BREAKING! SARS-CoV-2 Infections Can Also Cause Long Term Peripheral Nerve Demyelination And Axonal Loss!

A new study by researchers from the People’s Hospital, Hebei Province-China, the Peking University, Beijing-China, North China University of Science and Technology, Hebei Province- China and the Hebei University of Chinese Medicine-China has alarmingly found that many Post COVID individuals will suffer from long term peripheral nerve demyelination and axonal loss and the risk of such damage would be higher if they had been previously hospitalized with moderate or severe COVID-19!


 
Peripheral nerve demyelinating typically causes substantial damage to axons and glial cells, particularly Schwann cells (SC) in the peripheral nervous system (PNS) while axonal loss refers to the damage of axons which are thread-like structures attached to a nerve cell that send out signals away from the cell.
 
To date, there is a lack of studies on large-sample, medium-, or long-term follow-up data of peripheral neuropathy (PNP) in the COVID-19 survivors.
 
This is the first study to evaluate the characteristics and related risk factors of PNP in the medium- and long-term rehabilitation, which provided real-world study data for the complete recovery of COVID-19 patients.
 
The study was a prospective cohort study of the COVID-19 survivors. The study team collected data on baseline characteristics, symptoms at onset and after discharge during the 6-month and 12-month follow-up.
 
Peripheral nerves were measured by electromyography and inducible potentiometer.
 
The study team used multivariable logistic regression to analyze the influencing factors of PNP. Additionally, the team compared the difference between the two measurements among the population who completed both measurements.
 
A total of 313 patients were included in the study and all of them underwent nerve conduction study. 67 patients completed two measurements at 6-month and 12-month follow-up.
 
Commonly reported symptoms contained memory loss (86%), hair loss (28%), anxiety (24%), and sleep difficulties (24%). 232 patients (74%) were found with PNP, including 51 (16%) with mononeuropathy and 181 (58%) with generalized PNP.
 
Patients with measurement at 12-month follow-up had a higher prevalence of generalized PNP (p=0.006).
 
For pathological types, 64 (20%) patients had only axonal loss, 67 (21%) had only demyelination, and 101 (32%) had a mixed type.
 
Interestingly, there was no significant difference in the prevalence of accompanying symptoms after discharge between the two groups with or without PNP.
 
After adjustment, age was positively associated with PNP (OR=1.22 per 10-year increase of age, 95% CI, 1.05-1.41). Compared with less than the median amount of IgG at discharge, higher amount of IgG was associated with decreased risk of F-wave abnormality (OR=0.32, 95%CI, 0.11-0.82), but no significant difference in other types of PNP.
 
Corresponding author, Professor Dr Yubin Zhao from the People’s Hospital, Hebei told Thailand Medical News, “The study findings showed that SARS-CoV-2 could cause PNP in hospital survivors with COVID-19, which persisted and was as sociated with age, education, and IgG antibody at discharge, but had no significant correlation with symptoms after discharge.”
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.medrxiv.org/content/10.1101/2022.07.19.22277248v1
 
Past studies reflected the remarkable prevalence of neurological involvement in COVID-19 patients and the rate of neurological involvement ranged from 22.5% to 36.4%.
https://pubmed.ncbi.nlm.nih.gov/34454673/
 
https://pubmed.ncbi.nlm.nih.gov/35232750/
 
https://pubmed.ncbi.nlm.nih.gov/34078305/
 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8982477/

Most of the past studies on the nervous system however mainly focused on central nervous system, and most of the studies on PNP were case reports or focused on severe COVID-19 patients.
 
In most of such studies, electrophysiological testing was not performed, which may be related to the insufficient use of the equipment for electrophysiological examination. Additionally, PNP is relatively insidious, the clinical manifestations are not typical, and many cases gradually appear after acute infection. These reasons have resulted in the lack of large-scale studies of PNP in COVID-19 patients, especially on neurological recovery in long-term rehabilitation of the COVID-19 survivors. Nerve conduction study or NCS is not only important for the diagnosis of peripheral neuropathy, but also for prognosis and selection of the best therapy.
 
The study team by using NCS, found that most of the patients had persistent PNP, mainly for generalized PNP at 6 or 12 months after infection with SARS-CoV-2. PNP was positively associated with age. Prevalence of F-wave abnormality was relatively low and patients with high levels of IgG antibody at discharge had a reduced risk of F-wave abnormality.
 
Several past studies have confirmed that IgG antibodies play an important role in neutralizing the virus and protecting the body from virus reinfection.
https://pubmed.ncbi.nlm.nih.gov/33721517/
 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050884/
 
Through two measurements, the study team found among the pathological types, the mixed type (axonal loss combined with demyelination) had the highest rate.
 
The prevalence of median nerve injured was highest and both the motor and sensory branches were damaged, with demyelination mainly, and distal (carpal-palm) involvement; followed by the peroneal nerve with mainly axonal loss and in both proximal and distal ends. Compared with the measurement at 6-month follow-up, amplitude of the ulnar nerve and sural nerve increased, while the conduction velocity of the median nerve was decreased of 67 patients who completed 2 measurements, which indicated axonal loss of the ulnar nerve and sural nerve was relieved, and the demyelination of the median nerve was aggravated. 
 
The study findings suggest that COVID-19 patients are more prone to have PNP in the distal limb and had a higher prevalence in lower extremities especially in the long term of rehabilitation.
 
After the diagnosis of COVID-19 infection, physicians should pay more attention to the peripheral nerve condition of patients with old age and low IgG antibody level, especially those bedridden and immobilized.
 
The possible pathogenesis of PNP in COVID-19 survivors and the  specific mechanism is still unclear, and the current research only focuses on the following three aspects:
 
-Direct Neuroinvasive Effects of SARS-CoV-2
 
The nervous system damage of COVID-19 patients is mostly caused by acute nervous system infection due to SARS-CoV-2 virus. https://pubmed.ncbi.nlm.nih.gov/33464535/
 
Infection with SARS-CoV-2 puts patients at increased risk of neurological damage, and in some cases SARS-CoV-2 causes clinical manifestations of acute neurological damage or exacerbates pre-existing baseline neurological disease severity. Another factor to consider is the possible direct neuro-muscular damage caused by the SARS-CoV-2 virus. However, direct muscle damage by the virus has not been demonstrated, nor has it been reported in autologous muscle lesions.
 
-Autoimmune Response
 
Another past study involving the meta-analysis of more than 105 studies speculated that the infected virus may have epitopes similar to components of the peripheral nerve (activating autoreactive B or T cells) and result in PNP. https://pubmed.ncbi.nlm.nih.gov/34287509/
 
SARS-CoV-2 spikes interact with GM1gangliosides in peripheral nerves, leading to cross-reactivity and production of antibodies against these antigens, inducing a peripheral demyelinating pattern of GBS. https://nn.neurology.org/content/7/5/e781
 
-Persistent and Recurring Neuroinflammatory Responses and Damage
 
It was also hypothesized that after infection with SARS-CoV-2, immune dysregulation may persist in the form of persistent inflammation, immunosuppression and catabolic syndrome28.
 
This immune state is thought to be triggered by cytokine storms during acute infection and further contributed by the sustained release of endogenous alarmins or danger-associated molecular patterns, which can lead to chronic systemic inflammation. Chronic neuroinflammation associated with high levels of cytokines/chemokines may be involved in the pathogenesis and progression of neurological diseases. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2784918
 
On the whole, the study findings alarmingly indicate that peripheral nerve demyelination and axonal loss is a long-term health issue with many Post COVID individuals and physicians should focus also in this specific area during regular Post COVID health screenings of patients.
 
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