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COVID-19 is strongly associated with neurologic manifestations, including acute cerebrovascular diseases, impaired consciousness, and skeletal muscle injury, new research shows.

As previously reported by Medscape Medical News, small case and anecdotal reports suggest possible neurologic symptoms of COVID-19, but this is the first study to back these observations with scientific evidence.

Investigators based in Wuhan, China, analyzed data from more than 200 adult patients with COVID-19 and found that 36.4% had neurologic manifestations. In addition, close to half of those with severe disease had neurologic symptoms, compared to roughly one third of those with less severe disease.

“During the epidemic of COVID-19, when seeing patients with neurologic manifestations, clinicians should suspect severe acute respiratory syndrome coronavirus 2 infection as a differential diagnosis to avoid delayed diagnosis or misdiagnosis and lose the chance to treat and prevent further transmission,” the investigators, led by Bo Hu, MD, PhD, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, write.

The study was published online April 10 in JAMA Neurology.

Wuhan Data
Established clinical manifestations of COVID-19 include fever, cough, diarrhea, and fatigue, but “it has not been reported that patients with COVID-19 had any neurologic manifestations,” the authors note.

To examine whether the virus can present with neurologic manifestations, the researchers analyzed electronic health records of 214 consecutive hospitalized patients (mean [SD] age 52.7 [15.5] years, 40.7% male), who attended one of three specialized COVID-19 care centers in Wuhan between January 16 and February 19.

Using the American Thoracic Society guidelines for community-acquired pneumonia, patients were categorized as having either severe or nonsevere illness. Based on this categorization, 41.1% of patients had severe infection and 58.9% had nonsevere infection.

Those with severe infection were more likely to be older (mean [SD] age 58.2 [15.0] vs 48.9 [14.7] years; P < .001) and to have other underlying disorders such as hypertension and fewer “typical” COVID-19 symptoms such as fever and dry cough.

The researchers divided neurologic manifestations into different categories, which included:

The researchers divided neurologic manifestations into different categories, which included:

Central nervous system (CNS) symptoms such as dizziness, headache, and impaired consciousness.

Acute cerebrovascular disease, such as ataxia, and seizure.

Peripheral nervous system (PNS) symptoms including impaired taste, smell, or vision, and nerve pain.

Skeletal muscular injury symptoms.

mmunosuppression?
Nervous system manifestations of COVID-19 were “significantly more common” in severe versus nonsevere infection (45.5% vs 30.2%; P = 02).

Figure. Nervous system manifestations of COVID-19

Compared to patients with nonsevere infection, those with severe infection had more inflammation as indicated by higher white blood cell and neutrophil counts, lower lymphocyte counts, and increased C-reactive protein (CRP) and D-dimer levels. They were also more likely to have more laboratory findings of serious liver, kidney, and skeletal muscle damage.

In addition, COVID-19 patients with CNS symptoms had lower lymphocyte levels and platelet counts and higher blood urea nitrogen levels compared to their counterparts without CNS symptoms.

Narrowing the focus specifically to patients with severe disease, the investigators found that those with CNS symptoms also showed greater findings of inflammation, including lower lymphocyte levels and platelet counts and higher blood urea nitrogen levels versus those without CNS symptoms.

The low lymphocyte counts in patients with CNS symptoms “may be indicative of immunosuppression in patients with COVID-19 and CNS symptoms, especially in the severe subgroup,” the authors suggest.

Patients with PNS symptoms showed no differences in laboratory findings compared to those without PNS symptoms.

On the other hand, compared to patients without muscle injury, those with muscle injury — regardless of illness severity — had significantly higher levels of creatine kinase, as well as higher neutrophil counts, lower lymphocyte counts, higher CRP levels, and higher D-dimer levels.

A Red Flag
Commenting on the study for Medscape Medical News, S. Andrew Josephson, MD, professor and chair, Department of Neurology, University of California at San Francisco, who was not involved with the study, called it “the largest look to date at the neurologic complications from COVID-19.”

“The take-home point is that there are a lot of neurological complications from this disease, but many are fairly nonspecific and common to people who are severely ill with viral disorders,” he said.

The public and medical personnel alike need to be aware that there may be neurological manifestations of COVID-19 and such symptoms indicate a need for prompt medical attention.

“It should raise the eyebrows of first-line responders and physicians who are seeing patients with neurologic conditions to consider if those could also be a manifestation of COVID,” said Josephson, who is also editor-in-chief of JAMA Neurology and coauthor of an accompanying editorial.

Also commenting on the study for Medscape Medical News, Robert Stevens, MD, associate professor of anesthesiology and critical care medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, said a key caveat of the study is that “just because a patient has COVID-19 and presents with neurological symptoms doesn’t mean these two phenomena are necessarily linked.”

“Rather,” he said, “they could be coexisting in the same patient, so it is too early to say that we know definitively that COVID causes neurological symptoms, although we think it does,” he said.

In addition, Stevens noted that the study “does not provide supporting mechanistic evidence for the association between COVID and neurological symptoms and did not systematically obtain imaging such as MRI or neuron- or brain-specific biomarkers.”

He added that his group is initiating a multicenter neurological COVID registry, under the auspices of the Neurological Critical Care Society, to “better document the epidemiology of neurological symptoms in patients with COVID and go further, in terms of systematic imaging and measurement of biomarkers, to get a much more detailed understanding of this association.”

The study was supported by the National Key Research and Development Program of China, the National Natural Science Foundation of China, and the Major Refractory Diseases Pilot Project of Clinical Collaboration With Chinese and Western Medicine. The investigators and Stevens have reported no relevant financial relationships. Josephson has reported receiving personal fees from JAMA Neurology and Continuum Audio outside the submitted work.

JAMA Neurol. Published online April 10, 2020. Full text, Editorial