Absence of central functional cholinergic deficits in myasthenia gravis.

Sporadic reports have suggested central involvement in myasthenia gravis, a disorder in which there is an antibody-mediated loss of peripheral nicotinic acetylcholine receptors. Five patients with symptomatic myasthenia gravis performed an auditory vigilance test of ability to direct and sustain attention, presumed to reflect central cholinergic function. No deficits were found, either in comparison with the same subject's performance when muscle strength had improved after plasma exchange, or compared with that of healthy controls. The results thus failed to substantiate reports of functionally significant central cholinergic deficits in myasthenia gravis.     

Abnormal sympathetic hyper-reactivity in patients with myasthenia gravis: A prospective study

Introduction

Patients with myasthenia gravis, especially those in crises, are not infrequently observed to demonstrate wide fluctuation in heart rate and blood pressure.

Objective

This study was conducted to assess autonomic function in patients with myasthenia gravis.

Methods

Patients with myasthenia gravis diagnosed on the basis of typical clinical details, edrophonium or neostigmine test, decremental response on repetitive nerve stimulation testing and anti acetyl choline receptor antibody testing, were compared with age and gender matched controls. Apart from detailed clinical evaluation, all subjects underwent tests of autonomic function, viz. heart rate and blood pressure response on orthostatic tests and isometric handgrip test, Valsalva maneuver, R–R interval variation (RRIV) and the sympathetic skin response (SSR). Results were compared with those in the control group using repeated measures ANOVA and the paired t-test.

Results

Sixty-four patients (27 males, 37 females) with a mean age of 40.5 ± 17 years) with myasthenia gravis of an average 3 ± 4 years duration, and 241 normal controls were enrolled. On the orthostatic tests, patients showed rise in heart rate, systolic and diastolic blood pressure, as did controls, however, the rate and the duration of rise was significantly higher than in the controls (p < 0.01). Similar difference between patients and controls, in rate of rise of these parameters was observed on the isometric hand grip test. No significant difference was observed between the two groups on tests of parasympathetic function (Valsalva ratio, RRIV). These effects could also partially be due to pyridostigmine, which all patients were receiving.

Conclusion

This study suggests sympathetic hyper-reactivity in patients with myasthenia gravis, which could be responsible for serious hemodynamic instability in patients in crisis.     

Elevated plasma arginine vasopressin levels in veterans with posttraumatic stress disorder

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with altered hypothalamic-pituitary-adrenal (HPA) axis functioning. Arginine vasopressin (AVP), in conjunction with corticotrophin releasing hormone, has shown to be an important modulator of the HPA axis. In order to evaluate the effect of trauma and PTSD on central AVP secretion we assessed plasma AVP levels in equally trauma exposed veterans with and without PTSD and a non-traumatized healthy control group. METHODS: Assessment of plasma AVP in 29 male veterans with PTSD, 29 traumatized veterans without PTSD, matched for age, gender, year and region of deployment (trauma controls), and 26 age matched healthy controls. RESULTS: Plasma AVP levels were higher in PTSD patients compared to both healthy controls (p = 0.004) and trauma controls (p < 0.001). In PTSD patients without a comorbid MDD a significant correlation was observed between plasma AVP levels and symptoms of avoidance measured with the Clinician Administered PTSD Scale (CAPS). CONCLUSION: Elevated plasma AVP levels are specifically related to PTSD and not to exposure to traumatic stress during deployment. Our results indicate that AVP may play a role as an anxiogenic factor, but they do not support a role for AVP in the altered response to dexamethasone in PTSD.     

Neuroendocrine effects of a short-term osmotic stimulus in patients with chronic schizophrenia.

We studied the effects of a short-term hypertonic stimulus on plasma levels of the stress hormones adrenocorticotropin (ACTH), cortisol, prolactin, and the blood volume- and electrolyte-controlling hormones arginine vasopressin (AVP) and atrial natriuretic peptide (ANP). Seven patients suffering from chronic schizophrenia with negative symptoms and ten healthy control subjects were investigated by a 20-minute infusion of 10 ml/kg body weight of hypertonic (2.5%) versus isotonic (0.9%) saline. All patients, who were medication-free for at least one week prior to the study, and all control subjects participated in two investigations in randomized order according to a single-blind cross-over design. During hypertonic infusion, plasma osmolarity and sodium levels were increased similarly in both groups and significantly more than during isotonic saline. Hypertonic saline caused a significant increase of plasma ACTH, cortisol and prolactin in patients in contrast to controls. AVP and ANP plasma concentrations were elevated after infusion of hypertonic saline, however, only patients showed a significant rise in plasma ANP. These results show that a dysregulation of the hypothalamic-pituitary-adrenal (HPA) system in a subset of patients with chronic schizophrenia may become overt during an osmotic stimulation, indicating an increased sensitivity of patients with schizophrenia to osmotic stress.     

