Clinical-Pathological Case Study
Section Editors: Neil R. Miller, MD
Sudden Bilateral Ptosis in a 61-Year-Old Woman
Gerard Hershewe, DO, Alyssa Eckert, BS, Timothy Koci, MD, Griffith Harsh, MD,
Donald Born, MD, Micaela Koci, BA/BS
Dr. Hershewe:
A 61-year-old woman reported a 2-month history of sud-
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den severe bilateral ptosis that had worsened slightly
since onset. The patient tilted her head backward “to see.”
The ptosis was worse in the morning and with fatigue, but
not worse in the evening. There was no associated diplopia,
dysphagia, or neck or proximal muscle weakness.
The patient’s medical history included hearing loss and
fibrocystic breast disease for which she had undergone 2
previous lumpectomies that were negative for malignancy.
There was no history of heart disease or stroke. She did not
smoke and had 2–3 alcoholic beverages weekly. Family
history included colon cancer in her mother and lung cancer
in her father. There was no family history of myasthenia
gravis (MG) or ptosis.
Neuro-ophthalmologic examination revealed visual acu-
ity of 20/20 in both eyes with intact color vision. Pupils
measured 3.0 mm in each eye, and were briskly reactive to
light without evidence of light-near dissociation or a relative
afferent pupillary defect. Eye movements were full with a 3-
prism diopter comitant exotropia at distance and near.
There was no evidence of convergence-retraction nystag-
mus. Ophthalmoscopy was unremarkable.
The patient maintained a chin-up position. There was
marked bilateral ptosis (Fig. 1). She was unable to open the
eyes voluntarily, although there was normal eyelid elevation
on upgaze. The palpebral fissures measured 4.5 mm on both
sides, and levator function was 15 mm on both sides. There
was 1–2 mm of fatigable ptosis after sustained upgaze. There
was also a Cogan lid twitch (i.e., as the patient made a sac-
cade from downward gaze to primary position, the ptotic lid
overshot briefly before resuming its previous ptotic position).
There was minimal lid hopping (i.e., an upward twitch of the
lid on glancing quickly to the side from primary position
[during refixation]). Bienfang sign was negative (i.e., an
excessive upward excursion followed by downward drift of
University of Nevada Reno School of Medicine (GH, AE, MK), Reno,
Nevada; Section of Neuroradiology (TK), Department of Radiology,
Renown Medical Center, Reno, Nevada; Department of Neurosur-
gery, Stanford Hospital (GH), Palo Alto, California; and Department
of Neuropathology, Stanford Hospital (DB), Palo Alto, California.
The authors report no conflicts of interest.
Address correspondence to Gerard Hershewe, DO, Clinical Faculty,
University of Nevada Reno School of Medicine, 75 Pringle Way, Suite
605, Reno, NV 89502; E-mail: hershkey@gmail.com
Hershewe et al: J Neuro-Ophthalmol 2018; 38: 375-378
Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.
Janet Rucker, MD
the upper eyelid immediately on eye opening after a period of
forced eyelid closure).
There was mild percussion myotonia involving both
thumbs (i.e., a localized myotonic prolonged contraction of
the muscles in response to percussion, such as tapping the
muscles on the palm at the base of the thumb with the
examiner’s finger or a reflex hammer, followed by delayed
relaxation).
The differential diagnosis included ocular MG, myo-
tonic dystrophy, and central ptosis secondary to a midbrain
lesion. An ice test and acetylcholine receptor antibody panel
were negative. Additional normal or negative laboratory
studies included a complete blood count, Westergren
sedimentation rate, magnesium, C-reactive protein, TP
antibody, free T4, thyroid stimulating hormone, vitamin
B12, folate, anticardiolipin antibodies, and antinuclear
antibody assay. MRI of the brain was performed.
Dr. Koci:
MRI without contrast shows a T1-hypointense (Fig. 2A)
and fluid-attenuated inversion recovery image–
hyperintensive (Fig. 2B) midbrain mass. The midbrain
lesion enhances (Fig. 3A) after intravenous contrast and is
surrounded by T2 hyperintensity (Fig. 3B). This could
represent an infiltrating tumor, vasogenic edema, or both.
Dr. Hershewe:
A lumbar puncture was performed. The cerebrospinal fluid
showed 2 white blood cells and normal glucose and protein
concentrations. Cytology was negative. Flow cytometry was
normal with no evidence of lymphoma. Computed tomog-
raphy of the chest revealed no lesions. Brain biopsy was
performed.
