Ocular Myasthenia Gravis Accompanied by Anosmia

CASE REPORTTOPIC Ocular myasthenia gravis accompanied by anosmia

Chen Ying, Wang Li, Zhou Li, Gao Ying aa Chen Ying, Zhou Li, Gao Ying, Second Encephalopathy De- an elderly gentleman. Before the initial consultation, partment, Dongzhimen Hospital Affiliated to Beijing Univer- he had suffered from loss of olfaction (anosmia) for 2 sity of Chinese Medicine, Beijing 100700, China years as well as flaccidity and drooping in the right up- Wang Li, Rehabilitation Department, Lichuan People's Hos- per eyelid for 4 months. pital in Hubei Province, Lichuan 445400, China After hospitalization, he was diagnosed with a droop- Correspondence to: Gao Ying, Encephalopathy Depart- ing eyelid and anosmia in terms of Traditional Chinese ment, Dongzhimen Hospital Affiliated to Beijing University Medicine (TCM), and as having ocular MG with anos- of Chinese Medicine, Beijing 100700, China. gaoying973@ mia in terms of Western Medicine. Analyses of the 126.com pathologic evidence suggested that the olfactory disor- Telephone: +86-10-84013209; +86-13366275973 der could be manifestation of MG. We speculate that Accepted: September 21, 2015 MG accompanied by anosmia is a special subtype of MG.

Abstract CASE REPORT We report a case of ocular myasthenia gravis (MG) The patient was a 76-year-old man. He complained of accompanied by anosmia. A 76-year-old man had anosmia of 2-year duration, and flaccidity and droop- idiopathic anosmia of 2-year duration. Four months ing of the right upper eyelid for 4 months, and was before consultation, he began to have drooping in hospitalized on 22 November 2012. He had developed the right upper eyelid along with muscle soreness, anosmia with no obvious predisposing factor in 2010 distension, and pain in the nape. His tongue was and received no treatment. In July 2012, he went fish- dark-red with a thin and white coating; his pulse ing and suddenly felt weak and found that his right was wiry and slippery. According to Traditional Chi- upper eyelid was drooping, but he did not seek medi- nese Medicine, eyelid drooping and anosmia are cal attention. The condition worsened gradually, and the main signs of liver constraint and spleen defi- he tended to feel better in the morning than in the evening. ciency. In Western Medicine, the diagnosis was ocu- In August 2012, his vision was blocked partially by the lar MG and idiopathic anosmia. Our patient, along drooping eyelid and his nape felt sore and painful. He with the literature, suggests that anosmia may be sought help from our hospital. No abnormalities were an early symptom before MG. MG accompanied by found upon CT of the chest and he refused medications. anosmia could be a special subtype of MG accord- On 22 November 2012, his symptoms worsened and ing to antibody production and symptoms. he was admitted to the Department of Encephalopathy of our hospital. His manifestations were anosmia, a © 2016 JTCM. Open access under CC BY-NC-ND license. drooping right upper eyelid, muscle soreness, and dis- Key words: Myasthenia gravis; Olfaction disorders; tension and pain in the nape. Diplopia, indifferent fa- cial expressions, drooling, weakness in rotation of the Eyelids; Antibody neck, dyspnea, or weakness in the extremities were not observed. INTRODUCTION He had a history of scrofula that had resolved. He had been diagnosed with coronary disease, but had never We report a case of ocular myasthenia gravis (MG) in taken any medications for it. He did not smoke but

JTCM | www. journaltcm. com 125 February 15, 2016 |Volume 36 | Issue 1 | Chen Y et al. / Case Report consumed a small amount of alcohol. His father had a ber 2014, he informed us by telephone that there was history of eyelid drooping from at the age of 90 no improvement in olfaction. Since June 2014, his left years, but no diagnosis had been made or treatment eyelid began to feel weak and a drooping eyelid had de- administered. veloped. Currently, he is taking pyridostigmine tablets Clinical examination revealed: anosmia; drooping of the (30 mg, t.i.d.) and his condition is under control. right upper eyelid: fissure in the right eyelid of 6 mm; fissure in the left eyelid of 10 mm; flexible movement of the eyeballs; pupil diameter (both sides) of 2.5 mm; DISCUSSION both pupils sensitive to direct and indirect light reflex. The tongue and uvula protruded on the midline. Dip- Pathogenesis of MG lopia or forceful closing of the eyes was not identified. MG is an acquired autoimmune disease that occurs Breathing movement was symmetric on both sides, mainly due to a defect/absence of nicotinic acetylcho- and muscle strength in the four extremities was