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.11—19 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.