Acute Bilateral Blindness in the Setting of Sudden Onset of Bilateral Proptosis and Ophthalmoplegia

Abstract

Purpose of Review

Acute bilateral blindness has an extensive differential diagnosis that requires a careful history and physical examination to narrow down. In this article, we discuss the pathophysiology and radiographic findings of each possible diagnosis for acute bilateral blindness.

Recent Findings

Visual pathology with respect to bilateral blindness can be broadly broken down into 3 anatomic categories: media (i.e., the anterior and posterior chamber of the eye), retina, and neural visual pathway. Possible causes of rapid onset bilateral blindness include bilateral occipital infarcts, endogenous bacterial endophthalmitis, orbital cellulitis, orbital compartment syndrome, cavernous sinus thrombophlebitis, thyroid disease, and bilateral nonarteritic ischemic optic neuropathy.

Summary

In this case, we present a patient with acute onset of bilateral blindness, in addition to bilateral ophthalmoplegia, proptosis, and orbital chemosis. We believe that this rare case of acute bilateral blindness is thought provoking and aids in the understanding of the differential diagnosis and underlying pathophysiology of visual loss.

Acute bilateral blindness has an extensive differential diagnosis that requires a careful history and physical examination to narrow down. Visual pathology with respect to bilateral blindness can be broadly broken down into 3 anatomic categories: media (i.e., the anterior and posterior chamber of the eye), retina, and neural visual pathway.¹ Anatomically, the orbits are symmetrically confined compartments separated by the nasal cavity and paranasal sinuses. The orbit contains the globe, orbital fat, lacrimal gland, extraocular muscles, and neurovascular structures.^2,3 Fat tissue surrounding the orbits facilitates the movement of the eye and acts as a protective cushion for extraocular muscles and the globe. The orbital septum is a connective tissue that serves as an anterior border between the facial skin and the orbital contents. It prevents infection from spreading into the orbit; thus, it is an important landmark in distinguishing between orbital cellulitis and periorbital cellulitis.

Because of the orbit's limited capacity, an increase in intraorbital pressure can result in orbital compartment syndrome (OCS) that compromises the blood flow to the optic nerve and globe. OCS can lead to permanent visual impairment possibly due to damage to the optic nerve from prolonged ischemia.² Hence, any process that increases intraorbital pressure acutely can lead to compartment syndrome. Common causes include thyroid-associated orbitopathy, intraorbital hemorrhage due to trauma or surgery, spontaneous retrobulbar hemorrhage, accumulation of fluid within the orbit, orbital cellulitis, expanding tumor, and orbital emphysema.^2,4 Bilateral acute blindness is a rare phenomenon, and in this case report, we illustrate how the etiology can be multifactorial including OCS, orbital cellulitis, cavernous sinus thrombophlebitis, and bilateral nonarteritic ischemic optic neuropathy (NAION) as potential players in our patient's permanent vision loss. Table illustrates the most common differential diagnoses for acute onset bilateral vision loss with bilateral proptosis.

Table.

Most Common Differential Diagnoses for Acute-Onset Bilateral Vision Loss With Bilateral Proptosis

Case

Sixty-nine-year-old man arrived at emergency department by ambulance after being down on the ground for at least 2 days. His medical history included squamous cell carcinoma of the tongue status postresection surgery, submandibular cancer with radiation therapy complicated by jaw necrosis, history of left upper extremities deep vein thrombosis (on warfarin), cardiomyopathy status postpacemaker, bicuspid valve regurgitation, and iron deficiency anemia. The patient was found on the ground in his home by his neighbors. Per emergency medical services report, neighbors had not seen the patient for 1 week and found him lying on the ground covered in ants and urine.

During the initial interview in the emergency department, the patient stated that he felt like he had the stomach flu for a week and developed general body aches that progressively worsened. He believed that he was on the ground for about 2 days. He stated that he had not taken his warfarin for about 1 week. Initially, he denied any shortness of breath, chest pain, abdominal pain, seizure, headache, or visual change. He denied smoking or using any illicit drugs and reported drinking 1 beer per night.

