We eagerly read the article by Poisson et al. about a SARS-CoV-2 positive 8yo female, who was diagnosed with cerebral vasculitis upon two brain biopsies [1]. Since IgM antibodies against SARS-CoV-2 were positive in the cerebro-spinal fluid (CSF), vasculitis was attributed to COVID-19 [1]. The study is appealing but raises concerns which require discussion. The condition presented in the case report could be also interpreted as acute, haemorrhagic, necrotising encephalitis (AHNE). This condition has been recently described in an adult patient with tuberculosis and COVID-19 [2]. Thus, it is crucial that cerebral tuberculosis had been excluded by culture, immune-histology, and PCR in the CSF and the brain tissue at autopsy. Cerebral tuberculosis is accompanied by cerebral vasculitis in a quarter of the cases [3]. Unfortunately, only serum antibodies against mycobacterium tuberculosis had been determined in the index patient. Missing are the results of conventional digital subtraction angiography (DSA), computed tomography angiography (CTA), or magnetic resonance angiography (MRA) to confirm the histological diagnosis. Vascular imaging may not only help to confirm the histological diagnosis but also to delineate between vasculitis of large, medium-sized, or small arteries. 

We do not agree with the notion that neuro-COVID only includes stroke, venous sinus thrombosis (VST), seizures, meningitis, encephalitis, ADEM, acute fulminant cerebral edema, posterior reversible encephalopathy syndrome (PRES), headache, myelitis, Guillain-Barre syndrome (GBS), cranial neuropathies, and myositis. The spectrum of neuro-COVID is much broader and additionally includes reversible cerebral vasoconstriction syndrome (RCVS), acute, haemorrhagic, necrotising encephalitis (AHNE), hypophysitis, cerebellitis, myoclonus syndrome, immune encephalitis, multiple sclerosis, neuromyelitis optica spectrum disorder, ventriculitis, pontine myelinolysis, subarachnoid bleeding, Wernicke encephalopathy, insomnia, psychosis, myasthenia, and myasthenic syndrome.

Overall, the elegant study has limitations which challenge the results and their interpretation. Cerebral tuberculosis should be excluded by appropriate means. 

We read with interest the review by Gabis et al. about the association between SARS-CoV-2 vaccines and autism-spectrum disorders(ASD) in children.[1] It was concluded that SARS-CoV-2 vaccines are safe in children, that SARS-CoV-2 vaccines do not cause ASD, and that the myth that SARS-CoV-2 vaccines cause ASD still persists and affects parental attitudes towards vaccination and increases vaccination refusal rates.[1] The study is appealing but raises concerns.

We do not agree that fear from autism is the reason for parents’ hesitancy to immunise their children. According to a search in PubMed not a single pediatric patient with autism triggered by a SARS-CoV-2 vaccination has been reported. More likely than fear from autism, is fear from severe adverse events (SAE) that is responsible for the parent’s hesitancy. SAE of SARS-CoV-2 vaccinations that have been described in children include MIS-C,[2], myocarditis,[3] peri-myocarditis,[4], Guillain-Barre syndrome (GBS), [Finsterer, submitted] thrombocytopenia,[5] facial palsy,[6], vulvar aphthous ulcer,[7], and hypersensitivity reactions.[8],

Parents’ fear from vaccinating their children may be supported by the complications of SARS-CoV-2 infections in children, which include stroke, intracerebral bleeding, subarachnoid bleeding, micro-hemorrhages, venous sinus thrombosis, immune encephalitis, reversible splenial lesions, ADEM, MIS-C, transverse myelitis, GBS, cranial nerve lesions, meningo-encephalitis, encephalopathy, benign intracranial hypertension, and myositis.[9]

A further reason for concerns of parents about SARS-CoV-2 vaccinations in their children is the limited knowledge about the safety profile of SARS-CoV-2 vaccinations in children, which results from the fact that only few children were vaccinated so far compared to adults.

Following the preliminary results available about side effects of SARS-CoV-2 vaccines in children, it is comprehensible why parents have reservations against immunising their children. In addition to medical reasons hesitancy may originate from disinformation through social media. Health care authorities, scientists, and media are obliged to provide valid and reliable data about the pros/cons of SARS-CoV-2 vaccinations in children.   

