COVID Brain

Research is piling in regarding the neurological effects of COVID-19 and the depth of the research is giving us some really concrete information to help guide treatment, screening, and monitoring strategies. The anecdotal evidence is continuing to build quickly so I’ve significantly updated this post to reflect some of the more recent changes and findings.

We are going to go through a few of these. Some you may not have heard of, and others may be more familiar. We previously thought that patients who have more severe cases of COVID-19 are more likely to end up with neurological deficits, but that is no longer true. Research is finding that even mild respiratory cases of COVID-19 can present acutely or delayed onset with significant neurological symptoms.

This is a respiratory virus! How does this happen? There is evidence that ACE2 receptors are also located in spinal neurons and several parts of the brain:

• substantia nigra
• ventricles
• middle temporal gyrus
• posterior cingulate cortex
• olfactory bulb

There are also suggestions that SARS-CoV-2 enters the neurological system through the olfactory epithelium, as there are ACE2 receptors on the surface and within the cells, which can take about seven days after initial infection. So that would mean that neurological infection takes place up to seven days before respiratory symptoms can begin to present. Based on these and other findings indicating that the actual olfactory nerves do not express ACE2 receptors, anosmia – or lack of ability to smell – may be cause by damage to the olfactory epithelium, no the olfactory nerve itself. Infection may also occur due to the virus crossing the blood-brain barrier through damage to the endothelium – or capillary cells – within the barrier itself, allowing increased permeability, or by way of infected white blood cells.

So, it is definitely possible that some patients who will eventually end up positive for COVID-19 will initially present with neurological symptoms such as confusion, AMS, weakness, myalgias, headaches, dizziness, and a host of other symptoms that would indicate neurological involvement. What seems to be the difference is that the neurological symptoms have a fast onset and fast progression in severity, unlike the respiratory symptoms which tend to progress more slowly and take longer to present at all. A recent study found that up to 36% of COVID-19 patients demonstrated severe neurological symptoms, like a stroke or impaired consciousness. Let’s take a look at some of the documented neurological diagnoses that have been directly linked to COVID-19…

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Hypoxic Brain Injury. This one is kind of obvious but maybe we didn’t think of it before. Patients with COVID-19 are well known to be significantly hypoxic for long periods of time, possible even before they seek assistance or before they show symptoms. This hypoxia results in several metabolic process going awry and the brain tissues swelling. If this goes on long enough, the damage can be permanent. Intracranial edema is one of the fastest growing concerns as it can be present for extended periods of time before a person begins to show symptoms and seek medical help.

Immune-Mediated Injury. This is what I’ve actually been hearing the most about. Those “cytokine storms” we keep hearing about don’t just have negative effects on the lungs. They are a total body inflammatory response so all the other organs are also affected. The brain can be on the end of this storm and receive that damage just like any other organ. (We briefly discussed this here.)

Encephalopathy/Encephalitis. Headaches were reported in 40% of patients as a COVID-19 symptom. Confusion/altered mental status is also a very prevalent symptom. This is believed to be due to the cytokine storm, which crosses the blood-brain barrier. Some patients also present with seizures or altered levels of consciousness. There has been at least one case of a child patient presenting in this manner with a COVID-19 infection. Growing bodies of evidence out of the UK are now showing larger populations with this issue and age is no longer a factor. Many people hospitalized with forms of encephalitis have been between 30 and 40 years old.

This particular category of conditions is of the largest concern in recent research. In a recent study in BRAIN, 31 of 43 patients who presented with neurological complications demonstrated these types of pathologies. Intracranial edema is a growing issue in hospitalized and nonhospitalized patients, with increased hemorrhage rates. Medical providers are even seeing clinical encephalopathy/encephalitis without any changes to imaging findings. Reports of delusions, hallucinations, altered consciousness, and decreased cognitive impairment have all been reported as a primary symptom for these patients with confirmed COVID-19, all with little to no respiratory symptoms.

Myelitis. Also attributed to the cytokine storm, myelitis can develop at any spinal level with presentation of flaccid paralysis below that level. Acute Disseminated Encephalomyelitis (ADEM), a rare form of myelitis that typically only effects children, is also becoming a more frequent concern, especially in young adults. Mechanisms for this may include direct anterior horn cell viral damage.

Cerebrovascular Accident (CVA). The providers in my social media groups are no longer asking questions about hypercoagulation. Now we just know it’s there. The questions are moreso circulating around best ways to treat it. We have definitely found that early use of anticoagulants is crucial for survival in many patients hospitalized with COVID-19. CVAs continue to vary in etiology. Both ischemic and hemorrhagic are being reported at increased frequency, but ischemic significantly moreso. They are also being seen in people who have no hypertensive history and with normal PT/INRs. However, those at highest risk are those 60 year old or more with a history of hypertension or other comorbid risk factor for stroke. Large vessel ischemic strokes in patients of all ages are becoming a hallmark sign of stroke related to COVID-19.

