Myasthenia gravis: an update for the clinician.

This paper provides a thorough overview of the current advances in diagnosis and therapy of myasthenia gravis (MG). Nowadays the term 'myasthenia gravis' includes heterogeneous autoimmune diseases, with a postsynaptic defect of neuromuscular transmission as the common feature. Myasthenia gravis should be classified according to the antibody specificity [acetylcholine, muscle-specific receptor tyrosine kinase (MuSK), low-density lipoprotein receptor-related protein 4 (LRP4), seronegative], thymus histology (thymitis, thymoma, atrophy), age at onset (in children; aged less than or more than 50 years) and type of course (ocular or generalized). With optimal treatment, the prognosis is good in terms of daily functions, quality of life and survival. Symptomatic treatment with acetylcholine esterase inhibition is usually combined with immunosuppression. Azathioprine still remains the first choice for long-term immunosuppressive therapy. Alternative immunosuppressive options to azathioprine include cyclosporin, cyclophosphamide, methotrexate, mycophenolate mofetil and tacrolimus. Rituximab is a promising new drug for severe generalized MG. Emerging therapy options include belimumab, eculizumab and the granulocyte- macrophage colony-stimulating factor. One pilot study on etanercept has given disappointing results. For decades, thymectomy has been performed in younger adults to improve non-paraneoplastic MG. However, controlled prospective studies on the suspected benefit of this surgical procedure are still lacking. In acute exacerbations, including myasthenic crisis, intravenous immunoglobulin, plasmapheresis and immunoadsorption are similarly effective.

Fatigue in multiple sclerosis is closely related to sleep disorders: a polysomnographic cross-sectional study.

BACKGROUND: Sleep disorders can cause tiredness. The relationship between sleep disorders and fatigue in patients with multiple sclerosis (MS) has not yet been investigated systematically. OBJECTIVE: To investigate the relationship between fatigue and sleep disorders in patients with MS. METHODS: Some 66 MS patients 20 to 66 years old were studied by overnight polysomnography. Using a cut-off point of 45 in the Modified Fatigue Impact Scale (MFIS), the entire cohort was stratified into a fatigued MS subgroup (n=26) and a non-fatigued MS subgroup (n=40). RESULTS: Of the fatigued MS patients, 96% (n=25) were suffering from a relevant sleep disorder, along with 60% of the non-fatigued MS patients (n=24) (p=0.001). Sleep-related breathing disorders were more frequent in the fatigued MS patients (27%) than in the non-fatigued MS patients (2.5%). Significantly higher MFIS values were detected in all (fatigued and non-fatigued) patients with relevant sleep disorders (mean MFIS 42.8; SD 18.3) than in patients without relevant sleep disorders (mean MFIS 20.5; SD 17.0) (p<0.001). Suffering from a sleep disorder was associated with an increased risk of fatigue in MS (odds ratio: 18.5; 95% CI 1.6-208; p=0.018). CONCLUSION: Our results demonstrate a clear and significant relationship between fatigue and sleep disorders.

[Myasthenia gravis and myasthenic syndromes]. / Myasthenia gravis und myasthene Syndrome.

Neuromuscular transmission is compromised in a variety of disorders due to immunological, toxic or congenital mechanisms. Myasthenia gravis (MG) is the most frequent among these disorders. In about 15% of cases, MG is associated with a second autoimmune disorder mainly seen in rheumatologists. Some of the drugs used in rheumatology can exacerbate MG or even trigger immunologically the occurrence of MG. In most MG patients, antibodies to the acetylcholine receptor (AChR) are present, but around 10% have AChR antibodies that are only identified by novel methods, and up to 5% have muscle-specific kinase antibodies which define a different subgroup of myasthenia. Among those MG patients with anti-AChR antibodies, a number of clinical subtypes can be identified including early-onset MG (onset

[Intermittent apomorphine injections as rescue therapy for advanced Parkinson's disease. Consensus statement]. / Intermittierende Apomorphin-Injektionen als Rescue-Therapie beim fortgeschrittenen M. Parkinson. Konsensusstatement.

