Good recovery of immunization stress-related responses presenting as a cluster of stroke-like events following CoronaVac and ChAdOx1 vaccinations.

BACKGROUND: Immunization stress-related responses presenting as stroke-like symptoms could develop following COVID-19 vaccination. Therefore, this study aimed to describe the clinical characteristics of immunization stress-related responses causing stroke-like events following COVID-19 vaccination in Thailand.
METHODS: We conducted a retrospective study of the secondary data of reported adverse events after COVID-19 immunization that presented with neurologic manifestations. Between March 1 and July 31, 2021, we collected and analyzed the medical records of 221 patients diagnosed with stroke-like symptoms following immunization. Two majority types of vaccines were used at the beginning of the vaccination campaign, including CoronaVac (Sinovac) or ChAdOx1 (AstraZeneca). Demographic and medical data included sex, age, vaccine type, sequence dose, time to event, laboratory data, and recovery status as defined by the modified Rankin score. The affected side was evaluated for associations with the injection site.
RESULTS: Overall, 221 patients were diagnosed with immunization stress-related responses (stroke-like symptoms) following CoronaVac (Sinovac) or ChAdOx1 (AstraZeneca) vaccinations. Most patients (83.7%) were women. The median (interquartile range) age of onset was 34 (28-42) years in patients receiving CoronaVac and 46 (33.5-60) years in those receiving ChAdOx1. The median interval between vaccination and symptom onset for each vaccine type was 60 (16-960) min and 30 (8.8-750) min, respectively. Sensory symptoms were the most common symptomology. Most patients (68.9%) developed symptoms on the left side of the body; 99.5% of the patients receiving CoronaVac and 100% of those receiving ChAdOx1 had a good outcome (modified Rankin scores ≤2, indicating slight or no disability).
CONCLUSIONS: Immunization stress-related responses presenting as stroke-like symptoms can develop after COVID-19 vaccination. Symptoms more likely to occur on the injection side are transient (i.e., without permanent pathological deficits). Public education and preparedness are important for administering successful COVID-19 vaccination programs.

Introduction

Immunization stress-related responses (ISRR) are defined by the World Health Organization (WHO) as symptoms and signs of bodily responses to vaccination [1]. These events are not caused by side effects due to vaccine components. Instead, they arise from the stress reaction to the vaccination process/cascade, which could be precipitated or potentiated by the pain or other common side effects of the injections. The symptoms may develop immediately (within 5 minutes) following vaccination, such as vasovagal reaction, or later, such as non-epileptic seizures, abnormal movements after COVID-19 vaccination [2] or motor and sensory symptoms which demonstrate positive neurological signs (Hoover’s sign) which were diagnosed of functional neurological disorders [3].

Since the initiation of the COVID-19 vaccination campaign in Thailand on February 28, 2021, 17,685,974 doses have been administered through the study follow-up date of July 31, 2021. Serious or concerning adverse events occurring within 30 days after the vaccination as well as event clusters were reported to the Adverse Event Following Immunization (AEFI) committee at the Department of Disease Control (Thailand Ministry of Public Health). All cases were reviewed by the AEFI committee. Causality and relationships to vaccination were determined by consensus.

The first ISRR cluster was identified at the start of April 2021; the committee identified five patients with stroke-like symptoms. These patients were healthcare workers (HCWs; i.e., the first group to receive the vaccine in the country). Similarly, within one week, we identified many clusters of stroke-like symptoms reported following vaccination, all of which occurred in HCWs.

This information spread rapidly through social networks and caused vaccine hesitancy. Impurity or high vaccine specificity was suspected as probable causes. However, the relevant vaccine types were investigated and found within regulated quality without identifiable toxins or contamination. The AEFI committee convened to review these cases in a timely fashion and found that most of the reported cases were those of ISRR. Thus, herein, we report on the clinical features of clustered ISRR presenting with neurologic manifestations to inform public health education, epidemic preparedness, and vaccine administration programs.

Materials and methods

Study design and participants

Thailand initiated a nationwide COVID-19 vaccination campaign on February 28, 2021. The AEFI report system for the routine vaccine in the National Immunization Program (NIP) has been established in every public hospital for over twenty years. The dedicated hospital staff reports any serious AE or AE of special interest or AE that occurred in the cluster through the national AEFI surveillance program (AEFI-DDC) hosted by the Department of Disease Control, Ministry of Public Health. A medical record and imaging scan copy would be submitted for systematic review by the AEFI committee. In some cases of doubt, the treating clinician was contacted for additional information. The AEFI committee convened promptly to determine causality as well as the relationships of the presenting symptomology with vaccination status and timing. The primary physicians may primarily diagnose ISRR; however, all were confirmed by the AEFI committee composed of neurologists, internists, pediatricians, cardiologists, hematologists, and allergists. In some cases of doubt, the committee would seek further external expert neurologist consultation.

We conducted a retrospective study using the data received from the National AEFI surveillance program (AEFI-DDC) and the copy of the medical records of the cases that were determined to be ISRR by the AEFI committee. We requested only the specific data relevant to the ISRR from the Department of Disease Control, Ministry of Public Health. Specifically, we evaluated ISRR with a neurologic presentation that occurred between March 1 and July 31, 2021. The data evaluated in this secondary analysis were obtained without direct contact with patients or their attending healthcare workers. Neurological ISRRs were diagnosed based on the presence of clinical neurological symptoms compatible with dissociative neurological symptom reactions [1].