grade line receptors at the post-synaptic neuromuscular junc- 5. Volume and tone of muscle were normal. Tendon re- tion. MG involves antibody-mediated destruction of flexes of the four extremities were symmetric, bilateral acetylcholine receptors, is dependent on cell immunity, Babinski sign (and its equivalent signs) were negative, and is associated with complement. Causative factors superficial and deep sensations of the trunk and four include autoimmunity, passive immunity, and drug extremities were symmetric, and the ataxia test was neg- use. The typical clinical manifestation is fluctuating ative. His tongue was dark red with a thin, white coat- weakness and fatigue of certain groups of striated mus- ing. His pulse was wiry and slippery. cles (mostly extraocular muscles), a condition that is On 27 November 2014, a fatigue test of the upper eye- much milder in the morning and more severe in the lids showed an initial fatigue time for the right upper evening, and which is aggravated by exertion and remit- eyelid to be 32 s (score, 1) whereas that of the left up- ted by rest. The most common initial symptom is per eyelid was > 60 s (score, 0). The neostigmine meth- asymmetric ptosis and / or bilateral diplopia due to ylsulfate test showed a grade of ≥ 60%. weakness of extraocular muscles. On 29 August 2012, routine and contrast-enhanced According to the Osserman classification, MG can be CT of the chest showed an old lesion in the right up- categorized into five types. In type 1, only extraocular per lung, as well as interstitial changes in the right low- muscles are affected and no other muscle groups are in- er lung. On 23 November 2012, MRI of the head volved within 2 years of the diagnosis. In type 2, mild, showed ischemic infarction in bilateral frontal and pari- generalized MG involving at least one muscle group is etal lobes, basal ganglia, and around the lateral ventri- observed. Type 3 is characterized by severe, generalized cle; senile encephalic changes and minor inflammation MG that occurs and progresses drastically, and respira- of the ethmoid sinus were also observed. tory muscles are often involved within 6 months of the On 29 November 2012, routine CT with three-dimen- diagnosis. In type 4, delayed, severe, generalized MG sional reconstruction of paranasal sinuses showed local occurs in an insidious and gradual fashion, and respira- thickened mucus in the maxillary sinus and a bulging tory muscles are involved within 2 years of the diagno- inferior nasal concha. Physicians from our ENT De- sis. In type 5, skeletomuscular atrophy is noted within partment carried out nasal endoscopy, which showed 6 months of the diagnosis.1 mild congestion of nasal passages, no obvious swelling, Recent studies have shown that multiple antibodies and no neoplasm in the nasal septum or olfactory cleft. take part in MG, among which the mechanism of ac- The patient refused an electrophysiology test. Caus- tion of antibodies against acetylcholine receptors is rela- ative factors of anosmia remained unknown. On 25 tively well characterized.2 December, 2012, a serum test was positive for antibod- Antibodies against titin are present in MG patients ies against titin, ryanodine receptors, and muscle-specif- with antibodies against acetylcholine receptors, and ic tyrosine kinase (MuSK), but negative for acetylcho- suggest MG accompanied by a thymoma (MGT).3,4 line receptors and acetylcholine. The possibility of a thymoma cannot be excluded even In terms of TCM, the diagnosis was a drooping eyelid if a MG patient does not have antibodies against titin.5 and anosmia with a symptom pattern of liver con- Studies have shown that MGT is associated with MG straint and spleen deficiency. In terms of Western Med- severity.6,7 icine, the diagnosis was ocular MG and idiopathic an- Antibodies against MuSK are usually present in the se- osmia. rum of MG patients who do not have antibodies During hospitalization, the patient refused to take hor- against acetylcholine receptors.8 Its relevance is related mone and pyridostigmine therapies. Only cobamamide to test methods, patient ethnicity9-14 and MG type.15,16 was administered to nourish the nerves. The TCM regi- This type of MG occurs acutely and often involves the men was based on soothing the liver, strengthening the respiratory muscles.17 It responds poorly to cholinester- spleen, boosting Qi, and lifting Yang. ase inhibitors and removal of the thymus gland.18,19 A The patient was discharged on 30 December 2012 possible mechanism of action is that antibodies against with an improved right upper eyelid. On 27 Septem- MuSK influence accumulation of acetylcholine recep-

