Journal of the Neurological Sciences 356 (2015) 5–6

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Journal of the Neurological Sciences

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Editorial

Chemosensory disturbances-associatednanocholinergic dysfunction: The case of, notonly, myasthenia gravis

Keywords:AcetylcholineMyasthenia gravisSmellTaste

The first description of myasthenia gravis (MG) made in 1672, byThomas Willis, showed fluctuating weakness in human voluntarymuscles from limbs and face, that recovered after a period of rest [1].Simpson, in 1960, proposed autoimmunity as the cause of MG [1].Since 1976, a number of antibodies against the different nicotinic andmuscarinic constituents of the acetylcholine receptor have been discov-ered in MG [1,2].

Antibodies in MG, triggered by exogenous or endogenous noxa,including fetal cells or placental tissues [3], can be generated inside oroutside of the central nervous system (CNS), or both [4]. Antibodiesare found in both blood and in cerebrospinal fluid, and can cross toand from the CNS through a lesioned blood–brain barrier (BBB) [5].Antibodies may well go directly through the area postrema, a regionlocated at the dorsal surface of the medulla without BBB [6]. Geneticdefects in a number of portions of the acetylcholine receptor, inheritedat birth, also may cause MG [7], named as myasthenic syndromes. Thementioned antibodies or the genetic defects preclude the action ofacetylcholine at neuromuscular junction. As a result, muscles becomeweaker during and after activation, and improve after resting. For centu-ries, non-muscle involvement was forgotten in MG, misleading clini-cians and researchers.

Among the non-musclefindings, smell and taste disturbances inMG,were anecdotally reported until recent years [8]. We were the first toquantitatively test smell function in MG [9] using the University ofPennsylvania Smell Identification Test (UPSIT). It was discovered thatthe scores obtained from MG patients were significantly lower thanthose from healthy controls and patients with polymyositis [9]. In thisissue, Tekeli et al. replicated our findings of smell dysfunction in MG,using a different smell test, in a group of patientswithMG [10]. Anosmiawas found in 13,3% of MG patients whereas 86,7% were hyposmics.

Further, Tekeli et al. expanded the chemosensory research, andfound that taste, a function unrelated to muscle strength, was also ab-normal in the same group of patients [10]. Specific abnormal flavor de-tection was not found but a positive correlation between the smell andtaste dysfunction was. Patients from Tekeli et al. [10], like ours, did nothave thymoma; importantly, the lower scores these authors foundwere proven not due to medications administered to control MG [9,10]. These findings agree with a number of published case reportswhich showed that medications used to treat MG did not worsen but

http://dx.doi.org/10.1016/j.jns.2015.06.0520022-510X/© 2015 Elsevier B.V. All rights reserved.

improved chemosensory disturbances [7]. Moreover, in rats, physostig-mine the first medication used, in 1934, to treat MG, enhanced signal tonoise ratios within the olfactory bulb improving odor discrimination[11], and neostigmine enhanced spontaneous discrimination betweenchemically related odorants [12]. Therefore, smell and taste disordersin MG should no longer be misjudged as side effects of drugs used forchemotherapy and immunotherapy in MG, but the deleterious actionof autoimmunity.

It is conceivable that the chemosensory deficit in MG involves anti-bodies directed against cholinergic neural transmission within theolfactory and/or gustatory pathways for a number of reasons. First, inhumans, the muscarinic acetylcholine receptor antagonist scopolamineimpairs odor detection ability [13]. Second, the olfactory responses gen-erated by the activation of M3 subtype muscarinic receptors that pre-dominate in nasal tissue, were enhanced by agonists, and blocked byatropine [14]. Third, mice lacking alpha7-nicotinic acetylcholine recep-tors found on the nerve terminals of olfactory bulb cells of rodentsshowed decreased odor detection/discrimination performance [9]; suchdysfunction improved in both rats andmice following intraperitoneal in-jection of physostigmine andneostigmine [9]. Fourth, the development ofboth the olfactory bulbs and the neuromuscular junction ismodulated, inDrosophila, by Limk protein, a key regulator of the actin cytoskeleton,which in turn is a protein modulating taste pore physiology [9,15]. Fifth,acetylcholine involved in cell-to-cell communication within taste budreceptors, increases taste-induced activity in afferent gustatory fibers offrogs and rats [9]. Sixth, nicotine activates the taste bud-associatedchorda tympani nerve [9]. Seven, downregulation of alpha-gustducin,a G-protein subunit modulated by nicotinic acetylcholine receptors,was put forward as responsible for MG-related dysgeusia [16,17].

