| Identifier |
Bilateral_Ptosis |
| Title |
Bilateral Ptosis |
| Creator |
Shirley H. Wray, MD, PhD, FRCP |
| Affiliation |
(SHW) Professor of Neurology, Harvard Medical School; Director, Unit for Neurovisual Disorders, Massachusetts General Hospital, Boston, Massachusetts |
| Subject |
Bilateral Ptosis; Full Eye Movements; Facial Weakness; Tongue Atrophy; MuSK Antibody Myasthenia Gravis |
| History |
This case, previously reported in 2007, is published courtesy of John Newsom-Davis, M.D., FRCP, FRS, CBE. Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford. This patient was unusual in presenting in early childhood and the development of persistent facial muscle and tongue atrophy. At age 3 years, she presented with severe facial weakness and partial bilateral ptosis. When she was 14 years old, single fiber EMG (SF-EMG) detected a disorder of neuromuscular transmission at the neuromuscular junction and a diagnosis of myasthenia gravis (MG) was made. To establish whether she had an acquired form of myasthenia she underwent plasma exchange, resulting in clear clinical improvement. She was then started on corticosteroid treatment. As soon as her condition stabilized, she was weened off steroids but at the age of 15 her symptoms relapsed with profound facial weakness and moderate axial and limb weakness. Steroids were re-introduced and she was started on azathioprine as a steroid-sparing agent, but she failed to respond to the latter so this was switched to cyclosporin together with prednisolone, and she responded well. Although her axial and limb problems had been, up to 2007, in remission, her severe facial weakness persisted and she developed marked nasal speech, although no dysphagia for solids or liquids. A striking clinical finding was severe wasting of the tongue with a triple furrowed appearance. MRI of the facial and tongue muscles confirmed muscular atrophy and an abnormal high signal replaced most of the intrinsic tongue musculature. Antibody studies: The patient tested seronegative for anti-acetylcholinesterase antibodies (AChR) and positive for antibodies to the muscle specific tyrosine kinase (MuSK). MuSK is another protein of the post synaptic membrane of the neuromuscular junction, and plays a role in agrin-induced AChR clustering. In the original report of this child, the authors described altogether four AChR antibody negative-MuSK antibody positive patients to illustrate the phenotypes of this neurological rarity. The four cases had typical features of MuS-MG. The patients are young females presenting between 10 and 40 years of age. However, about 1 in 8 patients are male and, with increased awareness of this disorder by neurologists, older cases are now being identified. Patients often present with bulbar and ocular symptoms, but profound neck or respiratory weakness without other signs may occur. Limb and axial muscle involvement may be present in the acute phase of the disease but is seldom severe and usually responds readily to treatment. These patients can deteriorate rapidly, relatively frequently requiring ventilatory and nutritional support. Dysphagia and weight loss may at first suggest motor neuron disease, and some patients may not complain of typical myasthenic fatigue. In contrast to AChR antibody-positive patients, the tensilon test may be only weakly positive. SF-EMG studies on limb muscles may be normal at presentation, and this has been noted frequently in MuSK patients studied following treatment. Muscle atrophy particularly of the facial and bulbar muscles, seems to be a relatively common long-term consequence of the disease perhaps because the condition is relatively difficult to treat effectively, frequently responding poorly to steroids and azathioprine and sometimes requiring other immunosuppressive agents as in this case. It has also been noted that the patients may not respond well to acetylcholinesterase inhibitors such as pyridostigmine (mestinon), although ambenonium chloride (mytelase) may be tolerated better and can be helpful in some patients. None of the four reported cases were treated with thymectomy, which is of doubtful benefit in MuSK antibody-positive cases. Two studies reported in 2005 have shown that the histology of the MuSK-MG thymus is normal or near normal. Conclusions: MuSK phenotype • MuSK-myasthenia gravis often presents with predominantly bulbar and ocular symptoms. • Facial muscle atrophy is relatively common in long-standing MuSK-MG • The age range at onset is wide although to date most patients are young adult females • There is no substantial thymus pathology • Limb symptoms may remit with treatment while facial and bulbar weakness persists. • Patients are seronegative for AChR antibodies. There are no other diagnostic serum markers for this disorder. • Neurophysiological studies usually show evidence of a transmission defect in facial muscles but may be normal in the limb muscles. • Response to plasma exchange is usually very good. Response to conventional treatments with prednisolone and azathioprine can be poor, and additional immunosuppressive drugs may be required. |
| Anatomy |
