Unilateral Ptosis

Unilateral Ptosis; Unilateral Lid Retraction; Myasthenic Lid Twitch; External ophthalmoplegiaPowerPoint Presentations: Myasthenia/Thymoma: http://library.med.utah.edu/NOVEL/Wray/PPT/Myasthenia_Thymoma.ppt Shirley H. Wray, M.D., Ph.D., FRCP, Harvard Medical School Chest CT: Thymoma:http://library.med.utah.edu/NOVEL/Wray/PPT/Chest_CT_Thymoma_guest_lecture.ppt Robert A. Novelline, M.D. Professor of Radiology, Massachusetts General Hospital Myasthenia Gravis: http://library.med.utah.edu/NOVEL/Wray/PPT/Myasthenia_Gravis_guest_lecture.ppt Shirley H. Wray, M.D., Ph.D., FRCP, Harvard Medical SchoolTransient double visionThe patient is a 46 year old woman who presented in July 1977 with horizontal double vision lasting two weeks. Three weeks later the left upper eyelid started to droop and by the end of the day the eye was closed. She had no ptosis of the right eye and no generalized fatigue. She consulted an internist: a glucose tolerance test was normal. She was referred to a neurosurgeon, who noted weakness of the medial rectus muscle - third nerve palsy. CT brain scan: normal. She was referred to the Neurovisual Clinic, Massachusetts General Hospital. Past History: Negative for previous attacks of diplopia, ptosis or fatigue. Neuro-ophthalmological examination: Visual acuity: 20/30, J1 OU. Visual fields, pupils and fundus examination normal Eyelids: • Partial ptosis left eye (OS) • Lid retraction right (OD) • Bilateral overaction of the frontalis muscle • Myasthenic lid twitch OS • Slight increase in ptosis OS on fatigue • No recovery of ptosis on gentle eye closure • Impaired ability to bury her eyelashes fully Ocular motility: • Mild weakness of the medial rectus muscle bilaterally, left > right • Poor convergence • Vertical gaze normal Intravenous Tensilon Test (edrophonium chloride): The test dose of 0.2 ml was adequate to produce a positive response with elevation of the ptotic left eyelid and correction of lid retraction OD. (Figures 1-3) The response lasted 30 seconds and then the left eyelid drooped. A further 0.3 ml of tensilon again resulted in correction of ptosis OS. The full 1 ml (10 mg) dose of tensilon was not given. Diagnosis: Ocular myasthenia gravis. Hematological tests: Thyroid studies normal Anti-skeletal muscle antibodies positive (The presence of antibodies to striatal muscle suggests that the patient harbors a thymoma) Tests for antibodies to the nicotinic acetylcholine receptor (AChR) were not available at that time. Chest x-ray PA and Lateral: A large anterior mediastinal mass was found consistent with an enlarged thymus gland. (Figures 4 and 5) CT of the chest: Multiple transverse sections through the mid-thorax showed the presence of a softly demarcated rounded mass in the anterior mediastinum directly contiguous and anterior to the inferior portion of the transverse aortic arch. The mass measured approximately 4 cm. and was surrounded by fat, and had diminished attenuation in the center indicating the presence of a moderate amount of fat or liquid within the tumor. (Figures 4 & 5) Tomograms revealed the mediastinal mass to be homogeneous without evidence of calcification or lobulation. There was no hilar adenopathy. Diagnosis: Thymoma Thymectomy: On August 8, 1977 a thymectomy was performed and encapsulated tumor completely excised. Pathology: The specimen contained a partially cystic mass and a solid portion which comprised approximately one half of the tumor. The cystic mass was 5 x 4 x 1 cm. and the overall dimensions of the tumor 11 x 5 x 1 cm, weighing 45 grams. Diagnosis: Thymolipoma Post operative status: On day one she complained of diplopia in mid-afternoon and marked drooping of her eyelids. At that time she had: • Bilateral asymmetrical ptosis, OS > OD • Palpebral fissure OD 9, OS 7. • Increased