Unexplained Coma in a Toddler

In May 2008, a previously healthy 2-year-old girl presented to the pediatric emergency department with a 2-day history of fever, difficulty in moving her lower limbs and abnormal behaviors in the form of biting objects, picking at clothes, and not recognizing her parents. Upper extremity weakness and labored breathing with occasional gasping developed within a day of the onset of the initial symptoms. In addition, the child had intermittent episodes of tonic posturing and teeth clenching on the day before presentation. By the time the child was brought to the hospital, she was unresponsive and limp. Her past was notable for a dog bite 2 months before the onset of symptoms, and trauma to her legs after a fall 20 days earlier. The child had received no vaccinations except for oral polio vaccine during the pulse polio immunization program. No similar illness was reported among her household members or her neighborhood. The patient and her family resided in the state of Uttar Pradesh in India. On physical examination at admission, the child appeared malnourished and weighed only 7.8 kg. She had a core temperature 37.2°C with cool extremities, a heart rate of 120 beats/min with nonpalpable peripheral pulses, an unmeasurable blood pressure, and a respiratory rate of 18 breaths/min. Her breathing efforts were shallow with minimal chest rise. She was comatose and despite painful stimulation she had no eye opening or verbal response. She did, however, make attempts to withdraw her upper limbs to painful stimuli. Her Glasgow coma score was 6. Neurologic examination was notable for preservation of the pupillary reaction to light but absence of oculocephalic, corneal, and gag reflexes. None of the superficial reflexes was elicitable and deep tendon reflexes were elicitable only in the upper limbs. The child was hypotonic and her upper extremity strength was 2 of 5 while that of the lower extremities was 0 of 5. Except for the presence of shallow respiratory efforts, the examination of the respiratory system including the upper respiratory tract was normal. Examination of the heart was also normal, and there was no evidence of organomegaly. Soon after presentation, she was intubated, mechanically ventilated, received fluid boluses, and inotropes. Over the next 8 hours hemodynamic stabilization was achieved, but the child showed neurologic deterioration with disappearance of muscle movement and reflexes. Her Glasgow coma score reached a nadir of 3. Laboratory testing revealed a white blood cell count of 14,500/mm3, with differential of 58% neutrophils and 42% lymphocytes, hemoglobin of 9.8 g/dL, and platelet count of 258,000/mm3. Peripheral blood smear was negative for malarial parasites. Plasma sodium was 137 mEq/L, potassium was 4 mEq/L, and alanine aminotransferase and aspartate aminotransferase were elevated at 149 and 148 IU, respectively. Contrast-enhanced computed tomography of the head was normal. MRI of the brain and spine on the second day of hospital stay revealed T2 hyperintensity in the brainstem, indicating focal edema (Fig. 1, Supplemental Digital Content 1, https://links.lww.com/A975). The cervical and thoracic cord showed symmetric enlargement and T2 hyperintensities predominantly involving the anterior part of the cord (Fig. 1, Supplemental Digital Content 1, https://links.lww.com/A975), consistent with a demyelinating process. A lumbar puncture was not performed because of the patient's initial hemodynamic instability. However, with the history of dog bite, corneal impressions were examined to rule out rabies and were negative. Though the possibilities of herpes simplex and arboviral encephalitis were considered, serologic testing, and EEG were not performed because the MRI findings were not consistent with either. Because the clinical presentation and the MRI features were suggestive of acute disseminated encephalomyelitis, the child was administered high dose intravenous methylprednisolone (30 mg/kg/d) for 5 days followed by oral prednisolone (2 mg/kg/d). By the 10th day of her ICU stay, she had purposeful spontaneous eye opening. She tried to obey simple commands, but these attempts were limited by persistent motor weakness that allowed only flickering movements of her fingers. Although ventilatory support was weaned to minimal settings and the child was no longer encephalopathic, further improvement in her motor strength was minimal. Additional diagnostic studies revealed the diagnosis. Denouement On hospital day 25, an electrophysiological nerve conduction study revealed normal conduction velocities but a decreased amplitude in the right ulnar nerve recording and no response in the other nerves. These findings were suggestive of a severe asymmetric sensory motor neuropathy of possible axonal pathology and did not support the initial diagnosis of acute disseminated encephalomyelitis. The next day, wild-type poliovirus 3 was isolated from a stool viral culture, which had been obtained upon admission as part of a national acute flaccid paralysis (AFP) surveillance program. Based on this, a revised diagnosis of paralytic bulbospinal poliomyelitis with polio encephalitis was made, and supportive care was continued while awaiting spontaneous improvement. After 44 days of hospitalization, the child was weaned off of mechanical ventilation. She had gradual improvement in upper limb strength but had residual weakness of the right arm and of the lower extremities as well as residual right-sided facial nerve palsy. She was discharged after 59 days of hospitalization. In this child, poliomyelitis presented in its most severe form with paralysis, encephalitis, and coma. Less than 1% of children infected with poliovirus develop paralytic disease, and encephalitis due to the virus is far less common. Polio encephalitis is usually seen in children less than 3 years of age, particularly in infancy. Clinical manifestations include convulsions, extreme restlessness, and delirium progressing to coma. The pattern of motor weakness may be either spastic or flaccid. These features often make the condition difficult to differentiate