First comments about results and flow diagram.
The flow diagram (Figure 1) shows that we did not identify any publication regarding SIH/SD effusion/COVID-19 in our extensive research of the available medical literature. Therefore, we consider that this comorbidity or tardive neurological manifestation of COVID-19 is exceptionally uncommon. Later, we discuss possible pathophysiology for this finding and deliver our hypothesis for answering question two.
Brief comments about the investigation done.
Our second comment is related to an elevated white cell count, low lymphocyte count, elevated D-dimer level, and creatine kinase during her ICU admission suggested severe illness. Other authors also reported these findings when comparing these parameters among in and out ICU admissions [64]. We also found abnormal albumin levels, lactate dehydrogenase, and C-reactive protein probably associated with the lungs’ acute injury during ICU admission. We could not check the status of angiotensin in plasma and viral load, which abnormalities have been reported by other authors as well [65]. Our patient belongs to blood group A, said in severe COVID-19 and respiratory failure [66, 67]. Findings of CD4 count below 400/μL associate with the severity of the SARS-CoV-2 infection have been reported too [46]. These authors also confirmed that T cell numbers related to IL-6, IL-10, and TNF-α concentration in the serum in COVID-19 patients were negative. When the total T cells account is below 800/μL, those patients need urgent intervention, including a case with no apparent critical illness. Sooner or later, they will develop remarkable deterioration. It is essential to highlight that a notable of the lymphocytes’ levels are part of the cases’ characterization, presenting a severe COVID-19 [45,46, 68]. Hypokalemia is the most relevant electrolyte imbalance in COVID-19 [47]. Apart from those mentioned before, another laboratory abnormality is relevant to determine the severity of the patient’s condition and predictors of death, such as neutrophil/lymphocyte ratio, ferritin level, and hypophosphatemia hypofibrinogenemia, and platelet/lymphocyte ratio [47].
Other authors established that around 50% of the critically ill COVID-19 patients present cytokine elevation, fever, high ferritin levels, and cytopenia [69,70]. It has known that SARS-CoV-2 causes an immunosuppressive effect on the body by exhausting and diminishing T lymphocytes working with inhibitory receptors on natural killers and NKG2A, TIM-3, and PD-1 (T cells), as we mentioned before. Therefore, immunomodulators plus immunostimulant and anti-inflammatory activities can influence the severity of COVID-10 and minimize the risk of multiorgan failure and death [47]. Severe COVID-19, apart from causing neuronal and glial cells dysfunction, can develop other neurovascular complications and leptomeningeal injury [70].
Considering that SIH is a frequent consequence of CSF leak at any level along the neuroaxis, and this situation can alter the necessary equilibrium between the volume of arterial and venous blood, CFS, and brain parenchymal. That mechanism referred to the relationship between the intracranial components’ pressure-volume inside the skull’s no expansible compartments. It had been explained magisterially by Alexander Monro (1733-1817), a Scottish physician, and George Kellie (1720–1779). a Scottish general surgeon [71,72]. Their hypothesis combines the intracranial volume of the brain (~1400 mL) with the total volume of the venous and arterial blood (~150 mL) and the volume of the CSF (~150 mL) to keep a dynamic equilibrium. When the volume of any component diminishes, the other two volumes increase to keep the intracranial volume average in adults (~ 1700mL) [73]. One relevant mechanism controls the low-pressure venous system that displaces blood volume [72]. Suppose we apply the Monro-Kelly hypothesis to our patients. It is easier to understand the mechanism of low intracranial pressure in this case and why upright posture leads to the dilation of the nociceptive cerebral venous system explaining why orthostatic headache. On figure 3, we list the most common causes of SIH.
Some authors recently found evidence of neuronal degeneration, neuronophagia, mild oedema around nerve cells, and the small veins within the COVID civets’ brain [74]. Based on this information, we can hypothesize about the subdural effusion mechanism caused by SARS-CoV-2 facilitated by a cytokine storm.