Evidence that central nicotinic-acetylcholine receptors are involved in the modulation of basal and stress-induced adrenocortical responses

We investigated the involvement of central nervous system nicotinic-acetylcholine receptors in the secretory activity of the hypothalamic-hypophyseal-adrenal axis. Antiacetylcholine receptor antibodies derived from rabbits immunized with purified Torpedo-acetylcholine receptor or from myasthenia gravis patients were injected intracerebroventricularly into adult male rats for 5 consecutive days. Treatment with both preparations caused increased basal corticosterone concentrations, inhibition of the corticosterone response to ether stress, and neurological signs and motor dysfunctions. The adrenocortical response in experimental autoimmune myasthenia gravis Lewis rats with high circulating antiacetylcholine receptor antibodies was also tested. These rats exhibited a marked increase in basal corticosterone concentrations and a normal response to ether stress. The results showed that antinicotinic-acetylcholine receptor antibodies, either circulating or intraventricularly administered, can modulate both basal and stress-induced adrenocortical secretion.     

The Autonomic Nervous System and the Immune System in Juvenile Rheumatoid Arthritis

This study demonstrates that juvenile rheumatoid arthritis is associated with a dysregulation of the autonomic nervous system as well as with disturbances in the capacity of the immune system to respond to mediators of the autonomic nervous system. In patients with active disease heart rate at rest is higher than in healthy controls. In addition, 3-hydroxy-4-phenoxyphenylglycol levels in urine are higher in all patients than in the control group. Cardiovascular responses to an orthostatic stress test (tilt up) are reduced in patients with active and nonactive disease. Plasma norepinephrine responses to tilt up are reduced in subjects with active juvenile rheumatoid arthritis. In summary, our data show that patients with juvenile rheumatoid arthritis have an altered function of the autonomic nervous system associated with increased central noradrenergic outflow, presumably leading to increased vasoconstriction, resulting in a decreased response to an orthostatic stressor. The altered function of the autonomic nervous system is associated with changes in the response of leukocytes to mediators of the autonomic nervous system via β2-adrenergic receptors. Leukocytes of patients with active juvenile rheumatoid arthritis have a lower cAMP response to a β2-adrenergic agonist, presumably due to increased cAMP–phosphodiesterase activity in these cells.     

家族性重症肌无力临床特点及其与人类白细胞抗原DQA1基因多态性的相关性研究

目的探讨家族性重症肌无力(MG)的临床特点及其与人类白细胞抗原(HLA)DQA1基因多态性的相关性。方法对15例家族性、36例散发性MG患者的临床特点进行研究,并运用聚合酶链反应序列特异性引物(PCR SSP)对HLA DQA1基因多态性进行分型。结果与散发性MG相比,家族性MG患者发病年龄较早(两者分别为18 7、34 4岁,P=0 006),病情较轻,预后较好;与散发MG组及健康对照组比较,家族性MG患者的DQA1 0301基因频率增高(三者分别为40 0%、19 4%和20 2% ),差异有统计学意义(P<0 05),这种差异在眼肌型的患者中同样存在,但未发现患者性别与DQA1相关。结论家族性MG有其独特的临床特点,DQA1 0301是家族性尤其是眼肌型MG的易患基因,提示家族性MG与散发MG可能有着不同的免疫遗传机制。     

