By Fabliha A. Mukit, MD, and Joseph W. Fong, MD
Edited by Ahmad A. Aref, MD, MBA
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Papi Aidema* is a 76-year-old man who presented to the ophthalmology clinic for a delayed follow-up for diabetic macular edema of the left eye. When asked about his missed intravitreal injection appointment, he shared that he had been hospitalized because of recurrent falls and increasing confusion. He said that he hadn’t been experiencing any decreased vision, flashes of light, floaters, or other visual symptoms.
During his recent hospital workup, the neurology service had suspected normal pressure hydrocephalus and started treatment with acetazolamide. Despite this, his wife reported that he continued to be lethargic and weak while also experiencing poor appetite and limited mobility. She said that he has been using a wheelchair for the last month.
We Get a Look
History. Mr. Aidema’s medical history is significant for well-controlled type 2 diabetes, hypertension, chronic kidney disease stage 2, coronary artery disease, and gastroesophageal reflux.
His ocular history includes bilateral pseudophakia and mild nonproliferative diabetic retinopathy of both eyes, with diabetic macular edema of the left eye.
Exam. Mr. Aidema’s BCVA was 20/20 in both eyes. Pupillary function, IOP, and confrontation visual fields were unremarkable. Extraocular movements were significant for mild upgaze paresis in both eyes, but no nystagmus or strabismus was present.
External examination and anterior segment exam were unremarkable.
The dilated fundus exam revealed bilateral grade 5 disc edema with marked obscuration of all major vessels and prominent peripapillary splinter hemorrhages (Fig. 1).
OCT of the retinal nerve fiber layer (RNFL) demonstrated increased global thickness. This had increased from 94 μm to 218 μm in the right eye and from 93 μm to 283 μm in the left eye compared to a study performed four months prior (Fig. 2). OCT of the macula revealed intraretinal fluid extending from the optic nerve into the papillomacular bundle in both eyes.
Ambulatory issues. Mr. Aidema also demonstrated a broad-based, magnetic gait pattern when asked to ambulate in the clinic. He was able to only walk a few steps before returning to his wheelchair.
Sent to the ED. The neurology service was notified of the findings, and the patient was immediately sent to the emergency department (ED) for urgent workup of suspected elevated intracranial pressure.
Further Testing
In the ED. In the ED, Mr. Aidema’s vital signs were unremarkable, and all labs were normal except for blood urea nitrogen of 45.9 mg/dL (normal range, 7-20 mg/dL). His hemoglobin A1c was 6.0%.
Imaging. MRI of the brain and spine with and without gadolinium contrast revealed ventriculomegaly, flattening of the posterior sclera, dilated optic nerve sheaths, and cervical spinal stenosis secondary to ossification of the posterior longitudinal ligament (Fig. 3).
Lumbar puncture. A lumbar puncture (LP) was performed, and the opening pressure was found to be 15 cm H2O with a normal cerebrospinal fluid (CSF) profile. He was admitted to the medicine service for further workup, and the neurosurgery service was consulted.
Differential Diagnosis
The differential diagnosis for optic disc edema is broad and requires a careful patient history as well as a thorough exam that may include elements outside the scope of a routine eye exam. These elements may include parts of the neurologic exam, such as gait testing and cerebellar testing, as well as careful evaluation of ocular balance and motility with the use of alternate cover testing.
The four primary causes of optic disc edema include 1) elevated intracranial pressure, 2) vascular insults including ischemic optic neuropathy and hypertensive optic neuropathy, 3) infectious optic neuropathies such as syphilis and cat-scratch disease, and 4) inflammatory optic neuropathies such as optic neuritis and sarcoidosis.
The mechanisms of elevated intracranial pressure include infectious and noninfectious meningitis, hydrocephalus, venous sinus thrombosis, idiopathic intracranial hypertension, and mass lesion resulting in outflow obstruction.
Of note, infectious and inflammatory optic neuropathies and vascular insults of the optic nerve are rarely asymptomatic.
Our patient was a nonobese, elderly man with high-grade optic disc edema in the setting of normal opening pressure recorded on LP. MRI of the brain and spine did not demonstrate a mass lesion causing outflow obstruction. The patient appeared nontoxic with normal vital signs, no leukocytosis, and normal CSF profile, ruling out meningitis. He was normotensive on blood pressure medications, and his blood sugars have been tightly controlled.
Because he lacked visual symptoms, we did not suspect a vascular insult such as ischemic optic neuropathy.