The data used for this analysis, including sex, age, vaccine type, sequence dose, time to event, clinical manifestations, laboratory data, and recovery status (which was defined according to the patients’ modified Rankin scale [mRS] scores, with higher scores indicating a greater level of disability) were abstracted from the study database provided by the AEFI committee. The mRs scores were selected as the primary outcome measure for defining recovery status. A good outcome was defined as an mRS score of 0–2 (indicating slight or no disability), a poor outcome as an mRS score of 3–5 (indicating moderate to severe disability), and mortality was categorized as an mRS score of 6.

This study was approved by the Ethical Review Committee for Research in Human Subjects at the Thailand Ministry of Public Health approval No. 15/2564. The requirement for informed consent was waived due to the retrospective nature of this study and the fact that we conducted a secondary analysis of anonymized and de-identified data.

Statistical analysis

When evaluating baseline demographic and medical data, we report medians and interquartile ranges (IQR) for continuous data (some variables were not normally distributed), whereas categorical variables are presented as counts and percentages. Demographic and medical data were dichotomized by vaccine type (CoronaVac [Sinovac Biotech, Beijing, China], ChAdOx1 [AstraZeneca, Cambridge, UK]). Also, we evaluated the distributions and characteristics of adverse events by injection site. All statistical analyses were performed using GraphPad Prism 9 software (San Diego, CA, USA).

Results

Following a total of 17,685,974 COVID-19 vaccine doses that were administered as of July 31, 2021 (including 8,699,803 doses of the CoronaVac vaccine, 8,000,079 doses of the ChAdOx1 vaccine and 986,092 doses of the BBIBP-CorV), 293 patients with severe neurological complications were reported to the AEFI committee. These included 278 and 15 patients who had received the CoronaVac and ChAdOx1 vaccines, respectively.

ISRR was diagnosed in 263 patients. Other neurological diseases were identified in 18 patients, including five patients with stroke (two with ischemic stroke and three with hemorrhagic stroke), four patients with neuropathy, four with provoked seizure, one with severe headache, one with severe myalgia, one with facial edema and numbness, one experiencing syncope, and one with aggravated back pain due to spinal stenosis. For 12 patients who reported severe neurological symptoms, the AEFI committee determined the causality as inconclusive due to incomplete medical records. Of the 263 patients reported to have ISRR, 221 had adequate data available for this secondary analysis. All patients had normal findings on the brain CT computed tomography (CT) and magnetic resonance imaging (MRI) scans. Table 1 shows demographic data, clinical symptomology, and health outcomes in the identified patients experiencing adverse vaccine-associated events.

Table 1

Clinical and demographic data for immunization stress-related responses (ISRR).

	CoronaVac vaccine (n = 211)	ChAdOX1 vaccine (n = 10)
Sex
Female (%)	177 (84)	8 (80)
Male (%)	34 (16)	2 (20)
Median age of onset (years, IQR)	34, 28–42	46, 33.5–60
Mean BMI (SD)	24.7, 4.8	24.8, 4.5
Median time from vaccination to symptom onset (min, IQR)	60, 16–960	30, 8.8–750
Number of patients following each dose
1st dose	165	10
2nd dose	46	-
Injection side
Left	50	7
Right	4	0
Unknown	157	3
Median time to recovery (days, IQR)	2, 1–4	1, 4 hours—11 days

IQR, interquartile range; SD, standard deviation

Most of these patients were females (185/221, 87%); the median age of onset was 34 years (IQR, 28–42) for patients who received the CoronaVac vaccine and 46 years (33.5–60) for those who received the ChAdOx1 vaccine. The median interval between vaccination and symptom onset was 60 min (IQR, 16–960) for the CoronaVac vaccine and 30 min (8.8–750) for the ChAdOX1 vaccine. Most of these adverse events (175/221, 79.2%) occurred following the first vaccination dose. The median time from injection to recovery was 2 days (IQR, 1–4) and 1 day (IQR, 4 h to 11 days) for CoronaVac and ChAdOX1 recipients, respectively.

A total of 209 patients (94.5%) had sensory, motor, or combined sensorimotor symptoms. Of these, 144 (68.9%) patients developed symptoms on the left side of the body. Of the 61 patients whose injection side was known, 45 (73.8%) developed symptoms on the same side as the injection site. Table 2 shows clinical characteristics regarding neurological symptoms stratified by the vaccine injection site. In CoronaVac recipients (211 patients), 74.8% were fully recovered, and 99.5% had good outcomes (mRS 0–2). Only one patient had an mRS score of 3. This patient had clinical symptoms and laboratory data compatible with ISRR; the causes of the symptom recurrence and persistent high mRS score, which was inconsistent and likely to be functional deficits, are explored by a multidisciplinary team, including the psychiatrist. All 10 ChAdOX1 recipients had good outcomes (mRS 0–2). The mean BMI of participants with information on this variable (214 patients) was 24.67 kg/m2 (standard deviation, 4.78). None of the patients in this study had ISRR after both doses of vaccines.

Table 2

Clinical characteristic with respect to neurological symptoms stratified by the vaccine injection site.