NGF对AChRAb脑内注射所致中枢神经损害的保护作用

目的　探讨神经生长因子 (NGF)对乙酰胆碱受体抗体 (ACh RAb)脑内注射所致重症肌无力 (MG)大鼠中枢神经系统 (CNS)损害神经细胞凋亡的影响。方法　分别从 MG患者和健康者血中提取 Ig G,注入大鼠脑室系统。以原位末端标记法 (TUNEL)检测脑细胞凋亡情况及动态变化。另一组在注入 ACh RAb后予以 NGF并观察结果。结果　 MG组脑阳性细胞于注 ACh RAb后第 2周出现 ,脑内多部位均有凋亡细胞且逐渐增多 ,以皮层和海马区较明显。NGF组凋亡细胞数少于 MG组 (P <0 .0 5 )。结论　脑室注入 MG患者 ACh RAb可引起大鼠CNS功能障碍 ,神经细胞发生凋亡 ,细胞凋亡在 MG脑损害中可能起重要作用。 NGF能减轻凋亡程度 ,补充NGF可能有助于防治 MG CNS损害。     

重症肌无力中枢神经系统损害与Fas关系

目的 探讨细胞凋亡与重症肌无力（MG）中枢神经系统（CNS）损害之间关系。方法 将MG患者血中提取的IgG注入大鼠脑室系统，建立大鼠MGCNS损害模型。用免疫细胞化学方法观察Fas在脑组织中的表达。结果 在MG组脑内Fas抗原表达于大脑皮质区和海马的神经元胞膜和树突上，而正常对照组脑内无阳性Fas抗原表达。结论 Fas-FasL凋亡过程在MG CNS损害中可能起一定作用。     

Seronegative myasthenia gravis: a plasma factor inhibiting agonist-induced acetylcholine receptor function copurifies with IgM.

Anti-acetylcholine receptor antibodies cannot be detected by standard radioimmunoassay in 10 to 15% of patients with generalized myasthenia gravis (seronegative myasthenia gravis). We investigated the effect of seronegative myasthenia gravis plasma on 22Na+ flux through acetylcholine receptors and voltage-gated sodium channels in the human rhabdomyosarcoma cell line, TE671. Fourteen of 19 seronegative MG plasmas inhibited acetylcholine receptor 22Na+ flux; none inhibited voltage-gated sodium channel flux. The inhibitory activity was found in the IgG-depleted fraction, and copurified with IgM after gel-filtration chromatography. Inhibitory activity was absent from the plasma of 8 healthy control subjects and of 6 patients with the Lambert-Eaton myasthenic syndrome, but was present in the IgG-depleted plasma fraction of 4 of 6 seropositive patients with myasthenia gravis and all 5 patients with demyelinating polyneuropathy. We conclude that a low-affinity serum factor, probably an IgM antibody, found in a high proportion in patients with seronegative and those with seropositive myasthenia gravis may contribute to the muscle weakness in myasthenia gravis, but its role in these and other neuroimmunological disorders requires further investigation.     

Ice pack test for myasthenia gravis

A common symptom of myasthenia gravis is eyelid ptosis. Often, the edrophonium test is negative, particularly in ocular myasthenia gravis. Myasthenic weakness is often improved by cold. We applied ice packs to the eye in 10 myasthenic patients and 7 disease controls. Eight of 10 patients with myasthenia gravis improved, whereas none of the controls improved. The ice pack test is useful in the diagnosis of myasthenia gravis.     

Stapedius reflexometry: A diagnostic test of myasthenia gravis

Contraction of the stapedius muscle can be measured by electroacoustic impedance bridge. Muscle weakness and easy fatiguability which are cardinal features of myasthenia gravis (MG) are manifested by increased threshold and early decay of the stapedius reflex. This can be used as an objective test in the diagnosis of myasthenia gravis. Stapedius reflex was measured using Madsen Zo72 electroacoustic impedance bridge in 10 patients with myasthenia gravis and in an equal number of controls. The test was done before and 30 min after intramuscular injection of neostigmin.All patients with myasthenia gravis showed an elevated reflex threshold and 5 patients showed reflex decay. These findings reverted to normal after neostigmin injection. Stapedius reflexometry is a simple objective test for the diagnosis of myasthenia gravis.     