On the other hand, in critically ill COVID-19 patients, if possible, to see cerebral microbleeds (CM) damaging different areas of the brain, mainly the corpus callosum. This process’s pathogenesis is still unknown, but the direct and indirect effect of SARS-CoV-2 on the endothelial tissue caused by the cytokine cascade is specific, apart from the hypoxemic development blood-brain-barrier (BBB) injury [75]. The best study to visualize CM is an MRI of the brain that we could not perform on our patients because of limited access to the machine due to our COVID protocol.
The pathogenesis of the brain lesions is related to astrocyte’s disorder. This glial cell is the brain’s primary homeostatic cell from one side. The other reactive astrocytes can release chemokines to activate specific receptors from invading microglia and macrophages, attracting them to the lesions. These astrocytes may modulate the immune response delivering TNF-α, IL-12, IFN-γ, TGF-β, and IL-10 and controlling the pro-/anti-inflammatory phenotype of macrophage [76].
The neuroinflammatory reactive astrocytes can stimulate naïve precursor T-cells and produce pro-inflammatory (Th1) or anti-inflammatory (Th2) phenotypes via pro-inflammatory cytokines (IFN-γ, TNF-α, IL-17) and anti-inflammatory cytokines (IL-10, TGF-β).
Nevertheless, Th1 cells stimulate macrophages’ activation and worsening the inflammatory reaction by releasing IL-2, IFN-γ, TNF, while Th2 cells cause inhibition of the macrophage’s inflammatory activity by releasing IL-4, IL-5, IL-6, IL-10, and IL-13 through humoral immunity. The BBB integrity also depends on the astrocyte function by secreting VEGF, TGFα, bFGF, TNF-α, IL-1β, IL-3, IL-6, Ang-1, BAFF, which support the endothelial cell control from one side of the barrier and the other by glial-derived neurotrophic factor. The nervous system’s large glutamate sink is in the astrocytes, which control its function [76]. (See Figure 4).
Undoubling, astrocytes play an essential role in the mechanism of brain damage in human beings, depending on the predominance of cytokines released.
It has also known that many pathogenic agents cross the BBB by paracellular path, via transcytosis mechanism inside entering monocytes according to the Trojan Horse hypothesis or by the hijacking of β-adrenergic receptors [77]. The two BBB alterations are called non-disruptive and disruptive. The first one happens when there is molecular damage and its permeability if affected increasing or decreasing regulations of receptors and transportation across the barrier associate to astrocyte dysfunction, cytokine production and augmenting neuroinvasion of pathogen agents and the disruptive modality follow to anatomical modifications, including mitochondrial lesion, loss of tight junctions integrity, breakdown of glia limitans, degradation of the glycocalyx, increased vehicular traffic, re-induction of fenestrae, astrocytopathy, and apoptosis [78,79]. Astroglia-produced cytokines, [IL-1β, IL-6, TNF-α], and prostaglandins mediate both BBB modalities [80].
Astroglia cells may release both anti/pro-inflammatory factors that can provoke and or control the neuroinflammatory brain process.
Among these anti-inflammatory agents’ astrocytes released are:
· A.- cytokines and growth factors (IL-6, IL-10, IL-11, IL-19, IL-27, TGF-β, SHH).
· B.- intracellular signalling factors (CRYAB; Gal9, STAT3, and A20)
· C.- receptors (Dopamine D2 receptors, estrogenic receptor-α, glycoprotein 130.
· D.- small intercellular effector molecules (MicroRNAs, retinoic acid: miR-181, miR-17-5p, and Dicer1).
Pro-inflammatory activity is listed here: (See Figure 4).
· A.- chemokines: monocyte chemoattractant protein-1 (MCP-1/CCL2), CCL5 (RANTES), CCL7, CCL8, CCL12, CXCL1, CXCL8 (IL-8), CXCL9, IFN-γ-inducible protein-10 (IP-10/CXCL10), CXCL12, CXCL16.
· B.- cytokines and growth factors: IL1-β, IL-6, IL-11, IL-15, IL-17, TNF-α, BAFF, vascular endothelial growth factor (VEGF).
· C.- intracellular signalling factors: NF-κB, SOCS3, Act1.
· D.- small intercellular effector molecules: PGE and NO [81,82].
