We read with interest the article by Nigatu et al. about a 70 years old male who developed quadruparesis and respiratory failure requiring intubation and mechanical ventilation one week after onset of mild COVID-19 [1]. The patient was tested positive for SARS-CoV-2 and diagnosed with Guillain-Barre syndrome (GBS) based upon the clinical presentation, nerve conduction studies (NCSs) and cerebrospinal fluid (CSF) investigations [1]. The patient was treated with glucocorticoids and achieved an incomplete recovery at the last follow-up three weeks after admission [1]. It was concluded that early identification and management of SARS-CoV-2 associated GBS (SC2aG) can improve the clinical outcome and that screening for SARS-CoV-2 in patients presenting with GBS is warranted. The study is appealing but raises concerns that need to be discussed.

We disagree with the notion that since the outbreak of the SARS-CoV-2 pandemic “some case reports of COVID-19 associated GBS” have been published [1]. As per the end of December 2020, at least 220 patients with SARS-CoV-2 associated GBS (SC2aG) have been reported [2]. As per the end of 2021 at least 400 patients with SC2aG have been published (Finsterer, submitted).

The patient was diagnosed with GBS subtype acute, motor and sensory, axonal neuropathy (AMSAN) [1]. However, distal latencies were prolonged, nerve conduction velocities reduced, particularly in the lower limbs, and F-wave latencies were prolonged, suggesting demyelination. We should be told why the patient was diagnosed with AMSAN and not with acute, inflammatory, demyelinating, polyneuropathy (AIDP) or mixed axonal and demyelinating polyneuropathy. 

Since AMSAN can be associated with autonomic dysfunction due to affection of the peripheral autonomic nervous system (ANS), we should know if the index patient manifested with involvement of the ANS. Even AMSAN patients with severe pulmonary hypertension have been reported [3].

The patient had elevated liver transaminases, which were attributed involvement of the liver in COVID-19 [1]. However, the patient also had received antibiotics [1]. We should be told when liver function parameters normalised again and if transaminases normalised with discontinuation of the antibiotics. Since COVID-19 can be complicated by autoimmune hepatitis [4], we should know how immune hepatitis was excluded as the cause of liver transaminases.

We read with interest the article by Rastogi et al. about a 59yo female who experienced gait disturbance, incoordination, dizziness, diplopia, perioral paresthesias, right hand numbness, and lethargy 12 days after the second dose of a SARS-CoV-2 vaccine (Moderna) [1]. She had received the first dose (Astra Zeneca) three months earlier with no side effects [1]. Cerebral MRI showed numerous enhancing lesions in the cortex, deep grey matter, brainstem, and cerebellum [1]. No treatment was applied and the lesions resolved spontaneously almost completely within 10 days [1]. The study is valuable but raises concerns that warrant discussion.

We disagree with the term “binocular diplopia” [1]. There is no such thing as mono-ocular diplopia, so this term should be replaced.

There is a discrepancy between the patient’s initial description of symptoms including “lethargy” and the description on clinical examination that there was no change in personality or behaviour [1]. Lethargy is a change in behaviour.

The blood sedimentation rate and the determination of anti-nuclear antibodies (ANA) and anti-neutrophil cytoplasmic antibodies (ANCA) are missing. Cerebral vasculitis should have been ruled out, as it has previously been described as a complication of SARS-CoV-2 vaccinations [2]. There is no magnetic resonance angiography (MRA) or black blood sequences to document abnormalities of the cerebral arteries. 

There is no electroencephalography (EEG). The patient was described as having lethargy. An EEG should have been performed to rule out a non-convulsive status epilepticus.

How was acute, disseminated encephalomyelitis (ADEM) ruled out? ADEM has been reported as a side effect of SARS-CoV-2 vaccination [3] and is associated with spinal cord lesions but spinal MRI has not been performed. 

Has the gait disturbance been attributed to involvement of the cerebellum or is a spinal cord lesion conceivable? 

There is no determination of the CSF for cytokines and chemokines which have been shown to be upregulated in patients with CNS lesions after SARS-CoV-2 infection [4]. 

There is no determination of the CSF for the entire panel of autoantibodies associated with immune encephalitis and the determination of anti-ganglioside antibodies.

There is no explanation of the increased CSF glucose which should tell us if the patient was a diabetic or not.

SARS-CoV-2 vaccinations can be complicated by hypercoagulability and a propensity for thrombosis [5]. We should be told if the D-dimer and other blood coagulation parameters were normal and how venous sinus thrombosis (VST) had been excluded.