	Left side injection	Right side injection	Unknown
	(n = 57)	(n = 4)	(n = 160)
Lateralization of symptoms
Left side	42	1	101
Right side	4	3	29
Bilateral	6	-	14
Unknown	2	-	7
Non-stroke-like	3	-	9
Sensory symptoms
Sensory (NA)	2	-	7
Sensory, left side	20	1	59
Sensory, right side	1	2	19
Sensory, bilateral	2	-	5
Motor symptoms
Motor (NA)	-	-	-
Motor, left	2	-	5
Motor, right	1	1	2
Motor, bilateral	1	-	5
Sensorimotor (SM) symptoms
SM (NA)	-	-	-
SM, left	20	-	37
SM, right	2	-	8
SM, bilateral	3	-	4

NA, not applicable

Discussion

Several well-recognized neurological complications are associated with many forms of vaccination, including Guillain-Barré syndrome and acute disseminated encephalomyelitis. The immunological mimicry can explain the effects of vaccine antigens on the relevant myelin protein. However, stroke has not been recognized as an AEFI.; there are several reports of non-epileptic seizure, abnormal movement [2] or motor/sensory symptoms like stroke [3] from COVID19 vaccination. Moreover, to the best of our knowledge, stroke-like syndromes occurring as clustered events have not been reported as adverse vaccine-associated events to date.

ISRR is considered an alternative term for functional neurological disorders (FND). FND were described thoroughly in a recent report [4]. Instead of representing structural damage to the central nervous system, FND arises due to disordered neurological function which is not explained or explainable by any other recognized neurological disorder. Symptoms and signs in these patients are real and nonvolitional (in contrast to what has been perceived in the past). These may be the typical responses of the body to the normal physiological processes occurring after immunization (i.e., pain or inflammation), and stress or fear of side effects may aggravate this symptomology. Well-characterized functional disorders in other systems include irritable bowel syndrome, vasovagal syncope, stress-associated dyspepsia, and stress-aggravated migraine headache [1].

A theory that may explain the occurrence of vaccine-associated stroke-like symptomology based on a mechanism involving complex regional pain syndrome and FND has been proposed in a prior report [5]. This review proposed that the peripheral inflammation or pain, in this case, after a vaccine injection, along with anxiety or excessive self-monitoring, intertwined with widespread central nervous system maladaptation. Such a physiologic response to acute pain is characterized by the redistribution of muscular activity, resulting in stiffening, limitation, and slow movement [6]. Normally temporary and under conscious control, this response may grow beyond conscious control and manifest as weakness. It was observed that most patients develop clinical symptoms of dysesthesia or numbness in the same limb as the immunization site. Further, the patients with stroke-like symptoms reported in our cohort had good prognoses; most patients recovered fully, and none had structural deficits.

Based on our findings, we encourage more comprehensive health education regarding this ISRR for both vaccine recipients and administering healthcare workers, who are responsible for effective clinical decision-making, meticulously monitoring patients’ health, and reassuring patients that their symptoms are transient responses and that they will recover. These adverse events should not impede vaccination campaigns, especially during the pandemic. Appropriate follow-up investigation is also essential so as not to miss structural neurological deficits as well as to provide appropriate investigation and treatment when necessary.

The ISRR clusters evaluated in our study were reported when the worldwide vaccine phobia wave initially emerged due to widespread and frequently inaccurate information regarding the side effects of vaccination, which was highly prevalent on social media at the time. Following the first stroke-like events cluster reported to the Thai Ministry of Public Health in April 2021, highlighted by social media, many subsequent clusters were reported from several provinces around the country [7]. Vaccine constituents were the suspected culprits at the start of the vaccine phobia wave. Many patients were diagnosed with stroke and received thrombolytic or antiplatelet therapy because the normal brain CT scan and the clinical presentations could not confidently exclude stroke. These events quickly spread by social media led to vaccine hesitancy due to false belief of vaccine toxicity, causing many people to decide not to be vaccinated.

Following the appropriate investigation and a confirmation of the occurrence of ISRR, preparedness and management strategies were introduced on a nationwide scale. The number of reported cases was thus reduced substantially.

The first case report of stroke-like symptomology occurring after CoronaVac vaccination reported to the Ministry of Public Health was proposed to be an acute prolonged motor aura [8]. However, most later patients did not develop headaches. We also recorded that these adverse events were likely to be lateralized to the side of the injection. Therefore, we propose that the underlying mechanisms for vaccine-associated ISSR may be of peripheral origin (e.g., pain following vaccination) and be integrated with an autonomic response (i.e., a response resembling a reflex sympathetic response, as in complex regional pain syndrome). Further, according to previous research, this symptomology may involve the central nervous system, as demonstrated by abnormalities in the postcentral gyrus and inferior parietal cortex, which are responsible for afferent information processing [9, 10]. This may explain the transient clinical weakness seen in some of our enrolled patients.

ISRR was previously perceived as psychogenic within the medical community. However, these symptoms are caused by functional physiologic changes rather than structural damage following the vaccination procedure. The same situation has been reported with many vaccines in the past [11-15]. Most of these were presented as non-epileptic seizures, fainting and dizziness mostly in the adolescent groups. In these reports, there were weaknesses in some cases, but no detailed pattern of weakness was recorded. In our report, all participants were adults (which may reflect the vaccination campaign firstly done in adults), and the pattern of weakness was similar to stroke (acute hemisensory deficit or hemiparesis). Most of our patients were female, which could be due to the initial target population of the nationwide vaccine campaign, which initially comprised HCWs who received preferential vaccination at the start of the vaccine campaign, most of whom were young females (e.g., nurses, therapists). Many underlying mechanisms have been proposed, including pain due to the vaccination process or inflammation occurring after vaccination, which may activate the peripheral nerves and the sympathetic nervous system, as explained in a previous description of the proposed complex regional pain syndrome mechanism [5].

