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COVID-19 Causes Neurological Injury in 1 out of 7 Patients

While we are now used to seeing images of people with COVID-19 on ventilators because of acute lung illnesses, debilitating and even deadly neurological illnesses may be affecting far more people with the novel severe acute respiratory syndrome coronavirus 2(SARS-CoV-2). COVID-19 causes neurological injury in 1 out of 7 patients hospitalized with the infection.1

One coronavirus, many neurological illnesses

For a virus that does not appear to directly invade nerve tissue2,3, the number of neurological complications associated with COVID-19 is impressive and saddening. Neurological conditions associated with COVID-19 infection include:4-6

  • Acute disseminated encephalomyelitis/Acute hemorrhagic necrotizing encephalopathy
  • Anosmia (inability to smell)
  • Cranial nerve deficits
  • Delirium
  • Dysgeusia (inability to taste)
  • Encephalopathy 
  • Guillain-Barré syndrome
  • Headache
  • Hemorrhagic stroke
  • Ischemic stroke
  • Meningoencephalitis
  • Myalgias
  • Myoclonus
  • Paralysis
  • Posterior reversible encephalopathy syndrome
  • Seizures

Muscle aches, headache, and encephalopathy occur most frequently in COVID-19. As many as 80% of patients infected with the novel coronavirus report an inability to taste, to smell, or both.7 Ischemic stroke occurs about 2 percent of patients and hemorrhagic stroke in almost 1 percent.8,9

COVID-19 is not neurotropic, but is neurologically damaging

COVID-19 appears to cause neurological injury through hypoxemia, immune dysfunction, and hypercoagulability.

Hypoxemia in COVID-19

The hypoxemia associated with COVID-19 infection has been one of the more peculiar features of the disease.10 People with the disease exhibit blood oxygen levels that are remarkably low—low enough that under normal circumstances a person would usually require endotracheal intubation and mechanical ventilation. Astonishingly, patients with these very low blood oxygen levels are not short of breath. Instead they experience “happy hypoxia” or silent hypoxemia.10This phenomenon is the result of the way the brain reacts to low levels of oxygen and increased in carbon dioxide levels in the blood. In short, patients are not short of breath because the biological sensors that normally respond to these changes are acting inappropriately. The result is a state of chronic hypoxia and hypercarbia that causes encephalopathy and neurological damage.11

Immune dysfunction in COVID-19

Major alterations in the immune system are now a classic feature of COVID-19, even for such a young disease. Many cases of severe COVID-19 are associated with a “cytokine storm” with exceptionally levels of proinflammatory cytokines such as peripheral tumor necrosis factor (TNF) and interleukin 6 (IL-6).12The inflammation is widespread, and evidence suggests that it also involves the walls of arteries in the brain. For example, brain magnetic resonance angiography showed endothelialitis(inflammation of the endothelium)in the basilar arteries and posterior cerebral arteries that was associated with encephalopathy resolved with high-dose steroids.13

Hypercoagulability in COVID-19

Many patients with have a persistent fever and elevated levels of inflammatory markers such as D-dimer and fibrinogen, which are also pro-thrombotic, i.e. a state that tends to form blood clots. The complement system is activated is severe infection that can cause microvascular injury and thrombosis.14 While stroke is infrequently the presenting symptom in COVID-19 infection, when it occurs it usually happens about 2 weeks after the onset of other novel coronavirus symptoms. Indeed, COVID-19 is an independent risk factor for stroke in hospitalized patients.15

Diagnosing and managing COVID-19 encephalopathy

Encephalopathy is a common feature among hospitalized patients with COVID-19.5 Unfortunately, the diagnosis is largely clinical and made difficult by the severe physical illnesses that co-occur with the neurological insult.It is likely that COVID-19 encephalopathy is brought on or sustained by persistent hypoxia, but since hypoxia is so common in people with moderate to severe illness, it does not provide a diagnostic clue.

MRI may show indicators of encephalitis such as FLAIR signal abnormalities in the cortex and subtle leptomeningeal enhancement; however, MRI is normal just as often as it is abnormal in these patients.5 Given the supportive care measures required such as mechanical ventilation and supplemental oxygenation, obtaining MR imaging is an onerous task (prohibition against metal in the MR room) and usually too difficult to conduct in routine practice without the evidence of a focal neurological finding to guide diagnosis.

Lumbar puncture and cerebrospinal fluid analysis—again, somewhat difficult to perform and obtain in patients in the ICU—is usually unremarkable.