Without a doubt, SARS-CoV-2 cause brain inflammatory reaction as has been mentioned-before then; in that situation, astrocytes tend to up-regulate the production of IL1-β, IL-6, IL-11, IL-15, IL-17, TNF-α, BAFF, VEGF and develop remarkable delayed pro-inflammatory phenotype, even more than microglia [83,84].
One of the most relevant pro-inflammatory activity in the pathogenesis of the septic process is provided by IL-1β inducing astroglia cells to produce thymidine phosphorylase (TYMP/endothelial cell growth factor 1, ECGF1). Vascular endothelial growth factor A (VEGF-A) contributing to the downregulation of TJ protein expression in BECs, leading to BBB breakdown [85]. At the same time, astroglia cells attenuate microglia activation releasing TGF-β as well [86]. The before-mentioned activation of astrocytes with IL-1β supports the up-regulation of mRNA plus protein expression of IL-6 and TNF-α [87]. On the other hand, some authors found in a transgenic model that overexpression of IL-6 (constitutive astrocytes) linked with a breakdown of the BBB, angiogenesis, increased expression of complement proteins, astrogliosis, and neurodegeneration [88,89].
Other researchers also reported that SARS-CoV-2 infection increase levels of cytokines such as TNFα, interleukin (IL)-1β, IL-6, IL-12, and INFγ, a phenomenon known as “cytokine storm” (See Figure 4) [90-92].
Based on previous reports, SARS-CoV-2 cause neurodegeneration, demyelination, and cellular senescence, which accelerate the ageing process of the brain and increase neurodegenerative pathology [93-97] and we have hypothesized that damage persists beyond the acute phase of the disease because we could not identify a proper mechanism able to reverse these processes or accelerate the neurogenesis all over the brain.
Apart from the enunciated postulates about direct/indirect damage on the brain caused by SARS-CoV-2 through pro-inflammatory cytokines, chemokines, and growth factors; now we want to comment about other CNS damage seen in post-acute COVID-19 infection. In this regard, some authors confirmed enlargement of Rolandic operculum, insulas lobes, hippocampi, olfactory cortices, Heschl’s gyrus, and cingulate gyrus by MRI images and reported from those prospective studies a general decline of mean diffusivity, axial and radial diffusivity accompanied by an increase of fractional anisotropy in the white matter of the right corona radiata, superior frontal-occipital fasciculus, and external capsule. Based on their findings, these authors suggest a disruption of the brain’s micro-structural components and functionality in the recovery stages of COVID-19 [98].
To answer our second research question is necessary first to review the most acceptable pathophysiologic of ISH.
A dural tear is the cause of the syndrome in patients presenting connective tissue disorders like autosomal dominant polycystic kidney disease, Ehrler Danlos’ syndrome (Type II), or Syndrome Marfan’s Syndrome. In the case of dural ectasis leading to CSF leakage into the epidural or subdural space, this mechanism can explain why orthostatic headache and cranial nerves (V-VIII) disorders accompany this process [99]. Other conditions cause SIH like diabetic coma, hyperpnoea, uremia, dehydration, and even severe systemic illness [100]. Nevertheless, there are not COVID cases reported during the previous or current pandemic.
Based on observation of patients presenting SIH clinical manifestations with normal CSF pressure, we believe that reducing the CSF volume rather than a reduced CSF pressure is the primary pathophysiology of this syndrome but can be both processes together. Decrease CSF volume can be a consequence of the arachnoid membrane’s rupture, leading to CSF leakage into the subdural space [101] how probably happened in our patient (See Figure 2). However, if this theory is correct, why are there not more COVID patients reported? Unfortunately, we have not a convincing answer to the previous question. Therefore, we can accept that this presentation may be comorbidity like a simple coincidence. Besides that, we still hypothesize that SARS-CoV-2 present in the CSF can cause damage to the arachnoids membrane until proven otherwise.
As we know, CSF’s buoyancy plus pain-sensitive structures are the primary support of the brain. These structures are the meninges layers of the blood vessel (cerebral and cerebellar veins), some cranial nerves (5th, 9th, and 10th), and C1-C3 spinal nerves [102].