JTCM | www. journaltcm. com 126 February 15, 2016 |Volume 36 | Issue 1 | Chen Y et al. / Case Report tors by blocking the combination of MuSK and (AD), Lewy body dementia (LBD), schizophrenia, mul- low-density lipoprotein receptor-related protein (LRP) tiple sclerosis, and Parkinson's disease (PD).34 Studies 4.20 have shown that anosmia or hyposmia is a main symp- Antibodies against ryanodine receptors influence mus- tom of AD, LBD and PD. cle contraction by inhibiting opening of ryanodine re- Olfactory disorders in AD are associated with pigment ceptor channels and calcium release. Studies suggest formation in the central nervous system and neuronal that having antibodies against ryanodine receptors is re- degeneration. The pathogenesis involves loss of olfacto- lated to MGT and manifests mainly as delayed, severe ry functions, alteration of olfactory nervous pathways, MG.21,22 MGT may render weakness due to damage to as well as morphologic and changes in concentrations excitation-contraction coupling.23 of neurotransmitters.35 The latter include changes in Having antibodies against LRP4 can cause muscular levels of acetylcholine,36 noradrenaline,37 dopamine,38 as weakness: they can damage the structure of the neuro- well as the transporters and receptors of 5-hydroxytryp- muscular junction and disturb the combination of tamine.39,40 agrin and LRP4 to influence accumulation of acetyl- LBD has similar clinical characteristics and pathologic choline receptors.24,25 Antibodies against Kvl4 mainly af- changes to those seen in PD, including anosmia.41 fect voltage-activated potassium channels on the sur- Olfactory dysfunction among PD patients is related to face of muscle fibers, thereby influencing membrane re- genetics, proteins, the environment, and changes in polarization and maintenance of the resting potential.23 neurotransmitter levels.42 Studies have shown that Antibodies against acetylcholine are often present in changes in levels of acetylcholine, noradrenaline, dopa- MG patients who do not have antibodies against acetyl- mine, 5-hydroxytryptamine and other neurotransmit- choline receptors and who have a poor reaction to the ters may be involved in the olfactory dysfunction seen prostigmine test. A combination of antibody and syn- in PD.43 In particular, cholinergic denervation of ar- aptic acetylcholine inactivates acetylcholine and hin- chicortex is a strong factor for olfactory dysfunction in ders its hydrolysis. Then, acetylcholine acts on PD.44 post-synaptic membranes to depolarize them, thereby A common feature of olfactory dysfunction in AD and influencing subsequent nerve transmission.26 PD is cholinergic damage. Olfactory dysfunction oc- Presynaptic membrane antibody can indicate damage curs in AD and PD before the onset of motor or ner- to presynaptic membranes and is strongly associated vous symptoms. Therefore, olfactory examination can with having antibodies against acetylcholine receptors.27 help to screen and diagnose AD and PD at an early Some studies have shown matrix metalloproteinases28 stage. to be associated with MG. Mitochondrial dysfunction has also been associated with MG.29,30 An important fac- Etiology and pathogenesis of anosmia and the tor in neuromuscular diseases is mitochondrial dysfunc- "wilting symptom pattern" (WSP) in TCM tion, which can result in energy deficiency.31 In TCM, MG is termed the WSP or "drooping eyelid" if it manifests mainly as blepharoptosis. The WSP is re- Anosmia and diseases of the nervous system lated to invasion by exogenous pathogens and dysfunc- The olfactory system comprises the olfactory epitheli- tion of the lungs, spleen, liver and kidneys. The com- um, olfactory nerves, olfactory bulb, olfactory tract, mon syndromes of MG and its therapies and herbal and connections to the nervous system. According to formulas are clear.45-47 Studies have shown that TCM severity and characteristics, olfactory disorders can be can be efficacious against WSP.47 Progress has been classified into anosmia, hyposmia, hyperosmia, paros- made in treating MG by TCM. For example, using mia and olfactory hallucination. TCM, a functional relationship between the spleen Anosmia refers to no reaction to olfactory stimulation and mitochondria,48 the intervention effect of TCM on and can be subdivided into entire, part and special antibodies against acetylcholine receptors,49 and regula- types.32 Uniform diagnostic methods and standards for tory functions in the immune system50 have been illus- measurement of olfactory dysfunction are lacking. trated. Commonly used methods are subjective olfactory tests, In TCM, olfactory dysfunction is in the scope of "loss objective olfactory