ptosis bilaterally on prolonged upgaze • Full horizontal and vertical gaze • No facial weakness • Bulbar muscles normal • Neck flexion 3/4 mild weakness • Proximal strength in the limbs good • Ventilatory capacity normal. Patient made an excellent recovery and was discharged home without any medication. Second Admission: In September 1977, six weeks post-op, she was readmitted with increasing ptosis, diplopia and generalized fatigue. At the end of the day she had fatigue chewing and weakness of the jaw and neck. Importantly, she had no difficulty swallowing or breathing and no change in the quality of her voice. She had become depressed and anxious. Ocular motility: • Bilateral symmetrical ptosis with weakness of the orbicularis oculi, and an inability to bury her eyelashes • Increased ptosis on fatigue • Myasthenic lid twitch OS • Fatigue of horizontal saccades after rapid gaze right and left, to the point where the eyes came to a standstill Neurological examination: • A mild bulbar palsy • Bilateral facial weakness with difficulty pursing her lips • Inability to sustain the arms elevated for long periods • Normal vital capacity Electrophysiological studies: Repetitive stimulation The technique for repetitive stimulation studies is similar to motor nerve conduction studies. Rather than a single supramaximal stimulus trains of repetitive stimuli are delivered at a rate of 3 stimuli per second, with 6 to 10 stimuli in a train. The compound muscle action potential of the first response is compared with the fifth response and the percentage decrement measured. A decrement of greater than 10% represents a positive test for myasthenia gravis (MG). In this patient the study revealed decrements in the right deltoid, right biceps, and inferior orbicularis oculi muscle confirming a diagnosis of generalized myasthenia gravis. Stimulated Single-fiber EMG (SF-EMG) was performed in the right digitorum communis. Seven pairs were recorded. Jitter was abnormal in one pair. MCD ranged from 15.7 to 134.8 ųsec. Blocking was present. SF-EMG is the more sensitive electrophysiological method for the diagnosis of myasthenia. This is a special technique for the recording of single-muscle-fiber action potentials and is used to measure fiber density and so-called jitter. Jitter is the variability of the interpotential interval of successive discharges of two singe-muscle-fibers belonging to the same motor unit. This phenomenon is due largely to the very slight variability of delay at the branch points in the distal axon and by synaptic delay at the neuromuscular junction. Diagnosis: Myasthenia Gravis Treatment: Mestinon (pyridostigmine bromide) 60 mg q.3 hours Prednisone 40 mg daily. Hospital Course: Twenty-four hours after starting medication there was striking improvement. By day four, she had fully recovered. In July 1980 she was admitted for the third time with acute difficulty swallowing, shortness of breath, ptosis, diplopia, and limb weakness. Her relapse was due to her starting to taper her own prednisone dose down from 5 mg/day to 2.5 mg/day because she was mildly cushionoid. In the ER she had on examination: • A mild bulbar palsy • Moderate weakness of proximal muscles • Bilateral ptosis • Easy fatigue of her eye movements • Vital capacity normal Medication: Prednisone was increased to 10 mg b.i.d. Mestinon 60 mg 4x/day She rapidly recovered back to her normal baseline and was discharged home. In May 1998 she was admitted as an emergency with occlusion of the right dorsalis pedis and anterior tibialis arteries. A thrombectomy was performed. Hematological studies revealed a hypercoagulable state. Prothrombin time 15.6 Partial thromboplastin time 24.1. CEA level of 120 Hematocrit 26.7. The presence of a hypercoagulable state and elevated CEA level led to