Recently, two cases were reported wherein the patients developed a clinical level of stroke-like weakness after receiving an mRNA-based COVID-19 vaccine [3]. Another case report described hemiparesis on the same side at the injection site that lasted for 40 min. However, this patient developed hypoesthesia on the alternate side, and the neurological examination revealed midline splitting of the sensory deficit; this patient had normal brain CT and magnetic resonance imaging findings. The authors hypothesized that increased attention toward body signals and abnormal expectations regarding the symptoms of vaccination-induced injury might be responsible for this symptomology [16]. This report confirms that the process of incident vaccine-associated neurological disorders is more likely due to the vaccination process rather than specific vaccine constituents since these events have occurred within various vaccine platforms.

As COVID-19 mass vaccination has been widely implemented among high-risk populations with underlying diseases, we found that some confirmed stroke cases were simply temporally associated with vaccination within this study. This caveat provides precautionary information and informs the provision of appropriate, timely treatment (vs. empirically treating ISRR in the absence of differential diagnosis).

We acknowledge several limitations of this report. Specifically, this evaluation was based on a retrospective study within the secondary data, and we may have missed some critical information (especially with respect to outcome data). Moreover, we were unable to identify the factors associated with ISRR in this descriptive study and instead presented a descriptive evaluation only. Future studies should comprehensively evaluate risk factors and causality using multivariate modeling and a prospective design.

Conclusions

To the best of our knowledge, our study reports the largest series regarding ISRR associated with neurological symptoms identified to date. Stroke-like symptoms are more likely to occur on the left side. During the vaccination campaign, the non-dominant arm was encouraged for the side of vaccination. However, that the symptoms occurred on the same side of the injection was not ascertained as most cases had no record of the injection side in the medical record. We hypothesized that as most people are right-handed; thus most injections would mostly be on the left side and that the painful stimuli from the injection triggered and exaggerated self-attention. These would be the main mechanisms mediating the development of this transient symptom. A high degree of awareness concerning this symptomology is important to avoid over-investigation, which could result in unnecessary costs and complications. It is important to provide effective and comprehensive education regarding these events to the public as well as to the administering HCWs. These occurrences are real but transient and almost invariably present with excellent recovery prospects. This information and more comprehensive information obtained in future studies may reduce vaccine hesitancy and help ensure a successful nationwide vaccination program and inform interventions on a global scale.

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12 Jun 2022

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Reviewer #1: Thank you for the opportunity to review this paper. It is a retrospective case notes review of patients who were diagnosed with stroke-like illnesses following COVID-19 vaccination. In my opinion this is an important topic and the authors have summarised perhaps the largest data on this topic so far (at least that I am aware of) and should be commended for that. Nevertheless I have several suggestions for improvement.

Introduction

I think the introduction was okay but there was only a single reference.

I think the introduction could have included some discussion of previous data from the COVID-19 pandemic and beyond which have indicated the possibility of (functional) neurological symptoms post vaccination (for references please see Table 2 in the following: https://jnnp.bmj.com/content/jnnp/92/11/1144.full.pdf).

I think the language needs tightening up in places to make it more precise, for example 'However, the relevant vaccine types were investigated and no problems were found' is very imprecise. What does 'no problems' mean.

The authors do elaborate on this in the Discussion but I think the introduction would also benefit from some information on what ISRRs are (as we argue in our previous piece, we feel that many ISRRs are better seen as functional neurological disorders: https://neuro.psychiatryonline.org/doi/full/10.1176/appi.neuropsych.21050116)

Methods

The methods need to be clarified in some parts in my opinion. I didn't get a good sense of how the authors accessed the AEFI reports. My guess is that they are employed by the institution which manages the AEFI reports, but this is not clear.

Related to this, I think the reader should be given a sense of when and how a clinician might submit an AEFI report. I would also like to be given a better sense of the information that allowed the authors to conclude this was ISRR/FND - were the patients examined and found to have positive clinical signs, etc?

Results

'This patient had clinical symptoms and laboratory data compatible with ISRR; the causes of this adverse event are currently being explored by a multidisciplinary team.' - if the clinical picture is consistent with ISRR, why is the team currently investigating?

I don't think it's a particular issue, but it's a bit unclear what BMI has to do with anything.

Discussion

I think the discussion makes some good points but needs significant work. The structure is not always logical and the authors don't make enough attempts to situate their findings within the extant literature.

As with the introduction, the discussion is poorly referenced. The authors make several assertive points in the first paragraph without a single reference. There are frequent other areas of the discussion which are lacking in references.

I think the sentence 'stroke-like syndromes occurring as clustered events have not been reported as adverse vaccine-associated events to date' is possibly true, however there have been several published reports of neurological symptoms following vaccinations which were diagnosed as FND/mass psychogenic illness which probably warrant mention (see references above).

I don't think the sentence 'ISRR is considered an alternative term for conversion disorder and/or dissociative neurological symptomology' is empirically true in terms of what the WHO believe (although I am in agreement with the authors if that is representative of their own opinion). As well as this, the notion of 'conversion disorder' is a bit outdated, with patients (at least in the UK and US) preferring functional neurological disorder, which is more aetiologically neutral.

'FND are not malingering and are rather neurological deficits that are not caused by structural lesions and are instead characterized by changes in the functionality of neurons and glia as well as physiologic changes occurring in specific brain regions.' - this sentence is pretty wordy but doesn't say very much - I'd recommend something like 'Instead of representing structural damage to the central nervous system, FND arises due to disordered neurological function which is not explained or explainable by any other recognised neurological disorder.'

