[Two patients with mitochondrial respiratory chain disease]. / Twee patiënten met een mitochondriale myopathie.

A 23-year-old woman and a 13-year-old boy were diagnosed with mitochondrial respiratory chain disease. The woman had muscle pain, fatigue and bilateral ophthalmoplegia--symptoms consistent with Kearns-Sayre syndrome. The boy had aspecific symptoms; eventually, reduced activity of complex 1 was found to be the cause of the mitochondrial respiratory chain disease in the boy and his mother, who had suffered from unexplained fatigue and muscle pain for 15 years. Mitochondrial diseases often involve several organ systems. Diagnosis can be difficult, because laboratory tests such as serum and urinary lactate and creatine kinase have low sensitivity and specificity. Biochemical assessment of muscle biopsy can reveal reduced oxidation ATP synthesis and sometimes specific abnormalities in individual protein complexes. DNA analysis may be helpful in demonstrating mitochondrial or nuclear mutations or deletions. The goal of treatment is to increase mitochondrial ATP production, improve clinical symptoms and enhance stamina. Replacement of the following substances (also referred to as cofactors) may be attempted: co-enzyme Q10, antioxidants (lipoic acid, vitamins C and E), riboflavin, thiamine, creatine and carnitine. Evidence regarding the optimal treatment approach is lacking; one usually has to rely on observing effects in the individual patient.

The Lambert-Eaton myasthenic syndrome 1988-2008: a clinical picture in 97 patients.

BACKGROUND: Neuromuscular symptoms in patients with Lambert-Eaton myasthenic syndrome (LEMS) and a small cell lung cancer (SCLC) develop more rapidly than in LEMS patients without a SCLC. We studied how this clinical information, which is readily available at the first consultation, can be used to predict the presence of SCLC. PATIENTS AND METHODS: In our study we included 52 LEMS patients with SCLC and 45 non-tumor patients (NT-LEMS). We interviewed patients using a structured checklist and reviewed their clinical records. We compared frequency and onset of symptoms during the course of LEMS. RESULTS: In the first six months, over half the SCLC-LEMS patients had developed seven separate symptoms, while NT-LEMS patients developed only two symptoms. Proximal leg weakness and dry mouth were early symptoms in both groups. Rapid involvement of proximal arm muscles (p=0.0001), distal arm muscles (p=0.0037), distal leg muscles (p=0.0002), dysartria (p=0.0091) and the presence of erectile dysfunction (p=0.007) were found significantly more often in SCLC-LEMS patients in both cohorts. Cerebellar symptoms, although present in 9% of LEMS patients, were almost exclusively related to SCLC-LEMS. CONCLUSION: A rapidly progressive course of disease from onset in LEMS patients should raise a high suspicion of SCLC. Special attention should be paid to involvement of upper extremities, involvement of distal arm and distal leg muscles, to erectile dysfunction and probably ataxia in order to discriminate between SCLC-LEMS and NT-LEMS.

Strong association of MuSK antibody-positive myasthenia gravis and HLA-DR14-DQ5.

The authors studied the HLA profile of 23 white Dutch patients with muscle-specific kinase antibody-positive myasthenia gravis (MuSK Ab+ MG) and found an association with HLA-DR14-DQ5 (odds ratio 8.5; 95% CI 3.9 to 18.7; p = 4.9 x 10(-5)). Fifty-two percent of the patients carried the DR14 allele compared with 5% of the controls (p = 1.0 x 10(-8)). This association between MuSK Ab+ MG and a relatively rare HLA haplotype differs from the previously described association of early-onset acetylcholine receptor Ab+ MG with HLA-B8-DR3.

Association of the Fc gamma receptor IIA-R/R131 genotype with myasthenia gravis in Dutch patients.

