Concerning ocular infection by Covid-19, conjunctivitis caused by Covid-19 which have been described in previous studies2 are attributable to the straightforward inoculation of the conjunctiva due to a droplet transmission; the migration of upper respiratory tract infection through the nasolacrimal duct; the ematogenous infection of the lacrimal gland.
A study carried out by Loon et al. in 2004 demonstrated the presence of SARS-CoV RNA in tears3; however, no virus was detected in the tears or conjunctival secretions of patients without conjunctivitis.
Covid-19 has access to human tissue buy attaching the ACE-2 receptors, which are very distributed in aqueous humor and in the ocular surface4; it indicates they could be represent a target in COVID-19 infection.
Given the crucial role of the ACE-2 receptors in the pathogenesis of SARS-CoV-2 neurotropism, Netland et al.5 studied mice transgenic for human ACE-2 and demonstrated that the virus enters the brain through the olfactory bulb and rapidly spread to the connected regions of the cortex (piriform and infralimbic cortices), basal ganglia (ventral pallidum and lateral preoptic regions), and midbrain (dorsal raphe). Other areas, such as the parataenial nucleus of the thalamus, paraventricular nucleus of the hypothalamus, and the medial and basolateral amygdala, were also virus antigen positive. A feasible infection via oral uptake was demonstrated by the positivity of some regions such as the dorsal vagal complex, nucleus ambiguus, and hypoglossal nucleus.
Blepharospasm foresees three pathogenic hypothesis6:
an output from motor cortical regions to descending projections direct to the basal ganglia nuclei, the substantia nigra pars reticulata, and terminating in brainstem motor nuclei, (2) the embedded loops of the trigeminal blink reflex arc and the long sensorimotor circuit from trigeminal nucleus through thalamus to somatosensory cortex back through basal ganglia to the brainstem nuclei and (3) abnormalities in the basal ganglia dopamine 1 and 2 and serotonin system.
In our opinion, blepharospasm could represent a dystonia attributable to an abnormal functioning of the basal ganglia and diencephalic regions after Covid-19 transneuronal penetration, even in absence of olfactory or gustative symptoms.
We think that virus enters the olfactory filaments located in lamina papiracea, passing through the nasal ACE receptors, it arrives to the amigdala and cortico-medial nuclea, then to the amigdal baso-lateral nucleus, and lastly to the hypothalamus.
Thalamus plays a crucial role both in olfactive pathways than in orbicular muscles function.
Furthermore, we suggest that virus penetrates through the mouth, it gets through the taste filaments of the VII cranic nerve and it reaches the postero-medial nucleus of the thalamus.
We assume that VII cranic infection causes a bouncing dysregulation of the VII nerve somatic motor branch that belatedly manifests in a blepharospasm.
Based on the hypothesis formulated by Li et al7, Dopa Decarboxylase (DDC)
is a major enzyme of both the dopamine and the serotonin synthetic pathways as it converts L-3,4‐dihydroxyphenylalanine (L‐DOPA) into dopamine and L‐5‐hydroxytryptophan into serotonin. In addition, DDC also supports the conversion of histidine into histamine. That ACE-2 coregulates with DDC neurological circuits implicated in Covid-19 symptoms; that is due to a possible functional link between the ACE-2‐mediated synthesis of angiotensin (AT) 1‐7 and the DDC‐mediated synthesis of dopamine and serotonin.
According to Nataf8, ACE-2 and DDC may coexpress and coregulate in non-neuronal cell types in patients affected by COVID-19, who suffer from of a central autonomic failure of respiratory functions.
AT 1–7 are primarily formed by the degradation of AT II by ACE-2, and they do not cross the blood-brain barrier. AT receptors (AT1, AT2, and AT4) have been described during the last decades as located in the circumventricular organs, in cerebrovascular endothelial cells, cerebral cortex, basal ganglia9, in dopaminergic neurons, and glial cells in rats, as well as mesencephalic primary cultures10. AT II receptors were also identified in neurons and glial cells inside the blood-brain barrier and they seem to by product by astrocytes11.
The effects mediated by AT 1–7 are in direct opposition to the actions of the Renin-Angiotensin axis. Moreover, AT 1-7-mediated NF-κB inhibition has been also documented in several animal models, including hypertensive kidney disease12, pulmonary fibrosis13, and fatty liver disease14.
The neuroprotective effect of AT 1–7 was highlighted in an ischemic stroke model15 .
Autoradiographic studies reported a high concentration of AT 1 receptors in dopaminergic neurons, both in cell bodies of the substantia nigra, and their terminal neurons in the striatum of different mammals, including humans16,17. ACE receptors have been studies as a crucial elements in Parkinson disease.
Nevertheless, the dopamine system is implicated as a potential factor in many different forms of dystonia (Augood et al., 18; Perlmutter and Mink19; Breakefield et al.20, Wichmann21), in tardive dystonia due to neuroleptics whose initial presentation is commonly blepharospasm22.
In our hypothesis, the binding of COVID-19 to ACE receptors localized in basal ganglion, causes blepharospasm by altering the degradation of the L-DOPA to dopamine.
Consent to publish this case report has been obtained from the patient(s) in writing.
Acknowledgements and Disclosures