A high percentage of those with CVAs also present with pulmonary embolism and a disseminated prothrombotic state, and with no medical history of any condition that would lead to a CVA. Some studies are showing that about 6% of those infected with COVID-19 will have a CVA. However, of those who will require hospitalization for neurological symptoms, up to 77% will have a stroke. CVAs may also be copresent with encephalopathy which makes diagnosis more difficult.

Guillain Barre Syndrome (GBS). Ascending paralysis and/or parathesias caused by demyelinating polyneuropathy that presents without known cause or shortly after recovery from a respiratory viral infection would always be considered a HUGE red flag. But the chances of developing GBS after COVID-19 are higher than that of other viral infections such as influenza. This has been reported as “rapidly progressing” in many cases. Read more about this in the post dedicated to Guillain Barre Syndrome. Newer research is finding that some patients are developing GBS up to three weeks after their symptoms have resolved. Some cases of GBS after COVID-19 are deemed an axonal variant, meaning that only motor pathways of a given nerve distribution are affected while sensory function remains intact. This is called acute motor axonal neuropathy and you can read more about it here. Sympathetic nervous systems may also be affected by this variant and produce sympathetic symptoms.

Skeletal Muscle Damage. This is, so far, a lesser seen neurological effect of COVID-19 (estimated at about 5-6% of neurological cases, not all cases). These patients initially present with myalgias and elevated creatine kinase as a possible cause. Other mechanisms are believed to be involved including other aspects of the medical history. This is also thought to be due to the cytokine storm and is thought that it may be a different type of end-organ failure (similar to the renal and hepatic failure we have otherwise discussed). However, it could also be ischemic damage due to DIC. Rhabdo has also been implicated as a cause for this injury.

Seizures. Mostly present in children, especially those with pre-existing seizure disorders including febrile seizures, seizures have actually been one of the primary presentations of COVID-19 in infants.

Chemosensory dysfunction. (altered sense of taste or smell) was present in 82% and 86% of COVID-19 positive patients, respectively. If patients are reporting this as a new onset symptom, therapists need to strongly consider referring the patient for testing. Onset of these symptoms is sudden. See more details above on ACE2 receptor causes for this. These symptoms can occur in isolation and be the ONLY symptoms a person experiences. – Verified symptom now!

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The Lancet Neurology has created the following depiction of symptom onset for several of the above neurological associated conditions for patients who have COVID-19. You can see that GBS, encephalitis, and CVA can actually present prior to the onset of any other symptoms.

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So then, as a therapist, what do you need to know?

First off, you should note, especially when attempting to establish a neurological baseline on evaluation, that 67% of patients with “severe forms” of COVID-19 had positive upper motor neuron signs. So your Hoffman’s, Babinski, and Clonus may be positive. You may see increase muscle tone, hyper-reflexia, areflexia, or tongue deviation. These signs are never necessarily permanent because we know that lesions have some ability to heal, so you may notice them fading over time. You do need to know that, just because someone doesn’t have respiratory symptoms, doesn’t mean they don’t or won’t have a severe form of COVID-19. It’s really all about what end-organ system takes the brunt of the virus. If you suspect COVID-19, send the patient for testing.

How does this apply to you and how should it inform your practice?

Many PTs treat patients for headaches. Many more PTs also treat patients for dizziness. Sometimes the headaches and dizziness are co-occuring. Rehab therapists need to be on alert when patients begin reporting these symptoms during this time. Their social distancing and safety behaviors need to be discussed and they may need to be tested for COVID-19. These symptoms are the most commonly reported in patients who experience neurological presentations of COVID-19. Few have offered reasoning behind this other than that these are typical symptoms of the body’s immune response to a virus and that we all feel these things sometimes when we are sick. But, like we mentioned above, brain edema can go undetected and present with these symptoms. Given that information, therapists evaluating patients (or continuing to treat patients for other things, but the patients begin reporting these symptoms) need to give strong consideration to the risk of the patient having COVID-19. The therapist needs to thoroughly examine the patient’s risk profile and refer for testing through the referring provider, PCP, or directly to a testing center if available. This is especially true if the patient is also reporting changes in sense of taste or smell.

One of the larger concerns coming forth is something I’ve talked about here before. When even mild cases of COVID-19 can present with moderate to severe neurologic impairments and damage in the acute phase, you have to wonder about long term effects. Many neuroscientists are concerned about the long term effects of COVID-19, and that delayed onset of medical issues resulting from infection could significantly impair someone’s ability to work and function. Post-COVID syndrome is still a very real concern. Only time will tell. But, early diagnosis can improve outcomes so be the front line. Be the primary care provider you should be.

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There is a researcher at Cambridge who has opened a large-scale patient case study for those with COVID-19 who can take a series of tests related to their cognitive function. People can enroll in the study and take these tests to determine how their brain function may have changed as a result of COVID-19 infection. If you or your patients are interested in enrolling in the study, you can check out the link by clicking on the button below.