Myasthenia gravis (MG) susceptibility is partially determined by allelic heterogeneity of immune-modulatory genes. IgG receptors (FcgammaR) link the humoral and cellular branches of the immune system, and regulate immune responses and inflammation. Three FcgammaR subclasses (FcgammaRIIa, FcgammaRIIIa, and FcgammaRIIIb) exhibit functional polymorphisms, which affect efficiency of FcgammaR-mediated functions. FcgammaRIIa genotypes, but not FcgammaRIIIa and FcgammaRIIIb genotypes, were differentially distributed among 107 MG patients as compared to 239 healthy controls (Pz.Lt;0.01), with a relative increase of the FcgammaRIIa-R/R131 genotype (Odds ratio 2.4, 95% confidence interval 1.4-3.9). These data suggest that the FcgammaRIIa-R/R131 genotype is a marker for susceptibility to MG.

Difference in distribution of muscle weakness between myasthenia gravis and the Lambert-Eaton myasthenic syndrome.

BACKGROUND: Myasthenia gravis and the Lambert-Eaton myasthenic syndrome (LEMS) may have a similar distribution of muscle weakness. Deciding on a diagnosis of myasthenia gravis or LEMS on clinical grounds may therefore be difficult. OBJECTIVE: To compare the localisation of initial muscle weakness and the distribution of weakness at the time of maximum severity in patients with myasthenia gravis and LEMS. SUBJECTS: 101 patients with myasthenia gravis and 38 patients with LEMS. RESULTS: In myasthenia gravis, initial weakness involved extraocular muscles in 59%, bulbar muscles in 29%, and limb muscles in 12% of the patients. In LEMS no patient had ocular weakness, 5% had bulbar weakness, and 95% had weakness of the limbs as the first symptom (p < 0.001). At the point of maximum severity, weakness in myasthenia gravis was purely ocular in 25%, oculobulbar in 5%, restricted to the limbs in 2%, and present in both oculobulbar muscles and limbs in 68%. At this point, none of the LEMS patients had weakness restricted to extraocular or bulbar muscles (p = 0.002). The legs were affected in all LEMS patients, whereas in 12 patients with generalised myasthenia gravis limb weakness was restricted to the arms (p = 0.024). CONCLUSIONS: In a patient suspected to have a myasthenic syndrome whose first symptom is ocular weakness, LEMS is virtually excluded. Limb weakness confined to the arms is only found in generalised myasthenia gravis and not in LEMS. Muscle weakness in myasthenia gravis tends to develop in a craniocaudal direction, and in the opposite direction in LEMS.

Masticatory performance in patients with myasthenia gravis.

Masticatory muscle electromyograms (EMGs) were recorded while patients with bulbar myasthenia gravis chewed artificial food and compared with those of patients with ocular myasthenia gravis, patients in clinical remission who had previously suffered from bulbar myasthenia gravis and healthy individuals. Masticatory performance and EMGs were significantly smaller in the bulbar group. There were no indications of subclinical masticatory muscle weakness in patients with bulbar myasthenia gravis in remission and in patients with ocular myasthenia gravis. Patients with bulbar myasthenia gravis barely compensated for muscular weakness by chewing at a higher percentage of their maximal EMG. These quantitative findings, when combined with subjective reports of masticatory muscle weakness, show that a need to support the jaw is characteristic of patients with bulbar myasthenia gravis who produce low EMG activity.

HLA class I and II in Lambert-Eaton myasthenic syndrome without associated tumor.

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder, in which antibodies against voltage-gated calcium channels located at nerve terminals cause muscle weakness and autonomic dysfunction. In approximately half of the patients the autoimmune process is initiated by a tumor. In the other half of patients no tumor is found and the etiology is unknown. The aims of this study were to investigate the strength of HLA-associations with nontumor LEMS (NT-LEMS) and to study the relation of HLA-haplotypes with age at onset of LEMS and other clinical features. Therefore, typing of HLA class I and II was performed in 19 patients with NT-LEMS, who were clinically evaluated. NT-LEMS was significantly associated with alleles of both HLA-class I (i.e. HLA-B8) as well as -class II (i.e. HLA-DR3 and -DQ2). HLA-B8+ patients had significantly younger age at onset of LEMS and tended to be female. This study shows that HLA-class I haplotype is associated with a distinct phenotype in NT-LEMS.