Sympathetic skin response in patients with myasthenia gravis★ A comparative analysis

BACKGROUND: The examination of sympathetic skin response is an important index for assessing the autonomic nerve function, and patients with myasthenia gravis are always accompanied by dysautonomia. Therefore, it will be important to know whether sympathetic skin response can be used as the index for the clinical evaluation of myasthenia gravis. OBJECTIVE: To investigate the diagnostic value of sympathetic skin response in the damage of autonomic nerve function of patients with myasthenia gravis. DESIGN: A case-controlled comparative observation. SETTING: Department of Neurology and Room of Nerve Electromyogram, the Affiliated Hospital of North Sichuan Medical College. PARTICIPANTS: Thirty outpatients or inpatients with myasthenia gravis were selected from the Department of Neurology, the Affiliated Hospital of North Sichuan Medical College from May 2006 to May 2007, including 9 males and 21 females, aged 8–72 years with a mean age of (28±5) years old. They were all accorded with the diagnostic standards of myasthenia gravis, accompanied by different severity of autonomic nerve symptoms, including poor skin nutrition, sweating of hands and feet, pyknocardia, persistent hypotension, abdominal pain, constipation, etc. They all had not taken any drug affecting the autonomic nerve function before the examination. Informed consents were obtained from all the patients. Meanwhile, 30 healthy physical examinees were enrolled as the normal control group, including 10 males and 20 females, aged 10–75 years with a mean age of (31±5) years old. Approval was obtained from the hospital ethic committee. METHODS: After admission, the patients were examined with sympathetic skin response using DANTEC keypoint 2.0 electromyography evoked potential apparatus (Danmark). The changes of the latency and wave amplitude of sympathetic skin response were observed. The subjects in the normal control group were examined with the same methods at physical examination. Abnormality was judged by the disappearance of wave form, latency longer than that in the normal control group by Mean±2.5SD, or wave amplitude lower than the average value in the normal control group by 50%. MAIN OUTCOME MEASURES: The results of the latency and wave amplitude of sympathetic skin response were compared between the patients with myasthenia gravis and normal controls. RESULTS: All the 30 patients with myasthenia gravis and 30 healthy physical examinees were involved in the final analysis of results. There were no significant differences between the left and right upper and lower limbs in both the myasthenia gravis group and normal control group (P > 0.05). In the myasthenia gravis group, the abnormal rate of sympathetic skin response was 37% (11/30), the latency was prolonged and the wave amplitude was decreased as compared with those in the normal control group, and there were significant differences (P < 0.01). CONCLUSION: Sympathetic skin response can be used as an electrophysiological index for judging the damages of autonomic nerve function in patients with myasthenia gravis.     

T suppressor cell function in patients with myasthenia gravis

The activities of Con A-induced Suppressor Cells (Con-ASC) were determined in 50 patients with myasthenia gravis (MG) and 24 healthy controls. The ConA-SC activity of the patients with MG was significantly decreased as compared with that of the controls (10.06%) versus 25.28%, (P less than 0.01). Furthermore, the patients with generalized myasthenia gravis (GMG) had a lower ConA-SC activity than those with extraocular muscle myasthenia gravis (EMMG) (9.37% versus 12.13%, P less than 0.05), but their serum anti-acetylcholine receptor antibody titer was higher than that of patients with EMMG (20.55 x 10(-9) M versus 2.4 x 10(-9) M, P less than 0.01). No correlation found between the ConA-SC activity and the sex or duration of disease of the MG patients. And no effects of prednisone and thymectomy were found on the ConA-SC activity of MG patients. The results of the study suggested that the decreased function of suppressor T lymphocytes might play an important role in the pathogenesis of MG.     

Memory dysfunction in myasthenia gravis: evidence for central cholinergic effects

Two studies are presented that investigate the possible central cholinergic effects of myasthenia gravis as measured by cognitive dysfunction. In the first study, performance on a battery of cognitive tasks by 12 subjects with myasthenia gravis is compared with that of ten healthy control subjects and ten medical control subjects with chronic disease of a nonneurologic nature. The tests used were the Boston Naming Test, Rey Auditory Verbal Learning Test (AVLT), and the Logical Memory and Design Reproduction portions of the Wechsler Memory Scale (WMS). Results indicate that the myasthenic group was significantly impaired relative to both the medical and healthy control groups for performance on the Boston Naming Test, WMS Logical Memory, and WMS Design Reproduction. Both the myasthenic and the medical control groups were impaired relative to the healthy controls on the AVLT. In the second study, a myasthenic patient had plasmapheresis for treatment of her myasthenia on two separate occasions. Her memory was examined prior to as well as following each series of plasma exchanges with a variation of the Peterson-Peterson consonant trigram task. Results showed that this patient had significantly fewer interference effects and less rapid forgetting following plasmapheresis. The results of these two studies support the hypothesis that myasthenia gravis has central cholinergic effects manifested by cognitive dysfunction.     

