a natural experiment and determine their contribution to AIDP.
Methods
This cross‐sectional study used administrative and billing data from children's hospitals contributing to the Pediatric Health Information System. We included hospitalizations of children with a diagnosis of AIDP from (January 2017 through February 2021). Encounters for infection‐ (including respiratory, gastrointestinal, and COVID‐19) related diagnoses were measured as a marker of community incidence.
Results
A total of 1111 index encounters for AIDP were included. Pre‐COVID‐19, AIDP was not associated with respiratory or gastrointestinal infections, specifically, influenza or campylobacter. During the COVID‐19 period from March 2020 to February 2021, respiratory, gastrointestinal, and influenza infections decreased compared to expected (for the same time of year pre‐COVID‐19) by 59.6%–90.1%, 51.5%–68.9%, and 54.5%–97.9%, respectively. In contrast, AIDP hospitalizations and all hospitalizations only decreased by 11.5%–39.3% and 14.2%–25%, respectively. COVID‐19 was not positively associated with AIDP overall or at individual hospitals.
Interpretation
Common community‐acquired infections including COVID‐19 were not strongly associated with hospitalizations for AIDP in children. AIDP persisted despite the dramatic reduction in infection‐related encounters during the pandemic. These results suggest that recent antecedent community‐acquired infections were not the primary driver of AIDP and that alternative triggers should be explored.
Purpose of review:
Recent outbreaks of poliomyelitis in countries that have been free of cases for decades highlight the challenges of eradicating polio in a globalized interconnected world beset with a novel viral pandemic. We provide an epidemiological update, advancements in vaccines, and amendments in public health strategy of poliomyelitis in this review.
Recent findings:
Last year, new cases of wild poliovirus type 1 (WPV1) were documented in regions previously documented to have eradicated WPV1 and reports of circulating vaccine-derived poliovirus type 2 (cVDPV2) and 3 (cVDPV3) in New York and Jerusalem made international headlines. Sequencing of wastewater samples from environmental surveillance revealed that the WPV1 strains were related to WPV1 lineages from endemic countries and the cVDPV2 strains from New York and Jerusalem were not only related to each other but also to environmental isolates found in London. The evidence of importation of WPV1 cases from endemic countries, and global transmission of cVDPVs justifies renewed efforts in routine vaccination programs and outbreak control measures that were interrupted by the COVID-19 pandemic. After the novel oral poliovirus vaccine type 2 (nOPV2) received emergency authorization for containment of cVDPV2 outbreaks in 2021, subsequent reduced incidence, transmission rates, and vaccine adverse events, alongside increased genetic stability of viral isolates substantiates the safety and efficacy of nOPV2. The nOPV1 and nOPV3 vaccines, against type 1 and 3 cVDPVs, and measures to increase accessibility and efficacy of inactivated poliovirus vaccine (IPV) are in development.
Summary:
A revised strategy utilizing more genetically stable vaccine formulations, with uninterrupted vaccination programs and continued active surveillance optimizes the prospect of global poliomyelitis eradication.
Observed peaks of acute flaccid myelitis (AFM) cases have occurred biennially since 2014 in the United States. We aimed to determine if AFM etiology differed between peak and nonpeak years, considering that clinical features of AFM differ by virus etiology. We compared clinical and laboratory characteristics of AFM cases that occurred during peak (2016 and 2018, n = 366) and nonpeak (2015 and 2017, n = 50) years. AFM patients in peak years were younger (5.2 years) than those in nonpeak years (8.3 years). A higher percentage of patients in peak years than nonpeak years had pleocytosis (86% vs. 60%), upper extremity involvement (33% vs. 16%), and an illness preceding limb weakness (90% vs. 62%) and were positive for enterovirus or rhinovirus RNA (38% vs. 16%). Enterovirus D68 infection was associated with AFM only in peak years. Our findings suggest AFM etiology differs between peak and nonpeak years.
Background
Therapy of autoimmune diseases of the central and peripheral nervous system with intravenous IgG immunoglobulin (IVIg) is well established. Since IVIg is produced from pooled human plasma, autoantibodies can be found in IVIg products and, accordingly, in patient sera after transfusion. The de novo evidence or disappearance of anti-neural autoantibodies after IVIg treatment has so far not been systematically examined.
Methods
We screened 50 neurological patients before and after IVIg treatment for classical onconeural and the most common neurological surface autoantibodies as well as for ganglioside autoantibodies and 23 different antinuclear autoantibodies using immunoblot or cell-based indirect immunofluorescence assays. Furthermore, we screened 31 neurological patients with previously known seropositivity for disappearance of the corresponding antibody after treatment.
Results
After IVIg treatment, 90% of all sera were de novo positive for antinuclear antibodies, especially for Ro-52. In contrast, 94% of all sera did not show any de novo-positive anti-neural antibodies. In the remaining three cases, titers were very low. Importantly, 12.9% of all tested sera of patients with known antibody positivity turned false negative after IVIg treatment and titers were falsely low in 37% of the remaining sera.
Conclusions
Here, we present for the first time results of a broad screening for clinically relevant autoantibodies before and after IVIg treatment in neurological patients. We identified a high specificity but reduced sensitivity for anti-neural antibody testing after IVIg transfusion. In contrast, antinuclear antibody testing is not reliable after IVIg treatment. These results are of high practical importance for diagnostic of neuroimmunological diseases.
Enterovirus D68 (EV-D68) infections are on the rise worldwide. Since 2014, the United States has experienced biennial spikes in EV-D68-associated acute flaccid myelitis (AFM) that have left hundreds of children paralyzed. Much remains to be learned about the pathogenesis of EV-D68 in the central nervous system (CNS). Herein we investigated the mechanisms of EV-D68 CNS invasion through neuronal pathways. A better understanding of EV-D68 infection in experimental models may allow for better prevention and treatment strategies of EV-D68 CNS disease.
Acute flaccid myelitis (AFM) is a debilitating illness that is defined by the sudden onset of flaccid paralysis in the extremities with spinal magnetic resonance imaging (MRI) demonstrating a longitudinal lesion confined to the gray matter. The purpose of this study was to report the types of upper-extremity palsy and outcomes of surgical reconstruction in patients with AFM.
Methods:
Eight patients with a median age at onset of 3.8 years (range, 2.3 to 9.9 years) were identified. There was loss of shoulder abduction and external rotation in all patients, loss of elbow flexion in 5 patients, complete or partial loss of hand function in 3 patients, and spinal accessory nerve palsy in 2 patients. All patients underwent surgical reconstruction, which was categorized into 3 main groups: nerve transfer, secondary muscle transfer, and free muscle transfer.
Results:
The median follow-up period was 39 months (range, 30 to 94 months). Four patients obtained ≥90° of shoulder abduction whereas the other 4 patients had shoulder abduction of ≤70°. The 5 patients who received free muscle transfer or nerve transfer to restore elbow function obtained ≥140° of elbow flexion. Two patients treated with free muscle transfer to restore finger function obtained satisfactory total active motion of the fingers (180°).
Conclusions:
The patterns of paralysis and the strategy and outcomes of surgical reconstruction for patients with AFM differed from those for traumatic and obstetric brachial plexus palsy. All patients had loss of shoulder abduction, and 2 had spinal accessory nerve palsy. Restoration of shoulder function was unpredictable and depended on the quality of the donor nerves and recovery of synergistic muscles. Restoration of elbow and hand function was more consistent and satisfactory.
Level of evidence:
Therapeutic Level IV. See Instructions for Authors for a complete list of levels of evidence.
Since 2014, numerous outbreaks of childhood infections with enterovirus D68 (EV-D68) have occurred worldwide. Most infections are associated with flu-like symptoms, but paralysis may develop in young children. It has been suggested that infection only with recent viral isolates can cause paralysis. To address the hypothesis that EV-D68 has recently acquired neurotropism, murine organotypic brain slice cultures, induced human motor neurons and astrocytes, and mice lacking the alpha/beta interferon receptor were infected with multiple virus isolates. All EV-D68 isolates, from 1962 to the present, can infect neural cells, astrocytes, and neurons. Furthermore, our results show that sialic acid binding does not play a role in EV-D68 neuropathogenesis. The study of EV-D68 infection in organotypic brain slice cultures, induced motor neurons, and astrocytes will allow for the elucidation of the mechanism by which the virus infection causes disease.
