Polio-Like Illness Associated With Outbreak of Upper Respiratory Tract Infection in Children

Case 1

A 5-year-old, previously well, female presented in September 2014 with a 2-day history of progressive weakness of her right face and left arm with associated severe pain of her neck and arm. Four days prior she had a temperature of 38.3°C, upper respiratory tract infection symptoms, urinary frequency, and constipation.

On examination she was alert but frightened. She kept her head in left lateral flexion. She was afebrile with normal vital signs. Motor examination revealed lower motor neuron facial weakness, 0/5 strength at the level of the shoulder and elbow on the left, but full distal strength. Tone was decreased in the affected arm and deep tendon reflexes were absent. Sensation and cerebellar testing were normal.

Investigations revealed a normal complete blood count, electrolytes, and renal and liver function tests. Cerebral spinal fluid showed 13.3 (× 10⁶/L) white blood cells (normal range 0-5 × 10⁶/L) with 78% lymphocytes, 0.13 g/L protein, and 3.8 mmol/L glucose. Gram stain and bacterial cultures were negative. Nucleic acid testings of the cerebral spinal fluid for enterovirus, parechovirus, herpes simplex virus 1 and 2, varicella zoster virus, West Nile virus, adenovirus, and M. pneumoniae were negative. An Auger suction sample was positive for enterovirus/rhinovirus by the XTAG® Respiratory Viral Panel (Luminex, Austin, TX, USA). Typing, performed as previously described, ⁵ identified rhinovirus Species C. Nucleic acid testing of stool was negative for sapovirus, astrovirus, adenovirus, norovirus, rotavirus, and enterovirus. Polymerase chain reaction (PCR) assays on the serum for enterovirus/parechovirus, adenovirus, cytomegalovirus, and M. pneumoniae were negative. Magnetic resonance imaging (MRI) of brain and spine with gadolinium was normal. Electrocardiography revealed an incomplete right bundle branch block. Chest x-ray showed peribronchial and perihilar thickening with an opacity in the left lower lobe.

Empiric coverage with ceftriaxone, vancomycin, and acyclovir was instituted until cerebral spinal fluid cultures and viral PCR were confirmed negative. She was treated with intravenous immunoglobulin 1 g/kg/d for 2 days followed by a 7-day course of pulse IV methylprednisolone (30 mg/kg/d). Pain was managed with gabapentin. Improvement was noted 6 days into admission with 3/5 strength in neck extension and 1/5 strength left shoulder abduction. Reflexes returned on day 10 in her right upper extremity. Urinary frequency and urgency slowly improved. Repeat MRI at 2 weeks revealed enhancement of the cervical and lumbosacral nerve roots and normal brain and spinal cord (Figure 1). Nerve conduction studies conducted after 3 weeks of both upper limbs were normal. Electromyography (EMG) of the left deltoids showed active denervation with no motor unit recruitment.

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Figure 1.

MRI of patient 1. Postgadolinium MR images of the cervical spine (a, b) and lumbosacral spine (c, d) show abnormal enhancement of the nerve roots (arrows), with preferential involvement of the ventral roots.

Case 2

A 15-year-old, previously healthy, male of Chinese ancestry was treated with 2 days of oral prednisone for a left Bell’s palsy 1 week following an upper respiratory tract infection with a reported tactile temperature. Three days later, he developed dysphagia, dysarthria, and trismus, plus neck and back pain. He presented to the hospital on the same day as the first patient with acute, progressive, proximal, asymmetric arm weakness.

On examination, he was afebrile with stable vital signs. He was alert and cooperative with dysphonia, dysarthria, and increased secretions requiring frequent suctioning. Neurological exam was significant for meningismus, left lower motor neuron facial weakness, left sixth nerve palsy, and tongue deviation to the left. Shoulder abduction strength was 3/5 on the right with 10° of clearance from the body and 4/5 on the left. His right elbow flexion strength was 4/5. Strength in both lower extremities and in the distal upper extremities was full. Deep tendon reflexes were 3+ in the upper and lower extremities with clonus at the ankles. Plantar responses were flexor bilaterally. Sensation was intact.