It is not yet clear what role MuSK plays at the mature neuromuscular junction, or even whether MuSK antibodies cause disease. Acetylcholine receptor numbers at the neuromuscular junction appear normal and there is little complement deposition, probably because the MuSK antibodies are predominantly IgG4 which does not activate complement. In a prevalent study performed in Oxford, the proportion of MuSK antibody positive sera within AChR antibody-negative sera from different populations worldwide varied between 0 and 50%, perhaps reflecting an environmental or genetic susceptibility factor. (Vincent et al in preparation). All these observations have led to some concerns about the relevance of MuSK antibodies. Nevertheless, MuSK antibodies are very rare (less than 1:700) in community controls, and are absent in > 200 AChR antibody positive patients studied in Oxford. Moreover, as in AChR antibody positive MG cases, anti- MuSK antibodies correlate well with the clinical severity of MuSK myasthenia. Conclusion: MuSK antibodies are highly specific for a form of MG that, although quite rare, has no other diagnostic serum marker and anti-MuSK myasthenia needs to be considered in the differential diagnosis of patients with unexplained facial and bulbar weakness at all ages. |
| Disease/Diagnosis |
MuSK Antibody Myasthenia Gravis |
| Clinical |
There is no video available in this case. The facial appearance of this young child is illustrated by four photographs made available for publication by Professor John Newsom-Davis. At age 2 years, the little girl looked perfectly normal with no ptosis and a normal smile. At age 3 years, she had bilateral facial weakness and partial bilateral ptosis. By age 4 years, the facial weakness was more prominent, her mouth rests open and marked bilateral ptosis was present. At age 16 years, the picture shows a flat facial expression and complete ptosis. Electromyography: Repetetive nerve stimulation studies Right frontalis to orbicularis oculi • no spontaneous activity • no motor units under voluntary control • no activity on nerve stimulation. Right orbicularis oculi • few very small units • normal profile (duration 5 msec, not polyphasic) Her appearance at age 20 showed no change. |
| Presenting Symptom |
Facial weakness |
| Ocular Movements |
Bilateral Ptosis; Full Eye Movements |
| Neuroimaging |
Chest CT to rule out thymic enlargement MRI of face and tongue |
| Treatment |
See reference 3 |
| Etiology |
Autoimmune disease |
| References |
1. Bennett Dl, Millis KR, Riordan-Eva P, Barnes PRJ, Rose MR. Anti-MuSK antibodies in a case of ocular myasthenia gravis. J Neurol Neurosurg Psychiatry 2006;77:564-565. http://www.ncbi.nlm.nih.gov/pubmed/16543546 2. Caress JB, Hunt CH, Batish SD. Anti-MuSK myasthenia gravis presenting with purely ocular findings. Arch Neurol 2005;62-1002-1003. http://www.ncbi.nlm.nih.gov/pubmed/15956173 3. Evoli A, Tonali PA, Padua L, Monaco ML, Scuderi F, Batocchi AP, Marino M, Bartoccioni E. Clinical correlates with anti-MuSK antibodies in generalized seronegative myasthenia gravis. Brain 2003;126:2304-2311. http://www.ncbi.nlm.nih.gov/pubmed/12821509 4. Farrugia ME, Melms A. Vincent A. Myasthenia Gravis with MuSK antibodies. Pract Neurology 2005; 5:356-359. 5. 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 6. Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A, Vincent A. Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med 2001;7:365-368. http://www.ncbi.nlm.nih.gov/pubmed/11231638 7. Lauriola L, Ranelletti F, Maggiano N, Guerriero M, Punzi C, Marsili F, Bartoccioni E, Evoli A. Thymus changes in anti-MuSK-positive and - negative myasthenia gravis. Neurology 2005;64:536-538. http://www.ncbi.nlm.nih.gov/pubmed/15699390 8. Leite MI, Ströbel P, Jones M, Micklem K, Moritz R, Gold R, Niks EH, Berrih-Aknin S, Scaravilli F, Canelhas A, Marx A, Newsom-Davis J, Willcox N, Vincent A.. Fewer thymic changes in MuSK-antibody positive than in MuSK-antibody negative MG. Ann of Neurol 2005;57(3):444-448. http://www.ncbi.nlm.nih.gov/pubmed/15732104 9. McConville, J, Forrugia ME, Beeson D, Kishore U, Metcalfe R, Newsom-Davis J, Vincent A. Detection and characterization of MuSK antibodies in seronegative myasthenia gravis. Ann Neurol 2004;55:580-584. http://www.ncbi.nlm.nih.gov/pubmed/15048899 10. Nemoto Y, Kuwabara S, Misawa S , Kawaguchi N, Hattori T, Takamori M Vincent A. Patterns and severity of neuromuscular transmission failure in seronegative myasthenia gravis. J Neurol Neurosurg Psychiatry 2005;76:714-780. http://www.ncbi.nlm.nih.gov/pubmed/15834033 11. Ohta K, Shigemoto K, Kubo S, Maruyama N, Abe Y, Ueda N, Ohta M. MuSK antibodies in AchR Abseropositive MG vs AchR Abseronegative MG. Neurology 2004;62:2132-2133. http://www.ncbi.nlm.nih.gov/pubmed/15184636 12. Sanders DB, El-Salem K, Massey JM, McConville J, Vincent A. Clinical aspects of MuSK antibody positive seronegative MG. Neurology 2003;60:1978-1980. http://www.ncbi.nlm.nih.gov/pubmed/12821744 13. Shiraishi H, Motomura M, Yoshimura T, Fukudome T, Fukuda T, Nakao Y, Tsujihata M, Vincent A, Eguchi K.. Acetylcholine receptor loss and postsynaptic damage in MuSK antibody-positive myasthenia gravis. Ann of Neurol 2005;57(2):289-293. http://www.ncbi.nlm.nih.gov/pubmed/15668981 |
| Language |
eng |
| Format |
application/pdf |
| Format Creation |
Microsoft PowerPoint |
| Type |
Text |
| Relation is Part of |
210-1 |
| Collection |
Neuro-Ophthalmology Virtual Education Library: Shirley H. Wray Collection: https://novel.utah.edu/Wray/ |
| Publisher |
North American Neuro-Ophthalmology Society |
| Holding Institution |
Spencer S. Eccles Health Sciences Library, University of Utah |
| Rights Management |
Copyright 2002. For further information regarding the rights to this collection, please visit: https://NOVEL.utah.edu/about/copyright |
| ARK |
ark:/87278/s67jyfvt |
| Setname |
ehsl_novel_shw |
| ID |
2174178 |
| Reference URL |
https://collections.lib.utah.edu/ark:/87278/s67jyfvt |
