0
Get Alert
Please Wait... Processing your request... Please Wait.
You must sign in to sign-up for alerts.

Please confirm that your email address is correct, so you can successfully receive this alert.

1
Letter   |    
Evidence for a Central Cholinergic Deficit in Myasthenia Gravis
Fotis Fotiou, M.D., Ph.D.; Konstantinos N. Fountoulakis, M.D., Ph.D.
The Journal of Neuropsychiatry and Clinical Neurosciences 2000;12:514-515. doi:10.1176/appi.neuropsych.12.4.514
View Author and Article Information

Myasthenia GravisAcetylcholine Transmission

SIR: Myasthenia gravis (MG) manifests clinically with symptoms related to the dysfunction of acetylcholine (Ach) synaptic transmission in the neuromuscular junction. However, there is evidence that in MG patients, cholinergic transmission in the central nervous system (CNS) is also affected. This evidence includes observations of reduced REM sleep,1 electroencephalographic changes, and detection of Ach receptor antibodies in the cerebrospinal fluid of MG patients. Also, there are some studies on the mental status of MG patients. They manifest higher trait anxiety and greater suppression of anger, and nearly 20% of them were initially diagnosed as having a psychiatric disorder.2 They may show cognitive impairment3 as well.

Recently, pathological pattern-reversal visual evoked potentials (PR- VEPs) in MG patients have been reported from our research group. According to the international literature, the reason for these alterations in PR-VEPs may be a dysfunction of CNS Ach receptors or an eye movement disturbance, or even both. In a second study, because eye movements that are pathological in MG affect VEPs, we recorded eye movements (with an optical method), FLASH-electroretinogram, FLASH-VEPs, and PR-VEPs in 37 MG patients. Both the eye movements and the PR-VEPs were pathological.

To further investigate this issue,4 we studied 10 control subjects, 9 patients who suffered from newly diagnosed MG, and 5 patients with ocular myopathy (OM).5 Recordings of eye movements and PR-VEPs were simultaneous. PR-VEPs were obtained 1 month before and approximately 1 month after pyridostigmine treatment in MG patients. MG is considered to be a disease of the neuromuscular junction, whereas OM is a disease of the muscles and no neurotransmitters are involved in its pathogenesis. The rationale behind this design is that by studying and comparing two groups of patients with eye movement disorder, one can isolate and control for the effect of eye movements on PR-VEPs and in this way obtain a clearer picture of the possible effect of MG in the CNS.

Only the MG patients' PR-VEPs differed from those of normal control subjects both before and after pyridostigmine treatment. Those of OM patients did not. Both MG and OM patients' eye movements were significantly deficient in comparison to those of control subjects.

Impaired eye movements alone do not offer sufficient explanation of the pathological VEPs observed in MG patients. The results of our research group and the international literature provide substantial evidence for a CNS Ach deficit in MG. This possibility has important therapeutic implications.

Acetylcholine is related to several mental disorders, including mood and cognitive disorders. A search of the international literature yielded only a few studies dealing with the issue of mental disorders in MG patients. Generally, these patients are considered to be at higher risk for a mental disorder than patients with other neurological diseases.6 It is reported that MG patients manifest higher levels of trait anxiety. They also may inhibit the expression of anger.7 It has been theorized that these two characteristics may predispose to the development of myasthenia.

A retrospective study of MG patients revealed that almost 20% of them had initially received a psychiatric diagnosis.8 Young women are at increased risk to receive a diagnosis in this way. On the contrary, men usually receive a diagnosis of another somatic disorder. However, the authors of this particular study note that false psychiatric diagnosis is accompanied by higher scores on depressive scales. Depression seems to be related to the dose of anticholinesterase treatment needed and the self-reported muscular weakness.8

Apart from "pure" psychiatric symptomatology, it seems that MG patients manifest lower Mini-Mental State Examination scores and also score lower in various memory tests.9 MG patients may suffer from a disorder of higher cognitive functioning that responds to therapeutic intervention.10

The role of Ach in higher cognitive function is well studied and established.1119 However, this is not so concerning a possible role for Ach in the pathogenesis of depression. The Ach role in depression (if any) is not well studied. The inhibition of behavior produced by some agents (e.g., physostigmine) that are known to increase central Ach activity suggests that an Ach-norepinephrine imbalance is central in the pathogenesis of depression.20 However, other authors propose a relationship only to personality traits.21

It has also been suggested that the simultaneous increase reported in the activity of catecholamines and in measurements that reflect the hypothalamus-pituitary-adrenal axis in depressed patients indicates, in fact, an increase of Ach activity. The increase of the central cholinergic basal activity after the administration of centrally active agents like physostigmine, arecholine, and oxotremorine usually triggers or worsens the behavioral analogs of depression. Many authors suggest that pharmacologically induced changes in Ach activity could lead to the development of a model of depression by influencing other transmitter systems (e.g., GABA, serotonin, dopamine, or norepinephrine).22

On the basis of observations in Alzheimer's disease patients, several authors refer to a "cholinergic threshold" below which any experience of depressed mood is impossible.23 This thinking runs counter to the proposal that reduced Ach activity in the CNS could in itself produce depression. Of course, a psychomotor inhibition would be present, and this in combination with a cognitive deficit could produce the false impression and diagnosis of depression. However, drawing conclusions would be premature. The disorder of a single neurotransmitter in the CNS is never the sole disorder of this kind present. It is therefore necessary to assess and investigate in depth the clinical neurocognitive and psychiatric symptomatology and the functioning of the neuroendocrine system in MG patients.