Disruption of the blood brain barrier could be an explanation for the described lesion, but is not supported by published data.

It is not clear why the patient received no treatment. Particularly, it remains unclear why no steroids were given. Most side effects of SARS-CoV-2 vaccinations are immune-mediated, which is why it is crucial to at least try steroids or intravenous immunoglobulins (IVIG) and see if they have a positive effect.

Overall, the interesting study has limitations and inconsistencies that call the results and their interpretation into question. Clarifying these weaknesses would strengthen the conclusions and could add value to the study. Emerging enhancing cerebral lesions after a SARS-CoV-2 vaccination require a comprehensive work-up to elucidate the underlying pathophysiology.

Background: Present study aimed to evaluate the Blood eosinophil count and CT score among Patients suffering from Sinonasal Polyposis attending routine ENT OPD in Dr. RPGMC Tanda. Material and Methods: The present study was done as a hospital based cross sectional study in the department of ENT and Head and Neck Surgery, in Dr. RPGMC Kangra at Tanda. It was done in 30 patients of chronic rhinosinusitis with nasal polyposis (CRSwNP) from June 2018 to June 2019 who met the inclusion criteria. Data regarding Blood eosinophil count and CT score was retrieved. Results: There were a total of 30 patients out of which there were 16 males and 14 females. The mean age observed of patients was 42.47±13.68. Among the total, 17 were classified as Eosinophilic Chronic Rhinosinusitis with Nasal Polyposis (ECRSwNP) while 13 were classified as Non-Eosinophilic Chronic Rhinosinusitis with Nasal Polyposis (NECRSwNP). Absolute Blood eosinophil count observed in the patients of NECRSwNP was 181.3±89.61 and in ECRSwNP was 653.81±189.22. Lund Mackay CT score observed was more than double in ECRSwNP (18.18±4.69) as compared to NECRSwNP (8.38±4.05). There was statistically significant association between blood eosinophil count and CT score with p value of <0.0001. Conclusion: Blood eosinophil count and CT score was significantly more in ECRSwNP as compared to NECRSwNP also there was statistically significant association between blood eosinophil count and CT score.

Background: Present study aimed to evaluate the socio-demographic and clinical profile of patients suffering from Sinonasal Polyposis attending routine ENT OPD in Dr. RPGMC Tanda. Material and Methods: The present study was done as a hospital based cross sectional study in the department of ENT & Head and Neck Surgery, in Dr. RPGMC Kangra at Tanda. It was done in 30 patients of chronic rhinosinusitis with nasal polyposis from June 2018 to June 2019 who met the inclusion criteria. Data regarding Socio-demographic & Clinical characteristics was retrieved. Results: There were a total of 30 patients out of which there were 16 males and 14 females. The mean age observed of patients was 42.47±13.68. The most common presenting complaints were nasal obstruction (100%) followed by rhinorrhoea (70%) and excessive sneezing (56.67%). Most of the patients 70% (n = 21) had symptoms for more than 12 months followed by 20% patients (n = 6) with symptoms for duration less than 6 months. In the study both anti histamine and intra nasal steroids use was in 18 patients while only anti histamine and intra nasal steroids use was in 8 and 2 patients respectively. Maximum of patients (n = 18) enrolled had involvement of all sinuses (60%). The most common single sinus involved was maxillary sinus in 10 (33.3%) cases and maxillary and ethmoid sinuses were involved in 2 (6.6%) patients. Conclusion: Most of the patients suffering from Sinonasal Polyposis were males, presenting with complaints of patients were nasal obstruction, rhinorrhoea and excessive sneezing, had symptoms for more than 12 months, had premedication history of anti-histamine and intra nasal steroids use and had involvement of was maxillary sinus.

Former Soviet Union countries, and specifically Ukraine, are a frequent geographic area for children adopted abroad by Spanish families. The objective of this study was to describe the epidemiological characteristics and the health outcomes on arrival and long-term in children adopted from Ukraine. Material & Methods: Longitudinal observational study on 29 adopted Ukrainian children in Spain from 2002 to 2011, examined according to a standardized protocol at a specialized referral center. The pre-adoption history and the clinical, anthropometric, and laboratory post-adoption records were reviewed. Results: All children (females, 55.2%) were adopted from orphanages. 58.6% were terminated of parental rights for abuse/neglect, and 41.4% abandoned at birth. 17.2% were alcohol-exposed, 44.8% preterm birth, and 51.7% low birth weight. The mean age at orphanage entry was 15.9 months, and 42.2 months at adoption. The most frequent health problems on arrival were neurodevelopmental delays (51.7%), short stature (48.3%), self-regulation difficulties (34.5%), underweight (31%), and iron deficiency (27.6%). Twenty (69%) children had more than one health problem. 93% of children recovered their health problems five years after adoption. The most frequent health problems on long-term follow-up were externalizing behavior problems, especially in females. One female showed central precocious puberty, and one male was diagnosed with fetal alcohol syndrome. Conclusion: Most of health problems observed on arrival and long-term in adopted children from Ukraine were common conditions described in previous studies among internationally adopted children from the former Soviet Union countries. International adoption proved to be successful as a means of protecting children's well-being and physical, maturational, and emotional development.