Intermittent subcutaneous apomorphine therapy should be considered in patients with advanced Parkinson's disease who experience recurrent off periods despite optimised oral treatment (according to guidelines), for reliable and quick reversal of these otherwise refractory periods. Such treatment is also called rescue therapy. At present, apomorphine injections with the apomorphine pen are underutilised, considering its current indications and contraindications. In the present consensus statement, concepts for the use of apomorphine are presented and discussed based on existing study results, indications, and contraindications. Recommendations for a practical approach are also provided.

[Occurrence of chloroquine-induced myopathy after low-dose treatment of rheumatoid arthritis for seven years]. / Chloroquin-induzierte Myopathie. Folge einer siebenjährigen, niedrigdosierten Basistherapie bei primär-chronischer Polyarthritis.

The myotoxicity of chloroquine and hydroxychloroquine has been known for decades. Limb-girdle weakness due to a vacuolar myopathy may occur occasionally in a dose-dependent manner during the first 24 months on chloroquine. However, we report on a case in which muscular weakness developed after a daily intake of 250 chloroquine phosphate (= 155 mg chloroquine base) for a period of 7 years. Even after long-term and apparently well-tolerated chloroquine treatment, the occurrence of severe side-effects is possible.

Congenital myasthenic syndrome of Brahman cattle in South Africa.

A congenital myasthenic syndrome in Brahman cattle is caused by a homozygous 20 base pair deletion (470del20) in the gene coding for the epsilon subunit of the acetylcholine receptor at the neuromuscular junction. It causes a progressive muscle weakness starting either at birth or within the first month. A PCR-based DNA test, using blood or semen stored on FTA paper, was developed and validated; the test makes it possible to differentiate rapidly and accurately between homozygous wild-type, heterozygous and homozygous affected animals. Preliminary testing of Brahman cattle in South Africa has revealed several carrier animals, some of them influential animals in the breeding population.

Immature end-plates and utrophin deficiency in congenital myasthenic syndrome caused by epsilon-AChR subunit truncating mutations.

Congenital myasthenic syndromes (CMS) are inborn disorders due to presynaptic, synaptic, or postsynaptic defects of neuromuscular transmission. Some previously described kinships with typical signs of CMS showed a marked deficiency of acetylcholine receptors (AChR) and utrophin at the neuromuscular junctions. Additionally, the end-plate ultrastructure was immature, with reduced enfolding of the postsynaptic membrane. In two such families, we found truncating mutations of the epsilon-AChR subunit. In family 1, both affected siblings were heteroallelic for a epsilon911delT and a epsilonIVS4+1G-->A mutation within the AChR epsilon-subunit gene (CHRNE). In the affected member of family 2, a epsilon1030delC mutation and a previously described epsilonR64X mutation were found. These deleterious epsilonAChR mutations not only result in AChR deficiency, but also affect end-plate maturation, including the formation of secondary synaptic clefts during ontogenesis.

[Immunohistochemical detection of complement factors: a reliable method for the diagnosis of myasthenia gravis]. / Immunhistochemischer Komplementnachweis. Eine einfache Methode zur Sicherung einer Myasthenia-gravis-Diagnose.

A 57-year-old woman suffered from generalized muscular weakness without diplopia or dysphagia for about 2 years. An abnormal decremental response on low frequency nerve stimulation and improvement upon administration of edrophonium chloride suggested a diagnosis of myasthenia gravis. However, this diagnosis remained uncertain, since repeated tests for antiacetylcholine receptor antibodies were negative. In addition, the patient reported that she was never able to keep up with peers in prolonged physical activities since childhood. For this reason, a congenital myasthenic syndrome was suspected and an intercostal muscle biopsy performed for special end-plate studies. Immunohistochemistry of the muscle biopsy revealed membrane attack complex deposits at the end-plates. This finding definitely confirmed the diagnosis of autoimmune myasthenia gravis. In conclusion, immunohistochemistry for complement deposits at the end-plates is a simple and reliable method of confirming the diagnosis of myasthenia gravis in uncertain cases.