As far as everyday clinical practice is concerned, if there is a true acetylcholine disorder in the CNS of myasthenia gravis patients, as data tend to suggest, and this disorder is accompanied by psychiatric symptomatology and higher cognitive- function deficit, then a significant question concerning the need for treatment emerges. This treatment could well be based on agents recently developed for the treatment for Alzheimer's disease. On the other hand, the prescription of antidepressants in MG patients should be made with extreme caution because of the frequent anticholinergic side effects of these agents.

Papazian O: Rapid eye movement sleep alteration in myasthenia gravis. Neurology  1976; 26:310—313
 
Rohr W: Myasthenia gravis in the frontier of psychiatric diagnosis. Psychiatr Prax 1992; 19(5):157—163
 
Iwasaki Y, Kinoshita M, Ikeda K, et al: Neuropsychological function before and after plasma exchange in myasthenia gravis. J Neurol Sci  1993; 114:223—226
[CrossRef] | [PubMed]
 
Fotiou F, Goulas A, Fountoulakis K, et al: Changes in psychophysiology of vision in myasthenia gravis. Int J Psychophysiol  1998; 29:303—310
[CrossRef] | [PubMed]
 
Fotiou F, Papakostopoulos D, Hamlatzis P: Changes in the pattern reversal visual evoked potentials in myasthenia gravis. Electromyogr Clin Neurophysiol  1994; 34:171—175
[PubMed]
 
DePaulo JR, Folstein MF, Gordon B: Psychiatric screening on a neurological ward. Psychol Med  1980; 10:125—132
[CrossRef] | [PubMed]
 
Tennant C, Wilby J, Nicholson GA: Psychological correlates of myasthenia gravis: a brief report. J Psychosom Res  1986; 30:575—580
[CrossRef] | [PubMed]
 
Rohr W: Myasthenia gravis in the frontier of psychiatric diagnosis. Psychiatr Prax 1992; 19(5):157—163
 
Iwasaki Y, Kinoshita M, Ikeda K, et al: Cognitive dysfunction in myasthenia gravis. Int J Neurosci 1990; 54(1—2):29—33
 
Iwasaki Y, Kinoshita M, Ikeda K, et al: Neuropsychological function before and after plasma exchange in myasthenia gravis. J Neurol Sci  1993; 114:223—226
[CrossRef] | [PubMed]
 
Smith G: Animal models of Alzheimer's disease: experimental cholinergic denervation. Brain Res Rev  1988; 13:103—118
[CrossRef]
 
Mantione CR, Zigmond MJ, Fisher A, et al: Selective presynaptic cholinergic neurotoxicity following intrahippocampal AF64A injection in rats. J Neurochem  1983; 41:251—255
[PubMed]
 
Fisher A, Mantione CR, Abraham DJ, et al: Long-term central cholinergic hypofunction induced in mice by ethylcholine aziridinium ion (AF64A) in vivo. J Pharmacol Exp Ther  1982; 222:140—145
[PubMed]
 
Weinberger J, Greenberg JH, Waldman MTG, et al: The effect of scopolamine on local glucose metabolism in rat brain. Brain Res  1979; 177:337—345
[CrossRef] | [PubMed]
 
Whitehouse P, Price D, Struble R, et al: Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain. Science 1985; 215:1237—  1239
 
Murray CL, Fibiger HC: Learning and memory deficits after lesions of the nucleus basalis magnocellularis: reversal by physostigmine. Neuroscience 1985; 14:1025—  1032
 
Davis KL, Mohs RC, Davis BM, et al: Cholinergic treatment in Alzheimer's disease: implications for future research, in Alzheimer's Disease: A Report of Progress in Research, edited by Corkin S, Davis KL, Crowdon JH, et al. New York, Raven, 1982, pp 483—494
 
Davis KL, Yamamura HI: Cholinergic underactivity in human memory disorders. Life Sci 1978; 23:1729—  1734
 
Ezrin-Waters C, Resch L: The nucleus basalis of Meynert. Can J Neurol  1986; 13:8—14
 
Janowsky D, El Yousef M, Davis J, et al: A cholinergic-adrenergic hypothesis of mania and depression. Lancet 1972; ii:632—635
 
Fritze J, Lanczik M, Sofic E, et al: Cholinergic neurotransmission seems not to be involved in depression but possibly in personality. J Psychiatry Neurosci  1995; 20:39—48
[PubMed]
 
Janowsky DS, Overstreet DH: The role of acetylcholine mechanisms in mood disorders, in Psychopharmacology: The Fourth Generation of Progress, edited by Bloom FE, Kupfer DJ. New York, Raven, 1994, pp 945—956
 
