Neurological symptoms after COVID-19 vaccination: a report on the clinical presentation of the first 50 patients

Objectives Neurological symptoms associated with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) vaccination were discovered in the context of billions of administered vaccine doses. The clinical manifestations often resemble post Coronavirus Disease 2019 (post-COVID-19) syndrome (PCS) features and may be considered as post-COVID-19 vaccine syndrome (PVS). Data regarding frequency, severity and pathophysiological mechanisms are scarce. Methods We assessed routine clinical examinations in 50 patients reporting new-onset neurological symptoms after SARS-CoV-2 vaccination, including neurological examination, laboratory and electrophysiology tests, as well as self-report questionnaires measuring fatigue, depressive symptoms, anxiety, risk of somatic symptom disorder, and health-related quality of life. Patients were included when symptoms occurred after confirmed COVID-19 vaccination and without prior SARS-CoV-2 infection, and if no alternative diagnosis was found to explain the symptoms. Results The most frequently reported symptoms were paraesthesia (56%), fatigue (46%) and cognitive impairment (36%). Neurological, routine laboratory, and electrophysiological examinations did not yield distinct pathological findings. Neuropsychological testing of a subgroup revealed deficits in attention, executive function and memory. Discussion The spectrum of clinical manifestations post-vaccination poses a substantial overlap with PCS symptoms. As no pathological findings were obtained in routine diagnostics, uncertainty remains about the underlying pathophysiological mechanisms and requires further investigation beyond routine work-up.


Introduction
Post-COVID-19 syndrome (PCS) is known for its wide range of neurological and psychiatric symptoms, including fatigue, cognitive impairment, headache, depression, and anxiety [3,4,19].Vaccine development has been a major breakthrough not only to reduce the number of deaths and severe cases of Coronavirus Disease 2019 , but also to contain the spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) [6].Additionally, there is emerging evidence that vaccination decreases the risk of developing PCS after breakthrough infection [1].
Initially, all approved vaccines were found to be safe, with generally mild and transient side effects such as pain on the injection site, fever, or headache [17].A serious adverse event after vector vaccination is vaccine-induced immune thrombotic thrombocytopenia (VITT) [7], leading to predominant usage of mRNA-based vaccines in Germany.Other severe neurological adverse events following COVID-19 vaccination have been rarely described and involve e.g., Bell's palsy, Guillain-Barré syndrome, acute disseminated encephalomyelitis, and cerebrovascular events [16].Data on other symptoms in correlation with COVID-19 vaccination, commonly referred to as "post-COVID-19 vaccine syndrome" (PVS) [10], are scarce.
Here we report of 50 patients who presented to our neurological outpatient clinic due to neurological symptoms in temporal association to COVID-19 vaccination.

Methods
Fifty patients with neurological symptoms following COVID-19 vaccination presented to our outpatient clinic between October 2021 and July 2022.They were interviewed and examined by a neurologist.All patients had received at least one vaccination against SARS-CoV-2 and did not report of a concomitant disease explaining the symptoms.Patients with a confirmed SARS-CoV-2 infection before symptom onset were excluded.Diagnostic evaluation including blood tests was performed according to the guidelines of the German Society of Neurology.Patients filled out self-report questionnaires regarding fatigue (Fatigue Severity Scale, FSS) [11], depression (Beck Depression Inventory Version I, BDI) [2], anxiety (Generalized Anxiety Disorder Scale-7, GAD-7) [18], and risk of somatic symptom disorder (Somatic Symptom Disorder -B Criteria Scale, SSD-12) [21].Health-related quality of life was assessed using the Short-Form-36 Health Survey (SF-36) [23] and compared with a norm sample (n = 2471) [8].To screen for cognitive deficits, the Montreal Cognitive Assessment Scale (MoCA) [15] was performed.Neuropsychological examination covered test items regarding learning and memory, complex attention, executive functions, language, and perceptual motor function.
Electrophysiological examination was conducted in patients with paraesthesia and neuropathic pain.Skin biopsy was performed to assess intraepidermal nerve fibre density or pathological amyloid deposits in those patients whose electrophysiological assessment did not show pathological findings.

Results
The mean age of patients was 41 years (21-62 years) and the majority were female (60%).In 50% of patients, symptoms occurred after the first vaccination, in 26% after the second, and in 24% after the third (Table 1).Almost all patients (98%) developed symptoms after administration of an mRNA-based vaccine.Most patients (86%) received a homologous, mRNA-based vaccine regimen (82% BioNTech-Pfizer, 4% Moderna).Heterologous vaccine regimen were used in 14% of patients (10% mRNA-/mRNA-based, 4% vector-/ mRNA-based).The median latency between receiving the vaccination and onset of symptoms was three days, ranging from one hour to 30 days.A SARS-CoV-2 infection occurred in 16 patients (32%) after their vaccination and onset of reported symptoms.All 16 had a mild course, but 10 (63%) reported an exacerbation of pre-existing symptoms.

Discussion
We report of a comprehensive neurological assessment in 50 patients with persistent neurological symptoms in temporal relation to COVID-19 vaccination including clinical presentation, routine diagnostic, and self-report questionnaires.To date and in contrast to PCS, reliable data and a generally accepted definition of PVS are absent.
Our patients presented with central (cognitive impairment, fatigue, headache) and peripheral (paraesthesia, myalgia, fasciculations, neuropathic pain) neurological symptoms.Our data indicate that the spectrum of symptoms reported by PVS patients is similar to the spectrum we observe in PCS patients [3].Notably, paraesthesia (56%) as the most common reported symptom in PVS was less frequently observed in PCS, while fatigue (46%) and cognitive impairment (36%) seem to occur more often in PCS [3].As a limitation, our study did not include  follow-up examinations.These are needed to assess the time course of symptom severity, modification and potential recovery of symptoms.Self-report questionnaires showed an increased risk of somatic symptom disorder as assessed by SSD-12 in 75% of our 50 patients, moderate to severe anxiety measured by GAD-7 was present in 25%, and BDI indicated moderate to severe depressive symptoms in 16% of our patients.SF-36 showed low percentages in all scores, especially regarding physical health, underlining the severe impact on patient's quality of live.Since standard diagnostic was widely normal, inclusion of psychiatric and psychosomatic assessment should be considered.
Our cohort mainly involved patients vaccinated with mRNA vaccines, which are predominantly administered in Germany.Available literature however accuses vectorbased vaccines to be more frequently associated with (severe) neurological side effects [7,20].On the other hand, mRNA-COVID-19 vaccine side-effects have been attributed to a nocebo component in association with vaccine hesitancy [9].
Our data does not allow conclusions whether the symptoms occurred in temporal relationship to the COVID-19 vaccination, or whether the vaccine may be considered as a triggering factor or a cause of these symptoms.While there is limited data, several pathomechanisms have been suggested to explain the occurrence of diseases following SARS-CoV-2 vaccination, e.g., molecular mimicry, production of cross-reactive (anti-idiotype) autoantibodies, involvement of vaccine adjuvants, and persistence of spike protein [5,14,22].
Although neurological symptoms after COVID-19 vaccination have been reported, they appear to be rare considering the total number of vaccines administered.Current recommendations and guidelines favour COVID-19 vaccination as the risk of neurological complications during and after COVID-19 infection overweighs [13,16].Nevertheless, in-depth investigation of the individual patient, including diagnostic procedures beyond routine clinical care is needed, while research on pathophysiological mechanisms may provide further insights and might offer therapeutic options.

Table 1
Patient characteristics and details of vaccine regimens

Table 2
Reported symptoms