Controlled study of EMG activity of the jaw closers and openers during mastication in patients with myasthenia gravis.

Mastication was evaluated in patients with bulbar myasthenia gravis and compared with that of patients with ocular myasthenia gravis, patients in remission who previously suffered from bulbar symptoms, and healthy controls. Bulbar myasthenia gravis may impair mastication due to weakness of the masticatory muscles. The aim of the study was to objectively evaluate the influence of myasthenia gravis on mastication. The subjects chewed a piece of breakfast cake and chewed 1 min on a piece of chewing gum. Surface EMG of the masseter muscle, temporalis muscle and jaw opener muscles was recorded. Statistical analysis revealed that bulbar patients produced significantly less EMG activity in the closing phase of a chewing cycle in both experiments. The EMG of the masseter muscle expressed as percentage of the maximum EMG during maximal clenching showed significantly higher values in the bulbar group than in the other groups. This was not found for the temporalis muscle. It was suggested that bulbar patients use a strategy of limited effort to produce a bolus that can be swallowed. The ocular patients and the patients in remission showed no subclinical impairments in muscle function during chewing.

[Proximal muscle weakness, depressed tendon reflexes and autonomic dysfunction: the Lambert-Eaton myasthenic syndrome]. / Proximale spierzwakte, verlaagde peesreflexen en autonome disfunctie: Lambert-Eaton-myastheniesyndroom.

Three patients with Lambert-Eaton myasthenic syndrome (LEMS), two men aged 61 and 64 and a woman aged 55 years, all developed proximal weakness, depressed tendon reflexes and autonomic dysfunction. Although this clinical triad is highly suggestive for LEMS, the disorder had not been recognized initially. The woman had a small-cell bronchial carcinoma, treated successfully by chemotherapy, whereafter the LEMS symptoms gradually disappeared. The first man was treated with 3,4-diaminopyridine and azathioprine, whereupon his symptoms diminished. The other man had only slight complaints and refused drug treatment. The three cases illustrate that presentation and course of LEMS can vary between patients. Furthermore, clinical and electrophysiological features can suggest myasthenia gravis, myopathy or axonal polyneuropathy. Therapeutic options and the risk of underlying malignancy make early diagnosis important. In conclusion, in every patient presenting with unexplained proximal weakness, LEMS should be considered, especially if depressed tendon reflexes and autonomic dysfunction are found as well.

Tongue force in patients with myasthenia gravis.

OBJECTIVES: The aim was to study tongue force in patients with bulbar myasthenia gravis and compare it with that of patients with ocular myasthenia gravis, patients in clinical remission who previously suffered from bulbar myasthenia gravis, and healthy subjects. MATERIAL AND METHODS: Tongue force was measured with a tongue force transducer in cranial and lateral directions, which coincide with the directions in which the tongue exerts force during swallowing, speech, and mastication. RESULTS: Tongue force in lateral direction was significantly decreased in patients with bulbar myasthenia gravis. In addition, our findings suggest an incomplete recovery of lateral tongue force in the patients of the remission group. CONCLUSION: Our tongue force measurements may be useful for longitudinal evaluation of therapy in individual patients and also in studies of therapy efficacy in matched groups of patients if the influence of factors such as age, dental state, and sex is taken into account.

Maximal bite force and surface EMG in patients with myasthenia gravis.

