As coronavirus disease 2019 (COVID-19) concerns abate in a great part of the world, fresh worries arise about the long-term consequences of the infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Among these is the concern that movement disorders, particularly parkinsonism, could increase in prevalence.

A new review published in the Journal of Neural Transmission attempts to summarize all known about the relationship between viral illness and parkinsonian disorders to facilitate further research.

Introduction

Movement disorders following a viral illness are among the most common types of secondary movement disorders, manifesting most frequently as dystonia in children and parkinsonism in adults. For instance, encephalitis lethargica and post-encephalitic parkinsonism emerged following the Spanish flu (influenza A H1N1) pandemic a hundred years ago.

Parkinson’s disease (PD) has also been observed to result after influenza, herpes simplex, and hepatitis B and C infection. The pathophysiology of secondary PD is unknown, but it may be due to immediate or delayed damage to the neurons.

Para- and post-infectious parkinsonism

In the first scenario, para-infectious parkinsonism sets in within 15 days of the infection. This could be caused by the invasion of the nigrostriatal pathways by a neurotropic virus that invades and replicates within neurons, eventually causing their destruction. Such viruses could enter the central nervous system (CNS) along the nerves, by breaching the blood-brain barrier (BBB) or via the blood-cerebrospinal fluid barrier (BCSFB).

Alternatively, indirect damage might be caused via inflammation with microglial activation. This leads to the production of inflammatory chemicals and T-cell activation. The resulting elevation in cytokine levels causes vascular injury, reducing oxygen supply to the neuronal tissue, causing hypoxic brain damage.

Delayed or post-infectious parkinsonism may occur via autoimmunity, triggered by generalized immune activation or aberrant targeting of a specific host antigen by the host immune system. Such responses may result from molecular mimicry, as with herpes simplex, where host and viral antigens share similar structures, with resulting T and B cells activation against both.

Another possible mechanism is bystander activation. Here the virus-activated T cells attack infected cells expressing viral peptides, causing the release of cytokines such as nitric oxide (NO), tumor necrosis factor (TNF), or lymphotoxin (LT). These kill not only the infected cell but nearby healthy cells as well – termed bystander killing.

Alongside, the immune response begins to target not just the original peptides (epitopes) on the antigenic target but adjacent peptides as well, or even epitopes on other antigens. This “epitope spreading” results in a broader inflammatory response.

Finally, chronic infection in the host leads to both epitope spreading and independent triggering of B and T cells, causing autoimmunity, prolonged immune activation, and chronic inflammation. Neurologic damage is more likely in this scenario.

Examples

Human Immunodeficiency Virus (HIV)

HIV is estimated to have infected almost 40 million people, prone to life-threatening opportunistic infections unless properly treated and maintained on highly active anti-retroviral therapy (HAART). This is characterized by the destruction of CD4 T cells specifically, and the levels of these lymphocytes are proportional to the viral load.

Early CNS involvement is reported, with the virus entering the brain through infected white cells (the ‘Trojan horse’) or as free viral particles within infected endothelial cells. The virus then infects neurons as well as supporting glial cells.

With HIV, parkinsonism appears early, fails to respond to standard treatment, and has unusual features, especially early prominent postural tremors. Marked injury to the basal ganglia may cause parkinsonism and other features of HIV-related encephalopathy. Akinetic rigidity is often precipitated by dopamine antagonists.

With full-blown acquired immunodeficiency syndrome (AIDS), the parkinsonism patient often also shows signs of dementia, seizures, and damage to the white matter as well as peripheral nerves. The prognosis is poor due to a distinctive and severe nigral degeneration.

West Nile virus (WNV)

WNV has caused multiple outbreaks over the last 20 years, causing mild fever after an incubation period of 2 days to 2 weeks. In 1% of patients, acute neurologic symptoms manifest, such as meningitis or encephalitis, acute flaccid paralysis, and multiple movement disorders. Such patients are often elderly, alcohol addicts, or have a history of organ transplants.

The route by which the virus enters the human brain is unknown but may be through a disrupted BBB in response to virus-induced inflammatory cytokines produced peripherally. Retrograde axonal transport or endothelial cell transport of the virus is also possible.

Viral infection leads to neuronal death. Bilateral destruction of deep gray matter nuclei, especially the substantia nigra, for which the virus is specifically neurotropic, is probably responsible for parkinsonism in some patients. While most symptoms usually resolve spontaneously, the tremor may persist in one in ten cases, leading to disability.

