key: cord-0891139-e9gu9770
authors: Hixon, Alison M.; Thaker, Ashesh A.; Pelak, Victoria S.
title: Persistent visual dysfunction following posterior reversible encephalopathy syndrome due to COVID‐19: Case series and literature review
date: 2021-06-29
journal: Eur J Neurol
DOI: 10.1111/ene.14965
sha: 90a453db4ba42bcae04b726012216d743b86035c
doc_id: 891139
cord_uid: e9gu9770

BACKGROUND AND PURPOSE: The full spectrum of neurological sequelae in COVID‐19 is beginning to emerge. SARS‐CoV‐2 has the potential to cause both direct and indirect brain vascular endothelial damage through infection and inflammation that may result in long‐term neurological signs and symptoms. We sought to illuminate persistent neuro‐ophthalmological deficits that may be seen following posterior reversible encephalopathy syndrome (PRES) due to COVID‐19. METHODS: We identified three individuals with PRES due to COVID‐19 in our hospital system. One patient was identified on presentation to our neuro‐ophthalmology clinic. The other patients were identified through internal records search. These cases were compared to published reports of PRES in COVID‐19 identified through systematic literature search of PubMed/LitCOVID. RESULTS: All three patients were hospitalized with severe COVID‐19 and developed altered mental status with new onset seizures that led to the recognition of PRES through diagnostic imaging. During recovery, two patients had persistent visual dysfunction including visual field deficits. One patient also experienced hallucinatory palinopsia and visual hallucinations. Literature search identified 32 other cases of PRES in the context of COVID‐19. Visual disturbances were described in 14 cases (40%), with only seven cases (50%) reporting full recovery by the time of publication. CONCLUSIONS: As we learn about enduring neurological complications of COVID‐19, it is possible that complications may be underrecognized and underreported. Understanding the range of complications can help in postcare evaluation and management changes in the critical care setting to potentially allow intervention before persistent deficits occur due to COVID‐19.

of infectious virus, including "brain fog," fatigue, headache, memory impairment, and concentration difficulty [2] . These individuals, who have been referred to as "long haulers" in the popular press, are currently estimated to represent 10% of patients recovering from COVID-19 [3] .

The long-term consequences of SARS-CoV-2 infection on the CNS remain to be fully understood. In the next months to years of the pandemic, neurologists may begin to encounter patients experiencing neurological symptoms following COVID-19. It is vital to understand the range of post-COVID-19 neurological issues to provide the most appropriate treatments or referrals. Herein, we present a case series of two patients with persistent neuro-ophthalmological symptoms following posterior reversible encephalopathy syndrome (PRES) due to COVID-19. One patient presented to our clinic from within our health care system, whereas the other was discovered using an in-patient records search.

This study was conducted with approval by the institutional review board.

Our institution's EPIC charting system was interrogated with a built-in, self-service reporting tool called SlicerDicer. Population 

Patient data were extracted from chart review, including age, timing of diagnoses, brain imaging, COVID-19 hospital course, physical/ occupational therapy documentation, follow-up appointment specialty, and progress notes. International case reporting (CARE) criteria were followed [4] . Imaging was reviewed by a fellowship-trained neuroradiologist (A.A.T.) to rule out other possible causes for the symptoms, such as stroke.

The online database PubMed was searched with the query (posterior reversible encephalopathy syndrome) AND (COVID-19) from 

Descriptive statistics were employed. Graphs were created in Prism 8. 

A 69-year-old woman with a past medical history of hypertension and hyperlipidemia presented to an urgent care clinic with 5 days of cough and diarrhea. She had positive polymerase chain reaction (PCR) for SARS-CoV-2 RNA from a nasopharyngeal swab and had hypoxia requiring hospitalization. On hospital Day 4, she went into respiratory failure and was transferred to the intensive care unit (ICU) for mechanical ventilation. In addition to supportive care, she was treated with 2 days of azithromycin (1500 mg total), 4 days of hydroxychloroquine (1600 mg total), 7 days of ceftriaxone (7 g total), and an 8-day hydrocortisone taper (650 mg total). Her respiratory status improved, but she remained minimally responsive despite weaning from paralytics and sedatives.

On hospital Day 12, she was noted to have seizurelike jerking of her left face, arm, and leg and a leftward gaze deviation. She Six months after hospitalization, she sought follow-up care at our neuro-ophthalmology clinic for ongoing visual symptoms.

Anamnesis since time of discharge noted significant continuation of visual symptoms of blurry vision, difficulty seeing on the left side, reading difficulties, visual hallucinations that were confined to her blind field, and recurrence of visual hallucinations that would reappear with change in gaze, in a palinopsialike fashion. Visual hallucinations were described as "seeing dogs and dog [footprints]," "lights," and "squiggly lines," with recurrence of the same visual hallucination with change in gaze, similar to palinopsia with real images. Visual acuity was normal (20/20 in both eyes), and visual field testing revealed a left homonymous hemianopia ( Figure 1e ). Fundoscopic examination was normal except for symmetric optic disc cupping and epiretinal membrane changes in the right eye. Her Montreal Cognitive Assessment score was 27/30 (points lost for Trails B and cube copy), and the remainder of her neurologic examination was normal. All signs and symptoms of visual dysfunction, including visual field loss, were still present at her 12-month follow-up appointment.

A 55-year-old woman with a past medical history of diabetes mellitus and hypertension presented to our hospital system with a 4day history of shortness of breath, nausea, vomiting, and diarrhea and was found to be RNA-positive by PCR for SARS-CoV-2 from a nasopharyngeal swab. She went into respiratory failure on hospital Day 3 and was transferred to the ICU for mechanical ventilation. In addition to supportive care, she received 6 days of hydroxychloroquine (2000 mg total), 6 days of methylprednisolone (760 mg total), 10 days of ceftriaxone (12 g total), and 10 days of azithromycin (5000 mg total). Her respiratory status improved, and she was ex- (Table 1) [13, 26] . BP was reported in nearly all cases and was often described as poorly controlled or fluctuating, but continuous monitoring information was difficult to glean from case descriptions.