Masticatory muscle strength was quantified in patients with bulbar myasthenia gravis and compared with that of patients with ocular myasthenia gravis, patients in clinical remission (whether or not pharmacological) who previously suffered from bulbar myasthenia gravis, and healthy subjects. Maximal bite force and maximal activity of the masseter and temporalis muscles and of the submental muscle complex were measured. Bite force was decreased in the patients with bulbar myasthenia gravis, but was normal in the patients in the clinical remission group and in the ocular group. These findings were consistent with the results of electromyographic data. Although subjective reports of masticatory muscle weakness provide valuable information, quantitative measurements provide more information about the degree of muscle weakness of individual muscles. This is especially important for longitudinal evaluation of therapy in individual patients and for pharmacotherapeutic research.

What's in a smile?: Quantification of the vertical smile of patients with myasthenia gravis.

Many patients with myasthenia gravis who experience bulbar symptoms show a vertical smile, which may have a considerable, and often underestimated, impact on social life. Peri-oral muscle function can be quantified by calculating lip-length and snout indices, which indicate the degree to which a person is capable of smiling and of pursing the lips, respectively. In the present study patients with bulbar myasthenia gravis were compared to patients with ocular myasthenia gravis, patients now in remission (but previously suffering from bulbar myasthenia gravis), and healthy subjects. The lip-length and snout indices of patients with bulbar myasthenia gravis were significantly lower than those of the other groups. The facial impairments were no longer detectable in patients with bulbar myasthenia gravis in remission and no subclinical impairments in lip-length and snout indices were found in the ocular myasthenia gravis group. These findings were consistent with the patients' reports of impairment of smiling and other oral functions. The patients suffering from a vertical smile or other oral impairments were well aware of their condition, most probably because of the social consequences of being unable to smile. The indices could be of importance in the longitudinal evaluation of therapy in individual patients and in pharmacotherapeutical research. We found a low correlation between the lip-length and snout indices, which reflects the capricious pattern of involvement of separate muscles in myasthenia gravis. Therefore both indices deserve special attention if they are used for monitoring myasthenic symptoms.

Myasthenia gravis on the Dutch antilles: an epidemiological study.

We carried out an epidemiological study on the prevalence and annual incidence of myasthenia gravis on tropical islands Curaçao and Aruba in the period 1980-1995. Twenty-one patients (seven men and 14 women) were identified. The point prevalence increased from 29 per million in 1980 to about 70 per million in 1990-1995; the annual incidence over the total period was 4.7 per million. The female:male ratio was 2:1; purely ocular cases (2/21) comprised 9.5% and thymomas (4/21), 19%. These data are in accordance with most other epidemiological studies in non-tropical areas. No other studies on myasthenia gravis in tropical areas have been reported.

[Double vision as a symptom of a serious disorder]. / Dubbelzien als symptoom van een ernstige aandoening.

Three women, aged 54, 69 and 73 years, respectively, developed diplopia together with ptosis of an upper eyelid during light exercise or fatigue or continuous; in one patient the diplopia was followed by headache and vomiting. The diagnoses made were 'intracranial aneurysm', 'myasthenia gravis' and 'temporal arteritis'. Diplopia may be a symptom of a disorder timely diagnosis and treatment of which may prevent serious consequences.

Plasmapheresis in myasthenia gravis. A survey.

Plasmapheresis plays an important role in the acute management of patients with severe myasthenia gravis. Although plasmapheresis is now in use for more than 20 years, some controversies remain about the indication and the place in the therapy. It is generally found that the effect starts one week after the start of PP and lasts about 2-4 weeks after the last exchange; because of this temporary effect use of concomitant immunosuppressive medication is recommended. Compilation of data from 13 large series shows that about 75% of the patients react favourably. The relation between fluctuations of antibodies and the effect of PP is poor; even seronegative patients may improve as well.

[Favorable results of plasmapheresis in severe myasthenia gravis]. / Gunstige resultaten van plasmaferese bij ernstige myasthenia gravis.

