Infection | Brain
Neurology and COVID-19: Everything Researchers Know So Far
What is brain pathogen; why SARS-CoV-2 can be one; its neurological manifestations; how it can invade the brain; actions needed; why things aren’t so straightforward; is it the immune system or virus?
[Last updated on 21st April 2020].
Researchers with relevant background in neuroinfectious diseases would not be surprised if SARS-CoV-2 (that causes COVID-19) is capable of causing neurological or brain complications.
Corona virologist would say that’s pretty much expected — “Our experience with taxonomically related SARS-CoV patients in the past has proven beyond doubt the coronaviruses to affect the brain.” Indeed, before clinical cases of SARS-CoV-2 brain infections were reported, Chinese and Pakistani scientists have already emphasized on its neuroinvasive potential.
They were criticized as expected. A review by Chinese researchers published on 27th February, for example, was edited and republished wherein an entire ‘controversial’ section was removed. Similarly, Thailand Medical News covered an issue on neurological symptoms of COVID-19 on 5th March, but “many ignorant medical experts and even readers merely dismissed the report,” they say.
“CNS infections are frequently caused by viruses.”
1. What Defines a Brain Pathogen
2. Why SARS-CoV-2 Can Be a Brain Pathogen
3. Neurological Manifestations of SARS-CoV-2
- 25th Feb: Neurological signs
- 3rd Mar: Histopathological examinations
- 4th Mar: Encephalitis case
- 21st Mar: Encephalopathy case
- 28th Mar: Recurrent seizures case
- 31st Mar: Hemorrhagic necrotizing encephalopathy case
- 1st Apr: Guillain-Barré syndrome case
- 3rd Apr: Meningitis/encephalitis case
- 8th Apr: Smell loss without nasal obstruction case
- 10th Apr: Encephalitis case
- 13th Apr: More neurological cases
- 17th Apr: More Guillain-Barré syndrome-related cases
- 17th Apr: Meningoencephalitis (without respiratory symptom)case4. How SARS-CoV-2 Can Invade the Brain
5. What Actions Are Needed
6. Why Things Aren’t So Straightforward
7. Is it the Immune System or Virus?
What Defines a Brain Pathogen
It’s any microbes capable of invading and causing diseases in the brain. It can be bacteria, fungi, amoeba, or viruses, say researchers who specialize in brain infections in high-impact Clinical Microbiology Reviews. “Microbial infection involving the central nervous system (CNS) is an important and relatively common presentation,” they added.
Viruses are the most common type of microbial infection. Enteroviruses, cytomegalovirus, herpes simplex virus, varicella-zoster virus, West Nile virus, henipaviruses, Japanese encephalitis virus, chikungunya virus, Ebola virus, and rabies virus can all cause brain infection. Wikipedia listed more.
“CNS infections are frequently caused by viruses,” the brain infection specialists wrote. They use “axonal transport as a common route of infection.” Axonal transport means that the virus hijacks the neuron’s transport system, and gets propagated along neurons into the brain. This typically happens when the virus enters the eye, nose, mouth and infects nearby olfactory or trigeminal nerves.
Why SARS-CoV-2 Can Be a Brain Pathogen
- Reason 1: SARS-Cov-2 is a type of coronavirus and most previous coronaviruses like SARS and MERS are known to infect the brain. It’s unlikely that SARS-CoV-2 is an outlier coronavirus.
- Reason 2: SARS-CoV-2 enters a cell via the ACE2 receptor. Though this receptor is mainly expressed in the lungs, the brain has it as well.
- Reason 3: Previously known coronaviruses infect the brainstem, which receives neurons from the lungs and respiratory tract. A damaged cardiorespiratory function of the brainstem likely underlies some cases of respiratory failure in COVID-19 victims.
- Reason 4: COVID-19 patients show neurological symptoms such as confusion, nausea, headache, and loss of smell and taste. The last hints at a possible damaged olfactory system in the brain — and other coronaviruses are known to infect the olfactory bulb.
4 Clues That SARS-CoV-2 Invades the Brain
[updated 26/3/20] “They’re just not thinking that the brain could be the site of the problem,” says a neuropathologist.
Neurological Manifestations of SARS-CoV-2
On 25th February, researchers at Huazhong University of Science and Technology, Wuhan, China, reported that about 36% of COVID-19 patients suffered neurological symptoms. They identified three classes of neurological symptoms, which are “CNS symptoms (headache, dizziness, impaired consciousness, ataxia, acute cerebrovascular disease, and epilepsy), peripheral nervous system (PNS) symptoms (hypogeusia, hyposmia, hypopsia, and neuralgia), and skeletal muscular symptoms,” they wrote.