I am intrigued by your suggestion that there may be likes between ISRR and CRPS however was slightly disappointed that this wasn't elaborated on in any meaningful way. What is the mechanism you allude to?

'reassuring patients that their symptoms are normal responses' - I get what the authors are saying and agree with the broad thrust, but it's a bit of a stretch in my opinion to suggest these are 'normal' responses.

'miss real structural neurological' - I'd remove 'real' here - it implies that ISRR/FND is not real.

'In Thailand, case clustering has been reported throughout the country' - what does this mean? Where is the reference?

'Moreover, many patients were diagnosed with stroke and received unnecessary thrombolytic or antiplatelet therapy despite normal findings on brain CT and/or MRI' - I get what the authors are saying here, and certainly agree with the idea that we should not be unnecessarily treating FND as stroke - but the presence of a normal CT in the acute phase does not mean that an ischaemic stroke is not presence and is therefore does not necessarily mean thrombolysis is inappropriate. FND should be diagnosed and distinguished from stroke in other ways, for example via positive clinical signs.

'These and similar effects and phenomena severely impede the efficacy and reach of vaccination campaigns.' How? Why?

'WHO consultation and preparedness guidance were also extremely helpful in facilitating this process' - again this is quite informal and imprecise.

The paragraph which begins at 221 is very long and seems to deal with multiple points within the same paragraph. I am also questioning the need to elaborate so much on the case report.

'However, in our study, most patients did not develop headaches' - so what does this mean?

'ISRR was initially perceived as psychogenic within the medical community. However, these symptoms are real and not iatrogenic.' - I don't like the term psychogenic but it is not mutually exclusive with 'real' and therefore I think these sentences need to be reworded. I also disagree that they are not iatrogenic - they arise, by definition, from the medical procedure of vaccination.

We finally get to discussion of other clusters of post-vaccination neurological symptoms from the literature in line 238, however there is very limited discussion/comparison.

The paragraph from 243 - 247 could be removed without altering the usefulness of the discussion.

'The reported data regarding female predominance could be due to the initial target population of the nationwide vaccine campaign, which initially comprised HCWs who received preferential vaccination at the start of the vaccine campaign, most of whom were young females (e.g., nurses, therapists).' - this is not a limitation.

'will undoubtedly reduce vaccine hesitancy' - are you sure it will undoubtedly do so?

Kind regards,

Dr Matt Butler

Reviewer #2: The authors present descriptive results of individuals in Thailand reporting stress-related responses after either the CoronaVac or ChAdOx1 COVID-19 vaccines during a 5 month period. Authors find most symptoms were sensory and reported on the left side of the body. Most of the individuals recovered well. The manuscript will be strengthened if the authors consider the following points.

1. In the Abstract, authors should make clear that this study takes place in Thailand. They should also mention the two vaccines under consideration in the Methods section of the Abstract.

2. lines 127-28: Authors state they performed chi-square tests comparing between the vaccine types, but none of these results are provided. Also, given the small numbers in the ChAdOx1 vaccine group, Fisher's exact test may be more appropriate if they do in fact compare the groups.

3. line 128: it is not clear why BMI was compared to a theoretical mean of 25 and what the goal of this one-sided test is.

4. line 146: what data were missing to remove 42 patients from those reported to have ISRR?

5. Were there any individuals who had ISRR after both doses of the vaccine in this study? Authors should clarify this.

6. How is the median time to recovery calculated if not everyone fully recovered (authors state in line 165 that only 74.8% of those receiving the CoronaVac vaccine fully recovered).

7. lines 171-172: this is where it looks like authors present results from the one-sample t-test (point 3 above), but the interpretation that ISRR is not associated with being overweight or obese is not accurate based on this test. The t-test will test whether the mean BMI differs from 25. If the null hypothesis is not rejected (p>0.05), as in this case, all one can say is that BMI is not significantly different from 25. This is not a test of whether ISRR is associated with being overweight or obese.

Minor points.

1. lines 58 and 155: the upper bound of the IQR (42) for age of onset for those receiving the CoronaVac does not match what is stated in Table 1 (40).

2. line 61: it is not clear how the percentage for those developing symptoms on the left side was calculated (53.8%) since Table 2 has 144 individuals with symptoms on the left side (144/221 is not 53.8% nor is 144/209).

3. line 63: authors report 90% of those receiving ChAdOx1 recovered well, but they later report (line 169) that all ChAdOx1 recipients had good outcomes; both "recovered well" and "good outcomes" are defined in the same way. This inconsistency should be fixed or clarified.

4. line 136: authors should clarify that there were other vaccines available to people, since the sum of the doses of CoronaVac and ChAdOx1 is about 1 million less than the total number of doses administered stated in line 135.

5. Authors should be consistent in how they write ChAdOx1, since sometimes it is written as ChAdOX1.

6. line 162: authors say that the left side of the body was the injection side, but according to Table 1, only 57/221 were known to have the injection on the left side.

7. line 163: authors say that 50 patients had the injection side known, but Table 1 has 61 with known injection side. Authors should correct that and any related percentages in the text.

8. line 164: change "characteristic" to "characteristics"

9. lines 275-276: authors say stroke-like symptoms are more likely to occur on the same side as the injection, but this is not supported by the data, since the majority of participants have unknown side of injection.