We read with interest the article by Mudabbir et al. about a 41 years old male who was diagnosed with “acute cerebellar ataxia (ACA)” starting two weeks after complete resolution of a COVID-19 infection [1]. The patient profited from steroids and recovered completely within 10 days after starting the therapy [1]. The study is appealing but raises concerns that need to be discussed. We do not agree with the notion that the patient had SARS-CoV-2 associated cerebellitis [1]. The patient had pre-existing cerebellar atrophy on imaging [1]. Therefore, it is more likely that previously asymptomatic cerebellar atrophy became symptomatic from the viral infection.

There is a discrepancy between the three-day history of “walking difficulty” and the normal gait on clinical neurologic exam [1]. This discrepancy should be solved. 

We do not agree with the statement that the most common manifestations of neuro-COVID are stroke, cerebral hypoxia, epilepsy, and critical ill neuropathy/myopathy [1]. The most common manifestations of neuro-COVID are headache, ageusia, anosmia, and Guillain-Barre syndrome (GBS) [2]. Hypoxic encephalopathy is extremely rare as patients with respiratory insufficiency are usually well monitored for their oxygen saturation and immediately supplied with oxygen or even mechanically ventilated in case of desaturations.

Missing is an explanation of the cause of cerebellar atrophy. It is not conceivable that it developed during the SARS-CoV-2 infection but was rather pre-existing. We therefore should be told if the family history was positive for ataxia or a genetic disorder manifesting with ataxia.

Missing is the determination of the cytokine and chemokine profile in the CSF. Particularly, interleukine 6 (IL-6), IL-8, IL-1b, and TNF-alpha have been shown upregulated in the CSF of patients with neuro-COVID [3]. 

Missing is the MR venography to rule out venous sinus thrombosis.

Overall, the interesting study has some limitations and inconsistencies that call the results and their interpretation into question. Clarifying these weaknesses would strengthen the conclusions and could improve the status of the study. Affection of the cerebellum in COVID-19 is rather immune-mediated than infectious.

We read with interest the article by Murawska-Baptista et al. about a 71 years old male who developed respiratory distress due to severe COVID-19 requiring a high-flow nasal canula (HFNC) [1]. His past medical history was positive for arterial hypertension, hyperlipidemia, atrial fibrillation, ablation therapy, obstructive sleep apnea, and Guillain-Barre Syndrome (GBS) following an influenza vaccination, from which he recovered completely [1]. The patient recovered from COVID-19 under remdesivir and steroids [1]. The study is appealing but raises concerns that require discussion. Whether patients with a previous history of GBS are prone to experience a relapse of GBS during a SARS-CoV-2 infection is unknown but there are indications that patients with a previous history of demyelinating neuropathy have an increased risk to experience neuro-immunologic complications. The risk of experiencing a SARS-CoV-2 infection associated GBS may be particularly increased among those with clinical recovery but electrophysioloic evidence of persisting neuropathy. 

The patient presented with progressing respiratory failure despite treatment with remdesivir and steroids but it is unclear if worsening of respiratory insufficiency was due to COVID-19 pneumonia or due to exacerbation of GBS predominantly affecting the respiratory muscles. We should be told if the patient was seen by a neurologist and if there were any indications for relapse of the GBS. GBS is a well-known neurological complication of SARS-CoV-2 infection and has been reported in >400 patients as per the end of June 2021 [2, Finsterer, submitted]. 

We disagree with the statement that GBS following a SARS-CoV-2 vaccination is a rare complication of SARS-CoV-2 vaccinations [1]. Looking at table 1 of the index study it clearly indicated that >500 patients with post-SARS-CoV-2 vaccination GBS have been reported as per the end of December 2021 [1]. Assuming that most cases of SARS-CoV-2 vaccination associated GBS are never published or reported to a database, it is conceivable that the real-world prevalence of SARS-CoV-2 vaccination associated GBS is much higher than anticipated. 

We do not agree with the classification of the vaccine in the patient with SARS-CoV-2 vaccination associated GBS reported by Finsterer as “unknown” [3]. The patient developed GBS eight days after the first dose of a vector-based vaccine (Astra-Zeneca vaccine (AZV)) [1]. 