We read with interest the article by Öncül et al. about 16 pediatric patients with suspected mitochondrial disorder (MID) undergoing next generation sequencing for mtDNA variants [1]. Thirteen patients underwent mtDNA sequencing, 2 patients whole exome sequencing (WES), and 1 patient whole genome sequencing (WGS) [1]. Seven variants were found in protein-coding genes, 4 in tRNA genes, and 1 in an rRNA gene [1]. Only two variants were classified as pathogenic, three as likely pathogenic, and 7 seven as variants of unknown significance(VUS) [1]. The study is appealing but raises concerns that require discussion. 

A limitation of the study is that the pathogenicity of new mtDNA variants was assessed by in silico bioinformatic methods using the Protter and Phyre2 programs but not by functional tests. Pathogenicity of mtDNA tRNA variants is commonly assessed by application of the Yarham score relying on the number of independent reports, presence of heteroplasmy, segregation of the disease with the variant, biochemical investigations, segregation of the variant with biochemical investigations in single fiber studies, pathogenicity on trans-mitochondrial cybrid studies, normality on trans-mitochondrial cybrid studies, and the evolutionary conservation of the variant [2]. 

A further limitation is that only eight mothers were tested for mtDNA variants and that heteroplasmy rates were provided for none of these mothers tested for their offspring’s tDNA variant [1]. As heteroplasmy rates in inherited MIDs may increase in subsequent generations, it is crucial to know them for both mothers and their offspring. 

Patients 4 and 5 were negative for mtDNA variants despite suspicion of a MID. However, in the method section it is mentioned that the included patients did not have any other genetic disorders. How were other genetic disorders excluded in the two patients negative for mtDNA variants? We should know if these two patients carried mutations in nuclearly encoded genes involved in mtDNA maintenance or other mitochondrial functions.

Missing is the information how many of the 16 patients had consanguineous parents. This information is crucial as MIDs occur more frequently in offspring of consanguineous parents [3] and as consanguinity is more frequent in Turkey as compared to some other countries with a frequency of 24% [4].

We do not agree with the conclusion that patients with Leigh syndrome should be first investigated by mtDNA sequencing [1]. Since Leigh syndrome is predominantly caused by mutations in genes located on the nuclear DNA [5]. WES should be preferred. Only in patients with a maternal trait of inheritance or patients with non-informative WES, maternally inherited Leigh syndrome (MILS) should be excluded or confirmed by mtDNA sequencing.

Four patients had a visual disorder [1]. We should be told which type of visual problem was found by which means. How to explain that patients 1 and 16 had cataract surgery but now visual disorder? This discrepancy should be solved.

The term “low congenital myopathy” in table 1 is unclear [1]. We should know if the patient with suspected MID was lastly diagnosed with congenital myopathy. 

Overall, the interesting study has several limitations which challenge the results and their interpretation. Addressing these limitations may upvalue the conclusions.

Declarations

• The authors declare no conflicts of interest

• No funding was received

• Author contribution: JF: design, literature search, discussion, first draft, critical comments, FS: literature search, discussion, critical comments, final approval

• Informed consent: not applicable

• The study was approved by the institutional review board
   

We read with interest the article by Nagalli et al. about a 49 years-old female who developed lower limb weakness 10 days after the first dose of the mRNA-1274 (Moderna) anti-SARS-CoV-2 vaccine [1]. Muscle weakness progressed to the upper limbs and the respiratory muscles resulting respiratory insufficiency with the need for mechanical ventilation [1]. The patient was diagnosed with SARS-CoV-2 induced Guillain-Barre syndrome (GBS) not earlier than eight weeks after onset of muscle weakness [1]. The patient benefitted from plasmaphereses and reached partial recovery at discharge to a rehabilitation facility [1]. The study is appealing but raises concerns that need to be discussed.