Since 2012, the United States of America has experienced a biennial spike in pediatric acute flaccid myelitis (AFM)1,2,3,4,5,6. Epidemiologic evidence suggests non-polio enteroviruses (EVs) are a potential etiology, yet EV RNA is rarely detected in cerebrospinal fluid (CSF)². CSF from children with AFM (n = 42) and other pediatric neurologic disease controls (n = 58) were investigated for intrathecal antiviral antibodies, using a phage display library expressing 481,966 overlapping peptides derived from all known vertebrate and arboviruses (VirScan). Metagenomic next-generation sequencing (mNGS) of AFM CSF RNA (n = 20 cases) was also performed, both unbiased sequencing and with targeted enrichment for EVs. Using VirScan, the viral family significantly enriched by the CSF of AFM cases relative to controls was Picornaviridae, with the most enriched Picornaviridae peptides belonging to the genus Enterovirus (n = 29/42 cases versus 4/58 controls). EV VP1 ELISA confirmed this finding (n = 22/26 cases versus 7/50 controls). mNGS did not detect additional EV RNA. Despite rare detection of EV RNA, pan-viral serology frequently identified high levels of CSF EV-specific antibodies in AFM compared with controls, providing further evidence for a causal role of non-polio EVs in AFM.
Enterovirus A71 (EV-A71) is one of the common causative pathogens for hand foot and mouth disease (HFMD) affecting young children. HFMD outbreak can result in a substantial pediatric hospitalization and burden the healthcare services, especially in less-developed countries. Since the initial epidemic of predominantly EV-A71 in California in 1969, the high prevalence of HFMD in the Asia-pacific region and elsewhere around the world represents a significant morbidity in this age group. With the advent of rapid and accurate diagnostic tools, there has been a dramatic increase in the number of laboratory-confirmed EV-A71 infection over the past two decades. The population, cultural, and socioeconomic diversity among countries in the Asia-Pacific region all influence the transmission and morbidity associated with HFMD. This review summarizes the current state of epidemiology of EV-A71 in Asia-Pacific countries based on the most recent epidemiological data and available information on the prevalence and disease burden. This knowledge is important in guiding the prevention, control and future research on vaccine development of this highly contagious disease of significant socioeconomic implications in public health.
Following the 2014 outbreak, active surveillance of the EV-D68 has been implemented in many countries worldwide. Despite subsequent EV-D68 outbreaks (2014 and 2016) reported in many areas, EV-D68 circulation remains largely unexplored in Africa except in Senegal, where low levels of EV-D68 circulation were first noted during the 2014 outbreak. Here we investigate subsequent epidemiology of EV-D68 in Senegal from June to September 2016 by screening respiratory specimens from ILI and stool from AFP surveillance. EV-D68 was detected in 7.4% (44/596) of patients; 40 with ILI and 4 with AFP. EV-D68 detection was significantly more common in children under 5 years (56.8%, p = 0.016). All EV-D68 strains detected belonged to the newly defined subclade B3. This study provides the first evidence of EV-D68 B3 subclade circulation in Africa from patients with ILI and AFP during a 2016 outbreak in Senegal. Enhanced surveillance of EV-D68 is needed to better understand the epidemiology of EV-D68 in Africa.
Acute flaccid myelitis (AFM) is a polio-like disease that results in paralysis in previously healthy persons. Although the definitive cause of AFM remains unconfirmed, enterovirus D68 (EV-D68) is suspected based on 2014 data demonstrating an increase in AFM cases concomitant with an EV-D68 outbreak. We examined the prevalence in children and the molecular evolution of EV-D68 for 2009-2018 in Philadelphia, Pennsylvania, USA. We detected widespread EV-D68 circulation in 2009, rare detections in 2010 and 2011, and then biennial circulation, only in even years, during 2012-2018. Prevalence of EV-D68 significantly correlated with AFM cases during this period. Finally, whole-genome sequencing revealed early detection of the B1 clade in 2009 and continued evolution of the B3 clade from 2016 to 2018. These data reinforce the need to improve surveillance programs for nonpolio enterovirus to identify possible AFM triggers and predict disease prevalence to better prepare for future outbreaks.
Purpose:
To describe one institution's experience in the rehabilitation of children with acute flaccid myelitis (AFM). This study reviews the medical and rehabilitative course and functional outcomes of a cohort of children who underwent Activity Based Restorative Therapy (ABRT) at a single center.
Methods:
Children with AFM presenting for rehabilitation between March 2005 and January 2017 were identified and a retrospective chart review was conducted. Changes in medical and functional status were assessed using multiple standardized instruments, as well as a chart review of medical progress.
Results:
Thirty-one children with AFM treated at our institution in the study time period were identified. Of these, seventeen received inpatient treatment, and fourteen received solely outpatient interventions. Their medical and functional outcomes are described with use of standardized measures when available.
Conclusions:
Children with flaccid paralysis due to AFM undergoing structured, comprehensive rehabilitation interventions, even when these are initiated long after paralysis onset, can make significant neurologic and functional gains. Recovery of function and prevention of comorbidities are the main therapeutic targets for interventions in this population.
Acute flaccid myelitis (AFM) has caused motor paralysis in >560 children in the United States since 2014. The temporal association of enterovirus (EV) outbreaks with increases in AFM cases and reports of fever, respiratory, or gastrointestinal illness prior to AFM in >90% of cases suggest a role for infectious agents. Cerebrospinal fluid (CSF) from 14 AFM and 5 non-AFM patients with central nervous system (CNS) diseases in 2018 were investigated by viral-capture high-throughput sequencing (VirCapSeq-VERT system). These CSF and serum samples, as well as multiple controls, were tested for antibodies to human EVs using peptide microarrays. EV RNA was confirmed in CSF from only 1 adult AFM case and 1 non-AFM case. In contrast, antibodies to EV peptides were present in CSF of 11 of 14 AFM patients (79%), significantly higher than controls, including non-AFM patients (1/5 [20%]), children with Kawasaki disease (0/10), and adults with non-AFM CNS diseases (2/11 [18%]) ( P = 0.023, 0.0001, and 0.0028, respectively). Six of 14 CSF samples (43%) and 8 of 11 sera (73%) from AFM patients were immunoreactive to an EV-D68-specific peptide, whereas the three control groups were not immunoreactive in either CSF (0/5, 0/10, and 0/11; P = 0.008, 0.0003, and 0.035, respectively) or sera (0/2, 0/8, and 0/5; P = 0.139, 0.002, and 0.009, respectively).
IMPORTANCE The presence in cerebrospinal fluid of antibodies to EV peptides at higher levels than non-AFM controls supports the plausibility of a link between EV infection and AFM that warrants further investigation and has the potential to lead to strategies for diagnosis and prevention of disease.
During recent 20 years, enterovirus A71 (EV-A71) has emerged as a major concern among pediatric infectious diseases, particularly in the Asia-Pacific region. The clinical manifestations of EV-A71 include uncomplicated hand, foot, and mouth disease, herpanina or febrile illness and central nervous system (CNS) involvement such as aseptic meningitis, myoclonic jerk, polio-like syndrome, encephalitis, encephalomyelitis and cardiopulmonary failure due to severe rhombencephalitis. In follow-up studies of patients with EV-A 71 CNS infection, some still have hypoventilation and need tracheostomy with ventilator support, some have dysphagia and need nasogastric tube or gastrostomy feeding, some have limb weakness/astrophy, cerebellar dysfunction, neurodevelopmental delay, lower cognition, or attention deficiency hyperactivity disorder. Long term sequelae may be related to greater severity of CNS involvement or neuron damage, hypoxia and younger age of onset.
Acute Flaccid Myelitis (AFM) is a recently recognized, polio-like illness of children that can be functionally devastating. Severe cases can lead to ventilatory failure. Incomplete phrenic nerve injuries in other populations has been shown to respond to diaphragmatic stimulation. We therefore proposed an early assessment for incomplete denervation by laparoscopic direct stimulation of the diaphragm and placement of a diaphragmatic pacing system to enhance diaphragm function.
