Raised Intracranial Pressure (Pseudotumour Cerebri) Associated With Severe Acute Respiratory Syndrome Coronavirus 2

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Raised Intracranial Pressure (Pseudotumour Cerebri) Associated With Severe Acute Respiratory Syndrome Coronavirus 2 Rubika Balendra, MRCP, PhD, Matthew North, MRCP, PhD, Guru Kumar, MBBS, MRCP, Saad Qutab, MBBS, MRCP, Hamid Aminy Raouf, MRCP, Shane S. Delamont, FRACP, FRCP(Lond), MD, M. S. Chong, MD, FRCP, Shahir S. Hamdulay, PhD, FRCP, Mushtaqur Rahman, PhD, FRCP, Fergus J. Robertson, MRCP, FRCR, Chandrashekar Hoskote, FRCR, Fion D. Bremner, PhD, FRCOphth, Simon F. Farmer, PhD, FRCP, Laurence Watkins, FRCS(SN), Michael S. Zandi, PhD, Hadi Manji, MD, FRCP, S. Anand Trip, PhD, FRCP, Ross W. Paterson, MRCP, PhD, Orlando B. C. Swayne, MRCP, PhD S everal neurological sequelae of coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are now described (1). We describe a pair of cases demonstrating a novel association between COVID-19 and severely raised intracranial pressure (ICP). Patient 2 is included as part of a summary of 43 cases of COVID-19 neurology (1). A 29-year-old female nurse of Indian origin with a body mass index (BMI) of 25kg/m2 and a background of hypothyroidism developed intermittent, low-intensity headaches, particularly affecting the left hemicranium, 6 weeks after the onset of SARS-CoV-2 respiratory illness. These headaches became bifrontal after a week and were associated with intermittent blurring of distance vision and pulsatile tinnitus. She then developed neck pain and sudden-onset chest pain radiating across the anterior chest wall, into the back and down both arms with nausea and vomiting. Investigations showed a normal result for electrocardiogram, Troponin T test, and blood tests, except for a microcytic anemia; computerized tomography of the head was normal. She was discharged home. Two days later, she had a significant deterioration in her vision and was no longer able to use her cell phone or see faces clearly. She presented to hospital 2 days later National Hospital for Neurology and Neurosurgery (RB, FR, CH, FB, SF, LW, MSZ, HM, SAT, RP, OS), Queen Square, London; Northwick Park Hospital (MN, SH, MR, SAT, OS), Watford Rd, Harrow; and Darent Valley Hospital (GK, SQ, AR, SD, SC, RP), Darenth Wood Rd, Dartford. R. Balendra is funded by a National Institute of Health Research (NIHR) Academic Clinical Lectureship in Neurology. O. Swayne is supported by the UCLH NIHR Biomedical Research Centre. The serology study was supported by a grant from the UCLH NIHR Biomedical Research Centre. The authors report no conflicts of interest. Address correspondence to Orlando Swayne, MRCP, PhD, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG; E-mail: [e-mail] Balendra et al: J Neuro-Ophthalmol 2022; 42: e459-e462 and was admitted with ongoing severe chest and back pain, which was exacerbated in an upright posture and alleviated by lying flat. Her neurological examination revealed significantly reduced visual acuities (right eye 6/36 and left eye 1/60), and she was unable to read the Ishihara test plate for colour vision in either eye. She had Frisén Grade V papilledema bilaterally (Fig. 1A–D) and severely reduced visual fields, predominantly affecting the nasal hemifields bilaterally (Fig. 2A, B). Blood tests revealed a microcytic anemia with hemoglobin of 99 g/L (115–155 g/L) and mean corpuscular volume of 76 fL (80–99 fL). There was an iron deficiency with iron level of 3 mmol/L (6–35 mmol/L), transferrin saturations of 4% (20%–45%), and ferritin of 8 mg/L (13–150 mg/L). Erythrocyte sedimentation rate (ESR) was elevated at 77 mm/hr (1–20 mm/hr). SARS-CoV-2 serology was positive (Roche Immunoassay). Lupus anticoagulant was positive with negative cardiolipin and beta-2 glycoprotein antibodies. She had an elevated D-dimer of 940 mg/L (0–550 mg/L), elevated fibrinogen of 4.5 g/L (1.5–4 g/L), and normal coagulation protocol. Total protein was elevated at 84 g/L (60–80 g/L), and immunoglobulin G (IgG) and immunoglobulin A were normal with elevated immunoglobulin M (IgM) 4.2 g/L (0.4–2.3 g/L). Other results including a vasculitis and microbiology screen were normal. The day after the admission, she had MRI of the head with contrast, which demonstrated typical features of raised ICP with dilated optic nerve sheaths. Contrast opacification within the dural venous sinuses was normal. The next day, she had a lumbar puncture, which demonstrated a cerebrospinal fluid (CSF) opening pressure of .80 cmCSF, with normal constituents; with CSF drainage, the pressures were reduced down to 40 cmCSF. The next day, due to further deterioration in her vision to perception of light only, she had a further lumbar puncture, which demonstrated a CSF e459 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Ophthalmological assessments of Case 1. Case 1 A and B: Retinal photographs demonstrate marked bilateral papilledema (Frisén Grade 5) affecting the left eye (B) more than the right (A) with prepapillary and peripapillary hemorrhages and cotton wool spots. C, D. Spectralis optical coherence tomography (OCT) images of the right (C) and left (D) optic discs showing subretinal and intraretinal fluid tracking from the disc. E, F. Follow-up retinal photographs reveal that the papilledema has resolved in both the right (E) and left (F) eyes. G, H. Follow-up OCT images of the right (G) and left (H) optic discs showed thinning of the peripapillary retinal nerve fibre layer temporal to both optic discs, as well as some secondary subfoveal scarring. opening pressure of .110 cmCSF, and the pressures were reduced down to 20 cmCSF. She was transferred to a regional neurosciences centre as an emergency that evening, and a lumbar drain was inserted the following day. The radicular thoracic pain improved immediately after the lumbar drain. She had a catheter venogram, which demonstrated bilateral transverse/sigmoid sinus stenoses, with significant pressure drops of .20 mm Hg at each. She was started on acetazolamide at 250 mg twice daily. Venous stenting was considered, but after discussion, the transverse/ sigmoid sinus stenoses were thought to be secondary to the raised ICP. Nine days after the lumbar drain was inserted, the CSF pressures remained elevated whenever the lumbar drain was clamped, and therefore, a lumboperitoneal shunt was inserted. By 11 days after the shunt insertion, visual acuities had improved to 6/12 in her right eye and to 6/60 in her left eye. Colour vision was normal (13/13 Ishihara), with improving papilledema appearances and visual fields. Two months after discharge from hospital, her vision had e460 improved, with visual acuities of 6/9 (corrected to 6/6 with pinhole) in the right eye and of 6/36 in the left eye. Her visual fields had also improved, with only mild loss of sensitivity persisting in the nasal fields of both eyes (Fig. 2C, D). The papilledema resolved (Fig. 1E, F), but optical coherence tomography scanning now showed thinning of the peripapillary retinal nerve fiber layer temporal to both optic discs and some secondary subfoveal scarring (Fig. 1G, H). Repeat blood tests revealed that the ESR had reduced to 40 mm/hr (1–20 mm/hr). Lupus anticoagulant remained positive with negative cardiolipin and beta-2 glycoprotein antibodies. IgM was elevated at 3.25 g/L (0.4–2.3 g/L). A 16-year-old female patient of Sri Lankan origin with a normal BMI for her age of 23.4 kg/m2 (81st centile, normal range 3rd–90th centile) presented with a 5-day history of fever, back pain, vomiting, then headaches and a sore throat, suggestive of SARS-CoV-2 respiratory illness. The headache had no other significant features. She had a C-reactive protein (CRP) of 294 mg/L (0–5 mg/L) and Balendra et al: J Neuro-Ophthalmol 2022; 42: e459-e462 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 2. Visual field assessments of Case 1. Case 1 A and B: 24-2 Swedish interactive testing algorithm (SITA) fast visual field testing was performed. Humphrey visual fields of the left (A) and right (B) eyes demonstrate severely reduced visual fields, predominantly affecting the nasal hemifields bilaterally. C, D. Humphrey visual fields of the left (C) and right (D) eyes repeated 2 months after discharge from hospital demonstrate improved visual fields, with only mild loss of sensitivity persisting in the nasal fields of both eyes. pyrexia, an elevated troponin T of 1979 ng/L (0–14 ng/L), and an elevated D-dimer of 855 mg/L (0–550 mg/L). A chest radiograph demonstrated bibasal infiltrates. Clinically, this was consistent with a probable COVID-19 illness, as determined using World Health Organisation criteria (“Global surveillance for human infection with coronavirus disease [COVID-19]”). Four nasopharyngeal swabs for SARS-CoV-2 were negative. She did not have clinical serology testing performed because it was not clinically available at the time. However, she was recruited to a fluid biomarker study (1) of patients with clinically