mtDNA, point mutation, cardiac involvement, cardiomyopathy, multisystem, mitochondrial.

mtDNA, point mutation, cardiac involvement, cardiomyopathy, multisystem, mitochondrial.

mtDNA, mitochondrion, Leigh syndrome, brain, imaging, MRI.

mtDNA, respiratory chain, coronary heart disease, atherosclerosis, multisystem disease, mitochondrial disorder.

mtDNA, respiratory chain, multiple systemic lipomatosis, ketogenic diet, m.8344A>G.

We appreciated to read the review article by Al-Sarraj et al. about the pathophysiology of neurological impairment in SARS-CoV-2 infected patients with COVID-19 (neuro-COVID) [1]. The authors proposed four mechanisms to explain involvement of the central nervous system (CNS) or the peripheral nervous system (PNS) in COVID-19 and concluded that cerebral abnormalities probably represent a combination of direct cytopathic effects mediated by SARS-CoV-2 replication or indirect effects due to respiratory failure, injurious cytokine reaction, reduced immune response, or cerebrovascular accidents induced by coagulopathy due to viral infection [1]. Pathways via which the virus may enter the CNS include taste buds and olfactory epithelial cells, the hematogenous route, or via immune cells originating from the respiratory tract [1]. We have the following comments and concerns.

The authors do not consider side effects of drugs as causative for various neurological abnormalities. It is well known that steroids, chloroquine, protease-inhibitors (lopinavir/ritonavir), remdesivir, azithromycin, toclizumab, or cromstat can trigger neurological adverse reactions. Steroids can cause mitochondrial myopathy. Protease-inhibitors carry the risk of triggering sensory neuropathy [2]. Azithromycin is known to trigger rhabdomyolysis [3]. Toclizumab has been reported to cause facial palsy and diplopia [4]. Chloroquine may cause toxic myopathy [5] or even a myasthenic syndrome [6].

Since many COVID-19 patients with severe pulmonary compromise require mechanical ventilation and long-term stay on the ICU, it is conceivable that at least some of them may develop critical ill neuropathy or critical ill myopathy. Critical ill neuropathy/myopathy may strongly determine the duration of rehabilitation and outcome of COVID-19 patients [7]. 

Unfortunately, there is no mentioning of myasthenia [8] or myasthenic syndrome [6] as a neurological complication of COVID-19. Though MG has been reported as a manifestation of COVID-19 in three patients as of 18^th September [8], it is conceivable that MG induced by COVID-19 is more frequent but neglected, particularly in patients on the intensive care unit (ICU), where pulmonary compromise may dominate the clinical presentation. In a recent mini-review it has been found that exacerbation of MG in 50% of the MG patients with COVID-19 MG and SARS-CoV-2 triggered a myasthenic crisis in 20% of these cases [9]. There is also no discussion of mononeuropathies of cranial nerves associated with SARS-CoV-2.

Though it is conceivable that SARS-CoV-2 enters the CNS via taste buds or olfactory epithelial cells, presence of the virus has been only rarely documented within neurons, glial cells, endothelial cells, or the cerebrospinal fluid (CSF). In a mini-review about Guillain Barre syndrome (GBS) in 62  COVID-19  patients the virus respectively virus-RNA was not detected in any of the 62 included patients [10]. In a mini-review about 48 patients with infectious or immune-mediated CNS disease, the CSF was positive for the virus in only 4 cases [11]. From these preliminary results it can be concluded that the virus is present only temporarily in the CSF, resides in a hibernated form within cells of the CNS, or is not directly involved in the pathogenesis of neuro-COVID. More likely than a direct viral attack is a secondary reaction of the CNS or PNS to the immunological reaction against the virus. It has been postulated that antibodies against the virus may cross-react with receptors in the CNS/PNS and that a storm of cytokines may secondarily affect neurons, glial cells, vascular smooth muscle cells, or endothelial cells [12]. 

In conclusion, we definitively need more CSF investigations and autopsy studies for virus RNA during all stages of COVID-19. Only if a systematic and prospective study of COVID-19 patients for the presence of the virus-RNA is carried out, the pathophysiological role of the virus for neurological disease can be settled. 

We reviewed the article by [1] which presented a retrospective study of 220 patients with sudden unexpected death in epilepsy (SUDEP) from the North American SUDEP Registry (NASR), concluding that closer collaboration between death investigators and epilepsy communities is necessary to enhance the understanding of SUDEP. While the study is valuable, we raise concerns about the lack of brain autopsy data, which may miss alternative causes of death like ischemic stroke or intracerebral bleeding. Additionally, the absence of family history collection limits the identification of hereditary disorders. Another shortcoming is the lack of consideration of brain-heart connections, such as Takotsubo syndrome (TTS) and neurogenic pulmonary edema (NPE), which may contribute to SUDEP. We suggest comprehensive brain autopsy, detailed family history, and inclusion of TTS and NPE in future studies to improve the understanding of SUDEP mechanisms.

With interest we read the article by Pergolizzi et al. about a systematic review about the neurological manifestations of patients with COVID-19 [1]. It was concluded that SARS-CoV-2 enters the brain via ACE2-receptors, that neurological disease only rarely precedes the onset of pulmonary manifestations of a SARS-CoV-2 infection, that patients with pre-existing neurological conditions are at an increased risk of experiencing COVID-19 associated neurological abnormalities, that particularly patients with severe COVID-19 are at an increased risk of experiencing neurological disease, that drugs suppressing the immune response against SARS-CoV-2 are contraindicated for treating neurological involvement and that the neurological disease in COVID-19 patients may be easily missed [1]. We have the following comments and concerns.

The main shortcoming of the review is that it is highly speculative. There is no study available which clearly indicates that patients with pre-existing neurological disease are at an increased risk during a SARS-CoV-2 infection of developing additional neurological compromise. Entrance of SARS-CoV-2 2 to the brain via ACE2-receptors also remains unproven. There is no evidence available that particularly patients with severe infection are at an increased risk of experiencing neurological complications.

The authors do not mention a number of potential neurological manifestation of the SARS-CoV-2 infection. Central nervous system (CNS) abnormalities not included were sinus venous thrombosis, intracerebral bleeding, subarachnoid bleeding, acute, haemorrhagic, necrotic encephalopathy (AHNE), acute demyelinating encephalo-myelitis (ADEM), vasoconstriction syndrome, pituitary apoplexies’, psychosis, Parkinson’s disease, myelitis and plexitis [2-4]. Among the peripheral nervous system (PNS) abnormalities associated with SARS-CoV-2 the authors did not discuss dysgeusia, myasthenic syndrome, myositis, rhabdomyolysis and myasthenia [5].

Missing in the review is a discussion about secondary neurological compromise in COVID-19 patients due to side effects of drugs given to treat COVID-19. These drugs include chloroquine, azithromycin, steroids and others.

Overall, the review by Pergolizzi et al. has some limitations which should be met before drawing final conclusions. There is a need for prospective studies on the neurological involvement in SARS-CoV-2 infected patients. Neurological side effects of drugs given to treat COVID-19 should be included in a review about neurological disease in COVID-19.