A 3 year-old girl presented with AFM with clinically and electrodiagnostically severe involvement of all four limbs and muscles of respiration. Direct stimulation of the diaphragm demonstrated contraction and a diaphragmatic stimulator was placed at 3 weeks post presentation. The patient was immediately able to tolerate short bouts of reduced ventilation settings. Electromyography via the pacing wires demonstrated intact motor units consistent with partial denervation/reinnervation in the left hemidiaphragm, and no motor units in the right hemidiaphragm. At three months, she tolerated 6 h of pacing on pressure support setting. At 5 months she demonstrated larger tidal volumes with active pacing than without.
In our experience, AFM patients who require chronic ventilator support are rarely able to be weaned. Despite clinical and surface electrodiagnostic evidence of complete phrenic nerve involvement, the patient’s diaphragm responded to direct stimulation. The patient preferred pacing over non-pacing times and showed improved ventilatory ability with pacing as opposed to without, though remains ventilator-dependent. These findings support augmentation of diaphragm function and possible enhanced recovery of spontaneous function.
After a 2014 outbreak of severe respiratory illness caused by enterovirus D68 in the United States, sporadic cases of acute flaccid myelitis have been reported worldwide. We describe a cluster of acute flaccid myelitis cases in Argentina in 2016, adding data to the evidence of association between enterovirus D68 and this polio-like illness.
During 2018, the United Kingdom experienced an increase in reports of cases of acute flaccid paralysis (AFP). As at 21 January 2019, 40 cases had been identified with a peak in October 2018. The increase was temporally associated with an upsurge in enterovirus (EV) D68 activity. Enterovirus was detected in 15 cases, mainly from respiratory tract samples; nine were typed as EV-D68. A national task force has been established and investigations are ongoing. © 2019, European Centre for Disease Prevention and Control (ECDC). All rights reserved.
Objectives:
To compares 3 different myelin oligodendrocyte glycoprotein-immunoglobulin G (IgG) cell-based assays (CBAs) from 3 international centers.
Methods:
Serum samples from 394 patients were as follows: acute disseminated encephalomyelitis (28), seronegative neuromyelitis optica (27), optic neuritis (21 single, 2 relapsing), and longitudinally extensive (10 single, 3 recurrent). The control samples were from patients with multiple sclerosis (244), hypergammaglobulinemia (42), and other (17). Seropositivity was determined by visual observation on a fluorescence microscope (Euroimmun fixed CBA, Oxford live cell CBA) or flow cytometry (Mayo live cell fluorescence-activated cell sorting assay).
Results:
Of 25 samples positive by any methodology, 21 were concordant on all 3 assays, 2 were positive at Oxford and Euroimmun, and 2 were positive only at Oxford. Euroimmun, Mayo, and Oxford results were as follows: clinical specificity 98.1%, 99.6%, and 100%; positive predictive values (PPVs) 82.1%, 95.5%, and 100%; and negative predictive values 79.0%, 78.8%, and 79.8%. Of 5 false-positives, 1 was positive at both Euroimmun and Mayo and 4 were positive at Euroimmun alone.
Conclusions:
Overall, a high degree of agreement was observed across 3 different MOG-IgG CBAs. Both live cell-based methodologies had superior PPVs to the fixed cell assays, indicating that positive results in these assays are more reliable indicators of MOG autoimmune spectrum disorders.
A 2014 EV-D68 outbreak in the United States has been linked to the development of acute flaccid myelitis in children. Unfortunately, no treatment options against EV-D68 are currently available, and the development of effective therapeutics is urgently needed. Here, we characterize and validate a new EV-D68 drug target, the 2A pro , and identify telaprevir—an FDA-approved drug used to treat hepatitis C virus (HCV) infections—as a potent antiviral with a novel mechanism of action toward 2A pro . 2A pro functions as a viral protease that cleaves a peptide sequence corresponding to the VP1-2A polyprotein junction. The binding of telaprevir potently inhibits its enzymatic activity, and using drug resistance selection, we show that the potent antiviral activity of telaprevir was due to 2A pro inhibition. This is the first inhibitor to selectively target the 2A pro from EV-D68 and can be used as a starting point for the development of therapeutics with selective activity against EV-D68.
Acute flaccidmyelitis (AFM) is an emerging poliolike illness of children whose
clinical spectrum and associated pathogens are only partially described. The case definition is
intentionally encompassing for epidemiologic surveillance to capture all potential AFM cases.
Defining a restrictive, homogenous subpopulation may aid our understanding of this
emerging disease.
OBJECTIVE To evaluate the extent to which the US Centers for Disease Control and
Prevention (CDC) case definition of AFM incorporates possible alternative diagnoses and to
assess the plausibility of a case definition that enriches the biological homogeneity of AFM for
inclusion in research studies.
DESIGN, SETTING, AND PARTICIPANTS Retrospective case analysis of children younger than 18
years diagnosed as having AFM between 2012 and 2016 using the CDC case definition. Group
1 included patients recruited from the United States and Canada based on the CDC case
definition of AFM. Group 2 included patients referred to the Johns Hopkins Transverse
Myelitis Center for evaluation of suspected AFM. Patients’ records and imaging data were
critically reviewed by 3 neurologists to identify those cases with definable alternative
diagnoses, and the remaining patients were categorized as having restrictively defined AFM
(rAFM). Clinical characteristics were compared between patients with rAFM (cases) and
those with alternative diagnoses, and a case description distinguishing these AFM groups was
identified. Interrater reliability of this description was confirmed for a subset of cases by a
fourth neurologist. Data were analyzed between May 2017 and November 2018.
MAIN OUTCOMES AND MEASURES Proportion of patients with possible alternative diagnosis.
RESULTS Of the 45 patients who met the CDC AFM case definition and were included, the
mean age was 6.1 years; 27 were boys (60%); and 37 were white (82%), 3 were Asian (7%), 1
was Hispanic (2%), and 4 were mixed race/ethnicity (9%). Of the included patients, 34 were
classified as having rAFM, and 11 had alternate diagnoses (including transversemyelitis, other
demyelinating syndromes, spinal cord stroke, Guillain-Barre syndrome, Chiari Imyelopathy,
and meningitis). Factors differing between groups were primarily asymmetry of weakness,
lower motor neuron signs, preceding viral syndrome, symptoms evolving over hours to days,
absence of sensory deficits, and magnetic resonance imaging findings. A case description was
able to reliably define the rAFM group.
CONCLUSIONS AND RELEVANCE We present an approach for defining a homogeneous
research population that may more accurately reflect the pathogenesis of the prototypical
poliomyelitis-like subgroup of AFM. The definition of rAFM forms a blueprint for inclusion
criteria in future research efforts, but more work is required for refinement and external
validation.
Purpose of Review
Persons with spinal cord injuries (SCI) commonly experience individual risks and coalesced health hazards of the cardiometabolic syndrome (CMS). This review will examinethe role of exercise and nutritional intervention as countermeasures to these disease risks.
Recent Findings
The CMS hazards of overweight/obesity, insulin resistance, hypertension, and dyslipidemia are strongly associated with physical deconditioning and are common after SCI. Both the CMS diagnosis and physical deconditioning worsen the prognosis for all-cause cardiovascular disease occurring early after SCI. Evidence supports a therapeutic role for physical activity after SCI as an effective countermeasure to these risks and often represents the first-line approach to CMS abatement. This evidence is supported by authoritative systematic reviews and associated guidelines that recommend specific activities, frequencies, and activities of work. In many cases, the most effective exercise programming uses more intense periods of work with limited rest. As SCI is also associated with poor dietary habits, including excessive energy intake and saturated fat consumption, more comprehensive lifestyle management incorporating both exercise and nutrition represents a preferred approach for overall health management.
Summary
Irrespective of the interventional strategy, improved surveillance of the population for CMS risks and encouraged incorporation of exercise and nutritional management according to recent population-specific guidelines will most likely play an important role in the preservation of activity, optimal health, and independence throughout the lifespan.