Severe congenital myasthenic syndrome due to homozygosity of the 1293insG epsilon-acetylcholine receptor subunit mutation.

Recently, a congenital myasthenic syndrome (CMS) with end-plate acetylcholine receptor (AChR) deficiency due to missense mutations in the genes for the AChR subunit was described. The first observed patient with this CMS was heteroallelic for the two epsilon-AChR subunit mutations epsilon1101insT and epsilon1293insG. This patient had only a moderate phenotype with mild muscle weakness and abnormal fatigue. We have now found homozygosity for the epsilon1293insG mutation in a severely affected CMS patient, who lost the ability to walk in midchildhood and shows profound weakness and muscle wasting. Our observation allows a genotype-phenotype correlation illustrating how differences in the AChR mutation haplotype can profoundly influence disease severity.

Fluoroquinolone antibiotics block neuromuscular transmission.

Fluorinated 4-quinolones are widely used antibiotics. Several case reports describe the exacerbation of muscle weakness in myasthenia gravis patients treated with fluoroquinolones. We studied the effects of norfloxacin, ofloxacin, and pefloxacin on miniature endplate potentials (MEPPs) and currents. These antibiotics progressively decreased the amplitude of the MEPPs as drug concentrations were increased from 12.5 to 100 mg/L. Fluoroquinolones should be used only with great caution in disorders that compromise the safety margin of neuromuscular transmission.

Congenital myasthenic syndromes in two kinships with end-plate acetylcholine receptor and utrophin deficiency.

We studied two families with five affected members suffering from ptosis and slowly progressive limb-girdle muscle weakness. All patients had abnormal decremental response on low-frequency nerve stimulation, but there were no repetitive responses to single stimuli. The patients improved on anti-acetylcholinesterase drugs. Intercostal muscle was obtained for special studies from one patient of each family. In vitro microelectrode studies were done in Patient 1. Miniature end-plate potentials were of low amplitude, and the quantal content of the evoked end-plate potentials was normal. Light microscopy revealed a marked type 1 fiber predominance. Acetylcholinesterase reactivity was dispersed over increased length of individual fibers in Patient 2. On morphometry of the end-plate ultrastructure, the number of secondary synaptic clefts per neuromuscular junction and the expansion of the postsynaptic area were markedly reduced. In Patient 1, but not in Patient 2, the envelopment of the nerve terminal by Schwann cell was increased. Acetylcholine-receptor (AChR) density was reduced as judged by the reduced immunoreactivity to antibodies against different receptor subunits. Immunohistochemical analysis of proteins known to be involved in orchestrating the end-plate structure showed deficiency of the AChR-associated protein utrophin. These patients appear to have a defect in the development or maintenance of the postsynaptic clefts; whether this defect results from or causes a reduced expression of utrophin or AChR is unclear.

Sporadic adult-onset distal myopathy with rimmed vacuoles, 15-18 nm tubulofilaments and extensive rod formation.

Starting after the age of 35 years this German man had a slowly progressive distal myopathy greater in the legs than in the arms. First he realized gait difficulties with reduced ankle dorsiflexion. Serum creatine kinase activity was normal. Muscle biopsy studies showed myopathic changes, rimmed vacuoles and the presence of rods in 66% of the type 1 muscle fibers. Ultrastructural examination revealed cytoplasmatic aggregates of tubulofilaments measuring 15-18 nm in diameter, myeloid bodies and rod formation. The nosological situation of this distal myopathy with tubulofilamentous inclusions is discussed.

