Cases of Parkinsonism from Covid-19: What to Make of It?
Scientists called it the third silent wave, but there are a few things to consider.
To date, there have been three published case reports of Covid-19 patients developing parkinsonism — the symptoms of Parkinson’s disease (PD). PD impairs a person's movement coordination. They show trembling hands, legs, or jaw, stiff limbs, slow movement with sudden halts, and poor balance. Now, what might parkinsonism have to do with SARS-CoV-2 or Covid-19?
Parkinsonism cases following Covid-19
Let’s hear from Patrik Brundin, professor and director at the Center for Neurodegenerative Science in Van Andel Research Institute in Michigan, a world-leading expert with over 350 publications on PD.
His new paper, titled “Is COVID-19 a perfect storm for Parkinson’s disease?”, was published in Trends in Neurosciences last month. Herein he and co-workers detailed three case reports of patients developing parkinsonism within 2–5 weeks of SARS-CoV-2 infection.
Two of them, a 35-year female and 45-year male, responded to the standard dopaminergic treatment for PD and recovered. One of them, a 58-year man, healed spontaneously. Importantly, all cases showed reduced nigrostriatal system (that controls body movement) activities upon brain imaging, just like any other PD patients.
None of them had any early signs of pre-clinical PD or a family history of PD, indicating that these patients were not susceptible to PD, to begin with. Not to mention that PD typically struck people aged 60 and above.
Causation or association?
While it’s unclear if its causation or association, it’s probably somewhere in between. “Possibly, the reported patients were destined to develop PD and were on the cusp of losing the number of nigral dopamine neurons required for the emergence of motor symptoms, and the viral infection only accelerated an ongoing neurodegenerative process around a critical timepoint,” Prof. Brundin et al. wrote. “The rapid onset of severe motor symptoms in close temporal proximity to the viral infection is, however, still suggestive of a causal link.”
To this end, Prof. Brundin and others proposed three possible mechanisms of how SARS-CoV-2 might induce or accelerate parkinsonism:
- SARS-CoV-2 can infect the blood vessels, including those in the brain, which could damage the nigrostriatal system. This is similar to vascular parkinsonism caused by cerebrovascular diseases (e.g., stroke) that impair blood flow to or in the brain.
- Covid-19 can cause or exacerbate systemic inflammation. As it is systemic, it includes the brain where neuroinflammation of the nigrostriatal system may occur.
- SARS-CoV-2 can invade, replicate in, and damage brain neurons. And neurons in the midbrain, where the nigrostriatal system resides, is particularly rich in ACE2 receptors that enable SARS-CoV-2 entry.
It’s not just SARS-CoV-2
Viruses participating in chronic diseases is not a new concept. Hepatitis B and C viruses (HBV and HCV) cause chronic liver disease, human papillomavirus causes cervical cancer, herpes simplex virus type 1 (HSV-1) may accelerate Alzheimer’s disease, and adenovirus may accelerate obesity.
Similarly, in PD, viruses have been recognized as a possible trigger since the 1950s. It all started with the 1918 influenza pandemic that preceded the PD epidemic during the 1940-1950s, where diagnoses soared to 2.5–3% in the U.S. and returned to baseline at 1–2% in the subsequent decades. Animal models have further confirmed that the influenza virus can infiltrate and injure the brain's nigrostriatal system, resulting in PD.
“The world was caught off guard by the first wave of Covid-19, will we be ready for the third wave of neurological sequelae such as parkinsonism?”
Since then, researchers have identified more neuroinvasive pathogens linked to PD — such as HSV-1, Epstein-Barr virus (EBV), Varicella zoster virus (VZV), HCV, Japanese encephalitis virus (JEV), West Nile virus (WNV), human immunodeficiency virus (HIV), and Helicobacter pylori bacterium — as a 2018 research review summarized. For example, the review identified that prior VZV, HCV, or H. pylori infections increased the risk of future PD. Killing H. pylori even improved motor symptoms in PD patients. Others like HSV-1, EBV, HIV, and JEV are often more prevalent in PD patients than the general population.
A third silent wave
SARS-CoV-2 infection can be long-term in some cases, even though the virus may no longer be present as the immune system stays rampant. Patients with long-Covid — the long-haulers — is a stark example of this.
“Long-term systemic and/or neuro-inflammation due to Covid-19 might be “a perfect storm” for the development of PD,” Prof. Brundin added. “Thus, while acute parkinsonism in conjunction with Covid-19 appears to be rare, the spread of SARS-CoV-2 widely in society might lead to a high proportion of people being predisposed to developing PD later in life, especially as they are affected by normal aging processes.”
Many others have foreseen the same and voiced their concerns in formal scientific publications, even in the top ones like Nature and Lancet. For instance, researchers at the Florey Institute of Neuroscience and Mental Health in Australia asked: “The world was caught off guard by the first wave of Covid-19, will we be ready for the third wave of neurological sequelae such as parkinsonism?” In this light, these researchers in Australia are now advocating and applying grants for a national screening program to catch early signs of PD. PD has no cure, so it is best to intervene early.
A few considerations
This third silent wave is assuming that SARS-CoV-2 contributes to the progression of PD, which has not been confirmed with other human coronaviruses. The only hint is from a 1992 study that detected increased antibody production against common cold-causing coronaviruses in the cerebrospinal fluid of PD patients compared to non-PD persons. But this might indicate that PD patients are more susceptible to coronavirus infection rather than coronaviruses inducing PD, or somewhere in between.
However, evidence exists that many pathogens can accelerate PD progression, as discussed above. It’s not a surprise if SARS-CoV-2 happens to be one of them, given its capacity to infect the brain and induce parkinsonism in at least three cases already. Whether these observations translate to a heightened risk of PD in a longer period or broader scale can only be known in the future.
In a multifactorial disease like PD, multiple risk factors are involved and viruses may as well be one of the many.
At this point, it remains speculative whether SARS-CoV-2 would bring a third silent wave. The evidence thus far is hypothetical. There are yet any studies showing that SARS-CoV-2 injures the nigrostriatal system in human brain cells or animals. It’s also important to note that no single variable causes PD. In a multifactorial disease like PD, multiple risk factors are involved, and viruses may as well be one of the many. Other PD risk factors include old age, male sex, genetics, head trauma, exposure to toxic metals or pesticides, and certain psychiatric drugs. Whereas protective factors include exercise, vitamins D and E, antioxidants, and caffeine intake.
The literature has documented three cases of Covid-19 patients showing symptoms of Parkinson’s disease (PD) 2–5 weeks later. They had no family history or early signs of PD, yet they developed brain abnormalities in the nigrostriatal system that controls body movement. One recovered on his own; the other two required therapy that PD patients normally receive.
Indeed, several viruses, including SARS-CoV-2, are known for their ability to injure the brain. Researchers have suggested the possibility of a ‘third silent wave’ of PD, just like what happened after the 1918 influenza pandemic. But the evidence thus far is speculative. No studies have shown that SARS-CoV-2 could cause PD in animals, for instance. Lastly, there’s usually no single causal factor in a multifactorial disease like PD. So, the more plausible scenario is that SARS-CoV-2 could hasten PD progression in susceptible persons.
Thanks to Swcman