May 3, 2020

COVID-19: Neurologic Manifestations

The Novel Coronavirus 2019, was first reported on in Wuhan, China in late December 2019.  The outbreak was declared a public health emergency of international concern in January 2020 and on March 11th, 2020, the outbreak was declared a global pandemic. The spread of this virus is now global with lots of media attention.  The virus has been named SARS-CoV-2 and the disease it causes has become known as coronavirus disease 2019 (COVID-19).  This post will serve as a summary of emerging available evidence in regard to neurologic manifestations associated with COVID-19.

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Observational Series of 58 Patients in France [1]

  • Prospective observational series of 58 out of 64 consecutive patients admitted to ICU with ARDS COVID-19 pneumonia
    • 6 patients excluded due to neuromuscular blockade or because they died without neurologic examination
  • Sedation/Analgesia
    • Versed: 86% (Median duration of 4d)
    • Propofol: 47% (Median duration of 0d; Some patients received propofol for <1d)
    • Sufentanil: 100% (Median duration of 8d)
    • Neurologic Findings Prior to ICU Admission: 7/58 (14%)
    • Neurologic Findings After ICU Admission When Sedation and Neuromuscular Blocker Withheld: 39/58 (67%)
  • Any Neurologic Signs: 84%
  • Positive Findings on CAM-ICU: 26/40 (65%)
  • Agitation: 40/58 (69%)
  • Corticospinal Tract Signs: 39/58 (67%)
  • Dysexecutive Syndrome: 14/39 (36%)
    • Inattention, disorientation, or poorly organized movements in response to command
  • Brain MRI (13 patients):
    • Leptomeningeal Enhancement: 8/13 (62%)
    • Perfusion Abnormalities: 11/11 (100%)
    • Cerebral Ischemic Stroke: 3/13 (23%)
  • EEG (8 patients):
    • Nonspecific changes detected
  • CSF Analysis (7 patients):
    • Oligoclonal Bands with Same Pattern in Serum: 2/7 (29%)
    • Low Albumin Level: 4/7 (57%)
    • Negative RT-PCR for SARS-CoV-2 in CSF: 7/7 (100%)
  • Bottom Line: This study makes it seem that there are some neurologic abnormalities associated with COVID-19 but most had manifestations after admission to ICU when treatment was initiated (question of encephalopathy secondary to critical care illness)

Guillain-Barre Syndrome [2][3]

  • 5 patients in Italy who developed Guillain-Barre syndrome after onset of COVID-19
    • Bottom Line: It is unclear from this observational series if the neurologic deficits are typical features of COVID-19 associated Guillain-Barre syndrome or simply from a critical illness neuropathy/myopathy
  • Single case of patient with COVID-19 and presenting with acute Guillain-Barre syndrome
    • Unfortunately, there was an absence of microbiological testing on admission. An alternative explanation may be the patient coincidentally developed Guillain-Barre syndrome of unknown cause and happened to acquire SARS-CoV-2 nosocomially
    • Bottom Line: Again this case report suggests a possible association but not causation of SARS-CoV-2 and Guillain-Barre syndrome

 Anosmia [4]

  • Previous strains of coronavirus seem to invade the central nervous system through the olfactory neuroepithelium and propagate from within the olfactory bulb
  • Interestingly, nasal epithelial cells display the highest expression of the ACE2 receptor in the respiratory tree
  • Any altered sense of smell or taste: 130/202 (64.4%)
    • 95% CI 57.3 to 71.0%
  • Limitations:
    • This data is self-reported and based on a cross-sectional survey
    • The sample size was small
    • Severely ill patients were not included
  • Bottom Line: Anosmia may be a feature of COVID-19, and potentially useful in triage of patients 

Large Vessel Occlusion Strokes [5]

  • 5 cases of large vessel stroke in patients younger than 50 years of age in New York City over a 2-week period
  • For comparison, every 2 weeks over the previous 12 months, the ED had treated on average 0.73 patients younger than 50 years of age with large vessel stroke
  • Fibrinogen Level (mg/dL): 370 – 739 (Nl range: 175 – 450)
  • D-dimer Level (ng/mL): 52 – 13,800 (Nl range: 0 – 500)
    • The 2 patients in the ICU and stroke unit (i.e. not discharged) had the highest levels of d-dimer and ferritin)
  • Ferritin Level (ng/mL): 7 – 1564 (Nl range: 30 – 400)
  • Bottom Line: Small case series that most likely is showing a viral mediated inflammation and not due to COVID-19 itself

Overall Bottom Line:

  • From a clinical standpoint, I am not sure how useful this information is, as much as just something to pay attention to in patients presenting to EDs
  • The importance of neurologic manifestations (i.e. GBS, encephalopathy, agitation, dizziness, etc.) may simply be a result of the increased load of COVID-19 cases and not a result of COVID-19 itself. This may all simply be critical illness encephalopathy/neuropathy and nothing more
  • For other neurologic symptoms (i.e. Anosmia), the manifestations may be a feature of COVID-19 and may be helpful in triage of patients.
  • The increase in strokes are most likely a result of viral mediated inflammation and not due to COVID-19 itself. The treatment would be exactly the same as patients with strokes not diagnosed with COVID-19

Expert Peer Review/Comments

 

Evie G. Marcolini, MD
Emergency Medicine/Neuro Critical Care
Dartmouth-Hitchcock Medical Center
Lebanon, NH
Twitter: EvieMarcolini

The first and most important point to make when considering this topic is that we have little to no significant evidence to make any correlations between neurologic manifestations and Covid-19 illness.  We have case reports and observational series and need to remember that in the time of a scary pandemic with all its medical, social and economic implications, we are prone to making inferences that are not supported by evidence.It’s human nature!

We are seeing more frequent reports of neurologic manifestations such as anosmia, dysgeusia, vision deficits, and confusion in patients with COVID-19.  We are also seeing reports of distinct neurologic disease in these patients, such as Guillain Barre Syndrome, acute ischemic stroke, seizure, cerebral venous thrombosis and even hemorrhagic necrotizing encephalopathy.  But in fact, we see these diseases and neurologic manifestations in many critically ill patients.  Many of them have known association with viral agents, such as the connection between GBS and cytomegalovirus, Epstein Barr virus, and Zika.

Transmission of Covid-19 to the CNS is theorized to happen by hematogenous spread by breaking down the blood brain barrier, or through retrograde transport along nerve axons.  We know that many viruses, including coronaviruses have been shown to propagate from the nasal epithelium past the cribriform plate to infect the olfactory bulb.7

While it’s logical to try to make the connection between Covid-19 and these illnesses, we have to stick to the known guidelines of evidence-based medicine.

We know that inflammation is associated with cardiovascular and cerebrovascular thrombotic risk, and infection is associated with inflammation.It is tempting to connect those dots and suggest that the virus causes stroke, especially in the setting of seeing cases of large vessel occlusion in young patients without risk factors at an alarmingly high rate.  Wouldn’t it be nice if we could apply Occam’s razor to this and find a unifying diagnosis?

The focus for us should be threefold with respect to neurologic manifestations and Covid-19.

  1. Continue to look for neurologic signs and symptoms in your patients. Avoid anchoring on Covid-19, and recognize that many patients with other illnesses or injuries will have Covid-19, and vice versa.
  2. Protect yourself and your crew. Although stroke is a time sensitive disease, personal protection is the single most important concept when you go to work in this era.
  3. Encourage people in your community to call a doctor with any signs or symptoms that are concerning, and not to stay at home with a problem that may be time sensitive and life changing.

References:

  1. Helms J et al. Neurologic Features in Severe SRS0CoV-2 Infection. NEJM 2020. PMID: 32294339
  2. Cuzzoni MG et al. Gullain-Barre Syndrome Associated with SARS-CoV-2. NEJM 2020. [Epub Ahead of Print]
  3. Zhao H et al. Gullain-Barre Syndrome Associated with SARS-CoV-2 Infection: Causality or Coincidence? Lancet Neurol 2020. PMID: 32246917
  4. Spinato G et al. Alterations in Smell or Taste in Mildly Symptomatic Outpatients With SARS-CoV-2 Infection. JAMA 2020. PMID: 32320008
  5. Oxley TJ et al. Large-Vessel Stroke as a Presenting Feature of COVID-19 in the Young. NEJM 2020. [Epub Ahead of Print]
  6. Zagurly-Orly I et al. COVID-19 – A Reminder to Reason. NEJM 2020. PMID: 32343505
  7. Baig AM. Neurological Manifestations in COVID-19 Caused by SARS-CoV-2. CNS Neurosci Ther 2020. PMID: 32266761
  8. Lindsberg PJ et al. Inflammation and Infections as Risk Factors for Ischemic Stroke. Stroke 2003. PMID: 14500942

For More on This Topic Checkout:

Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)

Cite this article as: Salim Rezaie, "COVID-19: Neurologic Manifestations", REBEL EM blog, May 3, 2020. Available at: https://rebelem.com/covid-19-neurologic-manifestations/.
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Salim Rezaie

Emergency Physician at Greater San Antonio Emergency Physicians (GSEP)
Creator & Founder of REBEL EM
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