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First Report of COVID-19 Neurologic symptoms in China
More than a third of 214 confirmed COVID-19 cases in China had neurologic symptoms, researchers said.
Acute cerebrovascular events, impaired consciousness, and muscle injury were seen in 36.4% of patients and were more common (45.5%) in patients with severe infection who required mechanical ventilation, reported Bo Hu, MD, PhD, of Union Hospital and Huazhong University of Science and Technology in Wuhan, and colleagues.
Neurologic symptoms included central nervous system (CNS) manifestations such as dizziness, headache, impaired consciousness, acute cerebrovascular disease, ataxia, or seizure; peripheral nervous system manifestations such as taste and smell impairment, vision impairment, or nerve pain; and skeletal muscular injury manifestations.
"For those with severe COVID-19, rapid clinical deterioration or Worsening could be associated with a neurologic event such as stroke, which would contribute to its high mortality rate," the team wrote in JAMA Neurology. "During the epidemic period of COVID-19, when seeing patients with these neurologic manifestations, clinicians should consider SARS-CoV-2 [the virus that causes COVID-19] infection as a differential diagnosis to avoid delayed diagnosis or misdiagnosis and prevention of transmission."
COVID-19 and severe acute respiratory syndrome (SARS), which first appeared in China in late 2002, are similar in many ways clinically, noted S. Andrew Josephson, MD, of the University of California San Francisco, and colleagues, in an accompanying editorial.
"Although the SARS epidemic was limited to about 8,000 patients worldwide, there were some limited reports of neurologic complications of SARS that appeared in patients 2 to 3 weeks into the course of the illness, mainly consisting of either an axonal peripheral neuropathy or a myopathy with elevated creatinine kinase," the editorialists wrote. Pathology showed that patients with SARS had widespread vasculitis in many organs, including striated muscle, "suggesting that the clinical features in these neuromuscular patients might be more than just nonspecific complications of severe illness," Josephson and co-authors continued.
For the study, Hu and colleagues reported data on 214 consecutive laboratory-confirmed COVID-19 patients between Jan. 16 and Feb. 19, 2020. Patients had an average age of about 53 ± 15.5 years, and 41% were men.
About 41% of patients had severe infection and required mechanical ventilation. Those with severe infection were older, had more underlying disorders, especially hypertension, and showed fewer typical symptoms of COVID-19 such as fever and cough compared with people with non-severe infection.
Patients with more severe infection had a higher occurrence of acute cerebrovascular diseases (5.7% vs 0.8%), impaired consciousness (14.8% vs 2.4%), and skeletal muscle injury (19.3% vs 4.8%) than people with non-severe infection.
Of the 214 patients, 12 (5.6%) had taste impairment, 11 (5.1%) had smell impairment, and three (1.4%) had vision impairment. Five patients reported nerve pain.
Most neurologic manifestations occurred early in the illness; the median time to hospital admission was 1 to 2 days. Some patients without typical COVID-19 symptoms came to the hospital with only neurologic manifestations as their presenting symptoms, the researchers noted.
Angiotensin-converting enzyme 2 (ACE2) has been identified as the functional receptor for SARS-CoV-2, and "the expression and distribution of ACE2 remind us that the SARS-CoV-2 may cause some neurologic manifestations through direct or indirect mechanisms," the investigators wrote. "Autopsy results of patients with COVID-19 showed that the brain tissue was hyperemic and edematous and some neurons degenerated."
Neurologic injury has been confirmed not only in SARS, but also in Middle East respiratory syndrome (MERS), Hu and co-authors noted. CNS symptoms were the main form of neurologic injury in COVID-19 in this study, and the pathologic mechanism may be from the CNS invasion of SARS-CoV-2, similar to SARS and MERS viruses, the team speculated.
"As with other respiratory viruses, SARS-COV-2 may enter the CNS through the hematogenous or retrograde neuronal route," the researchers suggested. "The latter can be supported by the fact that some patients in this study had smell impairment."
People with severe infection had higher D-dimer levels than patients with non-severe infection, the investigators observed. Patients with muscle symptoms had higher creatine kinase and lactate dehydrogenase levels than those without muscle symptoms, and creatine kinase and lactate dehydrogenase levels in patients with severe infection were much higher than those of patients with non-severe infection.
Whether axonal neuropathy is part of COVID-19 is unknown from this study; the researchers could not obtain nerve conduction studies or lumbar punctures. "Given the likely shared vasculitic pathology of SARS and COVID-19, it seems probable that further studies will reveal neuropathy as another rare finding in COVID-19," Josephson and co-authors pointed out.
The more dramatic neurologic symptoms -- stroke, ataxia, seizure, and depressed level of consciousness -- were more common in severely affected patients, the editorialists observed. But these associations may reflect that people with more severe complications are more likely to have medical comorbidities, especially vascular risk factors like hypertension: "The occurrence of cerebrovascular events in critically ill patients with underlying high blood pressure and cardiovascular disease is therefore potentially unrelated to a direct effect of the infection itself or an inappropriate host response," Josephson and co-authors wrote.
They added: "It is clear that this small series does not reflect the entire spectrum of neurologic disease in COVID-19 disease, and much is left to be learned with thorough neurologic testing in large data sets of patients with COVID-19."
The research was supported by the National Key Research and Development Program of China, the National Natural Science Foundation of China, and Major Refractory diseases Pilot Project of Clinical Collaboration with Chinese and Western Medicine.
The researchers reported no conflicts of interest.
The editorialists reported relationships with the National Institute of Mental Health, the Weill Institute for Neuroscience, the Brain Research Foundation, the George and Judy Marcus Fund for Innovation, Viela Bio, Mylan, Bionure, Neurona, Pipeline Therapeutics, and Inception Sciences.