Another interesting finding in the study of Tekeli et al. [10] was thatchemosensory disturbances inversely correlated with disease activity.These findings clarify the subjective chemodisturbances found todebut earlier than the classical myasthenic – muscles – complains, in anumber of case reports. For example, smell problems were reportedby Musha et al. in their patients, two and five years before the musclesymptoms appeared [9]. Similarly, taste disorders have preceded thetongue atrophy [18], and were traced back to eight years before theonset ofMG [9]. Thus, chemosensory disturbancesmaywell predict dis-ease severity.

A limitation of the study done by Tekeli et al. [10], was that theseauthors studied patients who scored N28 in the mini-mental stateexamination (MMSE). Although the rational for studying individualswith such MMSE scores was addressed, it left the question open onthe chemosensory function of patients who have lower MMSE scoresthan 28, not uncommonly found in MG [19]. In Leon-Sarmiento et al.'sstudy [9], MG patients had subtle cognitive deficits, using the pictureidentification test, which is analogous to the UPSIT except that picturesrather than odors serve as test stimuli.

It remains to be studied whether other immune or genetically-mediated myasthenic syndromes also harbor chemosensory distur-bances. Although the study from Tekeli et al. [10] does not address this

6 Editorial

question, it would be possible. Having said that, the chemosensory dys-function anecdotally reported by some, discovered by us using theUPSIT, and now replicated and expanded by Tekeli et al. [10], should berecognized, from here on, as one of the key non-motor symptoms inMG. It may well contribute to a paradigm shift in its neurobiological un-derstanding, and must re-orient its classification.

Lastly, the case reports and the population-based studies publishedsupport the concept that chemosensory dysfunction in MG is temporaland biologically analogous to the dysfunction discovered in a numberof disorders having both chemosensory disturbances and acetylcholinereceptor antibodies (e.g., Parkinson's disease, Alzheimer's disease,Schizophrenia, Chagas disease). Altogether, these facts must be kept inmind, since they are shedding light to definitively disentangle a novelneuro-tautological complex characterized by a multiform impairmentdue to nanocholinergic dysfunction (MIND) that happens within thecentral, peripheral and autonomic nervous system of humans.

Acknowledgments

The authors would like to thank Mrs. Tammy Hansen Snell for theEnglish editing.

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Fidias E. Leon-SarmientoSmell & Taste Center, Department of Otorhinolaryngology,

Perelman School of Medicine, Philadelphia, PA, USACorresponding author at: Smell & Taste Center, Department of

Otorhinolaryngology, University of Pennsylvania, Philadelphia, PA, USA.E-mail address: feleones@gmail.com.

Juan S. Leon-ArizaMediciencias Research Group, Unicolciencias/Universidad Nacional,

Bogota, ColombiaVisiting Scholar, Department of Radiology, Perelman School of Medicine,

Philadelphia, PA, USA

Diddier G. PradaDepartment of Environmental Health,

Harvard T. H. Chan School of Public Health, Boston, MA, USA

Daniel S. Leon-ArizaMediciencias Research Group, Unicolciencias/Universidad Nacional,

Bogota, ColombiaFaculty of Health Sciences, UDES, Bucaramanga, Colombia

23 June 2015