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16 Jul 2022

Dear Editor

We would like to thank the Editor and Reviewers for their valuable time and feedback on our manuscript and appreciate the opportunity to submit the revised manuscript. We would like to respond to reviewers’ comments point-by-point as following:

Reviewer 1

1. Comment:

Introduction

I think the introduction was okay but there was only a single reference.

I think the introduction could have included some discussion of previous data from the COVID-19 pandemic and beyond which have indicated the possibility of (functional) neurological symptoms post vaccination (for references please see Table 2 in the following: https://jnnp.bmj.com/content/jnnp/92/11/1144.full.pdf).

Response: We have added the references in the introduction as suggested. (line 77-84)

Kim DD, Kung CS, Perez DL. Helping the Public Understand Adverse Events Associated With COVID-19 Vaccinations: Lessons Learned From Functional Neurological Disorder. JAMA Neurol. 2021;78(7):789-90.

Butler M, Coebergh J, Safavi F, Carson A, Hallett M, Michael B, et al. Functional Neurological Disorder After SARS-CoV-2 Vaccines: Two Case Reports and Discussion of Potential Public Health Implications. J Neuropsychiatry Clin Neurosci.33(4):345-8.

2. Comment:

I think the language needs tightening up in places to make it more precise, for example 'However, the relevant vaccine types were investigated and no problems were found' is very imprecise. What does 'no problems' mean.

Response: We revised the sentence to: “However, the relevant vaccine types were investigated and found within regulated quality without identifiable toxins or contamination.” (line 98-100).

3. Comment:

The authors do elaborate on this in the Discussion but I think the introduction would also benefit from some information on what ISRRs are (as we argue in our previous piece, we feel that many ISRRs are better seen as functional neurological disorders: https://neuro.psychiatryonline.org/doi/full/10.1176/appi.neuropsych.21050116)

Response: We added the following sentences to provide some information of ISRR in the first paragraph of Introduction: “These events are not caused by side effects due to vaccine components. Instead, they arise from the stress reaction to the vaccination process/cascade, which could be precipitated or potentiated by the pain or other common side effects of the injections. The symptoms may develop immediately (within 5 minutes) following vaccination, such as vasovagal reaction, or later, such as non-epileptic seizures, abnormal movements after COVID-19 vaccination [2] or motor and sensory symptoms which demonstrate positive neurological signs (Hoover’s sign) which were diagnosed of functional neurological disorders [3]” (line 77-84)

4. Comment:

Methods The methods need to be clarified in some parts in my opinion. I didn't get a good sense of how the authors accessed the AEFI reports. My guess is that they are employed by the institution which manages the AEFI reports, but this is not clear.

Response: We have clarified this in the second paragraph of Method line 120-122 as following “We conducted a retrospective study using the data received from the National AEFI surveillance program (AEFI-DDC) and the copy of the medical records of the cases that were determined to be ISRR by the AEFI committee.”

5. Comment:

Related to this, I think the reader should be given a sense of when and how a clinician might submit an AEFI report. I would also like to be given a better sense of the information that allowed the authors to conclude this was ISRR/FND - were the patients examined and found to have positive clinical signs, etc?

Response: We clarified this in the first paragraph of Methods line 107-113 as following: “The AEFI report system for the routine vaccine in the National Immunization Program (NIP) has been established in every public hospital for over twenty years. The dedicated hospital staff reports any serious AE or AE of special interest or AE that occurred in the cluster through the national AEFI surveillance program (AEFI-DDC) hosted by the Department of Disease Control, Ministry of Public Health. A medical record and imaging scan copy would be submitted for systematic review by the AEFI committee.”

The diagnosis of ISRR were further clarified in line 116-119 as following: “The primary physicians may primarily diagnose ISRR; however, all were confirmed by the AEFI committee composed of neurologists, internists, pediatricians, cardiologists, hematologists, and allergists. In some cases of doubt, the committee would seek further external expert neurologist consultation.”

6. Comment:

Results

'This patient had clinical symptoms and laboratory data compatible with ISRR; the causes of this adverse event are currently being explored by a multidisciplinary team.' - if the clinical picture is consistent with ISRR, why is the team currently investigating?

Response: This case is the very first case of ISRR in a large cluster and received high attention by the social medias at that time. She recovered from the symptoms of ISRR but then had recurrent of the same symptoms without receiving any further vaccination, and still had mRS score of 3 in the last follow-up. The psychiatric problem was suspected. We added more details in the sentence line 186-189 as following: “the causes of the symptom recurrence and persistent high mRS score, which was inconsistency and likely to be functional deficits, are explored by a multidisciplinary team, including the psychiatrist.”

7. Comment: I don't think it's a particular issue, but it's a bit unclear what BMI has to do with anything.

Response: Low BMI is known to associate with higher risk of vasovagal reaction and could have higher risk of ISRR. Therefore, we included the information of BMI in our report.

Reference: Yamada T, Yanagimoto S: Dose-Response Relationship between the Risk of Vasovagal Syncope and Body Mass Index or Systolic Blood Pressure in Young Adults Undergoing Blood Tests. Neuroepidemiology 2017;49:31-33. doi: 10.1159/000479698

8. Comment: Discussion

I think the discussion makes some good points but needs significant work. The structure is not always logical and the authors don't make enough attempts to situate their findings within the extant literature.

As with the introduction, the discussion is poorly referenced. The authors make several assertive points in the first paragraph without a single reference. There are frequent other areas of the discussion which are lacking in references.