At the time of arrival, the patient had a blood pressure of 90/40 and fever of 102.5 F. The rest of his vitals were normal. Sepsis alert was activated, and the patient received the standardized sepsis treatment including fluid resuscitation and empiric antibiotics. Initial physical examination was unremarkable. The neurologic examination did not show any focal sensory or focal motor deficits. He was alert and oriented ×4. His motor strength was 3 of 5 in all 4 extremities with intact sensation throughout. Mild conjunctival hematomas and proptosis were seen on both eyes, but no change in vision was noted. Initial labs were consistent with rhabdomyolysis (creatine kinase 13152), acute kidney injury (AKI) (blood urea nitrogen 76, Cr 5.910, glomerular filtration rate 10), thrombocytopenia (platelet count: 17), acute transaminitis (aspartate aminotransferase: 601, alanine transaminase: 119), and hyperbilirubinemia. Initial ECG and cardiac enzymes were elevated (troponin: 5.4). Furthermore, his concurrent renal failure resulted in delayed renal clearance of troponin.

The patient's pacemaker was not compatible with MRI. Imaging was limited to CT of the brain and orbits (Figures 1–3), spine, abdomen, and pelvis (all without contrast), with each initially reported as negative for acute pathology. Given his rhabdomyolysis, AKI, and sepsis, he was sent to the intensive care unit for higher level of care. He persisted to have leukocytosis, and his blood culture results came back positive for Streptococcus dysgalactiae, and sputum culture was positive for light yeast as well as methicillin-resistant Staphylococcus aureus. He received empiric antibiotic including IV infusion of vancomycin (per pharmacy protocol), cefepime 1 g every 24 hours for 5 days, and metronidazole 500 mg/100 mL every 8 hours for 5 days.

Figure 1. Orbital Compartment Syndrome Radiographic Findings on CT Orbit of Our Patient.

Axial contrast-enhanced CT image of the orbits reveals bilateral proptosis and globe deformity with a posterior globe angle of 115° on the left and 125 on the right indicating globe tenting (A). There is rim enhancing fluid collection (more on the left orbit) with stretching of the optic nerve. These imaging findings are consistent with orbital compartment syndrome (B).

Figure 2. Orbital Cellulitis' Radiographic Findings on CT Orbit of Our Patient.

(A) Opaque sinuses indicating a predisposing sinusitis. (B) Bilateral proptosis with soft tissue inflammation and retrobulbar inflammation along with left optic nerve sheath enhancement.

Figure 3. Cavernous Sinus From CT Brain of Our Patient.

There is no radiographic evidence of high-density thrombus in cavernous sinus.

Two days after admission, the patient became anuric, and repeat creatinine level was even higher than his initial value. He was placed on hemodialysis (HD) to replace the kidney function. During dialysis, 1 liter of fluid was removed, and his systolic blood pressure dropped from baseline (97–120s) to (70s) then stayed in the 80s for a few hours with fluctuation between the 70s and 80s. The lowest recorded blood pressure was 74/45 for almost 1.5 hours. Shortly after these fluctuations of systolic blood pressure, the patient reported acute onset of bilateral vision loss while watching television. The patient denied any previous vision problems. Ophthalmology was consulted and based on the initial evaluation; the patient had conjunctival edema and chemosis, with corneal edema and bilateral cataracts. Recommendations included moist packs, using artificial tears in both eyes, erythromycin eye ointment, and loteprednol 1–2 drops 4 times a day.

On the follow-up examination at bedside, the patient was demonstrably responsive as he could nod his head and follow some commands, moving his right arm when prompted. He exhibited exophthalmos and exudative secretions bilaterally. Ophthalmology described severe prolapse and swelling with edematous fluid noted in the inferior conjunctiva of the right eye and left eye as well as subconjunctival hemorrhage. On closure of the eyelids, the conjunctival chemosis prolapsed through both eyelids. On ocular examination, the cornea was hazy in both eyes. The anterior chamber also appeared to be deep. The iris was hazy. The pupils were fixed and nonreactive to light at 3.5 mm. There appeared to be a cataract in each eye. Corneal edema and nuclear sclerosis appeared to be obstructing the view to the posterior segment. Both eyes demonstrated a very dull red reflex and minimal horizontal movement on oculocephalic maneuver testing. He was able to move his right arm to command, which was at least a 4/5 in strength, but unable to move neither his left arm nor his legs. He could wiggle his toes intermittently. He demonstrated hyporeflexia with no Babinski.