Japanese encephalitis B virus (JEV)

Unlike other flaviviruses, JEV causes neurologic damage, including movement disorders, flaccid paralysis, or seizures, in many cases, resulting in lifelong disability. After the child is bitten by the Culex mosquito vector, the virus enters the circulation and infects the CNS via the endothelial cells of the CNS vasculature or through a disrupted inflamed BBB.

Direct and inflammatory injury causes neuronal apoptosis in dopaminergic neurons of multiple brain regions, including the thalamus, basal ganglia, midbrain, and cerebellum. Both dopamine and norepinephrine transmission are disrupted, causing the characteristic movement disorders associated with JEV about 2-6 weeks after the acute encephalitic phase.

JEV-related parkinsonism includes bradykinesia, rigidity, masked facies, and hypotonia, most of which resolve within 3 weeks except for a few patients who manifest a permanent loss of voice volume.

Influenza

Post-encephalitic parkinsonism (PEP) or encephalitis lethargica (EL) is a mysterious post-infectious phenomenon. Initially, it presented as an epidemic of neurologic impairment, with protean manifestations, including flu-like symptoms, sleepiness, issues with eye movements, and movement disorders in most cases. However, almost any kind of neurologic symptom may occur.

The underlying damage appears to be diffuse brain atrophy, marked neuronal loss, and gliosis, affecting the substantia nigra, with neurofibrillary tangles.

Many types of influenza A virus invade the nervous system after a systemic infection to infect the substantia nigra and hippocampus. This results in CNS inflammation with protein aggregates and degeneration in the dopaminergic pars compacta of the substantia nigra. Though this typically resolves, permanent microglial activation and neuroinflammation appear to persist, suggesting an autoimmune process.

The interval from illness to PEP stretches over months to years, with akinetic rigidity being the most common presentation. Some cases responded to levodopa.

Other post-viral parkinsonisms

Coxsackie, Western equine encephalitis, Ebstein-Barr virus (EBV), cytomegalovirus (CMV), poliovirus, and herpes simplex are also associated with parkinsonism. Meanwhile, other viruses have been linked to a higher risk of parkinsonian symptoms.

Apart from PEP, H1N1 may cause α-synuclein aggregates to form by inhibiting autophagosome formation, contributing to protein misfolding. The α-synuclein epitope seems to be involved in most post-viral encephalopathies, probably via the suppression of autophagic mechanisms that normally clear away toxic protein debris and prevent neurodegeneration.

Several studies have shown a higher risk of idiopathic PD after a diagnosis of influenza, supporting a contributing role of the virus.

Hepatitis C virus (HCV) infection is also associated with an increased risk of PD, though the link is unclear, and the PD risk may be due to liver disease rather than viral injury. This is borne out by the fact that non-alcoholic steatohepatitis is also a risk factor for PD.

Other research showed severe inflammatory damage after HCV infection, possibly triggering PD. Dopaminergic disruption by altered transporter functioning is another possibility.

With EBV, too, viral replication, BBB disruption, inflammation, and neuronal injury have all been implicated, while some suggest autoimmunity as the pathophysiologic mechanism.

Parkinsonism and COVID-19

People with PD (PWP) often have respiratory limitations due to the rigidity of the chest wall musculature, hindering free breathing, as well as the abnormal posture and weakened cough reflex. This makes them more vulnerable to severe illness if they contract SARS-CoV-2. In fact, up to 40% of older PD patients die of the illness, especially those with a longer history of the disease and those who require ventilation or other devices during treatment.

COVID-19 is also related to the post-COVID-19 worsening of muscular functions in PWP, in addition to the acute worsening described above. They may have to increase their anti-PD medication dosage and report brain fog, fatigue, poorer memory function, and sleep impairment.

A few cases of parkinsonism arising after a SARS-CoV-2 infection have been documented without a prior family history. Most had encephalopathy preceding this feature, with a few responding to dopamine agonists. Hypoxia, hyperglycemia-triggered osmotic demyelination, and basal ganglia stroke were identified in other cases, while a few cases occurred while already on neuroleptics. These could possibly account for secondary parkinsonism.

“However, with more than 5300 confirmed COVID-19 cases per 100,000 globally (as of February 2022) (Worldmeter.info 2021) and an annual incidence of about 15 PD cases per 100,000 (Tysnes and Storstein 2017), anticipating a parkinsonism wave based solely on the current 20 published cases sounds rather premature and susceptible to bias.” Further surveillance is necessary to catch such cases early and provide timely treatment in the coming years.

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.