EEG is a potentially useful study to conduct on patients with suspected COVID-19 encephalopathy. Bedside EEG may reveal subclinical seizure activity that is otherwise occult. Indeed, one should rule out regional or generalized status epilepticus in seemingly encephalopathic COVID-19 patients. One must consider if the patient is experiencing an acute confessional state or a deficit in vigilance. Is EEG activity periodic or rhythmic? How does EEG react to various stimuli? A lack of EEG reaction to external stimuli, for example, is a sign of poor prognosis and outcomes.16

Even in the absence of epileptic activity, EEG studies have revealed periodic discharges of high amplitude frontal monomorphic delta waves in patients with COVID-19 infection.17

The safety of EEG technicians is paramount

To minimize infection risk to EEG technicians, one should use disposable EEG leads. MemoryMD / Brain Scientificoffers a device called NeuroCap™ that is a sanitary, disposable, pre-gelled EEG headset with 19 channels and 22 electrodes.  The fixed electrode placement follows the international 10-20 system standard. NeuroCap™ is easy to place and can be setup in less than 5 minutes. NeuroCap™ is compatible with 3rd party amplifiers via a cable adapter.NeuroCap helps to protect staff from extended contact with a potentially infectious patient.

References

1.            Frontera JA, Sabadia S, Lalchan R, et al. A Prospective Study of Neurologic Disorders in Hospitalized COVID-19 Patients in New York City. Neurology. 2020:10.1212/WNL.0000000000010979. 10.1212/WNL.0000000000010979

2.            Boehme AK, Ranawat P, Luna J, Kamel H, Elkind MS. Risk of Acute Stroke After Hospitalization for Sepsis: A Case-Crossover Study. Stroke. 2017;48(3):574-580. 10.1161/STROKEAHA.116.016162

3.            Song E, Zhang C, Israelow B, et al. Neuroinvasion of SARS-CoV-2 in human and mouse brain. bioRxiv. 2020. 10.1101/2020.06.25.169946

4.            Ellul MA, Benjamin L, Singh B, et al. Neurological associations of COVID-19. Lancet Neurol. 2020;19(9):767-783. 10.1016/S1474-4422(20)30221-0

5.            Helms J, Kremer S, Merdji H, et al. Neurologic Features in Severe SARS-CoV-2 Infection. N Engl J Med. 2020;382(23):2268-2270. 10.1056/NEJMc2008597

6.            Fotuhi M, Mian A, Meysami S, Raji CA. Neurobiology of COVID-19. J Alzheimers Dis. 2020;76(1):3-19. 10.3233/JAD-200581

7.            Lechien JR, Chiesa-Estomba CM, De Siati DR, et al. Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study. Eur Arch Otorhinolaryngol. 2020;277(8):2251-2261. 10.1007/s00405-020-05965-1

8.            Klok FA, Kruip M, van der Meer NJM, et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis. Thromb Res. 2020;191:148-150. 10.1016/j.thromres.2020.04.041

9.            Mao L, Jin H, Wang M, et al. Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. 2020;77(6):683-690. 10.1001/jamaneurol.2020.1127

10.          Tobin MJ, Laghi F, Jubran A. Why COVID-19 Silent Hypoxemia Is Baffling to Physicians. Am J Respir Crit Care Med. 2020;202(3):356-360. 10.1164/rccm.202006-2157CP

11.          Solomon IH, Normandin E, Bhattacharyya S, et al. Neuropathological Features of Covid-19. N Engl J Med. 2020;383(10):989-992. 10.1056/NEJMc2019373

12.          Hojyo S, Uchida M, Tanaka K, et al. How COVID-19 induces cytokine storm with high mortality. Inflamm Regen. 2020;40:37. 10.1186/s41232-020-00146-3

13.          Pugin D, Vargas MI, Thieffry C, et al. COVID-19-related encephalopathy responsive to high-dose glucocorticoids. Neurology. 2020;95(12):543-546. 10.1212/WNL.0000000000010354

14.          Magro C, Mulvey JJ, Berlin D, et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases. Transl Res. 2020;220:1-13. 10.1016/j.trsl.2020.04.007

15.          Katz JM, Libman RB, Wang JJ, et al. Cerebrovascular Complications of COVID-19. Stroke. 2020;51(9):e227-e231. 10.1161/STROKEAHA.120.031265

16.          Andre-Obadia N, Zyss J, Gavaret M, et al. Recommendations for the use of electroencephalography and evoked potentials in comatose patients. Neurophysiol Clin. 2018;48(3):143-169. 10.1016/j.neucli.2018.05.038

17.          Vespignani H, Colas D, Lavin BS, et al. Report on Electroencephalographic Findings in Critically Ill Patients with COVID-19. Ann Neurol. 2020:10.1002/ana.25814. 10.1002/ana.25814