I think the sentence 'stroke-like syndromes occurring as clustered events have not been reported as adverse vaccine-associated events to date' is possibly true, however there have been several published reports of neurological symptoms following vaccinations which were diagnosed as FND/mass psychogenic illness which probably warrant mention (see references above).

Response: We revised the Discussion and have added the appropriate references as suggested. (line 201-205)

9. Comment:

I don't think the sentence 'ISRR is considered an alternative term for conversion disorder and/or dissociative neurological symptomology' is empirically true in terms of what the WHO believe (although I am in agreement with the authors if that is representative of their own opinion). As well as this, the notion of 'conversion disorder' is a bit outdated, with patients (at least in the UK and US) preferring functional neurological disorder, which is more aetiologically neutral.

Response: We replaced “conversion disorder” to “functional neurological disorder” in Line 206

10. Comment:

'FND are not malingering and are rather neurological deficits that are not caused by structural lesions and are instead characterized by changes in the functionality of neurons and glia as well as physiologic changes occurring in specific brain regions.' - this sentence is pretty wordy but doesn't say very much - I'd recommend something like 'Instead of representing structural damage to the central nervous system, FND arises due to disordered neurological function which is not explained or explainable by any other recognized neurological disorder.'

Response: We revised the sentence as suggested. (line 207-209)

11. Comment: I am intrigued by your suggestion that there may be likes between ISRR and CRPS however was slightly disappointed that this wasn't elaborated on in any meaningful way. What is the mechanism you allude to?

Response: We have explained the mechanism of CRPS and FND (ISRR) with reference in the line 218-223.

12. Comment: 'reassuring patients that their symptoms are normal responses' - I get what the authors are saying and agree with the broad thrust, but it's a bit of a stretch in my opinion to suggest these are 'normal' responses.

Response: We have changed “normal response” to “transient responses” which will be more precise. (line 231)

13. Comment: 'miss real structural neurological' - I'd remove 'real' here - it implies that ISRR/FND is not real.

Response: We removed “real” as you suggested. (line 233-234)

14. Comment: 'In Thailand, case clustering has been reported throughout the country' - what does this mean? Where is the reference?

Response:. We revised the sentence to: “Following the first stroke-like events cluster reported to the Thai Ministry of Public Health in April 2021, highlighted by social media, many subsequent clusters were reported from several provinces around the country [7].” (Line 239-241)

15 Comment: 'Moreover, many patients were diagnosed with stroke and received unnecessary thrombolytic or antiplatelet therapy despite normal findings on brain CT and/or MRI' - I get what the authors are saying here, and certainly agree with the idea that we should not be unnecessarily treating FND as stroke - but the presence of a normal CT in the acute phase does not mean that an ischaemic stroke is not presence and is therefore does not necessarily mean thrombolysis is inappropriate. FND should be diagnosed and distinguished from stroke in other ways, for example via positive clinical signs.

Response: We agree with the reviewer comment. We revised the sentences to: “Many patients were diagnosed with stroke and received thrombolytic or antiplatelet therapy because the normal brain CT scan and the clinical presentations could not confidently exclude stroke.” (line 242-244)

16. Comment:

'These and similar effects and phenomena severely impede the efficacy and reach of vaccination campaigns.' How? Why?

Response: We have clarified more on this sentence as “These events quickly spread by social media led to vaccine hesitancy due to false belief of vaccine toxicity, causing many people to decide not to be vaccinated.” (line 244-246)

17. Comment: 'WHO consultation and preparedness guidance were also extremely helpful in facilitating this process' - again this is quite informal and imprecise.

Response: We deleted this sentence.

18. Comment: The paragraph which begins at 221 is very long and seems to deal with multiple points within the same paragraph. I am also questioning the need to elaborate so much on the case report.

'However, in our study, most patients did not develop headaches' - so what does this mean?

Response: We agree with the reviewer. We have shortened this paragraph. We revised the first sentence of this paragraph to: “The first case report of stroke-like symptomology occurring after CoronaVac vaccination reported to the Ministry of Public Health was proposed to be an acute prolonged motor aura [8]. However, most later patients did not develop headaches.” (line 250-252)

19. Comment: 'ISRR was initially perceived as psychogenic within the medical community. However, these symptoms are real and not iatrogenic.' - I don't like the term psychogenic but it is not mutually exclusive with 'real' and therefore I think these sentences need to be reworded. I also disagree that they are not iatrogenic - they arise, by definition, from the medical procedure of vaccination.

Response: We agree with the reviewer and revised the sentence to: “ISRR was previously perceived as psychogenic within the medical community. However, these symptoms are caused by functional physiologic changes rather than structural damage following the vaccination procedure.” (line 261-263)

20. Comment: We finally get to discussion of other clusters of post-vaccination neurological symptoms from the literature in line 238, however there is very limited discussion/comparison.

Response: We have added more references and discussion. (line 263-266)

21. Comment: The paragraph from 243 - 247 could be removed without altering the usefulness of the discussion.

Response: We have removed this paragraph as suggested.

22. Comment: 'The reported data regarding female predominance could be due to the initial target population of the nationwide vaccine campaign, which initially comprised HCWs who received preferential vaccination at the start of the vaccine campaign, most of whom were young females (e.g., nurses, therapists).' - this is not a limitation.

Response: We moved these statements to line 268-272, not limitation.