probable COVID-19 infection and CNS presentations, in which approximately 85% of individuals had positive SARS-CoV-2 IgG in contemporaneous samples (the study ethics only permit grouplevel reporting). Her electrocardiograms showed T-wave inversion in V1–V3. An echocardiogram demonstrated a small pericardial effusion, and she was diagnosed with myopericarditis and started on colchicine. Blood tests, including a vasculitis and microbiology screen, were normal. Nine days after the onset of her COVID-19 symptoms, she reported double vision particularly looking to the right. By this point, she was systemically well, and the CRP had improved. She had right-sided headaches, worse on lying down and in the mornings, without significant photophobia or phonophobia. She had a right abducens palsy without papilledema (Fig. 3A– C). Two days later, the abduction failure had worsened. There was a partial left-sided lower motor neuron facial nerve palsy. Two days further on, she had developed a left abducens palsy and increased left orbicularis oculi weakness. An MRI head 2 days after the onset of diplopia was normal, but a repeat MRI head with venography 10 days later demonstrated signs consistent with raised ICP with no evidence of a venous sinus thrombosis. Balendra et al: J Neuro-Ophthalmol 2022; 42: e459-e462 A lumbar puncture 5 days after the onset of the diplopia demonstrated an elevated CSF opening pressure of 39 cmCSF, with normal CSF constituents. A repeat lumbar puncture 5 days later showed an opening pressure of 27 cmCSF. Acetazolamide was started the next day at 250 mg twice daily. The headaches, diplopia, and left facial nerve palsy improved over the subsequent few days, with full resolution by follow-up review at 8 weeks. DISCUSSION The proposed mechanisms of raised ICP in idiopathic intracranial hypertension include venous sinus stasis, reduced CSF drainage across arachnoid granulations, increased venous sinus pressure from venous sinus stenosis, and congestion of the glymphatic system, with contribution of inflammatory and thrombophilic factors (2,3). COVID-19 is associated with a prothrombotic coagulopathy and hyperviscosity (4), with microvascular and macrovascular thromboses (5). The second case had some features seen in children with multisystem inflammation with gastrointestinal and cardiac involvement, supporting an inflammatory mechanism in part (6). In this case series, we hypothesize that SARS-CoV-2 infection led to a proinflammatory and prothrombotic state evident on blood biomarkers, resulting in venous stasis, impaired glymphatic flow, raised ICP, and, consequently, venous sinus stenoses. The first case also had a slightly high BMI and an iron deficiency anemia, which could have been contributory factors (7). Initially, her most severe symptom was thoracic and chest pain, reflecting radicular pain, which has been described in raised ICP (8). The second case developed abducens palsies secondary to the raised ICP, and a left facial nerve palsy was also likely due to the raised ICP, which has been reported previously (9). e461 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 3. Eye movements of Case 2. Case 2: External photographs of the Case 2 patient’s right gaze (A), primary position (B), and left gaze (C). These demonstrate an esotropia in primary gaze, which worsens in right gaze, and there is an abduction deficit of the right eye. These findings are consistent with an abducens palsy on the right eye. In the context of the COVID-19 pandemic, there is a theoretical risk of infection transmission to clinicians when performing ophthalmoscopy (10). In light of the risk of missing raised ICP, and the potentially significant consequences illustrated by these cases, we advocate for funduscopy to be undertaken early and safely in patients presenting with headache and visual symptoms during the current COVID-19 pandemic. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: R. Balendra, M. North, G. Kumar, S. Qutab, A. Raouf, S. Delamont, S. Chong, S. Hamdulay, M. Rahman, F. Robertson, C. Hoskote, F. Bremner, S. Farmer, L. Watkins, M.S. Zandi, H. Manji, S. A. Trip, R. W. Paterson, O. Swayne; b. Acquisition of data: R. Balendra, M. North, G. Kumar, S. Qutab, A. Raouf, S. Delamont, S. Chong, S. Hamdulay, M. Rahman, F. Bremner, S. Farmer, L. Watkins, S. A. Trip, R. W Paterson, O. Swayne; c. Analysis and interpretation of data: R. Balendra, R. W. Paterson, O. Swayne. Category 2: a. 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