Infectious workup tests, including syphilis, tuberculosis, cat-scratch disease, Lyme disease, and toxoplasmosis, all returned negative. Inflammatory workup testing, including angiotensin-converting enzyme (ACE), lysozyme, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP), also returned within normal limits. Antimyelin oligodendrocyte glycoprotein and anti-aquaporin-4 serologies were negative for atypical optic neuritis.
Our Diagnosis and Confirmatory Testing
Based on the constellation of clinical findings—including mild upgaze paresis, Frisen grade 5 papilledema, broad-based gait, and cervical spinal stenosis with ventriculomegaly—we thought that the most likely diagnosis was noncommunicating hydrocephalus causing dorsal midbrain syndrome, which is also known as Parinaud syndrome.
We recommended a Queckenstedt procedure to determine if CSF pressure was elevated superior to the level of spinal stenosis despite a normal LP opening pressure.
Our neurosurgery colleagues elected to defer this maneuver and instead to proceed with urgent ventriculoperitoneal shunt placement, given the presence of high-grade papilledema and ventriculomegaly.
At three-week postoperative follow-up in the ophthalmology clinic, the papilledema (Fig. 4) and upgaze paresis had resolved. A baseline 24-2 Humphrey visual field revealed mild blind spot enlargement in the right eye and a normal visual field in the left eye (Fig. 5). The patient was able to ambulate easily with the aid of a walker, and his wife reported that his mental status had returned to his baseline.
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WE GET A LOOK. (1) Fundus photos revealing Frisen grade 5 papilledema with blurred margins, no visible cup, and obscured vessels with circumferential disc hemorrhages in both eyes. (2A) At an earlier visit, in June, the global thickness of RNFL in the right eye had been 94 μm; (2B) when we saw the patient four months later, in October, the thickness was 218 μm. (2C) In the left eye, the global thickness was 93 μm in June and (2D) 283 μm in October.
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MRI BRAIN FINDINGS. (3A, 3B) Ventriculomegaly. (3C) Cervical spinal stenosis. (3D) Flattening of the posterior sclera and dilated, tortuous optic nerve.
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POST-OP. (4) Fundus photos taken at postoperative week 3 show resolution of bilateral papilledema. (5) Humphrey visual fields at postoperative week 3 show slightly enlarged blind spot in the right eye (5B).
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Discussion
Clinical presentation. Parinaud syndrome arises from compression or injury to the dorsal midbrain, causing upward gaze palsy, convergence-retraction nystagmus, light-near dissociation, and lid retraction (also called Collier’s sign).1-3 Upward gaze palsy is the most common initial presentation, occurring in over 87% of patients with Parinaud syndrome; it results from injury to the vertical gaze center and rostral interstitial medial longitudinal fasciculus.4,5
Convergence-retraction nystagmus is an abnormal, oscillatory movement with globe retraction due to a loss of inhibition to the third nerve nucleus causing co-contraction of the horizontal rectus muscles, in addition to constant stimulation of the superior and inferior rectus muscles. Similarly, lid retraction is due to constant signaling to the levator palpebrae superioris with loss of inhibitory effect to the third nerve nucleus.
Light-near dissociation in Parinaud syndrome (also known as pseudo– Argyll Robertson pupils) is the reduction in pupillary constriction to light but preserved constriction to accommodation and convergence. Injury to the pretectal region of the midbrain causes damage to the pretectal nuclei and Edinger-Westphal nuclei. Injury to these nuclei results in loss of parasympathetic innervation to the iris sphincter muscle and subsequent loss of pupillary constriction. Pupillary fibers for accommodation and convergence are located more ventrally in the midbrain, resulting in preservation of associated pupillary response.5
The most common Parinaud symptoms are diplopia, blurry vision, ptosis, visual field defects, and ataxia. Diplopia can manifest from mass effect resulting in third or fourth cranial nerve palsies or compression of the sylvian aqueduct with raised intracranial pressure causing sixth nerve palsies. Over 25% of patients experience blurred vision attributed to accommodative spasms that cause pseudomyopia and decreased distance vision.5
Etiology. The etiology of Parinaud syndrome includes pineal gland tumors (most common cause), midbrain hemorrhage, ischemic infarction, demyelinating disease such as multiple sclerosis and neuromyelitis optica, infectious etiologies such as toxoplasmosis and cat-scratch disease, obstructive hydrocephalus, seizures, tectal tuberculoma, Miller Fisher syndrome, and arteriovenous malformation.4 Among tumors causing Parinaud syndrome, 40% are due to pineocytomas, and 7% are from germinomas.1,6 Decompensating hydrocephalic intracranial pressure can result in dilation of the third ventricle with extension to the suprapineal recess, causing compression of cranial nerve III in the tectal region of the midbrain. This causes the upgaze paresis seen in Parinaud syndrome, particularly noted in hydrocephalus.4,7,8
Vasculopathic etiologies such as infarction or hemorrhage are more common in the elderly population, while neoplasms are more common in younger patients.6
Workup. A careful history and physical examination are essential to determine the etiology of Parinaud syndrome. MRI is necessary to evaluate for obstructive, demyelinating, or vasculopathic causes of dorsal midbrain injury. A complete infectious and autoimmune workup as well as LP with opening pressure and CSF analysis should be performed in patients in whom a structural lesion is not clearly identified.
