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 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.