The repeat brain CT without contrast, 2 days postadmission, showed small mixed density subdural hematoma along the bifrontal cerebral convexities measuring up to 5 mm on the right and 3 mm on the left, stable to mildly increased in size since the initial CT brain. No findings were noted to suggest sinus thrombosis or ischemic stroke. erythrocyte sedimentation rate (28) and C-reactive protein (25.4) were not significantly elevated as would be seen in systemic vasculitis. Workup was negative for myasthenia gravis and thyroid disease by antibody labs (skeletal muscle antibody, thyroid antimicrosomal, and acetylcholine receptor antibody).

The CT of orbits with and without IV contrast, 5 days postadmission, showed abnormal thickening and stranding of the left globe on postcontrast images and had a discontinuous superior border of the globe, filled with fluid extending superiorly but remaining contained. This was a new finding compared with the earlier scan. There was also similar thickening and mild stranding about the right globe, but less inflammation compared with the left. The right globe also appeared slightly oblong along the superior border, but no appreciable discontinuity at this time.

Gram stain, anaerobic culture, and fungal culture were performed on both eyes. The culture result at 24 hours was negative. However, after 72 hours, the left eye culture result was positive for methicillin-resistant Staphylococcus aureus sensitive to vancomycin which patient was already receiving IV.

On follow-up evaluation, the chemosis of both conjunctiva and the left eye's subconjunctival hemorrhage were found to have reduced. There was more haziness of the anterior chamber of the left eye. The patient progressed into multiorgan dysfunction including hypoxic respiratory failure requiring intubation almost 6 days since admission. His overall condition deteriorated without improvement of mental status when weaning off sedation. The condition of his eyes deteriorated. Two weeks postadmission, he developed epistaxis while on a heparin drip. His family decided to change the goal of care to comfort care only with code status changed to DNR. He was placed on a morphine drip and subsequently weaned from ventilatory support. Following ventilatory discontinuation, the patient died a few hours la1ter.

Discussion

OCS, orbital cellulitis, cavernous sinus thrombosis (CST), thyroid-associated orbitopathy, NAION, and endophthalmitis are the most common differential diagnoses for acute bilateral vision loss with bilateral proptosis. In the following paragraphs, we will discuss each in more detail while comparing the CT imaging findings of our patient with the radiographic signs for each of the previously mentioned conditions.

The orbit is a confined compartment formed by strong orbital septum periosteum connections. Any expansive process posterior to the orbital septum can cause an acute rise in orbital pressure leading to OCS, causing impairment of perfusion to the intraorbital structures including the optic nerve and eventually ischemia of the optic nerve and retina.^2,4 The timely diagnosis and management of OCS is paramount as it can cause permanent vision loss. The diagnosis of OCS is completely made based on clinical findings, some of which are acute onset of pain, decreased vision, elevated intraocular pressures, ophthalmoplegia, proptosis, chemosis, and fixed dilated pupils.^2,4 The most common etiologies for OCS include posttraumatic retrobulbar hemorrhage, orbital emphysema, orbital cellulitis, orbital edema, thyroid-associated orbitopathy, and rapid growth of a neoplasm.^2,5 OCS can also be caused iatrogenically with orbital hemorrhage as a complication during eyelid, periocular, sinus surgery, craniofacial surgery, and neurosurgery.^2,5

In addition, bilateral OCS has been identified as a rare complication of neuropsychiatric systemic lupus erythematosus, Richter syndrome, and disseminated intravascular coagulation.²

The exact pathophysiologic mechanism of vision loss due to OCS has not been established, but Hargarden et al. conducted a simulation study, which illustrated that the vision loss from OCS is the result of damage to the optic nerve from ischemia.² Emergency orbit decompression procedures such as lateral canthotomy and cantholysis have remained the mainstay of treatment for reducing intraorbital pressure in OCS.^2,5

As depicted in Figure 1, the repeated CT image of the orbits for our patient reveals bilateral proptosis and globe deformity with a posterior globe angle of 115° on the left and 125° on the right, indicating globe tenting. There is rim enhancing fluid collection (more on the left orbit) with stretching of the optic nerve. These imaging findings are consistent with OCS.^6,7

Given our patient's constellation of symptoms such as proptosis, conjunctival chemosis, ophthalmoplegia, and nonreactive pupils, his bilateral acute vision loss could have been related to OCS. One possible etiology for OCS in his case is orbital cellulitis likely secondary to his sinusitis (found on CT imaging) or systemic infection via a vascular pathway. We will discuss the imaging findings of orbital cellulitis in next following paragraphs.

