What is a Brain Pathogen?

Brain pathogens are defined as microbes that can invade and harm the brain. These include various bacteria, fungi, amoebas, and viruses, as highlighted by experts in brain infections in Clinical Microbiology Reviews. "Microbial infections of the central nervous system (CNS) are a significant and relatively common occurrence," they added.

Viruses are particularly frequent culprits in such infections. Pathogens such as enteroviruses, cytomegalovirus, herpes simplex virus, varicella-zoster virus, West Nile virus, henipaviruses, Japanese encephalitis virus, chikungunya virus, Ebola virus, and rabies virus are known to cause brain infections.

"Viruses are a common cause of CNS infections," specialists have noted. They often utilize "axonal transport" as a means of infection, wherein the virus exploits the neuron’s transport system to spread into the brain. This typically occurs when the virus enters through the eye, nose, or mouth, subsequently infecting nearby olfactory or trigeminal nerves.

Why SARS-CoV-2 May Act as a Brain Pathogen

Before clinical cases of SARS-CoV-2 brain infections emerged, researchers in China and Pakistan presented several reasons supporting the idea that this virus could infiltrate the brain:

1. SARS-CoV-2 belongs to the coronavirus family, and past coronaviruses like SARS and MERS are known to infect the brain. It is improbable that SARS-CoV-2 is an exception.
2. The virus accesses host cells via the ACE2 receptor, which is present in the brain in addition to being primarily found in the lungs.
3. Previous coronaviruses have been shown to infect the brainstem, which integrates neuronal signals from the lungs and respiratory tract. Dysfunction in this area may explain respiratory failures in COVID-19 patients.
4. Neurological symptoms observed in COVID-19 patients, such as confusion and loss of smell, suggest potential damage to the olfactory system, known to be targeted by other coronaviruses.

Neurological Symptoms Associated with SARS-CoV-2

On February 25, a study from Huazhong University of Science and Technology in Wuhan revealed that approximately 36% of COVID-19 patients exhibited neurological symptoms. These were categorized into three main groups: CNS symptoms (headache, dizziness, impaired consciousness, ataxia, acute cerebrovascular incidents, and epilepsy), peripheral nervous system symptoms (reduced taste, smell, and vision along with neuralgia), and skeletal muscular symptoms.

On March 3, the National Health Commission of China updated potential health risks associated with COVID-19, revealing that various organs, including the brain, can be affected, with edema and partial neuronal degeneration noted in brain tissues.

On March 4, a 56-year-old COVID-19 patient was diagnosed with encephalitis at Beijing Ditan Hospital. This represented the first indication that SARS-CoV-2 could directly invade the nervous system, as the virus's genetic material was identified in the patient's cerebrospinal fluid.

On March 21, a case was reported involving a 74-year-old man with COVID-19 who developed encephalopathy, characterized by a loss of speech and seizures. This case underscored the importance of recognizing encephalopathy as a potential indicator of COVID-19.

On March 28, researchers documented a case of a previously healthy 30-year-old woman who experienced multiple seizures linked to her COVID-19 infection. They speculated that the seizures might be due to encephalitis or the inflammatory response associated with the virus.

On March 31, a case of "COVID-19-associated acute hemorrhagic necrotizing encephalopathy" was reported in a woman in her late 50s, suggesting a direct invasion of the brain by SARS-CoV-2, although some theorized that excessive systemic inflammation could have contributed to the condition.

On April 1, a case was reported in Lancet Neurology detailing a 61-year-old woman diagnosed with both COVID-19 and Guillain-Barré syndrome, suggesting a possible link between the virus and the neurological condition.

On April 3, Japanese researchers described a case of a 24-year-old man with meningitis/encephalitis associated with SARS-CoV-2, warning healthcare providers of potential CNS symptoms in patients.

On April 8, physicians in France reported a COVID-19-positive woman in her 40s who lost her sense of smell without nasal obstruction, indicating that SARS-CoV-2 might impair olfactory function rather than just inflaming nasal tissues.

On April 10, another encephalitis case was documented in a Wuhan male, although no viral genes were detected in his cerebrospinal fluid, leading researchers to speculate on the transient nature of the virus's presence.

On April 13, a study involving 62 COVID-19 patients in France found that 78% reported headaches and around 50% experienced loss of smell and taste, with one patient suffering from acute encephalitis.

On April 17, two cases in Spain were documented involving COVID-19-associated neurological syndromes related to Guillain-Barré syndrome, concluding that neurological symptoms may arise from an abnormal immune response to COVID-19.

On the same day, a report emerged concerning a 41-year-old woman in Los Angeles admitted for viral meningitis and encephalitis, despite not exhibiting respiratory symptoms.

How SARS-CoV-2 Can Access the Brain

Dr. Abdul Mannan Baig, a senior instructor at the Aga Khan University, has been an early advocate for understanding SARS-CoV-2's neuroinvasive potential. In a recent publication, he proposed several pathways for how the virus might infiltrate the brain.

"The hematogenous route is likely for SARS-CoV-2 to reach the brain, but direct access through the cribriform plate near the olfactory bulb should also be considered, especially in early COVID-19 cases exhibiting neurological symptoms," Dr. Baig explained.

The hematogenous route refers to the virus entering the bloodstream from the lungs and potentially crossing the blood-brain barrier. The cribriform plate serves as a pathway for olfactory nerves to connect directly with the brain, bypassing this barrier.

What Actions Are Needed

Dr. Sherry Chou, a neurology physician at the University of Pittsburgh, emphasizes the need for urgent information gathering regarding the neurocognitive effects of COVID-19. "We lack the technology to support brain function as we do for the lungs," she stated, stressing the importance of early diagnosis and intervention.

The pursuit of a reliable biomarker for neurological involvement in COVID-19 patients is ongoing. "Identifying a biomarker in the cerebrospinal fluid or serum of patients with neurological deficits would be ideal for diagnosing CNS involvement," Dr. Baig stated. However, in the absence of such methods, comprehensive strategies to address potential neurological damage are crucial.

A consensus report published in Stroke and Vascular Neurology highlighted the need for neurologists to be vigilant regarding neurological signs in COVID-19 patients. "Early identification can facilitate treatment and isolation, potentially preventing further clinical deterioration and virus spread."

Why Things Aren’t So Straightforward

It is important to recognize that most viruses do not primarily cause brain diseases. For instance, the herpes simplex virus typically leads to cold sores but can also cause encephalitis in some cases. Similarly, while COVID-19 primarily manifests as a respiratory illness, it can occasionally result in neurological complications such as meningitis or seizures.

In essence, while viruses can infect the brain, they do not always lead to brain diseases. The brain's immune defenses may be effective in preventing infection, or the virus may enter a latent state, remaining dormant until the immune system is compromised, which could lead to reactivation.

Is the Immune Response or Virus Responsible?

Some researchers propose that neurological symptoms may be an indirect consequence of COVID-19. Dr. Baig noted that neurological signs might result from hypoxia or metabolic issues during advanced stages of the illness. Dr. Anthony Geraci highlighted that COVID-19-related encephalopathy may stem from a "cytokine storm," where the immune response inadvertently damages brain tissue.

While inflammation is crucial for clearing pathogens from the CNS, lingering immune molecules and viral remnants could contribute to neurological dysfunction. This suggests that both an overactive immune response and the presence of SARS-CoV-2 in the brain may play a role in the development of brain-related issues.