Immunoactivation in the central nervous system in myasthenia gravis

To assess signs of immunoactivation within the central nervous system in myasthenia gravis (MG) we examined the cerebrospinal fluid (CSF) of 44 MG patients for certain immunological parameters. Altogether 73% of the patients had some protein and/or cellular abnormality in their CSF. 22 (50%) out of 44 patients had a lymphoid reaction, i.e. a pathologically elevated proportion of enlarged lymphoid cells, in their CSF. In 15 (37.5%) out of 40 patients an enrichment of anti-acetylcholine receptor antibodies in the CSF was observed in relation to serum antibodies. Our findings suggest involvement of the central nervous system in many myasthenia gravis patients.     

Soluble costimulatory factors sCD28, sCD80, sCD86 and sCD152 in relation to other markers of immune activation in patients with myasthenia gravis

The costimulatory factors CD28, CD80, CD86 and CD152 needed to start and turn off an immune response are present as membrane receptors and soluble proteins. There was no difference in the serum levels of soluble costimulatory molecules in 153 healthy controls and 118 patients with myasthenia gravis. However, we could confirm that the soluble forms of ICAM-1 and CD25 were increased in patients. The concentrations of the soluble costimulatory proteins seemed to be rather constant in individual patients, despite changes in clinical presentation. Thus, the soluble costimulatory factors do not seem to constitute reliable markers for disease activity in myasthenia gravis.     

Ice test as a simple diagnostic aid for myasthenia gravis

It is known that myasthenia gravis is improved by cold. In two previously reported studies performed on a limited number of myasthenic patients and controls, local cold application to the eyelid was suggested for use as a diagnostic test for ocular myasthenia gravis. In this study, ice test to the eyelid was evaluated as a diagnostic test on 12 myasthenic patients and 15 controls with blepharoptosis and the results were compared with those of edrophonium test.     

Acetylcholine receptors and myasthenia

Much progress has been made in the 26 years since initial studies of the first purified acetylcholine receptors (AChRs) led to the discovery that an antibody-mediated autoimmune response to AChRs causes the muscular weakness and fatigability characteristic of myasthenia gravis (MG) and its animal model, experimental autoimmune myasthenia gravis (EAMG). Now, the structure of muscle AChRs is much better known. Monoclonal antibodies to muscle AChRs, developed as model autoantibodies for studies of EAMG, were used for initial purifications of neuronal AChRs, and now many homologous subunits of neuronal nicotinic AChRs have been cloned. There is a basic understanding of the pathological mechanisms by which autoantibodies to AChRs impair neuromuscular transmission. Immunodiagnostic assays for MG are used routinely. Nonspecific approaches to immunosuppressive therapy have been refined. However, fundamental mysteries remain regarding what initiates and sustains the autoimmune response to muscle AChRs and how to specifically suppress this autoimmune response using a practical therapy. Many rare congenital myasthenic syndromes have been elegantly shown to result from mutations in muscle AChRs. These studies have provided insights into AChR structure and function as well as into the pathological mechanisms of these diseases. Evidence has been found for autoimmune responses even to some central nervous system neurotransmitter receptors, but only one neuronal AChR has so far been implicated in an autoimmune disease. Thus far, only two neuronal AChR mutations have been found to be associated with a rare form of epilepsy, but many more neuronal AChR mutations will probably be found to be associated with disease in the years ahead.     

重症肌无力CNS损害和神经细胞关系

目的　探讨神经细胞凋亡与重症肌无力 ( MG)中枢神经系统 ( CNS)损害之间的关系。方法　MG患者血中提取纯化的 Ig G注入 SD大鼠脑室系统 ,然后用透射电镜观察大鼠中枢神经细胞形态学变化。结果　侧脑室注射 MG患者 Ig G后 ,在大鼠大脑皮层、海马神经细胞中观察到神经细胞凋亡现象。结论　 MG中枢损害过程中 ,神经细胞凋亡可能起重要的作用。 MG患者乙酰胆碱受体抗体 ( ACh RAb)与 CNS神经 -ACh R结合 ,诱发神经细胞凋亡 ,从而可能致 MG CNS功能障碍。