One possible mechanism of how orbital cellulitis causes OCS has to do with the fact that the infiltration of the soft tissue, demonstrated by fat stranding that occurs in orbital cellulitis, could result in a sudden increase in intraorbital pressure. This increased pressure causes perfusion impairment of the intraorbital structures including the optic nerve that may lead to acute vision loss.⁶ Proptosis, an attempt to release the pressure by extruding the orbital contents, can cause optic nerve traction.

Orbital cellulitis, also known as postseptal cellulitis, is an infection involving the muscles and fat around the eye and orbit but does not involve the globe of the eyeball itself. The common causes of orbital cellulitis include dacryocystitis, orbital trauma with foreign bodies, ophthalmic surgery, peribulbar anesthesia, or immunodeficiency with infection of the sinuses, middle ear, or teeth.⁸ The most common infectious agents are Staphylococcus aureus, Streptococcus, and Haemophilus influenzae type B.^8,9 Orbital cellulitis is most common in pediatrics, but is possible in all age groups.

Clinical manifestations of orbital cellulitis include pain with eye movement, proptosis, and ophthalmoplegia with or without diplopia. Chemosis may also be common but is nonspecific (as it can also happen with pre-septal cellulitis). Edema of the eyelid itself may be present but is not a consistent feature.⁸ Imaging studies used to confirm orbital cellulitis include CT and MRI scans, with CT scans being most common due to accessibility.

With contrast-enhanced CT scans of the orbit and sinuses, the following features may suggest orbital cellulitis: inflammation of the extraocular muscles, fat stranding, and anterior displacement of the globe (causing the proptosis), although the last finding may be subtle.^8,9

Rhinosinusitis is the most common cause, so imaging may also show increased intensity of the sinuses that bleed into the global region. Complications may include subperiosteal or orbital abscesses, which would be seen on imaging as low-density collections.^8,9

As depicted in Figure 2, CT imaging of the orbital cellulitis often illustrates a source of infection nearby such as opaque sinuses indicating a predisposing sinusitis or ring enhancing, dense regions that normally indicate the formation of an abscess from cellulitis-related inflammatory processes. Other indications would be proptosis on imaging caused by structural disruption by edema as seen in our patient imaging.

CST is another diagnosis that was considered in our case. This condition is classically seen in those who have sinus/midface infection, with microbial spread via the valveless venous system present in the face that communicates with the cavernous venous system located on either side of the sella turcica within the sphenoid bone of the skull. The typical clinical course is a young patient, mean age of 22 years, that has a midface infection for 5–10 days before they complain of a frontal headache (the most common presenting symptoms) consistent with a V1-V2 distribution, that precedes fevers, periorbital edema/pain, and cranial nerve findings. When ocular symptoms occur, they occur primarily unilaterally; then, as the condition progresses, bilateral involvement occurs secondary to spread by communicating veins to the contralateral cavernous sinus within 24–48 hours.¹⁰ This precipitous bilateral involvement is pathognomonic of CST.

On presentation, the patient denied headache, vision changes, ocular pain, recent facial/dental infection, and lacked physical examination findings consistent with ocular pathology. In the latter half of the hospital course, the patient then developed ocular findings such as exophthalmos and chemosis concerning for other diagnostic possibilities, one being CST. With this in mind, it is important to consider that typical CST develops gross ocular examination findings in the terminal end of the disease course and that sepsis occurs secondary to systemic dissemination of the infection from the cavernous sinuses, most often with S aureus. Sepsis serving as the precipitating event for the development of CST is poorly supported in the literature.¹⁰ Apart from clinical presentation and course differences, neuroradiologic imaging is invaluable when differentiating the causes of acute ophthalmologic pathology. A clinical case published in the European Society of Radiology documented typical CST imaging findings that occurred in a 25-year-old patient with CT imaging demonstrating expansion of the cavernous sinus forming a lateral wall convexity and multiple filling defects in enhanced scans.¹¹ Other findings typical of CST include engorgement or dilation of the superior and/or inferior ophthalmic veins, bulging of the lateral margins of the cavernous sinuses, and unilateral or bilateral inflammatory changes the orbital soft tissues.¹² In our patient, CT findings demonstrated some bulging of ophthalmic veins with inflammatory changes of the orbital soft tissues. Although CT brain/orbit of our patient was not completely consistent with CST, it is one possible etiology of his bilateral vision loss given high-density thrombus in the cavernous sinus, only seen in CT imaging in approximately 25% of cases.¹³