Investigations revealed normal complete blood count and metabolic work up. Cerebral spinal fluid testing had 30 (x 10⁶/L) white blood cells (normal range 0-5 × 10⁶/L), 0.46 g/L protein and negative nucleic acid testing, including enterovirus. Stool nucleic acid testing and serum PCR were negative. Acute MRI of the head and neck revealed a nonenhancing T2 hyperintense lesion at the pontomedullary junction (Figure 2). MRI of the cervical spine revealed a T2 hyperintense lesion extending from C2 to T3 in the central gray matter. Enhanced spine images and further imaging of the thoracic and lumbar spine was deferred due to difficulties with airway management. A nasopharyngeal aspirate was positive for enterovirus D68. Electrocardiogram and echocardiogram revealed myocarditis.

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Figure 2.

MRI of patient 2. Sagittal T2-weighted MR image with fat saturation (a) reveals a focal hyperintense lesion in the pontomedullary junction (arrow), as well as ill-defined longitudinal T2-hyperintense lesions running along most of the length of the visualized spinal cord. Axial T2-weighted images at the level of the lower C3 vertebral body (b), C4-C5 disc (c), and mid T3 vertebral body (d) show T2-hyperintense lesions (arrowheads) that preferentially involve anterior horns of the gray matter of spinal cord. The MRI scan was aborted before images of the thoracic and lumbar spine were obtained due to difficulties with airway management. No postcontrast images were obtained. On follow up MRI at 1 week, the above-mentioned brainstem and spinal cord lesions are markedly improved (not shown). On the postcontrast images (e), mild abnormal enhancement of the anterior cervical nerve roots are noted (arrows, e), but the lumbosacral nerve roots showed no abnormal enhancement.

Treatment included empiric antibiotics, as well as intravenous immunoglobulin and pulse IV methylprednisolone as described for case 1. Eight days following admission, improvement of oral secretions and antigravity strength in right shoulder abduction to 45° body clearance and 4-/5 shoulder abduction on the left was noted. Pain improved with gabapentin. Follow up MRI at 1 week showed interval improvement of the pontomedullary junction and spinal lesions with enhancement of the cervical nerve roots (Figure 2). Nerve conduction studies of both upper limbs were normal. EMG performed at 3 weeks showed denervation of the right deltoid with neurogenic recruitment pattern.

Case 3

A 12-year-old male of Filipino descent presented 2 days following discharge from hospital for an asthma exacerbation associated with a positive nasopharyngeal aspirate for enterovirus/rhinovirus. He presented 1 day following the first 2 patients with a 2-day history of progressive bilateral, asymmetric lower extremity weakness, urinary retention and associated pain described as deep in the quadriceps muscles.

On examination, he was alert and cooperative. He was febrile (38.6°C) with otherwise normal vital signs. On motor examination, strength was normal in the upper extremities. He had 2/5 strength in the left hip, 4-/5 strength in the left knee, and 4/5 in the right hip. Distal lower extremity strength was full. Deep tendon reflexes were 3+ in the upper extremities and absent reflexes in the lower extremities. Plantar responses were flexor. Sensory and cerebellar testing was normal.

Investigations revealed a neutrophilia (white blood cells 20.0 [normal range 0-5 × 10⁶/L] with 14.2 neutrophils × 10⁹/L), thrombocytosis (468 × 10E ⁹ /L), hyponatremia (129 mmol/L), and normal liver and renal function. Cerebral spinal fluid revealed 20.8 (×10⁶) white blood cells with 78% lymphocytes, 0.35 g/L protein, and 3.8 mmol/L glucose. Gram stain, bacterial cultures, and nucleic acid testing were negative. An Auger suction sample was positive for enterovirus D68 and demonstrated a mixed infection with the enterovirus and with rhinovirus A38. Stool nucleic acid testing was negative. MRI of the spine revealed patchy T2 hyperintensities predominantly in the anterior lumbosacral spinal cord down to the level of the conus medullaris. MRI of the brain was normal. Enhancement of the nerve roots was not present at the cervical or lumbosacral level. Nerve conduction studies of the left peroneal and tibial nerves showed reduced compound motor action potential amplitudes. EMG performed at 3 weeks showed active denervation of the left vastus lateralis and iliopsoas muscles with neurogenic recruitment.

Treatment included empiric antibiotics, intravenous immunoglobulin and pulse IV methylprednisolone as described for previous cases. Improvement was noted 4 days into admission, with complete return of right leg proximal strength, 3/5 left proximal leg strength, decreased need for catheterizations, and return of reflexes in his right lower extremity on day 6. Pain was managed with gabapentin.

