Socio-Economic, COVID 19 Crisis, Death rates, RNA viruses, Home Culture, Violence, SARS-CoV-2, WHO survey
With interest we read the article by Khatoon et al. about suspected pathophysiology and clinical presentation of neurological involvement in patients with COVID-19 due to infection with SARS-CoV-2 [1]. We want to contribute the following points to the discussion.Neurological disease in SARS-CoV-2 infected patients may not only be due to a direct viral attack towards neurons, glial cells, or components of cerebral vessels or blood brain barrier, but also secondary due to the immune reaction against the virus, secondary to affection of the lungs, heart, or kidneys, or due to side effects of treatment applied during the acute infection. Additionally, pre-existing neurological disease may worsen during COVID-19. Affection of the central nervous system (CNS) by the virus is rare and may cause meningitis/encephalitis [2,3], manifesting as headache, seizures, confusion, ataxia, pyramidal signs, or impaired consciousness (table 1). Weakness of several studies on the neurological involvement in the infection is that most patients with clinical CNS manifestations do not undergo CNS imaging or investigations of the cerebro-spinal fluid (CSF). If patients undergo a spinal tap, the CSF is often not investigated for virus-RNA or negative for the virus. If the CSF would be routinely investigated for virus-RNA in COVID-19 patients, the virus would probably be more frequently detected in the CSF.
Neurological disease due to the immune reaction against the virus includes Guillain-Barre syndrome (GBS) [4], acute, hemorrhaghic, necrotising encephalopathy (AHNE) [5,6], transverse myelitis [7], cytokine, release syndrome (CRS) [8], or myositis [9] (table 1). GBS is an increasingly recognised complication of COVID-19 and has been reported in at least 62 patients with COVID-19 [unpublished]. Whether myositis in patients with COVID-19 is due to direct attack of the virus or secondary to the immune response remains speculative. In a recent case report about COVID-19 myositis, muscle biopsy showed inflammatory infiltration but the virus was not found on electron microscopy [9], suggesting that myositis is rather immune-mediated than infectious. A further argument for the immunogenic hypothesis of COVID-19 myositis provided a recent study on 20 patients with dermatomyositis showing that antibodies against immunogenic epitopes have high sequence identity to SARS-CoV-2 [10]. Another neuro-immunologic complication of COVID-19 is transverse myelitis [7,11]. However, in none of these patients was the CSF positive for virus-RNA [7]. A recently described neuro-immunologic entity in COVID-19 is CRS, clinically manifesting with confusion, coma, tremor, cerebellar ataxia, behavioral alterations, aphasia, pyramidal signs, cranial nerve palsy, dysautonomia, and central hypothyroidism [8]. Another new CNS complication of COVID-19 is myoclonus [12] but it remains speculative if myoclonus is infectious, immune-mediated, post-hypoxic, or due to concomitant renal insufficiency [12]. Additionally, it has to be mentioned that CNS/PNS disease in COVID-19 may secondarily result from affection of the heart or the kidneys (Table 1). Furthermore, CNS/PNS disease may be triggered by the anti-viral treatment or mechanical ventilation (Table 1). Lastly, pre-existing CNS/PNS disease may deteriorate during the acute viral infection (Table 1). Overall, the pathophysiology and clinical presentation of CNS/PNS involvement in COVID-19 is broader than usually anticipated.
Table 1: Neurological manifestations of COVID-19 according to the pathophysiological background
Category | CNS/PNS Manifestation | Clinical Manifestations | Virus RNA in CSF | Reference |
A. Direct viral affection of the CNS/PNS | Meningitis / Encephalitis | Headache, confusion, cognitive impairment, ataxia, spasticity, seizures, impaired consciousness | Yes | [2,3] |
Cerebellitis | Vertigo, ataxia | Yes | [13] | |
Olfactory neuropathy | Hyposmia, anosmia | Yes | [14] | |
Gustatory neuropathy | Hypogeusia, ageusia | Yes | [14] | |
B. CNS/PNS disease secondary to immune response | AHNE | Seizures, cognitive impairment | No | [5,6] |
Cytokine-release syndrome | Ataxia, tremor, confusion, aphasia, dysautonomia, coma | No | [8,15] | |
Myoclonus | Myoclonic jerks, tremor | No | [12] | |
ADEM | Weakness, sensory disturbance, urinary retention, dysarthria, ataxia | No | [16,17] | |
Limbic encephalitis | Dysarthria, seizures, cognitive impairment, hallucinations | No | [18] | |
Transverse myelitis | Quadriparesis, sensory disturbance | No | [7] | |
GBS (polyneuritis) | Ocular, facial and limb weakness, sensory disturbance | No | [7] | |
Mononeuritis | Facial palsy | No | [19] | |
Myositis | Myalgia, rhabdomyolysis | No | [10,20] | |
Myasthenia | Fatigability, exercise intolerance, weakness | No | [21] | |
Psychosis | Delusion, disorientation, hallucinations | No | [22] | |
Delirium | Hyperactive or hypoactive delirium | No | [23] | |
C. CNS/PNS complications due to affection of other organs | Cerebral hypoxia | Impaired consciousness, coma | No | [24] |
PRES | Headache, seizures, impaired consciousness, visual impairment | No | [25] | |
Ischemic stroke | Hemiparesis, impaired consciousness | No | [26] | |
Intracerebral hemorrhage | Impaired consciousness, dilated pupils | No | [27] | |
Sinus venous thrombosis | Hemiparesis, seizures, headache | No | [28] | |
Sleep disorder | Insomnia | No | [29] | |
D. CNS/PNS disease secondary to COVID-19 treatment | Critical illness neuropathy | Limb weakness | No | [12] |
Critical illness myopathy | Limb weakness | No | [12] | |
Chloroquine myopathy | Limb weakness | No | [30] | |
Ritonavir myopathy / rhabdomyolysis | Limb weakness, myalgia | No | [30] | |
Lopinavir myopathy / rhabdomyolysis | Limb weakness, myalgia | No | [30] | |
Neuroleptic malignant syndrome (NMS) | Fever, tachycardia, tachypnea, rigidity | No | [31] | |
E. Neurological disease deteriorating during COVID-19 | Myasthenia gravis | Exacerbation of weakness, myasthenic crisis | No | [32] |
ADEM: acute disseminated encephalo-myelitis, AHNE: acute, hemorhaghic, necrotising encephalitis, CI: cognitive impairment, HA: headache, IC: imp<ired consciousness, NMS: Neuroleptic malignant syndrome, PRES: posterior, reversible encephalopathy syndrome, RL: rhabdomyolysis, SD: sensory disturbancies
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