So, for all you therapists in the outpatient world out there treating those still in need, please keep your eyes peeled. Screening is key and early detecting and testing can save lives. Be on the lookout for symptoms of DVT and PE in addition to all the other COVID-19 symptoms we discussed here. As we see more patients transition to sub-acute, home, and outpatient settings, be sure to assess and document neurological baselines in your patients. These changes can literally be the difference between and ED visit and an ICU admission.

Be careful out there.

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While treating your patients who have COVID-19, have you noticed any pattern of neurological findings? Let me know in the comments!

References:

Ahmad, I.; Rathore, F.A. Neurological Manifestations and Complications of COVID-19: A Literature Review. Preprints 2020, 2020040453 (doi: 10.20944/preprints202004.0453.v1).

Avula, A., Nalleballe, K., Narula, N., Sapozhnikov, S., Dandu, V., Toom, S., Glaser, A., Elsayegh, D. (2020). COVID-19 presenting as a stroke. Brain, Behavior, and Immunity. 87:115-119. Retrieved from https://www.sciencedirect.com/science/article/pii/S0889159120306851

Chen,  R., Wang,  K., Yu,  J., Chen,  Z., Wen,  C., Xu,  Z. (2020). The spatial and cell-type distribution of SARS-CoV-2 receptor ACE2 in human and mouse brain. https://www.biorxiv.org/content/10.1101/2020.04.07.030650v1

Ellul, M. A., Benjamin, L., Singh, B., Lant, S., Michael, B. D., Easton, A., Kneen, R., Defres, S., Sejvae, J., Solomon, T. (2020). Neurological associations of COVID-19. The Lancet Neurology. [corrected proof in press] Retrieved from https://www.sciencedirect.com/science/article/pii/S1474442220302210

Kelland, K. (2020). Scientists warn of potential wave of COVID-linked brain damage. Reuters. Retrieved from https://www.reuters.com/article/us-health-coronavirus-brains/scientists-warn-of-potential-wave-of-covid-linked-brain-damage-idUSKBN24837S

Mao, L., Jin, H., Wang, M., et al. (2020). Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. Retrieved from https://jamanetwork.com/journals/jamaneurology/fullarticle/2764549

Mao, L., Wang, M., Chen, S., He, Q., Chang, J., Hong, C., Zhou, Y., Wang, D., Li, L., Jin, H., Hu, B. (2020). Neurological Manifestations of Hospitalized Patients with COVID-19
in Wuhan, China: a retrospective case series study. medRxiv. https://www.medrxiv.org/content/10.1101/2020.02.22.20026500v1.full.pdf

Owen, A. (2020). Participate in the COVID-19 Brain Study—a global study of how the virus affects cognition. The Cambridge Brain Institute. Retrieve from https://www.cambridgebrainsciences.com/studies/covid-brain-study.

Paterson, R. W., Brown, R. L., Benjamin, L., Nortley, R., Wiethoff, S., Bharucha, T., Jayaseelan, D. L., Kumar, G., Raftopoulos, R. E., Zambreanu, L., Vivekanandam, V., Khoo, A., Geraldes, R., Chinthapalli, K., Boyd, E., Tuzlali, H., Price, G., Christofi, G., Morrow, J., McNamara, P., McLoughlin, B., Lim, S. T., Mehta, P. R., Levee, V., Keddie, S., Yong, W., Trip, S A., Foulkes, A. J. M., Hotton, G., Miller, T. D., Everitt, A. D., Carswell, C., Davies, N. W. S., Yoong, M., Attwell, D., Sreedharan, J., Silber, E., Schott, J. M., Chandratheva, A., Perry, R. J., Simister, R., Checkley, A., Longley, N., Farmer, S. F., Carletti, F., Houlihan, C., Thom, M., Lunn, M. P., Spillane, J., Howard, R., Vincent, A., Werring, D. J., Hoskote, C., Jäger, H. R., Manji, H., Zandi, M. S. (2020). The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings. Brain. [accepted manuscript] awaa240. Retrieved from https://doi.org/10.1093/brain/awaa240

Steardo, L., Zorec, R., Verkhratsky, A. (2020). Neuroinfection may contribute to pathophysiology and clinical manifestations of COVID-19. Acta Physiol. (Oxf.) Article e13473

Woodward, A. (2020). The coronavirus may cause brain damage, even in patients with mild cases, a new study found. Retrieved from https://www.businessinsider.com/coronavirus-linked-brain-damage-delirium-neurological-problems-2020-7

Zubair, A. S., McAlpine, L. S., Gardin, T., Farhadian, S., Kuruvilla, D. E., Spudich, S. (2020). Neuropathogenesis and Neurologic Manifestations of the Coronaviruses in the Age of Coronavirus Disease 2019: A Review. JAMA Neurol. Published online. doi:10.1001/jamaneurol.2020.2065

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