We do not agree with the notion that GBS had a “subacute” onset as indicated in the title [1]. Distal lower limb weakness started 10 days after the vaccination, corresponding to an acute onset. We thus also disagree with the speculation in the abstract that the patient could have had chronic inflammatory demyelinating polyneuropathy (CIDP) [1]. 

It is unclear according to which criteria GBS was diagnosed [1]. Most commonly, the Brighton criteria are applied but GBS can be also diagnosed according to the Ashford, Besta, or Hadden criteria. Application of the Brighton criteria may prevent diagnostic uncertainty.

A further limitation is that the subtype of GBS was not specified. According to the presented findings of nerve conduction studies (NCSs) the patient had acute, motor and sensory, axonal neuropathy (AMSAN) [1]. Knowing the GBS subtype is crucial as the therapeutic management and outcome may vary significantly between the various subtypes. Patients with sensory and autonomic involvement usually have a worse outcome as compared to patients with only motor involvement [2]. 

A shortcoming of the imaging studies of the cervical, thoracic, and lumbar spine is that no contrast medium was applied. GBS cases may show enhancement of the nerve roots as has been repeatedly reported [3]. Ultrasound, particularly of the cervico-brachial nerve roots, frequently shows enlargement of ventral rami of C5-C7 nerves with blurred boundaries [4]. 

Another limitation of the study is that an infection with SARS-CoV-2 was not definitively excluded. No information is provided whether the patient had a history of previous SARS-CoV-2 infection or if a PCR–test had been ever carried out. Since hundreds of cases with SARS-CoV-2 associated GBS have been reported during the last two years since outbreak of the pandemic, it is crucial that a SARS-CoV-2 infection as the underlying cause of GBS had been appropriately excluded in the index patient.

We eagerly read the article by Chavez et al. about an 82 year old male who was diagnosed with late-onset myasthenia gravis being attributed to a SARS-CoV-2 vaccination with the BNT162b2 vaccine [1]. The patient profited initially from pyridostigmine, but experienced a relapse within two weeks after initiation of the treatment [1]. Not before re-starting pyridostigmine and adding steroids and intravenous immunoglobulins, the patient slowly recovered [1]. The study is appealing but raises concerns, which require discussion. 

We do not agree with the notion that the SARS-CoV-2 vaccination triggered newly onset myasthenia [1]. Bulbar symptoms had been present “for a few weeks” but the first jab of the vaccine was given only four weeks prior to symptom onset [1]. If symptoms of myasthenia had begun already prior to the vaccination, a causal relation between the vaccination and myasthenia is unlikely. Thus, we should be informed about the exact onset date of myasthenic symptoms, particularly what “for a few weeks” means. A further argument against a causal relation between vaccination and myasthenia is that, according to our knowledge, no case has been reported in which a SARS-CoV-2 vaccination triggered a myasthenic crisis. 

Arguments in favour of a causal link between vaccination and new onset myasthenia in the index patient, however, are, that previous cases with vaccination induced myasthenia had been reported, that it is well known that SARS-CoV-2 vaccinations may trigger new or flares of immunological disease [2], and that no other plausible trigger of myasthenia had been found in the index patient. In a previous report about the side effects among 232603 vaccinees from Germany, one of these patients developed new onset myasthenia [3]. In a study of 27 patients with SARS-CoV-2 vaccination associated immune-mediated disease, two had developed newly onset myasthenia [2].

It is not comprehensible why the patient did not receive immune-modulating or immune-suppressive treatment, with steroids, immunoglobulins, azathioprine, mycophenolate, rituximab, or bortezomib immediately after establishing the diagnosis. He had high acetyl-choline receptor antibodies, a decremental response on low-frequency repetitive nerve stimulation, was old, and had no thymoma. More than two months were letting past before steroids and immunoglobulins had been started. Within this period, the patient developed generalised manifestations of myasthenia. 

Missing in the case report is the exclusion of myasthenic syndrome by high-frequency repetitive nerve stimulation and determination of antibodies against the voltage gated calcium channels as the patient had a history of laryngeal carcinoma and as laryngeal carcinoma can trigger myasthenic syndrome [4]. Missing is the exclusion of a SARS-CoV-2 infection, considering that SARS-CoV-2 infections can trigger myasthenia [5]. Missing is the determination of acetyl-choline receptor antibodies after treatment. We should be told if immune-modulating treatment was also effective with regard to the antibody titres. 