a workup for an occult malignancy. Colonoscopy revealed a sigmoid mass approximately 2 x 2 cm obstructing the colon. A left colectomy and colorectal anastomosis was performed. Observations during surgery revealed metastatic spread with 4 nodules located in the right lobe of the liver. Pathology: Adenocarcinoma of the colon with 18/18 positive mesenteric lymph nodes. Patient died in 1999.The video of this patient illustrates eyelid signs of ocular myasthenia gravis. • Partial ptosis OS • Retraction of the upper eyelid OD • Myasthenic lid twitch OS (overshoot of the upper lid on looking up after full gaze down) • Full eye movements A positive intravenous tensilon test showed: • Full recovery of ptosis OS • Loss of lid retraction OD • Watering of the eyes • Frequent blinking Lid twitch - Cogan's sign In 1965 Cogan described a transient eyelid retraction occurring during refixation from downgaze to straight ahead gaze. The twitch is an "overshoot" of the eyelid. Cogan's lid twitch sign is not pathopneumonic for MG. It may occur with brainstem or peripheral ocular motor disorders. Hering's Law of equal eyelid innervation Unilateral ptosis and contralateral lid retraction demonstrates Hering's law of equal eyelid innervation. Thus, when the ptotic lid is manually raised, the contralateral lid falls to a normal position since a large innervation is no longer required. Ptosis: Ptosis is defined as the lid covering more than 2 mm of the cornea. Ptosis is measured by documenting the width of the palpebral fissure in millimeters with the eyes in primary gaze and the eyebrows held down straight. Approximately 50% of patients with MG present with ptosis. More than 90% eventually develop eye movement abnormalities and typical ocular myasthenia gravis. Of those patients who present only with ocular symptoms, half persist with purely ocular myasthenia and half go on to develop generalized MG. Of those who develop generalized MG, most do so within 2 years of the onset of the ocular symptoms as in this patient.CT and MRI of the mediastinum are the most sensitive radiologic techniques for detecting a thymoma. CT is superior in screening for thymoma. MRI may offer, however, better resolution in evaluating the extent or spread of a thymoma to the pleural cavity.Both thymic hyperplasia and thyoma are associated with MG. Thymic hyperplasia occurs in as many as 65 to 70% of all myasthenic patients, particularly younger patients. It is characterized by infiltration of the thymus with lymphocytes and plasma cells and the formation of lymphoid follicles (germinal centers). Thymoma occur in 5 to 20% of myasthenic patients. The incidence of this tumor increases with age. Patients with thymoma tend to have more severe disease, higher serum titers of AChR antibodies, and more severe abnormalities on EMG than patients without a thymoma. Associated autoimmune diseases: There is a 23% incidence of associated autoimmune disease in patients with thymoma, although no gender predisposition or HLA antigen has been found.MG is an autoimmune disease caused by sensitized T-helper cells and an IgG-directed attack on the nicotinic acetylcholine receptor of the neuromuscular junction (NMJ). The mechanism of antibody damage to the receptor and motor endplate probably involves several steps. 1. There is a complement-directed attack with the destruction of acetylcholine receptor and the junctional folds. 2. Binding of the antibody to the receptor can cause receptor blockade. 3. The abnormal and reduced numbers of acetylcholine receptors lead to impaired NMJ transmission. 4. In post synaptic disorders such as MG, the number of quanta of acetylcholine released by each nerve stimulus is normal, but the effect of each quantum on its receptor is reduced. 