Enterovirus D68 (EV‐D68) is an emerging infection associated with acute flaccid myelitis (AFM). Cases of AFM associated with EV‐D68 infection have increased in recent years and the evidence for a causal link is growing. However, our understanding of the epidemiology, clinical features, prognosis, and neurological sequelae of EV‐D68 requires ongoing surveillance and investigation. We report five cases of AFM in previously typically developing children (2–6y) from South East Scotland during September and October 2016 after infection with EV‐D68 (all detected in the nasopharyngeal aspirates). All cases presented with significant neurological symptoms, which were severe in two cases requiring intensive care support because of respiratory paralysis. At 18‐month follow‐up, two cases remain ventilator‐dependent with other cases requiring ongoing community rehabilitation. These cases represent one of the largest reported paediatric cluster of AFM associated with EV‐D68 in Europe. The epidemiology and clinical information add to the knowledge base and the 18‐month outcome will help clinicians to counsel families.
What this paper adds
Nasopharyngeal aspirate is more sensitive for viral isolation and isolated in all cases.
Clinical outcome at 18 months after enterovirus D68 with acute flaccid myelitis provides information on extent of recovery and level of disability.
Since the EV-D68 outbreak during the summer of 2014, evidence of a causal link to a type of limb paralysis (AFM) has been mounting. In this article, we describe a neuronal cell culture model (SH-SY5Y cells) in which a subset of contemporary 2014 outbreak strains of EV-D68 show infectivity in neuronal cells, or neurotropism. We confirmed the difference in neurotropism in vitro using primary human neuron cell cultures and in vivo with a mouse paralysis model. Using the SH-SY5Y cell model, we determined that a barrier to viral entry is at least partly responsible for neurotropism. SH-SY5Y cells may be useful in determining if specific EV-D68 genetic determinants are associated with neuropathogenesis, and replication in this cell line could be used as rapid screening tool for identification of neurotropic EV-D68 strains. This may assist with better understanding of pathogenesis and epidemiology and with the development of potential therapies.
Guillain-Barré syndrome is a heterogeneous disorder regarding the clinical presentation, electrophysiological subtype and outcome. Previous single country reports indicate that Guillain-Barré syndrome may differ among regions, but no systematic comparative studies have been conducted. Comparative studies are required to identify factors determining disease susceptibility, variation and prognosis, and to improve diagnostic criteria. The International Guillain-Barré Syndrome Outcome Study is a prospective, observational cohort study including all patients within the diagnostic spectrum, aiming to describe the heterogeneity of Guillain-Barré syndrome worldwide. The current study was based on the first 1000 inclusions with a follow-up of at least 1 year and confirmed the variation in clinical presentation, course and outcome between patients. The full clinical spectrum of Guillain-Barré syndrome was observed in patients from all countries participating in the International Guillain-Barré Syndrome Outcome Study, but the frequency of variants differed between regions. We compared three regions based on geography, income and previous reports of Guillain-Barré syndrome subtypes: 'Europe/Americas', 'Asia' (without Bangladesh), and 'Bangladesh'. We excluded 75 (8%) patients because of alternative diagnoses, protocol violations, or missing data. The predominant clinical variant was sensorimotor in Europe/Americas (n = 387/562, 69%) and Asia (n = 27/63, 43%), and pure motor in Bangladesh (n = 74/107, 69%). Miller Fisher syndrome and Miller Fisher-Guillain-Barré overlap syndrome were more common in Asia (n = 14/63, 22%) than in the other two regions (Europe/Americas: n = 64/562, 11%; Bangladesh: n = 1/107, 1%) (P < 0.001). The predominant electrophysiological subtype was demyelinating in all regions (Europe/Americas: n = 312/573, 55%; Asia: n = 29/65, 45%; Bangladesh: n = 38/94, 40%). The axonal subtype occurred more often in Bangladesh (n = 34/94, 36%) than in Europe/Americas (n = 33/573, 6%) and other Asian countries (n = 4/65, 6%) (P < 0.001). In all regions, patients with the axonal subtype were younger, had fewer sensory deficits, and showed a trend towards poorer recovery compared to patients with the demyelinating subtype. The proportion of patients able to walk unaided after 1 year varied between Asia (n = 31/34, 91%), Europe/Americas (n = 334/404, 83%) and Bangladesh (n = 67/97, 69%) (P = 0.003). A similar variation was seen for mortality, being higher in Bangladesh (n = 19/114, 17%) than in Europe/Americas (n = 23/486, 5%) and Asia (n = 1/45, 2%) (P < 0.001). This study showed that factors related to geography have a major influence on clinical phenotype, disease severity, electrophysiological subtype, and outcome of Guillain-Barré syndrome.
Background:
Enterovirus-D68 (EV-D68) is a respiratory virus within the genus Enterovirus and the family of Picornaviridae. Genetically, it is closely related to rhinovirus that replicates in the respiratory tract and causes respiratory disease. Since 2014, EV-D68 has been associated with the neurologic syndrome of acute flaccid myelitis (AFM).
Methods:
In October 2016, questionnaires were sent out to a European network including 66 virologists and clinicians, to develop an inventory of EV-D68-associated AFM cases in Europe. Clinical and virologic information of case patients was requested. In addition, epidemiologic information on EV testing was collected for the period between March and October 2016.
Results:
Twenty-nine cases of EV-D68-associated AFM were identified, from 12 different European countries. Five originated from France, 5 from Scotland and 3 each from Sweden, Norway and Spain. Twenty-six were children (median age 3.8 years), 3 were adults. EV-D68 was detected in respiratory materials (n = 27), feces (n = 8) and/or cerebrospinal fluid (n = 2). Common clinical features were asymmetric flaccid limb weakness, cranial nerve deficits and bulbar symptoms. On magnetic resonance imaging, typical findings were hyperintensity of the central cord and/or brainstem; low motor amplitudes with normal conduction velocities were seen on electromyography. Full clinical recovery was rare (n = 3), and 2 patients died. The epidemiologic data from 16 European laboratories showed that of all EV-D68-positive samples, 99% was detected in a respiratory specimen.
Conclusions:
For 2016, 29 EV-D68-related AFM cases were identified in mostly Western Europe. This is likely an underestimation, because case identification is dependent on awareness among clinicians, adequate viral diagnostics on respiratory samples and the capability of laboratories to type EVs.
Aim
To quantify characteristics in acute flaccid myelitis (AFM) at acute and convalescent stages.
Method
This was a retrospective case series of children with AFM evaluated at a single institution in the USA (2014–2017). Acute inflammatory/ischemic myelopathies were excluded. Neurological assessments and segmental quantitative analysis of signal abnormalities on magnetic resonance imaging (MRI) of the brain and spinal cord were performed.
Results
Sixteen patients (11 males, five females) were evaluated. Median age at onset was 4 years (interquartile range [IQR] 3–6y). All had parainfectious acute‐onset limb weakness, lower motor neuron examination, and spinal fluid pleocytosis. On acute spinal cord MRI, longitudinally extensive T2 hyperintensities were identified throughout the spinal cord mostly within grey matter; five out of 12 patients had dorsal brainstem T2 hyperintensities. At a median of 2 months follow‐up (IQR 2–3mo), spinal cord MRI improved in seven out of nine patients although focal T2 hyperintensities persisted in cervical and lumbar grey matter. At a median follow‐up of 4 months (IQR 2–6mo), Medical Research Council sum score rose from a median of 29 to 32; distal muscle groups improved more than proximal ones; four out of 16 patients were ventilator‐dependent; and two out of 16 patients were quadriplegic.
Interpretation
While patients may show marked improvement on neuroimaging from acute to convalescent stages, the majority of children with AFM have limited motor recovery and continued disability. Clinicians should consider the timing of clinical and neuroimaging exams when assessing diagnosis and prognosis.
What this paper adds
During the 2014 to 2017 acute flaccid myelitis outbreak in the USA, clinical recovery was better in distal than proximal muscle groups.
Lumbar spinal cord showed more residual abnormalities at convalescence.