OBJECTIVE: Evaluation of the additional effect of plasma exchange in treatment with steroids of severe myasthenia gravis. DESIGN: Retrospective study. SETTING: Department of Neurology, University Hospital of Groningen, the Netherlands. PATIENTS AND METHODS: The clinical course was analysed in 24 patients with a total of 28 plasma exchange treatments. Prednisone was introduced or its maintenance dose was increased in 19 cases. Another 13 patients with severe myasthenia gravis were included to study the effect of prednisone monotherapy. RESULTS: Of the patients treated with plasma exchange and steroids 71% improved within the first week of treatment as against only 15% of the patients treated with prednisone monotherapy. After two weeks of plasma exchange plus prednisone or prednisone monotherapy, 88% and 69%, respectively were ameliorated. None of the patients receiving plasma exchange deteriorated or experienced adverse effects or complications due to plasma exchange. Of the patients receiving prednisone monotherapy 31% deteriorated in the first week of treatment. CONCLUSION: Patients with severe myasthenia gravis may safely be treated with plasma exchange in combination with prednisone. In our patient group, a state of rapid aggravation was cut short more quickly by prednisone plus plasma exchange than by prednisone monotherapy.

Myasthenia gravis: diagnosis and follow-up of 100 consecutive patients.

One hundred consecutive patients with myasthenia gravis (MG) referred between 1985 and 1989 were analysed for epidemiological characteristics, evolution of early signs, delay in diagnosis, yield of diagnostic tests and effects of treatment. The female to male ratio was 1.6:1.0. Sixteen patients had a thymoma. Ocular MG occurred in 14. Associated autoimmune diseases were found in 15 patients. In 34% of the women and 10% of the men the diagnosis was delayed for more than 2 years. In the first 3 months progression was more rapid in men than in women. Anti-acetylcholine receptor antibodies were found in 94% of the patients with generalized MG and in 29% of the ocular patients. The neostigmine or the edrophonium test was positive in 84% of the generalized and in 60% of the ocular patients. Electromyography was diagnostic in 71% of the generalized and in 42% of the ocular patients tested. Thymectomy was performed in 56 patients (12 with thymomas). Fifty-one per cent were treated with one or more immunosuppressive drugs, at any time. After a mean follow-up of 9.6 years after onset remissions had occurred in 43%, considerable improvement in 25%, moderate improvement in 20% and 12% remained unchanged. There were no deaths due to MG. Thirty-six per cent remained dependent on immunosuppressive drugs. Medication-free remission was most frequent (35%) in the early-onset (< 50 years) group. Side-effects of pyridostigmine were noted in 34% of 99 patients, of prednisone in 65% of 49 patients, and of azathioprine in 54% of 28 patients, but these necessitated stopping the drug in only 1%, 10% and 14% respectively.

Acetylcholine release in myasthenia gravis: regulation at single end-plate level.

In myasthenia gravis, loss of acetylcholine receptors at motor end-plates is induced by antireceptor autoantibodies. At end-plates in rats in which myasthenia gravis-like symptoms are induced by chronic treatment with alpha-bungarotoxin, acetylcholine release is increased. Within muscles from such rats there is a strong correlation between the increase of acetylcholine release at an end-plate and the loss of postsynaptic acetylcholine receptors, caused by the toxin. The question is whether upregulation of acetylcholine release is a clinically relevant compensatory mechanism in myasthenia gravis or only a feature of the animal model using alpha-bungarotoxin. We investigated electrophysiologically the in vitro acetylcholine release at end-plates of muscles from patients with myasthenia gravis and rats with experimental autoimmune myasthenia gravis where acetylcholine receptor reduction is caused by autoantibody attack. In both human and rat autoimmune myasthenic muscle, the mean quantal content was considerably increased compared with control levels. At each individual myasthenic end-plate, the increase in quantal content appeared to be correlated with the reduction of the amplitude of the miniature end-plate potential. This finding suggests the existence of an important compensatory mechanism in myasthenia gravis, in which retrograde acting factors (i.e., from muscle fiber to nerve terminal) upregulate acetylcholine release.