Introduction
Since the identification of the first case of infection with the Middle East respiratory syndrome corona virus (MERS-CoV) in Saudi Arabia in June 2012 [
1], the number of laboratory-confirmed cases has exceeded 941 cases globally, of which 347 died [
2]. The disease presents as severe respiratory infection often with shock, acute kidney injury, and coagulopathy [
3]. We recently have reported the clinical manifestations and outcome in 12 patients with MERS-CoV infection admitted to the intensive care unit (ICU) [
4]. Here we report three cases presenting with severe neurologic syndrome. To our knowledge, these are the first identified cases of neurologic injury associated with MERS-CoV infection.
Discussion
Three patients were admitted with 3 different working diagnoses with fever as one of the initial symptoms. Each eventually developed symptoms raising an index of suspicion for MERS-CoV infection, which was confirmed by RT-PCR. In addition, all had neurologic symptoms: at presentation for patient 1 and on HD 5 and 24 for patients 2 and 3, respectively. The neurologic manifestations included altered mental level ranging from confusion to coma, ataxia, and focal motor deficits. Given the significant comorbidities and the severe critical illness, such neurological findings may easily be attributed to other common etiologies. However, the striking findings of the MRI from our first patient raised the concern for critically examining the subsequent two patients. Brain MRI revealed new-onset widespread, bilateral hyperintense lesions on T2WI within the white matter and subcortical areas of the frontal, temporal, and parietal lobes, the basal ganglia and corpus callosum, pons, cerebellum, and upper cervical cord. None enhanced with gadolinium. CSF examination in two patients was unremarkable with the exception of increased protein level. Besides the neurological manifestations, the three patients had several things in common; all had other organ dysfunctions involving respiratory, renal, and cardiovascular systems, all had persistent viral shedding from the respiratory tract, and had lymphopenia with a profound depression of T and B lymphocyte subsets. So the neurologic syndrome in the context of severe MERS-CoV infection and the distinct imaging patterns suggest that MERS-CoV infection may be responsible for the extensive CNS injury observed in our patients.
Although the clinical, radiological, and laboratory findings were suggestive of MERS-CoV associated neurological illness, several differential diagnoses were considered, given the lack of confirmatory test of brain infection namely the presence of corona virus in the brain tissue and/or in the CSF. In addition, the use of sedation as part of the management of severe ARDS may have masked the onset or the progression of neurologic manifestations. Because of the presence of risk factors, acute ischemic stroke was first sought but ruled out by brain imaging, except for patient 2. Other potential explanations to the neurologic findings such as air and fat embolism, or post-anoxic damage were also considered, although less likely. The two patients requiring high ventilator settings did not exhibit any evidence of barotrauma. Fat embolism appears unlikely given the lack of risk factors. None of the patient had sustained cardiovascular arrest. Although one of the patients had severe hypoxemia, it was not associated with neurologic abnormalities and resolved after intubation. Moreover, the MRI findings did not follow the typical changes associated neither with hypoxia–ischemia. Indeed, brain MRI of patient 1 is rather supportive of a viral etiology, more specifically of an acute disseminated encephalomyelitis (ADEM) [
6], an immune mediated disease that often occurs following viral infection [
7]. It is also consistent with encephalitis, albeit less probably due to the predominant white matter involvement and the striking restricted diffusion. In patient two, the MRI findings were suggestive of bilateral anterior cerebral artery stroke. It is known that patients with cardiovascular risk factors are at high risk of developing a cerebral stroke during sepsis or during their hospitalization in an ICU, independently to the etiology of the sepsis or the cause of admission to an ICU. However, in our case the CT angiogram performed after the onset of neurologic deficits showed patent ACAs. Stroke caused by viral vasculopathy has been described with other viruses including varicella zoster virus, cytomegalovirus, and human immunodeficiency virus [
8]. Therefore, it is conceivable that the observed non-occlusive stroke and myocardial infraction are associated with MERS-CoV vasculopathy.
MERS-CoV is one of the human corona viruses that include also five other strains: SARS-CoV, HCoV-OC43, HCoV-229E, HCoV-NL-63, and HCoV-HKU1. Although corona viruses are generally known for causing respiratory illness, both clinical and experimental studies have demonstrated their strong tropism to the CNS [
9‐
15]. SARS-CoV infection induced in mice model results in neuronal death without encephalitis [
16]. Brain necropsy study in eight confirmed cases of SARS revealed direct viral infection of neuronal cells located in the cortex and hypothalamus [
17] with edema and scattered red degeneration suggesting neuronal ischemia type of injury. Laboratory studies have shown that HCoV-OC43 and HCoV-229E also have the ability to infect human neural cells including neurons and glial cells [
12,
13,
18‐
20]. In addition, HCoV-OC43 has been detected in the CSF of a child with ADEM. Direct evidence that MERS-CoV is the cause of CNS damage observed in our patients is difficult to ascertain due to the lack of brain pathology samples. Our patients were severely ill, and no effective therapy exists to justify further invasive diagnostic approach. The negative CSF for MERS-CoV RT-PCR may be due to the timing of the test, the lack of meningeal involvement as shown on MRI or that the virus is intra-neuronal as reported with SARS-CoV [
21].
To the best of our knowledge, no neurologic involvement with MERS-CoV has been so far reported. Hence, our cases raise important questions. What are the pathogenic mechanisms that underlie the occurrence of neurologic injury in our patients? In other words, is it related to specific host factors in these patients or related to a newly acquired virulence leading to neurotropism of the MERS-CoV? [
9,
13] One interesting question raised from these cases is whether there is a link between the observed lymphopenia and the observed neurologic manifestations. The receptor for MERS-CoV was recently identified as dipeptidyl peptidase-4 (DPP4, also known as CD26) [
22]. DPP4 is expressed on T-cells and in the lung, kidney, placenta, liver, skeletal muscle, heart, brain, endothelium, and pancreas [
23]. The presence of these receptors may be linked to their susceptibility of these organs, including the brain, to infection [
24] but this needs further study.
Conclusion
MERS-CoV infection causes multiple organ damage including pulmonary, cardiovascular, renal, coagulation, gastrointestinal tract, and muscles. Our observation suggests that CNS may be another target of MERS-CoV infection, and thus should be considered in any patients with progressive or worsening CNS findings.