Discussion

The three patients had similar presentations (Table 1), with recent upper respiratory tract infection exposure, progression of asymmetric limb weakness over 24-48 hours affecting proximal more than distal limb muscles and preserved sensation. A mixed picture of upper motor neuron findings in the form of urinary retention or hyper-reflexia, and lower motor neuron findings in the form of decreased reflexes or lower motor neuron cranial nerve deficits were noted. Myalgia of affected muscle groups was present in all patients. Cardiac symptoms of myocarditis were seen in 1 patient.

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Table 1.

Clinical Case Summary.

Case	Age (y), gender	Preceding URTI	Pain	Limb weakness	Cranial nerve involvement	Enterovirus D68	Cerebral spinal fluid	MRI	EMG
1	5 F	Yes	Yes	L arm Proximal > distal	R LMN VIIth	Neg (NPA)	13.3 × 106 WBC 0.13g/L protein EV PCR Neg	T2 abn: none Cervical/lumbar nerve root enhancement	NCS: N EMG: insertional activity ↑, active denervation potentials. Recruitment ↓
2	15 M	Yes	Yes	Bilateral UE L > R	L LMN VIIth L VI Dysarthria Dysphagia	Pos (NPA)	30.3 × 106 WBC 0.46g/L protein EV PCR Neg	T2 abn: Dorsal pons C2-T3 gray matter No enhancement Cervical nerve root enhancement	NCS: N EMG: insertional activity ↑, spontaneous activity ↑, polyphasic potentials. Recruitment ↓
3	12 M	Yes	Yes	Bilateral LE L > R	None	Pos (NPA)	20.8 × 106 WBC 0.35g/L protein EV PCR Neg	T2 abn: C-spine to conus Gad enhancing	NCS: absent L peroneal F wave EMG: insertional activity ↑, spontaneous activity ↑, motor unit amplitude ↑. Recruitment ↓

Abbreviations: abn, abnormalities; C-spine, cervical spine; EMG, electromyography; EV, enterovirus; F, female; Gad, gadolinium; L, left; LE, lower extremities; LMN, lower motor neuron; M, male; MRI, magnetic resonance imaging; NCS, nerve conduction studies; Neg, negative; NPA, nasophyryngeal aspirate; PCR, polymerase chain reaction; Pos, positive; R, right; UE, upper extremities; URTI, upper respiratory tract infection; WBC, white blood cells; y, years.

The recent North American outbreak of enterovirus D68 resulted in 2 clinical presentations: upper respiratory tract infection and severe asthma exacerbation. ⁶ The Centers for Disease Control and Prevention (CDC) reported 36 pediatric upper respiratory tract infection cases in Missouri and Chicago, USA with entero/rhinovirus positive multiplex PCR. Thirty were positive for enterovirus D68. ⁷ Colorado has reported 9 cases of neurological deficits with nasopharyngeal aspirate swabs positive for entero/rhinovirus, 6 were confirmed as enterovirus D68. ⁴ Thus, the majority but not all of the Colorado cases were associated with confirmed enterovirus D68 infection. Similar to the authors’ cases, enterovirus D68 was not detected in the cerebral spinal fluid of any of these patients. ⁴ Absence of virus in cerebral spinal fluid is documented in other acute flaccid myelitis outbreaks. ^8,9

Patients 2 and 3 had confirmed enterovirus D68 on nasopharyngeal aspirate RT-PCR. All were from the greater Calgary area but not from the same subregion and had no shared contacts. All had completed primary poliovirus vaccination. A total of 52 cases of enterovirus D68 infections associated with upper respiratory tract infection symptoms or asthma exacerbations were documented in the Calgary area between January and October 2014. ¹⁰ This province-wide emergence of enterovirus D68 in Alberta mirrors that which occurred in the rest of North America. ¹¹

MRI characteristics of the three patients included (1) T2-hyperintense, nonenhancing lesions in anterior horns of spinal cord gray matter, and (2) abnormal enhancement of the cervical and lumbosacral nerve roots. These features were not present in all patients, nor on the same MRI scan. Patients 2 and 3 had intraaxial spinal cord lesions appreciable on MRI, and patients 1 and 2 had nerve root enhancement present on follow up scans in the subacute stage. Therefore, for patients with clinical suspicion of acute flaccid myelitis, if initial imaging is normal, a repeat scan might be warranted.