23. Comment: 'will undoubtedly reduce vaccine hesitancy' - are you sure it will undoubtedly do so?

Response: We have revised to “may reduce vaccine hesitancy”, line 313-314

Reviewer #2: The authors present descriptive results of individuals in Thailand reporting stress-related responses after either the CoronaVac or ChAdOx1 COVID-19 vaccines during a 5 month period. Authors find most symptoms were sensory and reported on the left side of the body. Most of the individuals recovered well. The manuscript will be strengthened if the authors consider the following points.

1. In the Abstract, authors should make clear that this study takes place in Thailand. They should also mention the two vaccines under consideration in the Methods section of the Abstract.

Response: We have add “in Thailand” as you suggested (line 46) and also mention the two vaccines in Methods section. (line 48).

2. lines 127-28: Authors state they performed chi-square tests comparing between the vaccine types, but none of these results are provided. Also, given the small numbers in the ChAdOx1 vaccine group, Fisher's exact test may be more appropriate if they do in fact compare the groups.

Response: As we have no data using Chi-square nor Fisher’s exact test, so we removed this sentence.

3. line 128: it is not clear why BMI was compared to a theoretical mean of 25 and what the goal of this one-sided test is.

Response: The low BMI is associated with higher risk of vasovagal reaction and could have higher risk of ISRR. But we agree that this cannot be compared to the theoretical mean of 25 so we deleted this statistical test and the descriptive data of mean BMI was remained.

4. line 146: what data were missing to remove 42 patients from those reported to have ISRR?

Response: The 42 patients were removed from the analysis due to lack of important information as following: time from vaccination to neurological symptoms onset 14 cases), time to recovery (42 case), age (29 cases), follow-up functional status (42 cases).

5. Were there any individuals who had ISRR after both doses of the vaccine in this study? Authors should clarify this.

Response: None of patients developed ISRR after both doses of vaccination. Most of the patients did not receive the same vaccine in the subsequent dose, and some refused to get the second dose of any vaccine. We have added this sentence in line 191.

6. How is the median time to recovery calculated if not everyone fully recovered (authors state in line 165 that only 74.8% of those receiving the CoronaVac vaccine fully recovered).

Response: We calculated using the most recent follow up dated as available in the medical records or July 31st, 2021, which ever was reached first.

7. lines 171-172: this is where it looks like authors present results from the one-sample t-test (point 3 above), but the interpretation that ISRR is not associated with being overweight or obese is not accurate based on this test. The t-test will test whether the mean BMI differs from 25. If the null hypothesis is not rejected (p>0.05), as in this case, all one can say is that BMI is not significantly different from 25. This is not a test of whether ISRR is associated with being overweight or obese.

Response: We presented only the descriptive analysis of BMI, and deleted the sentence that indicated the association.

Minor points.

1. lines 58 and 155: the upper bound of the IQR (42) for age of onset for those receiving the CoronaVac does not match what is stated in Table 1 (40).

Response: We corrected the data in Table 1.

2. line 61: it is not clear how the percentage for those developing symptoms on the left side was calculated (53.8%) since Table 2 has 144 individuals with symptoms on the left side (144/221 is not 53.8% nor is 144/209).

Response: We have corrected the error to 68.9% (line 64).

3. line 63: authors report 90% of those receiving ChAdOx1 recovered well, but they later report (line 169) that all ChAdOx1 recipients had good outcomes; both "recovered well" and "good outcomes" are defined in the same way. This inconsistency should be fixed or clarified.

Response: We revised the wording to be “all had good outcome” consistently (line 65-66 and 189).

4. line 136: authors should clarify that there were other vaccines available to people, since the sum of the doses of CoronaVac and ChAdOx1 is about 1 million less than the total number of doses administered stated in line 135.

Response: We have added the information of other vaccine (BBIBP-CorV) in line 154.

5. Authors should be consistent in how they write ChAdOx1, since sometimes it is written as ChAdOX1.

Response: We corrected all the typo errors (line 156).

6. line 162: authors say that the left side of the body was the injection side, but according to Table 1, only 57/221 were known to have the injection on the left side.

Response: We revised by deleting “injection side” (line 179).

7. line 163: authors say that 50 patients had the injection side known, but Table 1 has 61 with known injection side. Authors should correct that and any related percentages in the text.

Response: The data in the Table is correct. We revised the number in the line 181-182.

8. line 164: change "characteristic" to "characteristics"

Response: We corrected the error (line 183).

9. lines 275-276: authors say stroke-like symptoms are more likely to occur on the same side as the injection, but this is not supported by the data, since the majority of participants have unknown side of injection.

Response: We have clarified more on the line 301-308 as “Stroke-like symptoms are more likely to occur on the left side. During the vaccination campaign, the non-dominant arm was encouraged for the side of vaccination. However, that the symptoms occurred on the same side of the injection was not ascertained as most cases had no record of the injection side in the medical record. We hypothesized that as most people are right-handed; thus most injections would mostly be on the left side and that the painful stimuli from the injection triggered and exaggerated self-attention. These would be the main mechanisms mediating the development of this transient symptom.”

Sincerely,

Metha Apiwattanakul, MD

Corresponding Author

Submitted filename: Final response to reviewer .docx

Click here for additional data file.

9 Aug 2022

Good recovery of immunization stress-related responses presenting as a cluster of stroke-like events following CoronaVac and ChAdOx1 vaccinations

PONE-D-22-07310R1

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Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

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16 Aug 2022

PONE-D-22-07310R1

Good recovery of immunization stress-related responses presenting as a cluster of stroke-like events following CoronaVac and ChAdOx1 vaccinations

Dear Dr. Apiwattanakul:

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