[Acoustic hallucinations as a symptom of a REM sleep-associated parasomnia]. / Akustische Halluzinationen als Symptom einer REM-Schlaf-assoziierten Parasomnie.

This 52-year-old man suffered from auditory hallucinations that occurred during brief episodes of sleep paralysis at the end of REM sleep periods. During these episodes the patient experienced a dissociated state of consciousness with REM sleep intrusions into wakefulness. The occurrence of this mixed state, and of excessive sleep-onset REM periods during daytime polysomnography (MSLT = Multiple Sleep Latency Test), point to a disorder of REM sleep generation. The existence of narcolepsy could be ruled out. The observation of REM sleep-associated hallucinations has been reported earlier. In the presented polysomnographic sleep studies the existence of a REM sleep associated parasomnia characterised by hallucinations and sleep paralysis could be confirmed.

New mutations in acetylcholine receptor subunit genes reveal heterogeneity in the slow-channel congenital myasthenic syndrome.

Mutations in genes encoding the epsilon, delta, beta and alpha subunits of the end plate acetylcholine (ACh) receptor (AChR) are described and functionally characterized in three slow-channel congenital myasthenic syndrome patients. All three had prolonged end plate currents and AChR channel opening episodes and an end plate myopathy with loss of AChR from degenerating junctional folds. Genetic analysis revealed heterozygous mutations: epsilon L269F and delta Q267E in Patient 1, beta V266M in Patient 2, and alpha N217K in Patient 3 that were not detected in 100 normal controls. Patients 1 and 2 have no similarly affected relatives; in Patient 3, the mutation cosegregates with the disease in three generations. epsilon L269F, delta Q267E and beta V266M occur in the second and alpha N217K in the first transmembrane domain of AChR subunits; all have been postulated to contribute to the lining of the upper half of the channel lumen and all but delta Q267E are positioned toward the channel lumen, and introduce an enlarged side chain. Expression studies in HEK cells indicate that all of the mutations express normal amounts of AChR. epsilon L269F, beta V266M, and alpha N217K slow the rate of channel closure in the presence of ACh and increase apparent affinity for ACh; epsilon L269F and alpha N217K enhance desensitization, and epsilon L269F and beta V266M cause pathologic channel openings in the absence of ACh, rendering the channel leaky, delta Q267E has none of these effects and is therefore a rare polymorphism or a benign mutation. The end plate myopathy stems from cationic overloading of the postsynaptic region. The safety margin of neuromuscular transmission is compromised by AChR loss from the junctional folds and by a depolarization block owing to temporal summation of prolonged end plate potentials at physiologic rates of stimulation.

Effects of the quinoline derivatives quinine, quinidine, and chloroquine on neuromuscular transmission.

The quinoline derivatives quinine, its stereoisomer quinidine, and chloroquine may worsen or provoke disorders of neuromuscular transmission. In this study, we investigate effects of these drugs on neuromuscular transmission by conventional microelectrode as well as patch-clamp techniques. At 5 x 10(-5) M, quinine, quinidine, and chloroquine reduced the quantal content of the end-plate potential by 37-45%. Between 10(-6) and 10(-4) M, all 3 drugs progressively decreased the amplitude and decay time constant of miniature end-plate potential (MEPP) and miniature end-plate current (MEPC); at 5 x 10(-3) M, the MEPP became undetectable. The effect on the MEPP was not reversed by 1 microgram/mL neostigmine. Single-channel patch-clamp analysis of the effects of quinine showed that this agent causes a long-lived open-channel as well as a closed-channel block of AChR. Tests for competitive inhibition or desensitization of the acetylcholine receptor (AChR) by quinine in concentrations that had a marked effect on the MEPC and on single-channel open and closed intervals were negative. Because quinoline drugs adversely affect both presynaptic and postsynaptic aspects of neuromuscular transmission at concentrations close to those employed in clinical practice, they should not be used, or used with caution, in disorders that compromise the safety margin of neuromuscular transmission.