tests, and radionuclide imaging.33 of olfaction". TCM theory holds that the nose has The cause of olfactory disorders are peripheral damage abundant blood and vessels. Though it is an opening (blockage of the nasal cavity and injured olfactory mu- to the lungs, it can be attributed to the earth due to its cus cells) and central damage (disorder of the cerebral external location. Thus, it has a close relationship to cells responsible for sensing odors). the lungs and spleen. The heart, liver and kidneys can Several factors can lead to olfactory disorders. Com- also influence olfaction. mon factors are infection of the upper respiratory tract, The lungs govern Qi, control respiration, and have an aging, nasal diseases, brain trauma, smoking, diabetes opening to the nose. If exogenous pathogens attack the mellitus, depression, hearing disorders, epilepsy and lungs and the lungs fail to distribute fluids, then the in- drug use. Olfactory disorders can also be part of diseas- ternal organs, four extremities, tendons and vessels will es of the nervous system such as Alzheimer's disease lack nourishment, possibly leading to the WSP. Lung

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Qi stagnation in the nose results in loss of olfaction. tibodies against titin are found in MG patients with an- The spleen governs the muscles and is the source of tibodies against MuSK or no antibodies against se- generation of Qi and blood. Sufficient spleen Qi en- rum.19 However, our patient had antibodies against ti- sures abundant Qi, abundant blood, and strong mus- tin and MuSK, which merits further study. cles. However, weakness of spleen Qi will prevent it Leon-sarmiento et al 52 carried out a test for odor identi- from transporting and transforming water and food to fication for 27 MG patients, 27 healthy volunteers, produce nutrients for all parts of the body. Weakness and 11 patients with polymyositis. MG patients were and the WSP will occur if Qi and blood are not suffi- found to be significantly worse at identifying odors cient and muscles are not nourished. Lack of nourish- than the other two groups. Only ≈15% of MG pa- ment in the nose will lead to anosmia. The liver stores tients had olfactory dysfunction before the test. That blood, opens into the eyes and is associated with ten- study suggested MG patients have olfactory dysfunc- dons. Constraints in liver Qi, deficiency of liver blood, tion and that it may be associated with cholinergic and malnourishment of tendons and vessels will result damage to the central nervous system.52 in weakness and wilting of the body. Disorder of Qi movement can cause inhibited opening of the nasal cavity. The kidneys govern the bone, produce bone mar- CONCLUSIONS row, and store primordial Yin and Yang. Insufficient in- On the basis of our case study and the literature, we nate endowment, prolonged illness or aging can con- propose two hypotheses. First, though our patient did tribute to deficiency of kidney essence, Yin and Yang. not have antibodies against acetylcholine receptors and If the kidneys fail to nourish tendons, bones and mus- acetylcholine, we cannot exclude the possibility of de- cles, weakness and the WSP will occur; if they fail to tecting low affinity of acetylcholine receptors by warm nasal orifices, anosmia will develop. non-standard methods.53 Moreover, antibodies against Therefore, in terms of TCM, the WSP and anosmia MuSK can also inhibit aggregation of acetylcholine re- have similar etiologies and pathogenesis, which can ceptors. Anosmia in our patient could have been an ear- make them occur simultaneously. ly symptom before other MG manifestations. Second, Case characteristics MG accompanied by anosmia could be a new subtype Or patient did not have a history of acute infection of according to antibody production and symptoms. the upper respiratory tract, smoking, external trauma to the head, chronic sinusitis, or migraine. He was diag- REFERENCES nosed with coronary disease, but he was not treated for it. Contrast-enhanced CT of the chest did not reveal a 1 Neuro-Immunology Committee of Chinese Society for thymoma. CT of paranasal sinuses and consultations Immunology. Neuro-Immunology of Chinese Society of in the ENT Department showed that anosmia was not Neurology. Chinese experts' common consensus on the di- caused by sinusitis.51 Mini-mental state examination agnosis and treatment for myasthenia gravis. Zhong Guo did not show reduced cognitive function. Two years af- Shen Jing Mian Yi Xue He Shen Jing Bing Xue Za Zhi ter anosmia, the right side of the upper eyelid started 2012; 19(6): 401-407. to droop. 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