Dr. Harsh:
A biopsy of the midbrain lesion was performed using an
entry point in the left frontal area near the coronal suture
and a trajectory that was centered in the mass but avoided
the superficial vessels medial to the Sylvian fissure and
lateral to the frontal horn of the left lateral ventricle. A
special biopsy needle with a 5-mm fenestration was chosen.
A total length of 218 mm was calculated, with an additional
3 mm to place the fenestration within the center of the
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 Clinical-Pathological Case Study
FIG. 1. Marked bilateral ptosis is present with contraction
of the frontalis muscle to partially elevate the eyelids.
target. The needle was passed slowly into the brain and
stopped at the target point. Two tiny samples were ob-
tained. There was no significant bleeding.
Dr. Born:
Routine histologic sections reveal brainstem tissue with
infiltration by atypical, enlarged, hyperchromatic astrocytic
cells (Fig. 4A). Immunohistochemistry for Ki67 shows that
a portion of the enlarged nuclei are positive, and there is an
overall increased Ki-67 labeling index (8% of neoplastic
nuclei) (Fig. 4B). Additional immunohistochemistry shows
very low p53 nuclear labeling and retention of nuclear
ATRX. IDH1 (R132H) and H3K27M are both negative
(wild-type). The pathology is consistent with a WHO
Grade II astrocytoma.
Dr. Hershewe:
Treatment included radiation with a total dose of 58 Gy in
29 fractions and adjuvant temozolomide. The patient
received 250 mg/m2 temozolomide for the first 2 months
followed by 350 mg/m2 temozolomide for 10 months, for
a total of 12 months of treatment. After treatment, she
developed a large exotropia, a mild vertical gaze palsy with
slight improvement in her left ptosis. The remainder of the
FIG. 2. Sagittal MRI. A. Precontrast T1 image shows a hypointese midbrain mass (B). Fluid-attenuated inversion recovery
image reveals the mass to be hyperintense with signal tracking into the superior cerebellar peduncle (arrow).
376
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neurological examination remained stable. Posttreatment
brain MRI at 2 months and 6 months showed a slight
reduction in tumor size.
Final Diagnosis
WHO Grade II astrocytoma in the dorsal midbrain
produced isolated bilateral ptosis due to impaired supra-
nuclear input to the central caudal oculomotor nucleus.
Dr. Hershewe, Ms. Eckert, and Ms. Koci:
Our patient had a rare presentation of sudden, bilateral,
complete ptosis unassociated with pupillary light-near
dissociation or ocular motility disturbance. She had some
clinical features suggestive of ocular MG, including fatigable
ptosis and a Cogan lid twitch. The normal ice test and
negative acetylcholine binding antibodies failed to support
a diagnosis of ocular MG; however, sensitivity of the ice test
for myasthenic ptosis is between 79% and 97% (1,2), and is
even lower in the setting of complete ptosis (3). Further-
more, the reported sensitivity of acetylcholine receptor anti-
body testing in isolated ocular MG is much lower than in
generalized MG, variably reported in ocular MG to be
between 38% and 71% (4). To the best of our knowledge,
there has been one other case in which a midbrain glioma
produced features suggestive of myasthenia (5). However, in
that patient, the clinical signs differed from those of our
patient, and included upgaze paresis, hypometric saccades,
and absent vertical optokinetic responses. In addition,
although the patient had bilateral ptosis secondary to third
nerve nuclear involvement, she also had previous ptosis on
the left secondary to a partial unilateral third nerve palsy
with pupillary involvement.
It is clear that muscle fatigability can be caused by upper
motor neuron lesions. Direct stimulation of the tibialis
anterior muscle through its motor nerve in patients with
spastic paraparesis resulting from spinal trauma or MS leads
to increased muscle fatigue and slow relaxation of the
muscle (6). Thus, a central mechanism with a disordered
Hershewe et al: J Neuro-Ophthalmol 2018; 38: 375-378

FIG. 3. Axial MRI. A. Postcontrast T1 scan reveals enhancement of the midbrain lesion. B. T2 image shows hyperintense
signal beyond the enhancing component.
motor unit control may be a likely cause of fatigability in
our patient.
It is noteworthy that although our patient had bilateral
ptosis and was unable to open her eyes voluntarily, she had
normal eyelid elevation on upgaze. This dissociated
response indicates impaired supranuclear or premotor eyelid
control, rather than direct dysfunction of the central caudal
FIG. 4. Biopsy specimen. A. Brainstem tissue is infiltrated
with atypical, enlarged, hyperchromatic astrocytic cells with
irregular nuclear contours consistent with a diffuse astro-
cytoma (hematoxylin & eosin, ·100). B. Immunohisto-
chemistry for Ki-67 shows that a portion of the enlarged
nuclei are positive and there is an overall increased pro-
liferative index of 8% (Ki-67, ·100).