Zubenko GS, Moossy J, Kopp U: Neurochemical correlates of major depression in primary dementia. Arch Neurol  1990; 47:209—214
[PubMed]
 
+

References

Papazian O: Rapid eye movement sleep alteration in myasthenia gravis. Neurology  1976; 26:310—313
 
Rohr W: Myasthenia gravis in the frontier of psychiatric diagnosis. Psychiatr Prax 1992; 19(5):157—163
 
Iwasaki Y, Kinoshita M, Ikeda K, et al: Neuropsychological function before and after plasma exchange in myasthenia gravis. J Neurol Sci  1993; 114:223—226
[CrossRef] | [PubMed]
 
Fotiou F, Goulas A, Fountoulakis K, et al: Changes in psychophysiology of vision in myasthenia gravis. Int J Psychophysiol  1998; 29:303—310
[CrossRef] | [PubMed]
 
Fotiou F, Papakostopoulos D, Hamlatzis P: Changes in the pattern reversal visual evoked potentials in myasthenia gravis. Electromyogr Clin Neurophysiol  1994; 34:171—175
[PubMed]
 
DePaulo JR, Folstein MF, Gordon B: Psychiatric screening on a neurological ward. Psychol Med  1980; 10:125—132
[CrossRef] | [PubMed]
 
Tennant C, Wilby J, Nicholson GA: Psychological correlates of myasthenia gravis: a brief report. J Psychosom Res  1986; 30:575—580
[CrossRef] | [PubMed]
 
Rohr W: Myasthenia gravis in the frontier of psychiatric diagnosis. Psychiatr Prax 1992; 19(5):157—163
 
Iwasaki Y, Kinoshita M, Ikeda K, et al: Cognitive dysfunction in myasthenia gravis. Int J Neurosci 1990; 54(1—2):29—33
 
Iwasaki Y, Kinoshita M, Ikeda K, et al: Neuropsychological function before and after plasma exchange in myasthenia gravis. J Neurol Sci  1993; 114:223—226
[CrossRef] | [PubMed]
 
Smith G: Animal models of Alzheimer's disease: experimental cholinergic denervation. Brain Res Rev  1988; 13:103—118
[CrossRef]
 
Mantione CR, Zigmond MJ, Fisher A, et al: Selective presynaptic cholinergic neurotoxicity following intrahippocampal AF64A injection in rats. J Neurochem  1983; 41:251—255
[PubMed]
 
Fisher A, Mantione CR, Abraham DJ, et al: Long-term central cholinergic hypofunction induced in mice by ethylcholine aziridinium ion (AF64A) in vivo. J Pharmacol Exp Ther  1982; 222:140—145
[PubMed]
 
Weinberger J, Greenberg JH, Waldman MTG, et al: The effect of scopolamine on local glucose metabolism in rat brain. Brain Res  1979; 177:337—345
[CrossRef] | [PubMed]
 
Whitehouse P, Price D, Struble R, et al: Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain. Science 1985; 215:1237—  1239
 
Murray CL, Fibiger HC: Learning and memory deficits after lesions of the nucleus basalis magnocellularis: reversal by physostigmine. Neuroscience 1985; 14:1025—  1032
 
Davis KL, Mohs RC, Davis BM, et al: Cholinergic treatment in Alzheimer's disease: implications for future research, in Alzheimer's Disease: A Report of Progress in Research, edited by Corkin S, Davis KL, Crowdon JH, et al. New York, Raven, 1982, pp 483—494
 
Davis KL, Yamamura HI: Cholinergic underactivity in human memory disorders. Life Sci 1978; 23:1729—  1734
 
Ezrin-Waters C, Resch L: The nucleus basalis of Meynert. Can J Neurol  1986; 13:8—14
 
Janowsky D, El Yousef M, Davis J, et al: A cholinergic-adrenergic hypothesis of mania and depression. Lancet 1972; ii:632—635
 
Fritze J, Lanczik M, Sofic E, et al: Cholinergic neurotransmission seems not to be involved in depression but possibly in personality. J Psychiatry Neurosci  1995; 20:39—48
[PubMed]
 
Janowsky DS, Overstreet DH: The role of acetylcholine mechanisms in mood disorders, in Psychopharmacology: The Fourth Generation of Progress, edited by Bloom FE, Kupfer DJ. New York, Raven, 1994, pp 945—956
 
Zubenko GS, Moossy J, Kopp U: Neurochemical correlates of major depression in primary dementia. Arch Neurol  1990; 47:209—214
[PubMed]
 
+
+

CME Activity

There is currently no quiz available for this resource. Please click here to go to the CME page to find another.
Submit a Comments
Please read the other comments before you post yours. Contributors must reveal any conflict of interest.
Comments are moderated and will appear on the site at the discertion of APA editorial staff.

* = Required Field
(if multiple authors, separate names by comma)
Example: John Doe



Web of Science® Times Cited: 3

Related Content
Books
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 34.  >
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 42.  >
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 48.  >
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 48.  >
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 57.  >
Topic Collections
Psychiatric News
PubMed Articles