Management. Parinaud syndrome is treated by reversal of the precipitating cause. CSF-diverting procedures in hydrocephalus have a very high rate of resolution, as they mitigate the source of compression with minimal distortion of normal anatomy. Tumor resection to relieve elevated intracranial pressure may result in residual functional deficits due to the loss of neural tissue.3,4
Lessons From Our Case
This case highlights the importance of maintaining high clinical suspicion for elevated intracranial pressure in patients with normal opening pressure recorded on LP. It is important to note that opening pressure documented by LP may not accurately reflect the true intracranial pressure and should always be correlated clinically with the appearance of the optic nerves, constellation of symptoms, age of the patient, and diagnostic imaging studies. In Mr. Aidema’s case, his cervical spinal stenosis caused blunting of elevated intracranial pressure secondary to noncommunicating hydrocephalus. The presence of dorsal midbrain syndrome and high-grade papilledema was critical to the diagnosis of hydrocephalus despite normal LP opening pressure.
Queckenstedt procedure. A confirmatory Queckenstedt procedure can be considered to assess if cervical spinal stenosis is blunting elevation of opening pressure. This procedure is performed by placing manual pressure on the internal jugular vein, which causes increased pressure in the dural venous sinus system and resultant backflow pressure. This obstructs the resorption of CSF. In a patient without spinal stenosis, this maneuver would cause a concurrent increase in LP opening pressure. However, in the presence of spinal stenosis, any rise in intracranial pressure would be obstructed by the stenotic area, resulting in a falsely normal opening pressure in the lumbar region. This is considered a positive Queckenstedt maneuver.9
More at the Meeting
Diagnose This Live! If you enjoy the weekly Diagnose This quiz (aao.org/diagnose-this), you will love the Diagnose This Live! session (Sym08). With Jeffrey Henderer, MD, emceeing, a crew of panelists will present 19 mystery cases and ask the audience for the diagnosis or next step in managing the patient. After each question, the audience has 10 seconds to respond. The top 10 winners will receive a gift certificate for the Academy Store. When: Saturday, Nov. 4, 11:30 a.m.-12:45 p.m. Where: South 151-153. Access: AAO 2023 registration.
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Follow-Up
After the urgent placement of a ventriculoperitoneal shunt, our patient demonstrated rapid symptomatic and anatomic improvement in a three-week period, with complete resolution of papilledema and improved mentation and ambulation.
Mr. Aidema will continue to follow up in the ophthalmology clinic for routine monitoring of his nonproliferative diabetic retinopathy with quarterly dilated fundus examination. We will also continue to monitor for the development of post-papilledema optic atrophy as well as signs of shunt failure.
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*Patient name is fictitious.
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1 Shields M et al. Acta Ophthalmol. 2017;95(8):e792-e793.
2 Hankinson EV et al. J Neurosurg Pediatr. 2016;17(5):558-563.
3 Hoehn ME et al. J AAPOS. 2017;21(1):34-38.
4 Chattha AS, Delong GR. J Neurol Neurosurg Psychiatry. 1975;38(3):288-296.
5 Ortiz JF. Brain Sci. 2021;11(11):1469.
6 Iorio-Morin C et al. World Neurosurg. 2017;107:974-982.
7 George B et al. Nouv Presse Med. 1980;9(24):1685-1688.
8 Hamer J, Martin K. Neuropadiatrie. 1976;7(2):217-223.
9 Pearce JM. J Neurol Neurosurg Psychiatry. 2006;77(6):728.
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The authors thank Natalie S. Sullivan, BS, a third-year medical student, for her significant contributions to this article. Dr. Mukit is a third-year ophthalmology resident, and Dr. Fong is an Assistant Professor in Ophthalmology and Neurology and practices neuro-ophthalmology, adult strabismus surgery, and comprehensive ophthalmology. All are at the University of Tennessee Health Science Center (UTHSC) in Memphis. Financial disclosures: None.