Background
Understanding enterovirus D68 (EV-D68) circulation patterns as well as risk factors for severe respiratory and neurological illness is important for developing preventive strategies. Methods: Between 2010 and 2016, 11,132 respiratory specimens from hospitalised patients in Lyon, France, were screened for EV-D68 by PCR. Phylogenetic relationships of the viral-protein-1 sequences were reconstructed using maximum-likelihood and Bayesian-Markov-Chain-Monte-Carlo approaches. Results: Overall, 171 infections with a biennial pattern were detected, including seven, one, 55, none, 42, one and 65 cases annually during 2010-16. Children (< 16 years-old; n = 150) were mostly affected and 71% (n = 121) of the total patients were under 5 years-old. In 146 patients with medical reviews, 73% (n = 107) presented with acute respiratory distress. Among paediatric patients with medical reviews (n = 133), 55% (n=73) had an asthma/wheezing history, while among adults (n = 13), 11 had underlying diseases. In total, 45 patients had severe infections and 28 patients needed intensive care unit stays. No acute flaccid myelitis (AFM) was detected. We found genotypes A, B1, B2 B3 and D circulating, and no associations between these and clinical presentations. During the study, new genotypes continuously emerged, being replaced over time. We estimated that ancestors of currently circulating genotypes emerged in the late-1990s to 2010. Rises of the EV-D68 effective population size in Lyon coincided with infection upsurges. Phylogenetic analyses showed ongoing diversification of EV-D68 worldwide, coinciding with more infections in recent years and increases of reported AFM paediatric cases. Conclusions: Reinforcement of diagnostic capacities and clinical-based surveillance of EV-D68 infections is needed in Europe to assess the EV-D68 burden.
Rationale:
We present the first case of enterovirus (EV) D68, lineage B3 infection, associated with acute flaccid myelitis (AFM) in Taiwan. AFM caused by EV D68 is relatively rare. This report highlights the importance of clinical recognition of the disease and discusses treatments that can benefit such patients.
Patient concerns:
A 5-year-old boy experienced sudden onset of acute flaccid paralysis (AFP) involving left arm after fever and respiratory symptoms for 3 days.
Diagnoses:
Magnetic resonance imaging (MRI) of the spinal cord revealed signal changes over segments C1 to T5 on a T2-weighted image (T2WI), compatible with the diagnosis of AFM. The EV D68 strain, cultured from the throat of the patient was identified.
Interventions:
We administered intravenous immunoglobulin (IVIG, 1g/kg, twice), pulse steroid therapy (methylprednisolone, 30 mg/kg, twice) and oral prednisolone (1mg/kg/day). Rehabilitation was also arranged.
Outcomes:
The patient still had mild muscle atrophy over left arm after following-up for 1 year.
Lessons:
Early diagnosis and prompt management are essential for managing this kind of patient. IVIG, pulse therapy, and oral prednisolone may play crucial roles in controlling its clinical course.
Introduction:
Acute flaccid myelitis (AFM) is characterized by limb weakness with spinal cord grey matter lesion on imaging or electrodiagnostic evidence of spinal cord motor neuron injury. This Poliomyelitis-like illness is rare in children, and its natural course is not yet well defined.
Purpose of the study:
The purpose of the study was to report the clinical presentation, laboratory findings, management and outcome of children with AFM.
Materials and methods:
This is a prospective case series study.
Results:
Nine children met the case definition given by CDC. All cases presented with prodromal symptoms followed by acute onset asymmetrical limb weakness. Maximum weakness is reached within 4 days from the day of onset. Cerebrospinal fluid analysis shows that pleocytosis with viral markers for arboviruses and enteroviruses was negative. Electrophysiological study revealed decreased muscle action potential in all. MRI of the spinal cord showed predominantly grey matter involvement.
Conclusion:
AFM should be one of the differential diagnoses in any child presenting with acute flaccid paralysis.
Backgroud
Acute flaccid myelitis (AFM) is an acute flaccid paralysis (AFP) syndrome with spinal motor neuron involvement of unknown etiology. We investigated the characteristics and prognostic factors of AFM clusters coincident with an enterovirus D68 (EV-D68) outbreak in Japan during autumn 2015.
Methods
An AFM case series study was conducted following a nationwide survey from August to December 2015. Radiographic and neurophysiologic data were subjected to centralized review, and virology studies were conducted for available specimens.
Results
Fifty-nine AFM cases (58 definite, one probable) were identified, including 55 children and four adults (median age, 4.4 years). The AFM epidemic curve showed strong temporal correlation with EV-D68 detection from pathogen surveillance, but not with other pathogens. EV-D68 was detected in nine patients: five in nasopharyngeal, two in stool, one in cerebrospinal fluid (adult case), and one in tracheal aspiration, nasopharyngeal, and serum samples (a pediatric case with preceding steroid usage). Cases exhibited heterogeneous paralysis patterns from one- to four-limb involvement, but all definite cases had longitudinal spinal gray matter lesions on MRI (median 20 spinal segments). Cerebrospinal fluid pleocytosis was observed in 50/59 cases (85%), and 8/29 (28%) were positive for anti-ganglioside antibodies, as frequently observed in Guillain-Barré syndrome. Fifty-two patients showed variable residual weakness at follow-up. Good prognostic factors included a pretreatment manual muscle strength test unit score >3, normal F-wave persistence, and EV-D68-negative status.
Conclusions
EV-D68 may be one of the causative agents for AFM, while host susceptibility factors such as immune response could contribute to AFM development.
Background:
Enterovirus D68 (EV-D68) associated acute flaccid myelitis (AFM) is a devastating neurological disease for which there are no treatments of proven efficacy. The unpredictable temporal and geographic distribution of cases, and the rarity of the disease, make it unlikely that data from randomized controlled trials will be available to guide therapeutic decisions. We evaluated three widely used empiric therapies: (1) human intravenous immunoglobulin (hIVIG), (2) fluoxetine, and (3) dexamethasone, for the ability to reduce the severity of paralysis in a mouse model of EV-D68 infection.
Methods:
Neonatal mice were injected intramuscularly with a human 2014 EV-D68 isolate that reliably induces paralysis in mice due to infection and loss of spinal cord motor neurons. Mice receiving treatments were evaluated for motor impairment, mortality, and spinal cord viral load.
Results:
hIVIG, which contained neutralizing antibodies to EV-D68, reduced paralysis in infected mice and decreased spinal cord viral loads. Fluoxetine had no effect on motor impairment or viral loads. Dexamethasone treatment worsened motor impairment, increased mortality, and increased viral loads.
Conclusion:
Results in this model of EV-D68 associated AFM provide a rational basis for selecting empiric therapy in humans and establish this model as a useful system for evaluating other potential therapies.
In Italy in 2016, acute flaccid myelitis developed in a woman who had received a hematopoietic stem cell transplant. Enterovirus D68 viral genome was detected in respiratory and cerebrospinal fluid samples, and the viral protein 1 sequence clustered with lineage B3. Immunocompromised adults may be at risk for enterovirus D68–associated neurologic complications.
Enterovirus D68 (EV-D68) causes outbreaks of respiratory illness, and there is increasing evidence that it causes outbreaks of acute flaccid myelitis (AFM). There are no licensed therapies to prevent or treat EV-D68 infection or AFM disease. We isolated a panel of EV-D68–reactive human monoclonal antibodies that recognize diverse antigenic variants from participants with prior infection. One potently neutralizing cross-reactive antibody, EV68-228, protected mice from respiratory and neurologic disease when given either before or after infection. Cryo–electron microscopy studies revealed that EV68-228 and another potently neutralizing antibody (EV68-159) bound around the fivefold or threefold axes of symmetry on virion particles, respectively. The structures suggest diverse mechanisms of action by these antibodies. The high potency and effectiveness observed in vivo suggest that antibodies are a mechanistic correlate of protection against AFM disease and are candidates for clinical use in humans with EV-D68 infection.
Background:
Acute flaccid myelitis is a recently defined clinically distinct syndrome of polio-like acute flaccid paralysis. Acute flaccid myelitis cases show characteristic neuroradiological features of longitudinal spinal cord lesions with predominant gray matter involvement. Current evidence suggests injury to the anterior horn neurons as the underlying mechanism.
Methods:
We describe three patients with acute flaccid myelitis who developed flaccid upper limb weakness with diminished deep tendon reflexes after prodromal fever. Spinal magnetic resonance imaging (MRI) (axial and sagittal T1- and T2-weighted sequences) and brachial plexus MRI (coronal short tau inversion recovery sequence) at the acute stage were performed.
Results:
Spinal MRI showed extensive longitudinal lesion in the spinal cord with predominant gray matter involvement. We were able to demonstrate concurrent swelling and hyperintensity in the brachial plexus in all the three patients at the acute stage.
Conclusion:
The coexisting signal intensities suggest an extension of acute flaccid myelitis pathology to the brachial plexus, highlighting the possible peripheral nerve involvement in acute flaccid myelitis.
