Sudden Bilateral Ptosis in a 61-Year-Old Woman

Clinical-Pathological Case Study Section Editors: Neil R. Miller, MD Janet Rucker, 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 sudden 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 acuity 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 3prism diopter comitant exotropia at distance and near. There was no evidence of convergence-retraction nystagmus. 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 saccade 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 Neurosurgery, 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: [e-mail] Hershewe et al: J Neuro-Ophthalmol 2018; 38: 375-378 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, myotonic 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 tomography 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 375 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study 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 supranuclear input to the central caudal oculomotor nucleus. 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 obtained. 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 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). Furthermore, the reported sensitivity of acetylcholine receptor antibody 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 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 Hershewe et al: J Neuro-Ophthalmol 2018; 38: 375-378 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study 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 astrocytoma (hematoxylin & eosin, ·100). B. Immunohistochemistry for Ki-67 shows that a portion of the enlarged nuclei are positive and there is an overall increased proliferative index of 8% (Ki-67, ·100). Hershewe et al: J Neuro-Ophthalmol 2018; 38: 375-378 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 superior 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 apoplectic 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 377 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study low-grade gliomas. Thus, once an evaluation for metastatic disease and lymphoma was unrevealing, we elected to proceed 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 complication 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 suboccipital 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 hemorrhage, ranging from 0.4% to 4.7%. Risk factors for intraoperative or postoperative hemorrhage include hepatic cirrhosis, diabetes mellitus, antiplatelet therapy, and acquired immunodeficiency syndrome; lesion-related factors, 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 brainstem has evolved into a safe and effective method for determining 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 diagnosis, 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 counterparts, due, in part, to inadequate nonsurgical options. However, surgical resection of midline low-grade gliomas may be considered where technically feasible (13). Radiation therapy and chemotherapy may be considered in symptomatic patients or in patients whose tumors progress (15). In summary, our patient had the rare presentation of sudden, bilateral complete ptosis unassociated with nearlight 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 presumably interrupted the supranuclear/premotor input to the central caudal nucleus of the third nerve complex. 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