Then, when there is a stretching of these structures, some clinical manifestations of SIH are present. Considering the CSF’s buoyancy, as mentioned earlier, the effect may diminish when its volume decreases, leading to the brain sag downwards, which causes headaches with worsening by an upright position like our patient. The same mechanism can explain postural headache in other similar patients or cases of reduced brain volume [103]. It is opportune to recall that SARS-CoV-2 can cause brain atrophy, as we point out before. Finally, headaches can be secondary to the intracranial blood vessels [104].
One of our patient’s bedside tests with positive results was the Valsalva manoeuvre, which diminishes the venous return to the cardiac chambers and increases the venous volume intracranially, causing headaches even in a flat position. Some authors reported the presence of mononuclear pleocytosis, reticulocytes, elevated protein concentration, and xanthochromia in CSF of patients with SIH caused by diapedesis of protein and cells into the subarachnoid space [105], but we did not.
Here we briefly highlight some relevant signs seen on MRI in SIH cases. In this regard, Nadir Ali et al. [99] proposed a Mnemonic: SEEPS to remembering the five most relevant signs of SIH visible on MRI:
1. Sagging of brain or downward displacement of the brain.
2. Engorgement of venous structures
3. Enhancement of the pachymeninges
4. Pituitary hyperemia
5. Subdural fluid collection and the presence of extrathecal CSF.
Apart from reducing the angle between Galen vein and internal cerebral vein, collapsed superior ophthalmic vein, and spinal meningeal diverticula. However, the most characteristic MRI signs in SIH enhance the meninges, which is linear, non-nodular, and thick without the leptomeninges’ involvement, which serves to differentiated SIH from meningitis [99].
Around 50% of patients with SIH have bilateral subdural effusion without any appreciable mass effect resulting in a remarkable meningeal enhancement caused by a compensatory effect of the cerebral veins dilatation secondary to huge CSF volume loss [106].
At this bibliographic research level, we found that leptomeningeal enhancement is present in COVID-19 even associated with the presence of oligoclonal bands [107,108] and prominent subarachnoid spaces are quite common (47%) around the optic nerves adding another interrogate about intracranial pressure in SARS-CoV-2 infected patients apart these volumetric and micro-structural pathological changes in the olfactory cortices and white matter of recovered COVID-19 cases as before mentioned [93].
One crucial issue that needs to be deeper investigate is the distribution of the ACE-2 all over the brain and its relationship with the affected brain regions considering that SARS-CoV-2 penetrate the nervous cells by attaching to ACE-2 through Spike glycoprotein that indicates more severe brain damage going to be present where the ACE-2 be more abundant. In these regards, the expression of ACE-2 is higher in substantia nigra and second place the spinal cord, followed by the hippocampus, lentiform nucleus, caudate nucleus, thalamus, limbic system, and lastly, frontal lobe cortex [109].
Probable the coincidence of an essential expression of SARS-CoV-2 in the frontal lobe leading to more concentration of SARS-CoV-2, the proximity to the main entrance of the virus into the brain (olfactory gyrus) as the first functional area in the nervous system invaded by SARS-CoV-2 [110] (anosmia) plus the microstructural and functional integrity changes at the recovery stages [93] and the damage caused by the pro-inflammatory cytokines over the meninges layers and arachnoid rupture [70] may explain the subdural effusion and SIH present in this patient. Almost finishing this writing, another question arises. Why is affected the frontal lobe and no others? (See Figure 2) It is probably because of the same explanation delivered before: more concentration of ACE-2 in the frontal lobe than the others, then more concentration of SARS-CoV-2 resulting in more regional pathology leading to frontal subdural effusion SIH. This figure (SARS-CoV-2/ CT scan) also has the intention to bring into your mind that coronavirus can affect the brain after respiratory syndrome recovery. Now we have not a clear idea how the mutation happened in the spike protein can cause damage in the brain cortex/subarachnoid space leading to subdural effusion. It is only a mental excise to elaborate hypotheses and reminders that other investigators need to confirm or deny.