Background:
In May, 2018, Children's Hospital Colorado noted an outbreak of enterovirus A71 (EV-A71) neurological disease. We aimed to characterise the clinical features of EV-A71 neurological disease during this outbreak.
Methods:
In this retrospective observational cohort study, children (younger than 18 years) who presented to Children's Hospital Colorado (Aurora, CO, USA) between March 1 and November 30, 2018, with neurological disease (defined by non-mutually exclusive criteria, including meningitis, encephalitis, acute flaccid myelitis, and seizures) and enterovirus detected from any biological specimen were eligible for study inclusion. The clinical characteristics of children with neurological disease associated with EV-A71 were compared with those of children with neurological disease associated with other enteroviruses during the same period. To explore the differences in clinical presentation of acute flaccid myelitis, we also used a subgroup analysis to compare clinical findings in children with EV-A71-associated acute flaccid myelitis during the study period with these findings in those with enterovirus D68 (EV-D68)-associated acute flaccid myelitis at the same hospital between 2013 and 2018.
Findings:
Between March 10 and Nov 10, 2018, 74 children presenting to Children's Hospital Colorado were found to have enterovirus neurological disease; EV-A71 was identified in 43 (58%) of these children. The median age of the children with EV-A71 neurological disease was 22·7 months (IQR 4·0-31·9), and most of these children were male (34 [79%] children). 40 (93%) children with EV-A71 neurological disease had findings suggestive of meningitis, 31 (72%) children showed evidence of encephalitis, and ten (23%) children met our case definition of acute flaccid myelitis. All children with EV-A71 disease had fever and 18 (42%) children had hand, foot, or mouth lesions at or before neurological onset. Children with EV-A71 disease were best differentiated from those with other enteroviruses (n=31) by the neurological findings of myoclonus, ataxia, weakness, and autonomic instability. Of the specimens collected from children with EV-A71, this enterovirus was detected in 94% of rectal, 79% of oropharyngeal, 56% of nasopharyngeal, and 20% of cerebrospinal fluid specimens. 39 (93%) of 42 children with EV-A71 neurological disease who could be followed up showed complete recovery by 1-2 months. Compared with children with EV-D68-associated acute flaccid myelitis, children with EV-A71-associated acute flaccid myelitis were younger, showed neurological onset earlier after prodromal symptom onset, had milder weakness, showed more rapid improvement, and were more likely to completely recover.
Interpretation:
This outbreak of EV-A71 neurological disease, the largest reported in the Americas, was characterised by fever, myoclonus, ataxia, weakness, autonomic instability, and full recovery in most patients. Because EV-A71 epidemiology outside of Asia remains difficult to predict, identification of future outbreaks will be aided by prompt recognition of these distinct clinical findings, testing of non-sterile and sterile site specimens, and enhanced enterovirus surveillance.
Funding:
None.
Background:
Acute flaccid myelitis (AFM) is a neurologic condition characterized by flaccid limb weakness. After a large number of reports of AFM in 2014, the Centers for Disease Control and Prevention began standardized surveillance in the United States to characterize the disease burden and explore potential etiologies and epidemiologic associations.
Methods:
Persons meeting the clinical case criteria of acute flaccid limb weakness from January 1, 2015, through December 31, 2017, were classified as confirmed (spinal cord gray matter lesions on MRI) or probable (white blood cell count >5 cells per mm3 in cerebrospinal fluid [CSF]). We describe clinical, radiologic, laboratory, and epidemiologic findings of pediatric patients (age ≤21 years) confirmed with AFM.
Results:
Of 305 children reported from 43 states, 193 were confirmed and 25 were probable. Of confirmed patients, 61% were male, with a median age of 6 years (range: 3 months to 21 years; interquartile range: 3 to 10 years). An antecedent respiratory or febrile illness was reported in 79% with a median of 5 days (interquartile range: 2 to 7 days) before limb weakness. Among 153 sterile-site specimens (CSF and serum) submitted to the Centers for Disease Control and Prevention, coxsackievirus A16 was detected in CSF and serum of one case patient and enterovirus D68 was detected in serum of another. Of 167 nonsterile site (respiratory and stool) specimens, 28% tested positive for enterovirus or rhinovirus.
Conclusions:
AFM surveillance data suggest a viral etiology, including enteroviruses. Further study is ongoing to better characterize the etiology, pathogenesis, and risk factors of this rare condition.
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.
Objective:
To describe early functional outcomes of nerve transfer surgery in a relatively large cohort of patients with Acute Flaccid Myelitis (AFM).
Methods:
Retrospective case analysis of patients with AFM treated with nerve transfer surgery between 2007 and 2018. Surgical criteria were persistent motor deficits after 6 months from onset and available donor nerves. Thirty-two patients with AFM were evaluated, 16 underwent nerve transfer surgeries. Motor function was evaluated by a licensed occupational therapist using the Active Movement Scale (AMS) preoperatively and during follow-up examinations. Patients with 6 or more months of follow-up were included in the analysis. Patients with procedures other than nerve transfers were excluded.
Results:
Sixteen patients with AFM had nerve transfers, with a male predominance (75%) and median age of 2.5 years (range 4 months-12 years). Eleven patients had a minimum 6 months follow-up. Nerve transfers to restore elbow function had 87% excellent recovery for elbow flexion and 67% for elbow extension. Finger and thumb extension were full against gravity in one patient (100%). Shoulder external rotation was excellent in 50% of patients and shoulder abduction in only 20%. Nine out of 10 patients (90%) had resolution of shoulder pseudosubluxation following nerve transfer to the suprascapular nerve.
Interpretation:
Patients with AFM with persistent motor deficits after 6 to 9 months after onset benefit from nerve transfer surgery. Restoration of elbow function was more reliable than restoration of shoulder function. We recommend early referral of patients with incomplete recovery to an experienced center in nerve transfers for timely evaluation and treatment. This article is protected by copyright. All rights reserved.
Enterovirus D68 (EV-D68) is an atypical non-polio enterovirus that mainly infected the respiratory system of humans, leading to moderate to severe respiratory diseases. In rare cases, EV-D68 can spread to the central nervous system and causes paralysis in infected patients, especially young children and immunocompromised individuals. There is currently no approved vaccine or antiviral available for the prevention and treatment of EV-D68. In this study, we aimed to improve the antiviral potency and selectivity of a previously reported EV-D68 inhibitor, dibucaine, through structure-activity relationship studies. In total, sixty compounds were synthesized and tested against EV-D68 using the viral cytopathic effect (CPE) assay. Three compounds 10a, 12a, and 12c were identified to have significantly improved potency (EC50 < 1 µM) and a high selectivity index (SI > 180) compared to dibucaine against five different strains of EV-D68 viruses. These compounds also showed potent antiviral activity in neuronal cells such as A172 and SH-SY5Y cells, suggesting they might be further developed for the treatment of both respiratory infection as well as neuronal infection.
Background:
Previous studies suggest that patients with a history of poliomyelitis (PM) later in life experience a variety of symptoms. These studies were carried out in patients who later in life were admitted to hospital or became members of polio societies and may therefore not be representative of all polio patients. Little data have been published concerning patients actually discharged from hospital with a diagnosis of acute paralytic PM.
Objectives:
The aim of this study was to compare the prevalence of late symptoms in individuals with a history of paralytic PM with that of controls, and to study whether late symptoms in individuals with a history of PM were associated with symptoms at the acute stage of polio, and finally to compare the prevalence of symptoms in polio patients with postpolio syndrome (PPS) with the prevalence of symptoms in polio patients without PPS.
Methods:
A questionnaire concerning various symptoms was sent to a previously established cohort of patients, who during the polio epidemics were discharged from the Department of Infectious Disease at Blegdamshospitalet, Copenhagen, with a diagnosis of paralytic PM, and to age- and gender-matched controls without PM. Information about symptoms at the acute stage of disease was obtained from hospital records. Logistic regression analysis with adjustment for age and gender was applied to compare the occurrence of late symptoms in cases and controls and within the above-mentioned groups of individuals with a history of PM.