Overall, the interesting study has some limitations which challenge the results and their interpretation. Addressing these limitations may upvalue the conclusions. Patients with a previous history of GBS should not undergo vaccination for SARS-CoV-2 if there was only clinical but not electrophysiological recovery.

Objectives: Whether or not stroke-like-episodes also involve the optic nerve is under debate. Results: However, it is conceivable that oxidative stress also affects structures of the optic nerve and lead to visual impairment. Conclusions: the term stroke-like-episode should be restricted to typical stroke-like lesions in the cerebrum, which are radiologically well defined. 

We read with interest the article by Scarcella et al. on a 55 year-old female who presented with acute, left-sided, painful visual impairment, headache, and myalgia and was diagnosed with ischemic neuropathy respectively stroke-like episode (SLE) of the left optic nerve [1]. Like the index patient’s brother, who was diagnosed with mitochondrial encephalopathy, lactic acidosis, and stroke-like episode (MELAS) syndrome due to the variant m.3243A>G, she carried the same mtDNA variant with a heteroplasmy rate of 12% in urinary epithelial cells [1]. The visual defect remained unchanged under L-arginine and ubidecarenone [1]. The study is compelling but has limitations that should be discussed.

A limitation of the study is that heteroplasmy rates were only determined in urine epithelial cells where it was low (12%) [1]. Heteroplasmy rates were not determined in skin fibroblasts, hair follicles, buccal mucosa cells, leukocytes, or muscle. Knowing heteroplasmy rates in clinically affected tissues, particularly muscle, is crucial not only to explain the phenotype, to predict the course of the disease and thus the outcome of the condition, but also for genetic counselling. Regarding the low heteroplasmy rate in urine, it is hardly conceivable that the clinical manifestations were due to the m.3243A>G variant. 

A second limitation is that the current medication was not provided. Since the patient had a history of arterial hypertension and hyperlipidemia, it is conceivable that she received a novel drug for either of these conditions. From statins it is well-known that they can cause myalgia (statin myopathy), particularly in patients with a mitochondrial disorder (MID) [2]. A shortcoming in this respect is that creatine-kinase, lactate-dehydrogenase, aldolase, and myoglobin levels were not provided. Was there any indication for rhabdomyolysis? Was the urine ever cola-coloured?

A third limitation is that no lactate stress test (LST) was performed to assess whether or not serum lactate increased under workload below the anerobic threshold on a bicycle ergometer [3].

A fourth limitation is that cerebrospinal fluid (CSF) lactate was not reported. CSF exam is described as “unremarkable” [1]. However, it was not reported, whether or not CSF lactate was determined. CSF lactate can be elevated in MELAS patients even if serum lactate is normal. CSF lactate is particularly elevated if thereis a SLE. An argument for elevated CSF lactate is that magnetic resonance spectroscopy (MRS) depicted a lactate peak [1]. 

A fifth limitation is that no electroencephalography (EEG) was recorded. Since MELAS is characterised by the occurrence of seizures and SLEs, and SLEs can be triggered by seizures, it is crucial to know whether or not epileptiform discharges were recorded on EEG. 

There is a discrepancy regarding the diagnosis in the abstract (“SLE”) and the diagnosis in the title respectively case description (“ischemic optic neuropathy”) [1]. These are two completely different entities. SLEs are triggered by seizures or metabolic stress but are unrelated to impaired arterial perfusion. This discrepancy should be clarified not to confuse the reader. 

Not considered as pathophysiological mechanisms were spasms of arterioles supplying the optic nerve or enlargement of endothelial mitochondria in arterioles of the optic nerve [4]. 

Because the case is set during the SARS-CoV-2 pandemic and COVID infection or vaccination can be complicated by optic neuritis [5], it is crucial that SARS-CoV-2 infection or vaccination has been ruled out.

Overall, the interesting study has limitations that put the results and their interpretation into perspective. Addressing these issues would strengthen the conclusions and could improve the status of the study. SLEs of the optic nerve are not imaginable per definition. Alternative pathophysiologies of unilateral visual impairment in m.3243A>G carriers should be considered.