Introduction
SARS-CoV-2 SS mRNA (30 kb) virus belongs to Beta corona family, a novel corona virus identified first in Wuhan, a city in Hubei Province of China. In addition to conventional respiratory complaints of flu, COVID-19 positive patients also exhibit neurological signs and symptoms which can result from direct viral invasion across cribriform plate of ethmoid bone close to olfactory bulb or hematogenous route or hypoxic, toxic or immune mediated injury.1, 2 The neuroinvasion potential is documented in most human coronaviruses (OC-43, 229E, MERS and SARS) and in some animal coronaviruses (porcine haemagglutinating encephalomyelitis coronavirus).3 Neurological manifestations of COVID-19 include Anosmia, Ageusia, headache, insomnia, Epilepsy, stroke, rarely PRES, Guillian – Barre syndrome, Miller Fisher syndrome etc.1, 2, 4
Hinchey et al. in 1996 first described PRES, a clinico neuroradiological entity which is associated with acute cerebral endotheliopathy, consecutive disruption of the blood–brain barrier (BBB) resulting in vasogenic oedema due to abrupt rise of blood pressure in eclampsia.5, 6 The diagnosis is based on (1) at least 1 acute neurological symptoms (headache, visual disturbances, seizure, altered mental state etc); (2) CT/MRI with bilateral vasogenic oedema, cytotoxic oedema with PRES Patterns; and (3) with no other alternative diagnosis.7
Association between PRES and SARS-CoV-2 infection is not clear. Target receptor for SARS-CoV-2 is ACE2 receptor, which is expressed on several organs, endothelial cells. Entry of virus depends on interaction between spike protein, TMPRSS2, ACE2 receptor. Following virus entry, the expression and function of ACE 2 (ACE2) proteins are reduced, resulting in hypertension, endothelial inflammation that may induce PRES. The COVID related endothelitis8 could explain the systemic impaired microcirculatory function in different vascular beds. In the brain, this endothelitis induce increased permeability of the BBB, leading to a brain oedema. Other classical causes of PRES in these patients could be ARDS, tocilizumab, sepsis and acute kidney injury requiring haemodialysis,9 severe hypoxic pneumonia and treatment targeting SARS-CoV-2.
It is also suggested that the increased levels of cytokines (TNF-α, IFN-γ, IL-1) and inflammatory mediators in the course of the disease are responsible for cerebrovascular endothelial dysfunction and disruption of the blood-brain barrier.1
Materials and Methods
This is a prospective observational study conducted at GANDHI hospital, Secunderabad, a nodal centre for COVID-19 in Telangana and a tertiary care referral centre. This study was conducted on COVID -19 positive eclampsia patients during March 2021 to August 2021. This study was approved by Internal Institutional Ethics committee. All COVID-19 positive eclamptic women with neurological symptoms who had persistent headache, or visual disturbances even after 24 hours of magnesium sulphate (MgSo4) coverage who underwent neuro imaging study were included in this study.
Maternal outcomes expressed in terms of clinical presentations, associated maternal complications, need for mechanical ventilation, maternal mortality and neuro imaging to identify typical PRES changes and patients are being followed up after 4–6 weeks. The perinatal outcomes including birth weight, APGAR scores, NICU admissions and perinatal deaths were studied.
Results
A total of 471 covid-19 positive patients delivered from March 2021 to August 2021. Of these, 55 women were presented with eclampsia and 17 of them were PRES. Among 17 patients of PRES, Seven patients had severe COVID-19 disease out of which five patients required noninvasive ventilation and two patients required invasive ventilation. Out of 17 patients, 11(64.7%) had antepartum eclampsia, 6 (35.29%) had postpartum eclampsia. In our study Common age of the women at diagnosis of PRES was 21 – 25 years. Out of 17, 11 (64.7%) are of primigravida, 16(94.1%) are un-booked cases, 15 (88.2%) belong to low socio-economic status. Covid-19 related maternal complications are seen in 41.7% of cases. Eclampsia related maternal complications are seen in 29.4% of cases which increases with number of convulsions, convulsion to delivery interval and onset of convulsion to admission interval. There is one maternal death and 3 perinatal deaths, mostly due to prematurity. Most of them delivered term (11 out of 17). In the present study, 10 (58.8%) patients were delivered vaginally. The demographic and clinical characteristics are summarised in (Table 1).
Table 1
Table 2
|
Onset of convulsion to admission Interval |
Eclampsia related maternal complications |
|
|
Yes |
No |
|
|
< 6 |
1 |
11 |
|
> 6 |
4 |
1 |
|
Total |
5 |
12 |
Table 3
|
No. of Convulsions |
Eclampsia related maternal c omplications |
|
|
Yes |
No |
|
|
≤ 2 |
1 |
10 |
|
3-5 |
4 |
2 |
|
Total |
5 |
12 |
Table 4
|
Convulsion to delivery interval |
Eclampsia related maternal complications |
|
|
Yes |
No |
|
|
≤ 12 |
2 |
12 |
|
> 12 |
3 |
0 |
|
Total |
5 |
12 |
Mean systolic and diastolic blood pressures were 177±12 and 110±6 mm Hg respectively.
