Up High, Down Low, Too Slow

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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.

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.

MRI BRAIN FINDINGS. (3A, 3B) Ventriculomegaly. (3C) Cervical spinal stenosis. (3D) Flattening of the posterior sclera and dilated, tortuous optic nerve.

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).

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

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.