Overall, the interesting study has some limitations which    challenge    the results  and their interpretation. A causal link between vaccination and development of myasthenia remains unproven. Myasthenic syndrome needs to be excluded. Immuno-suppression should start early in myasthenia patients with high antibody titres, even if generalisation of myasthenic symptoms is not present yet.   

Declarations

The authors declare no conflicts of interest. No funding was received

Author Contribution

• JF: design, literature search, discussion, first draft, critical comments

• RG: literature search, discussion, critical comments, final approval

Informed Consent

Was obtained. The study was approved by the institutional review board. The study complies with the declaration of Helsinki

We eagerly read the article by Chiu et al. about a review of the safety profile of anti-COVID-19 drugs [1]. It was concluded that hydroxy-chloroquine, lopinavir/ritonavir, ivermectin, chloroquine, and favipiravir should not be used for the treatment of COVID-19 patients [1]. On the contrary, tocilizumab, remdesivir, and dexamthasone were recommended for COVID-19 patients under certain conditions [1]. The study is appealing but raises concerns which require discussion. 

Several adverse reactions following the use of tocilizumab were not acknowledged. One of the adverse reactions of tocilizumab is bowel ulceration [2]. Another adverse reaction not addressed is pyomyositis [3]. In a single patient lung and liver sarcoidosis-like reactions have been reported following the administration of tocilizumab [4]. There is also one report about tocilizumab-induced lupus [5]. In a 65yo male, treated with tocilizumab for rheumatoid arthritis, pericardial tamponade developed two months after initiation of the treatment [5]. According to an investigation by means of WHO’s “VigiBase”, tocilizumab increases the risk of reactivating hepatitis-B and tuberculosis [6]. According to this study the mean cumulative incidence of hepatitis-B and tuberculosis was 3.3% respectively 4.3% [6]. In a patient receiving tocilizumab for Takayasu arteritis, pyoderma gangrenosum developed following the anti-IL-6 therapy [7]. There are also indications that tocilizumab can reactivate psoriasis-like eruptions [8]. In a study of 74 patients receiving tocilizumab for COVID-19, 23% experienced late onset infections following tocilizumab use [9]. Bacteriemia and fungemia were also more frequently observed in the cohort receiving tocilizumab as comparted to the control group [9]. In a study of 2433 adverse reactions after tocilizumab reported to the worldwide FDA adverse event reporting system (WAERS), pancreatitis, and lung fibrosis were the most frequent in addition to liver injury [10]. 

In addition to the most commonly reported adverse reaction of remdesivir, liver injury, the drug potentially triggers a number of other side effects. In a study of the 12 COVID-19 patients in the US treated with remdesivir, three developed vomiting, rectal bleeding without other symptoms, nausea, and gastroparesis [11]. Additionally, remdesivir use can be complicated by kidney damage [12]. This is why remdesivir should not be used in patients with glomerular filtration rate <30 ml/min [13]. When evaluating 2922 adverse reactions to remdesivir reported to the FDA adverse reaction reporting system (FAERS), it was found 16,9% had kidney or urinary complications [12]. In a study of 86 pregnant females with severe COVID-19, treatment with remdesivir caused severe side effects in 16% of the included patients [14]. Side effects observed among these females included anemia, constipation, deep vein thrombosis, dysphagia, arterial hypertension, nausea, and pleural effusion [14], Which of these side effects were truly attributable to remdesivir and which to the COVID-19 infection remains speculative.

Not sufficiently addressed was the issue of combination anti-COVID-19 therapies. Frequently anti-COVID-19 drugs are given together with other amti-COVID-19 medication making it difficult to assess which of the compounds was effective respectively exhibited an adverse reaction.

Overall, the interesting review has several limitations which challenge the results and their interpretation. Adverse reactions of tocilizumab and remdesivir were not comprehensively assessed. Before recommending any compound as an anti-COVID-19 drug it has to be appropriately tested and reviewed for potentially severe adverse reactions not to additionally endanger COVIS-19 patients. If at all, tocilizumab and remdesivir should be applied with caution to COVID-19 patients.

Declarations

• Funding sources: No funding was received

• Conflicts of interest: None

• Acknowledgement: None

• Ethics approval: Was in accordance with ethical guidelines. The study was approved by the institutional review board

• Consent to participate: Was obtained from the patient

• Consent for publication: Was obtained from the patient

• Availability of data: All data are available from the corresponding author

• Code availability: Not applicable

• Author contribution: JF: design, literature search, discussion, first draft, critical comments, final approval