The clinical features of PRES were summarised in Figure 4.
Among 17 Covid-19 positive eclampsia with PRES cases 15 patients had thrombocytopenia;41.1% of patients between 0.5 – 1 lakhs/mm3.
Out of 17 women with PRES 5 (29.4%) had eclampsia related maternal complications like HELLP, AKI, DIC and pulmonary oedema, whereas 1 (5.8%) women required dialysis. There was 1 (5.8%) maternal death in the current study.
The site of lesions of PRES on MRI were summarized in Figure 5. 15 cases were reversible after 4-6 weeks, 1 had gliosis and 1 patient had intra cerebral haemorrhage.
Discussion
PRES is a rare complication of eclampsia and can also be associated with multiple clinical conditions like hypertensive encephalopathy, renal failure, auto immune disorders, and immunosuppressive drugs.10 Uncommon clinical conditions include Acute intermittent porphyria, cryoglobulinemia, recently COVID-19. The pathophysiology behind PRES is not clearly understood and shares the eclampsia pathophysiology.11 Two mechanisms have been put forth, failure of auto regulation due to abrupt rise of B.P and endothelial dysfunction resulting in vasogenicoedema.4, 5
The global incidence of PRES is unknown. Out of 253 eclampsia cases (Covid and Non-Covid), 17 (COVID positive) out of 50 PRES cases (covid and non covid) were COVID-19 positive with p value of 0.018, which is statistically significant. It implies that COVID -19 might be strongly associated with PRES in Eclampsia.
In present study, many were primigravida and common in age group 21-25 years as compared to Manavi PJ study12 (average age is 21 years, many were primigravida).
In the present study we observed 64.7% and 35.2% of patients had PRES during antepartum and postpartum period respectively and is similar to Manavi PJ study.12 According to Brewer J study13 there was no significant difference between antepartum and postpartum PRES cases.
In the present study common presenting symptom of PRES was headache (52.9%) and blurring of vision (23.5%) which is similar to several studies.6, 10, 13
Most common site of lesions of PRES in MRI: Occipito Parietal (41.1%) > Occipital (29.4%) > Atypical (11.7%). All our patients had cerebral oedema compared to Zeeman GG study.14 In the typical form, the abnormalities include bilateral symmetrical hyperintensities in subcortical white areas in occipitoparietal lobes. In the atypical forms, there can be unilateral or asymmetric pattern of involvement.15
According to the most accepted theory, an abrupt rise in blood pressure over a short period of time leads to a failure of normal auto regulatory mechanisms resulting in cerebral hyper perfusion, increased capillary pressure, vasodilatation, and therefore vasogenicedema especially in posterior circulation due to less sympathetic innervation and is usually reversible. So control of hypertension is the important component in PRES management. Labetalol is the drug of choice. 16
Seizure control in eclamptic women and termination of pregnancy in antenatal eclampsia is the main step of the treatment and Mgso4 is the drug of choice. Magnesium decreases neuronal excitability, prevents endothelial damage by free radicals, or reduces cerebral perfusion pressure. 17, 18 In CNS it may also protect the BBB (blood brain barrier) and therefore limit cerebral edema formation.
In the peripheral or cerebral vasculature, it acts as a vasodilator to decrease peripheral resistance.13, 17 82.3% cases were controlled with MgSO4 alone in our study and 17.6% cases were treated with MgSO4 and Mannitol, where as Shobhabhomalgi study reported only 67% responded to MgSO4.
Corticosteroids can be used to treat hemolysis, elevation of liver enzymes and lowering platelet count that occurs in HELLP syndrome. Review of literature says corticosteroids reduce vasogenicedema.19 Recent study by Mayama et al. showed that patient who received antenatal steroid to enhance lung maturation or for HELLP management revealed faster recovery of CNS functions in eclamptic patients with PRES.11, 20 In our study effect of corticosteroids on recovery is not studied.
Out of 17 PRES cases, 15 cases were reversible after 4-6 weeks, 1 had gliosis and 1 patient had intra cerebral haemorrhage. Maternal mortality in our study was 5.8% and perinatal mortality was 17.6% as compared to 11% perinatal mortality rate in Manavi et al. study.12
Conclusion
Incidence of PRES in covid-19 eclamptic cases was high probably due to neurotropism, endothelial dysfunction or immune mediated or direct cell injury causing cerebral/vasogenic oedema which is precipitated by acute raise of blood pressure in eclampsia which results in disrupted auto regulation of brain which precipitates vasogenicedema especially in posterior circulation of brain. However, the association between SARS-CoV-2 and PRES is not clear. Regular antenatal checkups, early referral to tertiary care centre, regular B.P monitoring would prevent eclampsia and its related complications. Early diagnosis and Multidisciplinary approach in PRES management would prevent some of its devastating sequelae such as permanent visual loss or irreversible neurological deficit.