Results:
(i) Compared with controls, individuals with a history of polio significantly more often reported muscle symptoms, pain, neuropathic sensory symptoms, and bulbar symptoms; (ii) the occurrence of symptoms did not seem to be related to symptoms of the initial PM; and (iii) symptom prevalence was significantly higher in individuals with a history of polio who reported PPS as compared with those who did not.
Conclusion:
Our data indicate that individuals with a history of PM late in life experience a variety of symptoms that cannot be attributed to lesions of the anterior horn. Furthermore, late symptoms do not seem to be related to initial symptoms of the acute stage of PM but to reported PPS. The last finding supports the perception that the cause of PPS is not just normal ageing.
Objecive:
To clarify the neuroimaging findings of children with acute flaccid myelitis during an outbreak of EV-D68 infection.
Methods:
We performed a detailed review of the spinal and cranial MRI results of 54 children with acute flaccid myelitis. We focused on the range of longitudinal lesions, the localization and appearance of lesions within a horizontal section, Gadolinium-enhancement, and changes over time.
Results:
All children had longitudinal spinal lesions involving central gray matter. Twenty-six children had lesions spanning the entire spine. Six of them had weakness in all limbs, whereas seven had weakness of only one limb. Thirty-eight children had lesions in both gray and white matter and limb weakness tended to be more severe in these children. During the acute period, spinal lesions showed bilateral ill-defined widespread T2 hyperintensity. During the subacute period, lesions were well defined and confined to the anterior horn. The distribution of limb weakness was correlated with the appearance of lesions during the subacute period. Gadolinium enhancement was performed in 37 children, and enhancement was seen in the cauda equina in 29 children. Enhancement was infrequent within 2 days after onset but was seen in almost all children thereafter. Twenty-two children had brainstem lesions continuous with spinal lesions.
Conclusion:
Extensive longitudinal spinal lesions were characteristic in children with acute flaccid myelitis. Lesions were usually bilateral and widespread during the acute period, whereas localization to the anterior horn could become obvious. Although enhancement of the cauda equina was often observed, its appearance was sometimes delayed.
Importance
Recognizing the characteristics of myelin oligodendrocyte glycoprotein autoantibody (MOG-IgG) myelitis is essential for early accurate diagnosis and treatment.
Objective
To evaluate the clinical, radiologic, and prognostic features of MOG-IgG myelitis and compare with myelitis with aquaporin-4–IgG (AQP4-IgG) and multiple sclerosis (MS).
Design, Setting, and Participants
We retrospectively identified 199 MOG-IgG–positive Mayo Clinic patients from January 1, 2000, through December 31, 2017, through our neuroimmunology laboratory. Fifty-four patients met inclusion criteria of (1) clinical myelitis; (2) MOG-IgG positivity; and (3) medical records available. We excluded 145 patients without documented myelitis. Myelitis of AQP4-IgG (n = 46) and MS (n = 26) were used for comparison.
Main Outcomes and Measures
Outcome variables included modified Rankin score and need for gait aid. A neuroradiologist analyzed spine magnetic resonance imaging of patients with MOG-IgG and control patients blinded to diagnosis.
Results
Of 54 included patients with MOG-IgG myelitis, the median age was 25 years (range, 3-73 years) and 24 were women (44%). Isolated transverse myelitis was the initial manifestation in 29 patients (54%), and 10 (19%) were initially diagnosed as having viral/postviral acute flaccid myelitis. Cerebrospinal fluid–elevated oligoclonal bands occurred in 1 of 38 (3%). At final follow-up (median, 24 months; range, 2-120 months), 32 patients (59%) had developed 1 or more relapses of optic neuritis (n = 31); transverse myelitis (n = 7); or acute disseminated encephalomyelitis (n = 1). Clinical features favoring MOG-IgG myelitis vs AQP4-IgG or MS myelitis included prodromal symptoms and concurrent acute disseminated encephalomyelitis. Magnetic resonance imaging features favoring MOG-IgG over AQP4-IgG or MS myelitis were T2-signal abnormality confined to gray matter (sagittal line and axial H sign) and lack of enhancement. Longitudinally extensive T2 lesions were of similar frequency in MOG-IgG and AQP4-IgG myelitis (37 of 47 [79%] vs 28 of 34 [82%]; P = .52) but not found in MS. Multiple spinal cord lesions and conus involvement were more frequent with MOG-IgG than AQP4-IgG but not different from MS. Wheelchair dependence at myelitis nadir occurred in one-third of patients with MOG-IgG and AQP4-IgG but never with MS, although patients with MOG-IgG myelitis recovered better than those with AQP4-IgG.
Conclusions and Relevance
Myelitis is an early manifestation of MOG-IgG–related disease and may have a clinical phenotype of acute flaccid myelitis. We identified a variety of clinical and magnetic resonance imaging features that may help clinicians identify those at risk in whom MOG-IgG should be tested.
Anti-myelin oligodendrocyte glycoprotein (MOG) antibodies (MOG-Abs) were first detected by immunoblot and enzyme-linked immunosorbent assay nearly 30 years ago, but their association with multiple sclerosis (MS) was not specific. Use of cell-based assays with native MOG as the substrate enabled identification of a group of MOG-Ab-positive patients with demyelinating phenotypes. Initially, MOG-Abs were reported in children with acute disseminated encephalomyelitis (ADEM). Further studies identified MOG-Abs in adults and children with ADEM, seizures, encephalitis, anti-aquaporin-4-antibody (AQP4-Ab)-seronegative neuromyelitis optica spectrum disorder (NMOSD) and related syndromes (optic neuritis, myelitis and brainstem encephalitis), but rarely in MS. This shift in our understanding of the diagnostic assays has re-invigorated the examination of MOG-Abs and their role in autoimmune and demyelinating disorders of the CNS. The clinical phenotypes, disease courses and responses to treatment that are associated with MOG-Abs are currently being defined. MOG-Ab-associated disease is different to AQP4-Ab-positive NMOSD and MS. This Review provides an overview of the current knowledge of MOG, the metrics of MOG-Ab assays and the clinical associations identified. We collate the data on antibody pathogenicity and the mechanisms that are thought to underlie this. We also highlight differences between MOG-Ab-associated disease, NMOSD and MS, and describe our current understanding on how best to treat MOG-Ab-associated disease.
Enterovirus D68 (EV-D68) is a causative agent of recent outbreaks of severe respiratory illness, pneumonia and acute flaccid myelitis (AFM) worldwide. The study of the pathogenesis, vaccines and anti-viral drugs for EV-D68 infection has been reported. Given the previously described mouse model of EV-D68, we sought to establish a neonatal mice model inducing both pneumonia and AFM. The neonatal BALB/c mice were inoculated intraperitoneally with the EV-D68 strain (named15296-virus) which was produced by the reverse genetics method. The infected mice displayed limb paralysis, tachypnea and even death, which were similar to the clinical symptoms of human infections. Moreover, the results of histopathologic examination and immunohistochemical staining showed acidophilic necrosis in the muscle, the spinal cord and alveolar wall thickening in the lung, indicating that EV-D68 exhibited strong tropism to the muscles, spinal cord and lung. Furthermore, the results of real-time PCR also suggested that the viral loads in the blood, spinal cord, muscles and lung were higher than those in other tissues at different time points post-infection. Additionally, the neonatal mouse model was used for evaluating the EV-D68 infection. The results of the anti-serum passive and maternal antibody protection indicated that the neonatal mice could be protected against the EV-D68 challenge, and displayed that both the serum of 15296-virus and prototype-virus (Fermon) were performing a certain cross-protective activity against the 15296-virus challenge. In summary, the above results proved that our neonatal mouse model possessed not only the interstitial pneumonia and AFM simultaneously but also a potentiality to evaluate the protective effects of EV-D68 vaccines and anti-viral drugs in the future.
Poliomyelitis, often termed “polio,” is an acute infectious disease caused by an enterovirus which damages the anterior horn cells of the spinal cord and brainstem. Progress to lower motor neurone cell death leads to disruption of motor units and subsequent muscle weakness or complete paralysis. Although the virus is mostly eradicated from the Western world, postpolio decline is prevalent among people aged 60 years and over. It is characterized primarily by fatigability and muscle weakness, but pain is also common. Reductions in lower-limb muscle strength, voluntary drive, and endurance are likely to contribute to the impaired balance control, slow gait, and dysfunctional lower-limb kinematics reported in polio survivors. Given these significant risk factors, polio survivors fall up to four times more often than their age-matched healthy peers. Interventions to improve function, reduce disability, and prevent falls in polio survivors are therefore clinically relevant but studies are lacking, limiting the evidence base. Balance training, cognitive behavioral therapy, and orthoses prescription might be recommended. Muscle-strengthening programs should be carefully designed and delivered due to their potential detrimental effects related to excessive use and potential dysfunction of motor neurones and their axons.