Ischemic optic neuropathy (ION), as our least expected differential, can result in sudden painless loss of vision. It was usually described as a blurring or cloudiness of vision and can be secondary to ischemia in 2 areas: anteriorly in the optic nerve head, causing anterior ION (AION), or posteriorly in the retrobulbar optic nerve, causing posterior ION.¹⁴ AION can be subcategorized into nonarteritic (NAION) vs arteritic (AAION), the latter indicating an inflammatory etiology caused by giant cell arteritis.¹⁵

NAION may be caused by diminished blood supply to structures such as the optic disc and the anterior optic nerve located by the posterior ciliary arteries.¹⁶ Localized processes that increase optic pressure or cause edema may contribute to prolonged tissue hypoxia near the optic nerve along with systemic processes that decrease blood flow such as septicemia, hypovolemic shock, or severe adult respiratory distress syndrome.¹⁷ Optic nerve damage and subsequent ION has also been noted to occur after surgical procedures such as coronary bypass surgery, bilateral neck dissection, and HD.¹⁸ Other causative associations with NAION include previous radiation and nocturnal hypotension, specifically from sildenafil use.

The 2 other well-known risk factors for ION that relate to our case are prior radiation exposure to the head and neck and acute hypotension, specifically post-HD. Starting off with radiation-induced optic neuropathy, secondary to radiation-induced vascular damage and CNS necrosis of the visual pathways, will typically manifest as disc swelling with exudates and flame hemorrhages on fundoscopy.^19,20 It is proposed that radiation may lead to optic nerve damage through vascular injury wherein progressive vascular injury from direct radiation can cause perivascular inflammation with hyaline deposits and eventual fibrosis of blood vessel walls decreasing lumen size increasing the potential for infarction and reactive gliosis.²¹ Radiation therapy can cause many ocular symptoms such as irritation, erythema, eyelid edema, corneal ulcerations, and cataracts as well. Patients who have radiation-induced optic neuropathy tend to have slow progressive loss of vision but have rarely been noted to have a sudden loss of vision with a mean time frame of about 30 months postradiation with a common range of 1.5–3 years.²² In cases that have resulted in bilateral vision loss, the lesions postradiation have involved the optic chiasm. AION has also been seen in patients post-HD due to its effects on systemic blood pressure and hematocrit and varies on the amount of fluid removed.¹⁸ One proposal of how this occurs is that the increase in hematocrit during the procedure, which in turn may increase vascular resistance, decreases optic nerve blood flow as well as systemic blood pressure leading to global hypotension.²³ Several case studies have been proposed where patients have had hypotension post-HD presenting with painless loss of vision the same or the next day with reduced vision loss of the contralateral eye within a week of the first incidence, which happened to a 26-year-old man who had been on chronic dialysis since age 6 years and a hypotensive episode as the main risk factor.¹⁹ HD can also result in sudden bilateral ION without the patient having a hypotensive event with imaging revealing bilateral occipital infarcts such as in the case of this 60-year-old man within 24 hours of HD.²⁰ In this case report, the imaging and clinical symptoms did not support bilateral occipital infarction.

Endogenous endophthalmitis is also a possible diagnosis for the acute-onset bilateral vision loss seen in this patient; it has been well documented throughout the literature that endophthalmitis with bilateral involvement is usually due to an exogenous source such as traumatic injury to the orbits bilaterally or after a surgical procedure penetrating the orbit itself such as cataract removal surgery or intraorbital injections.²⁴ Moreover, when endophthalmitis is attributed to an endogenous source, it is rarely seen to involve the eyes bilaterally, with some case studies reporting bilateral involvement to occur in less than 12%–19% of cases with confirmed endogenous endophthalmitis.^25,26 Onset of endophthalmitis is frequently seen at least 1 week after significant trauma or major surgical operation and presents with preceding conjunctivitis, progressive swelling, and pain, followed by gradual vision loss. Common radiographic findings are proptosis, intraorbital fat stranding, and scleral thickening.^25,26