On 3rd March, the National Health Commission of China updated the possible health consequences of COVID-19, based on the examination of several human tissue autopsy samples. “These [samples] showed that multiple organs are involved, including lungs, spleen and hilar lymph nodes, heart and blood vessels, liver and gallbladder, kidney, brain, adrenal gland, esophagus, stomach, and intestines,” the Chinese reported. “Specifically, edema and partial neuronal degeneration were observed in brain tissues.”
On 4th March, a 56-year-old man with COVID-19 contracted encephalitis in Beijing Ditan Hospital. Encephalitis is a brain inflammation that is usually caused by virus infection. They also detected SARS-CoV-2 genes in his cerebrospinal fluid (i.e., brain fluid). “This is the first evidence that SARS-CoV-2 has directly invaded the nervous system,” they said.
On 21st March, the neurologist, Dr. Asia Filatov, at Florida Atlantic University in Boca Raton reported a case of a 74-year-old man with COVID-19 who developed encephalopathy. Encephalopathy simply means any forms of brain damage. He lost his speech, ability to follow instructions, and had seizures. “Our case highlights the importance of identifying encephalopathy as a presenting sign of COVID-19,” Dr. Filatov and her colleagues wrote.
On 28th March, researchers at the Mazandaran University of Medical Sciences in Iran documented a case of a previously healthy 30-year-old woman with COVID-19 who suffered seizures about 5 times every 8 hours. “In our opinion, there is a hypothesis about this subject that the etiology of seizure may be due to encephalitis and invasion virus to the brain or toxic effect of inflammatory cytokines,” the Iran researchers said.
On 31st March, physicians at the Henry Ford Health System, Detroit, diagnosed a woman in her late 50s with “COVID-19–associated acute hemorrhagic necrotizing encephalopathy.” Hemorrhagic necrotizing encephalopathy means bleeding and swelling in the brain due to tissue damage.
Doctors think that SARS-CoV-2 invaded the brain directly, though some believed that the virus had triggered excessive systemic inflammation that damaged her brain. “Cytokines are chemicals that, among other functions, can cause small blood vessels to leak, and this can lead to small hemorrhages in many organs including the brain — this is well-known to occur as a consequence of several viral infections, including influenza,” remarks Anthony Geraci, a neurology physician at Northwell Health in Great Neck.
On 1st April, a case report published in Lancet Neurology identified a 61-year-old woman with was diagnosed with both COVID-19 and Guillain-Barré syndrome (i.e., a neurological condition when the immune system attacks the nervous system). “Considering the temporal association, we speculate that SARS-CoV-2 infection might have been responsible for the development of Guillain-Barré syndrome in this patient,” the researchers wrote.
On 3rd April, Japanese researchers at the University of Yamanashi published a paper detailing a case of a 24-year-old man having “meningitis/encephalitis associated with SARS-CoV-2.” Meningitis refers to the inflamed meninges (i.e., membranes surrounding the brain) whereas encephalitis is an inflamed brain. Like the first COVID-19 encephalitis case on 4th March, the Japanese also found SARS-CoV-2 in his cerebrospinal fluid. “This case warns the physicians of patients who have CNS symptoms,” they emphasized, in case it progresses into brain damage.
On 8th April, France physicians documented a COVID-19-positive woman in her 40s that experienced a loss of smell (not taste) without any nasal obstruction. This means that it’s more probable that SARS-CoV-2 has caused a loss of olfactory nerve function, rather than an inflamed nasal lining, which leads to the loss of smell.
On 10th April, another case report of COVID-19-associated encephalitis in a Wuhan male was published. The researchers did not find any SARS-CoV-2 genes in his cerebrospinal fluid, though he was positive for SARS-CoV-2. This could be that “SARS-CoV-2 dissemination is transient and its cerebrospinal fluid titer may be extremely low,” they explained. “We [also] speculate that SARS-CoV-2-induced immunologic response may cause inflammatory injury and edema, as a consequence, leading to alterations in consciousness.”
On 13th April, physicians examined 62 COVID-19 patients in the Nord Franche-Comté Hospital of France. Symptoms of headache were present in 78% of patients, and loss of smell and taste in about 50% of patients. And one COVID-19 patient had acute encephalitis.
“We wonder if there was an invasion of the olfactory receptors or damage of the first cranial nerves in the nasal cavity cell membrane…as described in post-viral olfactory loss with other viruses,” the France physicians say. “[There’s] increasing evidence that coronaviruses are not always confined to the respiratory tract and also invade the central nervous system inducing neurological disease.”
On 17h April, a Spain study detailed two cases of COVID-19-associated neurological syndromes called Miller Fisher syndrome and polyneuritis cranialis. Both are actually subtypes of Guillain-Barré syndrome — that happen when an overdriven immune system harms the nervous system. “Neurological manifestations may occur because of an aberrant immune response to COVID-19,” the authors concluded.