Hershewe et al: J Neuro-Ophthalmol 2018; 38: 375-378
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Clinical-Pathological Case Study
nucleus (7,8). Upward saccades typically are accompanied
by upward lid movements. In primates, it has been shown
that a burst of neuronal discharge occurs in the levator
palpebrae superioris motoneurons located in the central
caudal nucleus that is similar to the discharge rate of supe-
rior rectus motoneurons (9,10). The anatomical basis for
this coordination of upward eye and lid movements is
incompletely understood. The central caudal nucleus may
receive direct signals from superior rectus motoneurons or,
alternatively, both sets of neurons may receive premotor
signals from structures responsible for vertical gaze, such
as the rostral interstitial medial longitudinal fasciculus or
the interstitial nucleus of Cajal. We hypothesize that in
our patient, supranuclear input to the central caudal nucleus
was impaired by the infiltrating tumor for voluntary lid
elevation, but that there was preserved supranuclear input
to the central caudal nucleus and superior rectus subnucleus
for coordinated lid and eye movements with eye elevation.
Our case shows that patients who present with apoplec-
tic onset of bilateral complete ptosis should not only be
evaluated for MG but also for a structural lesion affecting
the dorsal midbrain such as a tumor or stroke. The
differential diagnosis for the neuroimaging findings in our
patient included primary glioma, solitary metastasis, and
lymphoma. The workup for lymphoma and metastatic
disease was unrevealing, necessitating a biopsy of the lesion,
which revealed a glioma.
Empiric treatment of adult brainstem lesions is not
prudent because there is a wide spectrum of diverse causes.
The diagnosis of adult brainstem tumors by neuroimaging
can be challenging, with diagnostic accuracy of brainstem
tumors being incorrect in up to 40% of cases. Rachinger
et al (11) found that MRI had a sensitivity and specificity
of 62.5% and 46.6%, respectively, for the diagnosis of
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 Clinical-Pathological Case Study
low-grade gliomas. Thus, once an evaluation for metastatic
disease and lymphoma was unrevealing, we elected to pro-
ceed with a stereotactic biopsy. This is a well-established
diagnostic method to guide the clinical management of
various brainstem lesions. It is associated with a low com-
plication rate and high diagnostic yield when using either
frame-based or frameless stereotaxy (12). Midbrain lesions
usually are approached through a transfrontal route,
whereas pontine lesions usually are approached by a suboc-
cipital transcerebellar route. Morbidity ranges from 0% to
16% and mortality from 0% to 3.9% in a mixed-patient
population (13). One of the major complications is hemor-
rhage, ranging from 0.4% to 4.7%. Risk factors for intra-
operative or postoperative hemorrhage include hepatic
cirrhosis, diabetes mellitus, antiplatelet therapy, and
acquired immunodeficiency syndrome; lesion-related fac-
tors, including glioma grade (high-grade more likely to
bleed) and lymphoma; and technical and anatomical factors
such as number of trajectories, number of aspirations, lesion
size and location, bleeding through the needle, and size of
the needle. Nevertheless, stereotactic biopsy of the brain-
stem has evolved into a safe and effective method for deter-
mining histopathology. One meta-analysis of 14 studies
using stereotactic biopsies of the brainstem demonstrated
94% histopathologic diagnosis on first attempt (14). In
a series of 166 patients with enhancing brainstem lesions,
high-grade glioma was the most common pathologic diag-
nosis, followed by low-grade glioma, metastasis, hematoma
(including cryptic arteriovenous malformation), lymphoma,
and demyelination (14).
Midline brainstem tumors have a poor prognosis in
both adults and children and are more likely to be
astrocytomas than lobar tumors. Overall survival rates of
midline gliomas are far lower than their lobar counter-
parts, due, in part, to inadequate nonsurgical options.
However, surgical resection of midline low-grade gliomas
may be considered where technically feasible (13). Radi-
ation therapy and chemotherapy may be considered in
symptomatic patients or in patients whose tumors prog-
ress (15).
In summary, our patient had the rare presentation of
sudden, bilateral complete ptosis unassociated with near-
light dissociation or ocular motility disturbance (16,17).
Although some features of the ptosis suggested MG, the
patient was found to have an infiltrating glioma that pre-
sumably interrupted the supranuclear/premotor input to
the central caudal nucleus of the third nerve complex.
Our case shows that the abrupt onset of isolated, bilateral
complete ptosis may indicate a structural lesion affecting the
dorsal midbrain, including stroke, trauma, and tumor.
378
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ACKNOWLEDGMENTS
The authors thank Josh Gratwohl for his assistance in the
technical preparation of the manuscript.
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