Since the introduction of poliovirus vaccination programs, poliomyelitis due to wild poliovirus is rare. ¹² Poliovirus has been eradicated in Canada since 1994 with the last wild poliomyelitis case in 1977; physicians currently practicing having never seen a case. ^13,14 Although rare in the developed world, surveillance programs have identified nonpolio enterovirus as being associated with acute flaccid myelitis. ³ Raising awareness of the spectrum of enterovirus serotypes associated with acute flaccid myelitis is crucial to early recognition and rehabilitation of patients presenting with severe symptoms similar to poliomyelitis.

Human enteroviruses belong to the Picornaviridae family and include rhinoviruses and enteroviruses. Rhinoviruses have a tropism that is restricted to the respiratory tract. Enteroviruses, including poliovirus, are transferred by fecal-oral or respiratory droplet routes and replicate in the oropharyngeal and intestinal mucosa, and possibly in the local lymphoid tissue. Central nervous system involvement is thought to occur through transient viremia or, possibly retrograde axonal transport. ¹⁵ The majority of enterovirus infections are asymptomatic but can result in upper and lower respiratory tract infections, exanthemata and enanthemata, myocarditis, neonatal sepsis, aseptic meningitis, and encephalitis.

Acute flaccid myelitis has been associated with many enteroviruses including EV71, EV70 Coxsackie A7, other Coxsackie A viruses, and echoviruses. ¹⁶ EV71 specifically, has been associated since 1988 in the Asia Pacific region with large outbreaks of hand, foot and mouth disease, and with rarer neurologic complications of acute flaccid myelitis and brain stem encephalitis. The latter can progress to life-threatening cardiogenic shock secondary to neurogenic pulmonary edema. ^17,18 Acute flaccid myelitis associated with EV71 is considered to be a result of lymphocytic invasion of anterior horn cells of the spinal cord and motor neuron necrosis. ¹⁹ Similarly, an autopsy of the 5-year-old male reported in 2011 with confirmed enterovirus D68 and acute flaccid myelitis revealed lymphocytic meningoencephalomyelitis with neuronophagia of the motor nuclei.¹⁹ Despite a presumed similar pathophysiology and presentation with acute flaccid paralysis, none of the patients had encephalopathy, severe cardiac manifestations, or pulmonary edema as seen with EV71. These cases displayed clinical features more similar to those previously reported with poliomyelitis. ¹

All 3 patients were treated with intravenous immunoglobulin and pulse steroids. Intravenous immunoglobulin is described as first line treatment in EV71 cases in Taiwan and is hypothesized to have potentially dual benefit in directly targeting the virus as well as secondary inflammation. ²⁰ The newly documented widespread penetration of enterovirus D68 in North America, suggests a low prior immunity of the population, thus decreasing the likely targeted effect. CDC guidelines published October 2014 report the lack of evidence for targeted treatments. ⁶ Similarly, EV71 cases in Taiwan reveal that despite treatment, motor function outcomes were not always favorable. Poor outcomes were more typically associated with spinal cord involvement. ²⁰ Improvements noted in these patients might be due to the natural history of the disorder rather than a result of treatment. Long-term motor outcomes for enterovirus D68 associated acute flaccid myelitis remain undetermined. ¹⁹

At the time of presentation, there had been recent media coverage regarding the recent association of enterovirus D68 and acute flaccid myelitis during the North American outbreak, however, little had been previously published. With poliovirus being eradicated in North America, many physicians have not seen a case of enterovirus-associated myelitis. As with poliovirus or EV71 in Taiwan, it is possible that recurrent outbreaks of enterovirus D68 associated acute flaccid myelitis could occur. ²¹ Given the historic morbidity with poliomyelitis and other neurologic complications seen with nonpolio enterovirus, and the cardiac concerns with EV71, further characterization of enterovirus D68 acute flaccid myelitis and heightened awareness is desirable so that standardized approaches for rapid identification and treatment can be devised. These cases contribute to the now growing literature of a suggested association between enterovirus D68 and acute flaccid myelitis, reminiscent of the other nonpolio enterovirus associated acute flaccid myelitis.