On 17th April, a report was made available online wherein a 41-year-old woman in Los Angeles was admitted to the hospital for viral meningitis and encephalitis —that is, meningoencephalitis. She didn’t show any respiratory issues but tested positive for SARS-CoV-2.
How SARS-CoV-2 Can Invade the Brain
Abdul Mannan Baig, MD and senior instructor at the Aga Khan University in Pakistan, is one of the earliest researchers to raise awareness about the neuroinvasive capacity of SARS-CoV-2.
In a recent paper published on 7th April, he outlined a few possible pathways by which SARS-CoV-2 can infiltrate the brain. “The hematogenous route appears to be the likely pathway for SARS-CoV-2 to reach the brain, but other routes to the CNS like across the cribriform plate of the ethmoid bone in proximity to the olfactory bulb should be taken into consideration in cases of early-phase COVID-19-affected patients who exhibit loss of smell and taste accompanied with neurological signs and symptoms,” Dr. Baig wrote.
Hematogenous means bloodstream wherein SARS-CoV-2 may enter the systemic circulation from the lungs and then reach and cross the blood-brain-barrier. The cribriform plate is where olfactory nerves of the nose cross and connect into the brain (i.e., the olfactory bulb of the limbic system); this route directly bypasses the blood-brain-barrier.
What Actions Are Needed
“We absolutely need to have an information finding mission, otherwise we’re flying blind,” asserts Sherry Chou, a neurology physician at the University of Pittsburgh School of Medicine and leader of the Neurocritical Care Society. “There’s no ventilator for the brain. If the lungs are broken we can put the patient on a ventilator and hope for recovery,” she adds. “We don’t have that luxury with the brain.” By this, she means that once SARS-CoV-2 established a complete infection in the brain, there’s nothing much technology can do.
Early diagnoses and interventions are, thus, of utmost importance. Scientists are now trying to find a convenient biomarker for this purpose. “A biomarker in CSF or serum of the COVID‐19 patients with neurological deficits would have been of ideal to diagnose cases of COVID‐19 with CNS involvement,” Dr. Baig wrote. “But with the unavailability of such methods, as of yet, smearing every possible method to include or exclude the COVID‐19 cases with neurological damage needs to be implemented.”
In early April 2020, a “consensus for prevention and management of coronavirus disease 2019 (COVID-19) for neurologists” was published in Stroke and Vascular Neurology. In this consensus report, they acknowledged that COVID-19 patients can show neurological signs.
“Healthcare providers and neurologists should [thus] pay close attention to these symptoms and have a high index of suspicion when evaluating patients in an endemic area,” the report concludes. “Early recognition may help initiate treatment and isolation early so as to prevent clinical worsening and spreading of the virus.”
Why Things Aren’t So Straightforward
An important note is that most viruses do not normally cause brain diseases as their primary symptom. Herpes simplex virus, for example, causes cold sores but also encephalitis in some cases. Likewise for COVID-19 as respiratory disease, but can be a brain disease — causing meningitis, seizures, encephalitis, and encephalopathy — in rare instances.
In other words, viruses can infect the brain, but they may not cause brain diseases. Either because the brain immune system prevents it or the virus remains non-infective in the brain. In the latter case, the virus becomes latent (or sleeps) in the brain owing to the control of the immune system. As follows, when the immune system is suppressed, viruses have the chance to reactivate and re-cause diseases— more details here:
First Case of COVID-19 Encephalitis: A Possibility of Virus Latency and Reactivation
New evidence that SARS-CoV-2 infiltrates the brain (and its ramifications)
Is it the Immune System or Virus?
Some scientists have even considered that brain diseases can be an “indirect result” of COVID-19. “It is also important to mention here that the neurological signs and symptoms observed in the COVID-19 cases could be a manifestation of hypoxia, respiratory, and metabolic acidosis at an advanced stage of the disease,” Dr. Baig himself argued against his propositions.
As mentioned above, Dr. Geraci also believed that the COVID-19-associated encephalopathy is due to the “cytokine storm” wherein the immune system damages the brain as collateral damage of fighting SARS-CoV-2. While this may be true, evidence of SARS-CoV-2 genes being found in the cerebrospinal fluid cannot be discounted.
“Although inflammation is critical for CNS pathogen clearance, lasting effects of immune molecules and pathogen by-products may represent an underlying mechanism of neurologic dysfunction,” explains Robyn Klein, MD and professor in the Departments of Medicine, Pathology & Immunology, and Neuroscience of Washington University. This means that an overdriven immune system and SARS-CoV-2 in the brain could both contribute additively to the development of brain diseases.
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