5. The net result is a lower endplate potential and a reduced safety factor of transmission at the NMJ. Clinically this manifests as pathologic fatigability, that is, progressive muscle weakness with use - the hallmark of MG. Patients typically improve after rest or upon arising in the morning, with worsening as the day passes. 6. In MG, fatigue is limited to muscular fatigue alone and often progresses to frank muscle weakness.AutoimmuneSee above1. Averbuch-Heller L. Poonyathalang A, von Maydell RD, Remler BF, Hering's law for eyelids: still valid. Neurology 1995;45:1781-1782. http://www.ncbi.nlm.nih.gov/pubmed/7675249 2. Bever CT, Aquino AV, Penn AS, Lovelace RE, Rowland LP, Prognosis of ocular myasthenia. Ann Neurol 1983;14:516-519. http://www.ncbi.nlm.nih.gov/pubmed/6651238 3. Cogan DG. Myasthenia gravis. A review of the disease and a description of lid twitch as a characteristic sign. Arch Ophthalmol 1965;74:217-221. http://www.ncbi.nlm.nih.gov/pubmed/14318498 4. Cogan DG, Yee RD, Gittinger J. Rapid eye movements in myasthenia gravis. I Clinical observations. Arch Ophthalmol 1976;94:1083-1085. http://www.ncbi.nlm.nih.gov/pubmed/938289 5. Daroff, RB. The Office Tensilon Test for Ocular Myasthenia Gravis. Arch Neurol 1986;43:843-844. http://www.ncbi.nlm.nih.gov/pubmed/3729767 6. Elrod RD, Weinberg DA. Ocular myasthenia gravis. Ophthalmol Clin N Am 2004;17:275-309. http://www.ncbi.nlm.nih.gov/pubmed/15337189 7. Golnik KC, Pena R, Lee AG, Eggenberger ER. An Ice Test for the Diagnosis of Myasthenia Gravis. Ophthal 1999;106:1282-1286. http://www.ncbi.nlm.nih.gov/pubmed/10406606 8. Hanisch F, Eger K, Zierz S. MuSK-antibody positive pure ocular myasthenia gravis. J Neurol 2006;253: 659-660. http://www.ncbi.nlm.nih.gov/pubmed/16311895 9. Kaminski HJ, LI Z, Richmonds C, Ruff RL, Kusner L. Susceptibility of Ocular tissues to Autoimmune Diseases. Ann N.Y. Acad Sci 2003;998:362-374. http://www.ncbi.nlm.nih.gov/pubmed/14592898 10. Kupersmith MJ, Latkany R, Homel P. Development of generalized disease at 2 years in patients with ocular myasthenia gravis. Arch Neurol 2003;60:243-248. http://www.ncbi.nlm.nih.gov/pubmed/12580710 11. Leigh JR,Zee DS. Diagnosis of Peripheral Ocular Motor Palsies and Strabismus. Ch 9:385-474. In: The Neurology of Eye Movements 4th Edition Oxford University Press, NY 2006. 12. Meriggioli MN, Sanders DB. Myasthenia gravis: diagnosis. Semin Neurol 2004;24:31. http://www.ncbi.nlm.nih.gov/pubmed/15229790 13. Moorthy G, Behrens MM, Drachman DB, Kirkham TH, Knox DL, Miller NR, Slamovitz TL, Zinreich SJ. Ocular pseudomyasthenia or ocular myasthenia "plus": A warning to clinicians. Neurology 1989;39:1150-1154. http://www.ncbi.nlm.nih.gov/pubmed/2771063 14 Pelak VS, Quan D. Ocular Myasthenia Gravis. In: UpToDate, Rose BD (Ed) UpToDate, Wellesley, MA. 2006. 15. Seybod ME. The Office Tensilon Test for Ocular Myasthenia Gravis. Arch Neurol 1986;43:842-843. http://www.ncbi.nlm.nih.gov/pubmed/3729766 16. Sommer N, Melms A, Weller M, Dichgans J. Ocular myasthenia gravis. A critical review of clinical and pathophysiological aspects. Doc Ophthalmol 1993;84:309-333. http://www.ncbi.nlm.nih.gov/pubmed/8156854 17. Valls-Canals J, Povedano M, Montero J, Pradas J. Stimulated Single-Fiber EMG of the Frontalis and Orbicularis Oculi Muscles in Ocular Myasthenia Gravis . Muscle Nerve 2003;28:501-503. http://www.ncbi.nlm.nih.gov/pubmed/14506723 18. Vincent A, Newsom-Davis J. Anti-acetylcholine receptor antibodies. J Neurol Neurosurg Psychiatry 1980;43:590-600 1980. http://www.ncbi.nlm.nih.gov/pubmed/7400823 19. Wittbrodt ET. Drugs and myasthenia gravis an update. Arch Intern Med 1997:157:399-408. http://www.ncbi.nlm.nih.gov/pubmed/9046891curriculum_fellow; GVSptosis; GVSmyastheniagravis; VPptosismyasthenic; KBDsurgendotensilontest; VPlidretraction; VPlidtwitch; RSmyastheniagravis; vpgeneralptosi