There is also the more remote possibility of thyroid eye disease (TED) as the culprit underlying bilateral blindness with proptosis. TED, also known as thyroid-associated ophthalmopathy, is a form of lymphocytic orbital inflammation. Although the pathogenesis remains incompletely understood, autoimmune activation of orbital fibroblasts, which express the thyroid stimulating hormone receptor and produce both proinflammatory molecules and extracellular matrix components, is thought to play a central role.²⁷ Hypertrophy of extraocular muscles and enhanced adipogenesis, together with deposition of nonsulfated glycosaminoglycans and hyaluronate, cause compression of the soft tissues within the confined bony orbit, with orbital functions impeded due to compressive congestion.^27,28 TED has an acute (dynamic) and chronic (static) phase. The acute phase is typified by orbital tissue expansion but normally halts within 2 years' time, whereas the chronic phase is marked by orbital tissue inactivity. The structures chiefly affected during the acute inflammatory phase of TED are the orbital extraocular muscles and orbital adipose tissue.²⁷ The classic presentation in the setting of acute Graves disease involves thyrotoxicosis, goiter, and bilateral exophthalmos. In 1 cohort of 120 patients with TED, clinical features included eyelid retraction 91%, exophthalmos 62%, extraocular muscle dysfunction 43%, ocular pain 30%, lacrimation 23%, and optic nerve disease 6%.²⁸ In relation to vision, as orbital congestion (and therefore venous permeability) increases, intercellular fluid, proinflammatory cytokines, and lymphocytes began to build within the tissues. This cycle of increased retrobulbar hydrostatic pressure and secondary inflammation leads to exophthalmos with bulging of the eyelid sulci and orbital congestion that manifests as conjunctival chemosis, raised intraocular pressure, impaired globe motility, and optic nerve compromise. Because a healthy orbital septum will retain orbital contents, progressive exophthalmos will eventually cause rapid escalation in retrobulbar orbital pressure and lead to optic neuropathy with few if any classic TED signs such as puffy, edematous upper and/or lower eyelids, or exophthalmos. This crowding effect described is most pronounced at the orbital apex, where efferent venous drainage, arterial perfusion pressure, and axonal flow within the optic nerve can be rapidly compromised. It should be noted that there is a relative arterial perfusion watershed at the posterior optic nerve, in which a rise in orbital pressure can lead to posterior ION and irreversible blindness.^28,29 Although severe TED is rare (affecting only 1 in 20 of all patients with TED), it carries a major risk of sight loss due to corneal exposure on exophthalmos and orbital congestion with consequent optic neuropathy.²⁷

Conclusion

This article discusses a case of a 69-year-old patient with a complex medical history who was found down for at least 2 days and had acute bilateral blindness 2 days after hospital admission. On initial admission, he was found to have rhabdomyolysis, AKI, transaminitis, non-ST segment elevation myocardial infarction, sepsis, and streptococcus bacteremia. The differential diagnosis for our patient's vision loss from highest to lowest likelihood, taking in consideration the additional manifestations of ophthalmoplegia, proptosis, and sepsis, favored endogenous bacterial endophthalmitis, orbital cellulitis, OCS, or cavernous sinus thrombophlebitis. Least likely is the diagnosis of bilateral NAION because it does not explain all the ophthalmologic manifestations displayed in this patient. Thyroid disease is not likely due to the patient's euthyroid labs. This article does not discuss central causes of bilateral visual loss and ophthalmoplegia as they are not applicable to this patient but should always be considered when clinically warranted. When postulating the pathophysiologic processes underpinning of the patient's progressive clinical course, he most likely had irreversible vision loss in one or both eyes associated with increased intraorbital pressure with secondary reduction of perfusion to the optic nerves, possibly due to severe proptosis causing posterior tethering of the optic nerve and subsequent stretching of the bilateral optic nerves and optic blood supply contained within. The hypotension he sustained could have further weakened perfusion to the optic nerves, leading to further ischemic injury (NAION). Orbital cellulitis could have also extended to the cavernous sinuses causing CST. Unfortunately, due to his pacemaker, MRI could not be performed to confirm the presence of CST. At this point, it seems that the patient had a perfect storm of events, which may have precipitated his acute onset vision loss.

Appendix. Authors

Study Funding

No targeted funding reported.

Disclosure

This research was supported (in whole or in part) by HCA Healthcare and/or an HCA Healthcare affiliated entity. The views expressed in this publication represent those of the author(s) and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.