Notably, 10 cases (28%) reported systolic BP greater than 200 mmHg [10, 21] , diastolic BP greater than 100 mmHg [13, 19, 26] , or mean arterial pressure greater than 100 mmHg [17, 20, 21] .

Altered mental status (57%, n = 20) and seizures (54%, n = 19)

were the most common neurological manifestations leading to a diagnosis of PRES (Figure 4b ). Other neurological signs or symptoms described were visual disturbances (40%, n = 14), limb paresis (29%, n = 10), dysphasia/aphasia (14%, n = 5), other sensory deficits (6%, n = 2), vertigo (6%, n = 2), and headache (3%, n = 1). Some cases had more than one manifestation. Many cases had complete resolution of neurological issues by the time of publication, but approximately one third of individuals had residual problems including cognitive deficits, vision loss, and weakness ( Figure 4b and Table 1 ). Death occurred in four (11%) cases ( Figure 4b and Table 1 ) [6, 18, 23, 25] .

Neuro-ophthalmologic issues related to PRES were described in 14 (40%) of the case reports (Table 1 ). Signs and symptoms described included visual field defects at any level (57%, n = 8), cortical blindness (21%, n = 3), palinopsia (14%, n = 2), and other visual hallucinations (14%, n = 2; Figure 4c and Table 1 ). Whereas half of these cases reported complete resolution of the visual issue, the other half of case reports described ongoing visual problems at the time of publication ( Figure 4c and Table 1 ).

We identified three patients in our health care system, one at presentation to neuro-ophthalmology and two through chart search, who developed PRES in the context of hospitalization for severe COVID-19. The three cases presented here had many features in common. All individuals experienced a protracted hospital course requiring ICU stay with mechanical ventilation due to COVID-19.

Furthermore, all experienced new onset seizures after weaning of sedation or extubation that led to MRI that detected posterior circulation predominant T2/FLAIR hyperintensities within white matter and cortex of the parieto-occipital regions consistent with a diagnosis of PRES. Of these three cases, two experienced visual complications following development of PRES. Two patients had known persistent visual abnormalities at the time of hospital discharge, but only one had neurologic and neuro-ophthalmic follow-up to confirm that visual deficits were still present at 12 months. Of note, Cases 2 and 3 were not fully examined by our team, and, therefore, their long-term neurological outcomes are unknown.

Literature review supported our finding that visual manifestations of PRES in the context of COVID-19 may persist and include visual field defects, cortical blindness, visual hallucinations, with palinopsialike images. One case described previously had transient hallucinatory palinopsia due to PRES, also in the context of COVID-19, that was described as previously seen images recurring over 2 days (Table 1 ) [14] . Our (Case 1) patient's experience was different from this prior report, with palinopsia of prior release visual hallucinations and not of previously seen real images.

Literature review also identified that other persistent cognitive, motor, and sensory neurological sequelae were common following What is the mechanism of neurological injury? A key component to PRES development is endothelial injury secondary to immune activation [28] . As such, PRES is known to occur more commonly in patients with severely elevated BP, pregnancy, specific immunomodulatory medications, and increased systemic inflammation, such as in autoimmune diseases, sepsis, and organ transplants, among other predispositions [28] . With endothelial dysfunction and vascular autoregulation, rapid increases in BP may increase risk of damage to brain structures by further increasing vasogenic edema [29] . In the case of our patients, only one had a systolic BP near 180 mmHg, with most pressures in the highnormal range less than 150 mmHg, which are well below the upper limit of normal for cerebral perfusion autoregulation [28] . Lack of severe BP elevation was similarly a feature of most literature cases, and has been supported by one postmortem study [30] . Susceptibility to PRES during (iv) Long-term neurological symptoms related to COVID-19 could be related to viral or inflammatory-related endothelial dysfunction and merit detailed scientific investigation to uncover further risk factors and disease mechanisms.

The authors report no conflicts of interest. 

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Alison M. Hixon https://orcid.org/0000-0002-8373-4311

Ashesh A. Thaker https://orcid.org/0000-0001-5238-0429

Victoria S. Pelak https://orcid.org/0000-0003-3147-8595 F I G U R E 4 Summary of literature review cases. Literature review resulted in inclusion of 35 cases of posterior reversible encephalopathy syndrome (PRES) due to COVID-19 across 22 publications. (a) Level of illness with COVID-19 was described as critical in 69% (n = 24/35), severe in 9% (n = 3/35), mild in 14% (n = 5/35), and asymptomatic in 6% (n = 2/35), and was not clearly described in 3% (n = 1/35). (b) PRES patients reported neurological manifestations that included altered mental status, seizures, visual disturbances, limb paresis, other sensory disturbances, vertigo, and headaches. Outcomes of PRES neurological manifestations were described as full recovery in 37% (n = 13/35), not full recovery in 31% (n = 11/35), and unclear recovery in 20% (n = 7). Death occurred in 11% (n = 4) of cases. (c) Visual problems were described in 40% (n = 14/35) of cases. Separating out the visual problems from the other neurological data revealed that full recovery was described in 50% (n = 7/14), whereas 43% (n = 6/14) were not recovered by the time of the case report, and 7% (n = 1/14) had unclear outcomes.

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Persistent visual dysfunction following posterior reversible encephalopathy syndrome due to COVID-19: Case series and literature review