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.

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

In this study, we found in hospital survivors with COVID-19, the main accompanying symptoms were memory loss, hair loss, anxiety, sleep difficulties, and fatigue. Most patients (74%) had PNP, including 51 patients (16%) with mononeuropathy and 181 patients (58%) with generalized PNP.

Patients at 12-month measurement had a higher prevalence of generalized PNP. 64 (20%) patients had only axonal loss, 67 (21%) had only demyelination, and 101 (32%) had a mixed type. Additionally, we found that the main influencing factors were age, education, and antibody IgG level at discharge.

Research Status of hospital survivors with COVID-19 and effects on Nervous System

Huang et al.¹² found that among 2,469 COVID-19 patients, most of them had at least one sequelae symptom at 6 months after discharge and its result was consistent with our findings. In our study, we found no significant association between any symptoms and PNP, which suggest all the COVID-19 survivors should pay attention to the observation of peripheral nerves during follow-up.

We found that most patients were found with PNP, which was consistent with previous studies. Oaklander¹⁴ found among 17 long-term COVID-19 patients, 59% of them had ≥1 test which confirmed the presence of PNP. Guerrero et al¹⁵ reviewed and summarized 143 studies about nervous system involvement by COVID-19.

A total of 10,723 COVID-19 patients were reported to be affected by SARS-CoV-2 in the central and peripheral nervous systems. The study reflected the remarkable prevalence of neurological involvement in COVID-19 patients and the rate of neurological involvement ranged from 22.5% to 36.4%.

However, previous studies on the nervous system mainly focused on central nervous system ^16-18, and most of the studies on PNP were case reports or focused on severe COVID-19 patients¹⁹.

In the studies mentioned above, 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.

NCS is not only important for the diagnosis of peripheral neuropathy, but also for prognosis and selection of the best therapy²⁰. A previous study²¹ assessed the correlation between electromyography (EMG) and NCS in COVID-19 patients and found that NCS was important for predicting COVID-19 prognosis and recovery.

Characteristics and Influencing Factors of NCS in hospital survivors with COVID-19

By using NCS, we 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 studies^22-24 have confirmed that IgG antibodies play an important role in neutralizing the virus and protecting the body from virus reinfection. Therefore, timely COVID-19 vaccination and booster vaccination to improve the antibody level may help reduce the prevalence and severity of PNP.

Through two measurements, we 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 results above 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, we should pay more attention to the peripheral nerve condition of patients with old age and low IgG antibody level, especially those bedridden and immobilized. Additionally, it reminds us to strengthen COVID-19 vaccination to avoid more severe neurological damage.

Possible Pathogenesis of PNP in COVID-19 survivors

However, the specific mechanism is still unclear, and the current research 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 virus²⁵. 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

Finsterer J²⁶ analyzed 105 studies on SARS-CoV-2-related PNP. It was 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. SARS-CoV-2 spikes interact with GM1 gangliosides in peripheral nerves, leading to cross-reactivity and production of antibodies against these antigens, inducing a peripheral demyelinating pattern of GBS²⁷.

Persistent and Recurring Neuroinflammatory Responses and Damage

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 diseases²⁷.

Limitations and Prospects

This study is only a preliminary analysis of the peripheral nerve

electrophysiology-related indicators and baseline data of patients in the recovery period of patients with COVID-19, trying to find the characteristics and related risk factors of PNP among COVID-19 survivors in the medium- and long-term rehabilitation. This study does not describe the intrinsic link between persistent multi-organ functional injury and PNP.

In the ongoing second part of the study, we will also comprehensively analyze more clinical data of COVID-19 patients during hospitalization and discharge, i.e., the blood biochemical test indicators, lung function, six-minute walk test, etc. Correlation analysis with the relevant indicators of peripheral nerve electrophysiology will be carried out to deeply reveal the relationship between PNP and the function of major organs of the body and provide real data for the complete recovery.