clinically from acute disseminated encephalomyelitis.1 Our patient had flaccid weakness with symptoms of brainstem dysfunction consistent with bulbospinal polio. However, the abnormal behavior, seizures, and profound coma suggested an associated encephalitic process. Available data on imaging in poliomyelitis, particularly polio encephalitis, among children is sparse. Because of the presence of bony artifacts on CT scan, MRI is the preferred modality for identifying and defining the spinal lesions of poliomyelitis. In a report of a child who developed vaccine-associated poliomyelitis, MRI findings included T2-weighted hyperintensities in the midbrain and medulla oblongata with no enhancement after gadolinium administration. The child had characteristic sparing of the pons. Postmortem pathologic sections revealed asymmetric discreet foci of cystic necrosis, correlating with the MRI findings.2 Others have reported contrast enhancement in the anterior portion of the cervical spinal cord.3 In cases of encephalomyelitis due to non-polio enterovirus infections, there have been sporadic imaging reports of similar findings of T2 hyperintensities extending from the dorsal pons to the upper thoracic cord. The T2 hyperintensities in the brainstem and anterior portions of the spinal cord observed in our patient were consistent with these previous descriptions. Interestingly, the cerebrum was normal in our case even though she had clinical features of encephalitis. Because MRI findings in polio and non-polio enteroviral infections may be similar, isolation of the virus is essential for confirming the diagnosis of poliomyelitis.4 Stool cultures have the highest yield of poliovirus. Throat cultures are rarely positive beyond the first week, and unlike other enteroviruses, poliovirus is only rarely cultured from the cerebrospinal fluid. Amplification of viral RNA in the cerebrospinal fluid by reverse transcription PCR using enteroviral probes is available but is not poliovirus specific. Poliovirus specific primers for RT-PCR are rarely used for diagnostic purposes.5 In India and other areas, polio cases are diagnosed through surveillance using a virologic classification scheme. Any patient with AFP from whom wild-type poliovirus is isolated in the stool sample is classified as confirmed polio. AFP cases with adequate stool specimens that are negative for wild type poliovirus are discarded as non-polio AFP. Those with inadequate specimens are re-examined at 60 days; if no residual weakness is found, the case is then discarded as non-polio AFP. Cases with residual weakness that have died or have been lost to follow-up are evaluated in detail by the Expert Review Committee and are classified as compatible with polio or discarded as non-polio AFP, depending upon the findings.6 Hence, the isolation of poliovirus in the stool of our child with acute onset of flaccid paralysis is unlikely to have been an incidental finding, and her picture was consistent with the case definition of poliomyelitis. Electrophysiologic nerve conduction testing is useful in identifying the anterior horn cell pathology of polio, and characteristic findings include reduced amplitude of the compound muscle action potential without significant alteration in the conduction velocity beyond that explained by the degree of axonal loss.5 In pure spinal poliomyelitis, electroencephalography abnormalities are not expected, but nonspecific slowing may be seen with cerebral involvement, even if only subclinical. These electroencephalography findings are nonspecific and occur in other acute encephalitic processes and hence do not help in confirming the diagnosis of poliomyelitis.7 The vaccination strategy in India since 2005 has been to use trivalent oral polio vaccine (OPV) during routine immunizations and either monovalent OPV-1 or trivalent OPV through the pulse polio immunization program. This strategy was followed by an upsurge in reported cases of wild-type poliovirus 3, and so beginning in the second half of 2007, monovalent OPV 3 has been used during subnational immunization activities in high transmission districts.8 Although India has made considerable progress in its efforts toward polio eradication, there are parts of the country, in particular the state that this child hailed from, where this disease continues to spread. In 2008, as of October 25th, there have been 437 cases of type 3 polio and 59 cases of type 1 polio reported in India.9 The continued occurrence of this disease has been attributed to both failure to vaccinate and vaccination failure. Vaccination failure can occur because of problems with the quality of the vaccine or vaccine storage. In addition, the high incidence of diarrhea and non-polio enteroviral infections related to substandard sanitation may reduce immunogenicity of the OPV through vaccine interference.10 A study evaluating antibody titers in 386 children after pulse polio vaccination found that after an average of 7.8 doses of vaccine, only 80.5% were protected against type 3 polio and 89.1% against type 1 polio.11 Although the parents estimated that our patient had received approximately 9 to 10 doses of OPV in the past year, she had received these as part of the pulse vaccination program. In the districts of eastern and southern Uttar Pradesh where this child resided, there had been less than 3 rounds of monovalent OPV 3 vaccinations through March 2008.8 Thus, it is likely she had received limited doses of vaccine specifically directed against the type 3 virus. This along with the other factors described above could have contributed to the occurrence of polio in this child. The case presented here highlights the need to consider poliovirus infection in children presenting with features of encephalitis, particularly if the child is a resident of or has recently visited an area where polio continues to be reported. Although the number of cases reported in India are at a low record, continued surveillance and efforts toward eradication are necessary both locally and globally to ensure that no child will ever again suffer from the crippling effects of polio.