Objective To determine the safety, tolerability, and efficacy of fluoxetine for proven or presumptive enterovirus (EV) D68–associated acute flaccid myelitis (AFM).Methods A multicenter cohort study of US patients with AFM in 2015–2016 compared serious adverse events (SAEs), adverse effects, and outcomes between fluoxetine-treated patients and untreated controls. Fluoxetine was administered at the discretion of treating providers with data gathered retrospectively. The primary outcome was change in summative limb strength score (SLSS; sum of Medical Research Council strength in all 4 limbs, ranging from 20 [normal strength] to 0 [complete quadriparesis]) between initial examination and latest follow-up, with increased SLSS reflecting improvement and decreased SLSS reflecting worsened strength.Results Fifty-six patients with AFM from 12 centers met study criteria. Among 30 patients exposed to fluoxetine, no SAEs were reported and adverse effect rates were similar to unexposed patients (47% vs 65%, p = 0.16). The 28 patients treated with >1 dose of fluoxetine were more likely to have EV-D68 identified (57.1% vs 14.3%, p < 0.001). Their SLSS was similar at initial examination (mean SLSS 12.9 vs 14.3, p = 0.31) but lower at nadir (mean SLSS 9.25 vs 12.82, p = 0.02) and latest follow-up (mean SLSS 12.5 vs 16.4, p = 0.005) compared with the 28 patients receiving 1 (n = 2) or no (n = 26) doses. In propensity-adjusted analysis, SLSS from initial examination to latest follow-up decreased by 0.2 (95% confidence interval [CI] −1.8 to +1.4) in fluoxetine-treated patients and increased by 2.5 (95% CI +0.7 to +4.4) in untreated patients (p = 0.015).
Importance
Spinal cord infarction (SCI) is often disabling, and the diagnosis can be challenging without an inciting event (eg, aortic surgery). Patients with a spontaneous SCI are often misdiagnosed as having transverse myelitis. Diagnostic criteria for SCI are lacking, hindering clinical care and research.
Objective
To describe the characteristics of spontaneous SCI and propose diagnostic criteria.
Design, Setting, and Participants
An institution-based search tool was used to identify patients evaluated at Mayo Clinic, Rochester, Minnesota, from January 1997 to December 2017 with a spontaneous SCI. Patients provided written consent to use their records for research. Participants were 18 years and older with a diagnosis of spontaneous SCI (n = 133), and controls were selected from a database of alternative myelopathy etiologies for validation of the proposed diagnostic criteria (n = 280).
Main Outcomes and Measures
A descriptive analysis of SCI was performed and used to propose diagnostic criteria, and the criteria were validated.
Results
Of 133 included patients with a spontaneous SCI, the median (interquartile range) age at presentation was 60 (52-69) years, and 101 (76%) had vascular risk factors. Rapid onset of severe deficits reaching nadir within 12 hours was typical (102 [77%]); some had a stuttering decline (31 [23%]). Sensory loss occurred in 126 patients (95%), selectively affecting pain/temperature in 49 (39%). Initial magnetic resonance imaging (MRI) spine results were normal in 30 patients (24%). Characteristic MRI T2-hyperintense patterns included owl eyes (82 [65%]) and pencil-like hyperintensity (50 [40%]); gadolinium enhancement (37 of 96 [39%]) was often linear and located in the anterior gray matter. Confirmatory MRI findings included diffusion-weighted imaging/apparent diffusion coefficient restriction (19 of 29 [67%]), adjacent dissection/occlusion (16 of 82 [20%]), and vertebral body infarction (11 [9%]). Cerebrospinal fluid showed mild inflammation in 7 of 89 patients (8%). Diagnostic criteria was proposed for definite, probable, and possible SCI of periprocedural and spontaneous onset. In the validation cohort (n = 280), 9 patients (3%) met criteria for possible SCI, and none met criteria for probable SCI.
Conclusions and Relevance
This large series of spontaneous SCIs provides clinical, laboratory, and MRI clues to SCI diagnosis. The diagnostic criteria proposed here will aid clinicians in making the correct diagnosis and ideally improve future care for patients with SCI. The validation of these criteria supports their utility in the evaluation of acute myelopathy.
Background
Acute flaccid myelitis is associated with enterovirus D68 -induced inflammation and destruction of cervical anterior horn cells. To date, no medical intervention has altered the disease course.
Methods
We report two pediatric patients who were treated with nerve transfer in three limbs with sustained upper extremity neuropathy. Postoperative outcomes included muscle strength, graded on the British Medical Research Council (BMRC) scale, range of motion, and electromyography.
Results
Two years postoperatively, Patient 1 had improved elbow flexion to BMRC grade 4+, 125° of flexion, and discrete to decreased motor unit recruitment in targeted muscles. Twenty-one months postoperatively, Patient 2 demonstrated right brachialis flexion to BMRC grade 4+/5 and deltoid firing with simultaneous pectoralis major recruitment, and limited but active flexor digitorum profundus flexion.
Conclusions
Both patients continue to demonstrate functional recovery two years postoperatively. These outcomes suggest a promising reconstructive technique for this emerging and devastating viral endemic.
Background:
Anti-myelin oligodendrocyte glycoprotein (MOG) antibody associated disorders frequently manifest as optic neuritis, transverse myelitis, and acute disseminated encephalomyelitis. While their clinical phenotypes overlap with relapsing inflammatory Central nervous system (CNS) conditions such as multiple sclerosis and neuromyelitis optica spectrum disorder, MOG-related syndromes frequently occur in a younger age group. In children, longitudinally extensive transverse myelitis (LETM) is less specific for anti-aquaporin-4 associated neuromyelitis optica spectrum disorder, and has also been reported in pediatric multiple sclerosis, idiopathic transverse myelitis, and acute flaccid myelitis.
Methods:
We summarize two patients with positive MOG antibodies and myelitis.
Results:
We identified two individuals with anti-MOG associated LETM that demonstrate primarily gray matter involvement. Clinically these patients exhibited hyperreflexia and had rapid improvement with immunotherapies.
Conclusions:
Anti-MOG diseases can cause LETM with gray matter predominance mimicking acute flaccid myelitis, but clinically these patients can have retained reflexes and respond favorably to immunotherapies.
Japanese encephalitis is a severe disease caused by Japanese encephalitis virus, genus Flavivirus, family Flaviviridae, which is endemic to most of rural Asia and for which no specific treatment exists.
Japanese encephalitis causes loss of more disability-adjusted life years than any other arthropod-borne virus owing to the frequent neurological sequelae of the condition.
Pathogenesis studies indicate that inhibition of viral replication, viral spread and the host response are needed in combination for optimal therapy.
Animal models and in vitro experiments highlight a number of compounds that are potentially suitable for treatment of Japanese encephalitis in humans that could be tested without delay.
The minimum clinically significant treatment effect has probably been underestimated, and previous clinical trials of Japanese encephalitis have been too small; larger, pragmatic trials are needed.
Increased circulation of enterovirus D68 in 2014 and 2016 temporally and geographically coincided with increases in cases of acute flaccid myelitis, an uncommon condition of paralysis due to lesions in the anterior horn of the spinal cord. The identification of enterovirus D68 in respiratory specimens from cases of acute flaccid myelitis worldwide further supports an association, yet the absence of direct virus isolation from affected tissues, infrequent detection in cerebrospinal fluid, and the absence, until recently, of an animal model has left the causal nature of the relationship unproven. In this Personal View we evaluate epidemiological and biological evidence linking enterovirus D68 and acute flaccid myelitis. We applied the Bradford Hill criteria to investigate the evidence for a causal relationship and highlight the importance of comprehensive surveillance and research to further characterise the role of enterovirus D68 in acute flaccid myelitis and pursue effective therapies and prevention strategies.