Distinct segregation of the pathogenic m.5667G>A mitochondrial tRNAAsn mutation in extraocular and skeletal muscle in chronic progressive external ophthalmoplegia

Chronic progressive external ophthalmoplegia (CPEO) is a frequent clinical manifestation of disorders caused by pathogenic mitochondrial DNA mutations. However, for diagnostic purposes skeletal muscle tissue is used, since extraocular muscle tissue is usually not available for work-up. In the present study we aimed to identify causative factors that are responsible for extraocular muscle to be primarily affected in CPEO. We performed comparative histochemical and molecular genetic analyses of extraocular muscle and skeletal muscle single fibers in a case of isolated CPEO caused by the heteroplasmic m.5667G>A mutation in the mitochondrial tRNA^Asn gene (MT-TN). Histochemical analyses revealed higher proportion of cytochrome c oxidase deficient fibers in extraocular muscle (41%) compared to skeletal muscle (10%). However, genetic analyses of single fibers revealed no significant difference either in the mutation loads between extraocular muscle and skeletal muscle cytochrome c oxidase deficient single fibers (extraocular muscle 86% ± 4.6%; skeletal muscle 87.8 %± 5.7%, p = 0.246) nor in the mutation threshold (extraocular muscle 74% ± 3%; skeletal muscle 74% ± 4%). We hypothesize that higher proportion of cytochrome c oxidase deficient fibers in extraocular muscle compared to skeletal muscle might be due to facilitated segregation of the m.5667G>A mutation into extraocular muscle, which may explain the preferential ocular manifestation and clinically isolated CPEO.     

经蝶切除垂体腺瘤术后继发眼肌麻痹的防治（附8例报导和文献复习）

目的 探讨经蝶切除垂体腺瘤术后继发眼肌麻痹的原因,提出防治措施。方法 分析8例经蝶手术切除垂体腺瘤术后继发不同程度眼肌麻痹患者的临床资料,并结合文献加以讨论。结果 8例均在术后3日内继发眼肌麻痹。经保守治疗,2例眼肌麻痹恢复正常,5例不同程度改善,1例术后2年加重。经长期随访,垂体腺瘤临床治愈4例,缓解3例,复发1例。结论 继发眼肌麻痹属少见的经蝶手术并发症,多为暂时性,主要与手术时直接损伤、继发鞍内血肿、鞍内填塞过紧等原因有关。随着术者经验的积累、技术的熟练和提高,这一并发症是可以避免的。     

TSH receptor protein is selectively expressed in normal human extraocular muscle

Thyroid-associated ophthalmopathy is a common manifestation of Graves' disease. Its pathophysiology is not well understood but an antigen shared between the thyroid and orbit is thought to play a role. Using immunohistochemistry, we have demonstrated the presence of the autoantigenic target of Graves' disease, the thyroid-stimulating hormone receptor, in normal human extraocular muscle. These results support previous findings of the full length and splice variant thyroid-stimulating hormone receptor cDNA in extraocular muscle. The observation of the autoimmune target--the thyroid-stimulating hormone receptor protein--being shared between the thyroid and extraocular muscle lends greater support to the notion that an extraocular muscle thyroid-stimulating hormone receptor is also a likely target autoantigen in thyroid-associated ophthalmopathy.     

Extraocular muscle biopsy in chronic progressive external ophthalmoplegia

A quantitatives assessment of the pathological changes in extraocular muscle is presented in 8 patients with chronic progressive external ophthalmoplegia (CPEO). Serial cross-sections of extraocular muscle were stained with a battery of histochemical and immunohistochemical techniques and compared with 36 normal extraocular muscles and 1 muscle from a patient who had longstanding third nerve plasy with anomalous reinnervation. Several of the patients had a striking increase in the number of ragged-red fibers in extraocular muscle, particularly if frequent ragged-red fibers also were found on limb muscle biopsy. One patients demonstrated extrajunctional acetylcholine receptor (AChR) in a small percentage of fibers, although this finding was not present in the reinnervated muscle. Numerous darkly staining central regions were noted in the ocular muscle fibers of a patient with Stephens syndrome (CPEO, peripheral neuropathy, and cerebellar disease) and in the reinnervated muscle. A patient with myotubular myopathy had single central nuclei in both limb and ocular muscle. All patients demonstrated in their extraocular muscles variation in both the size and distribution of each of the three histochemical fiber types. Extraocular muscle biopsy proved to be a safe, reliable technique. As a similar quantitative analysis is applied to the study of further patients, a better understanding of the pathogenesis of CPEO should be possible.     

Expression of cardiac alpha-actin spares extraocular muscles in skeletal muscle alpha-actin diseases--quantification of striated alpha-actins by MRM-mass spectrometry

As with many skeletal muscle diseases, the extraocular muscles (EOMs) are spared in skeletal muscle alpha-actin diseases, with no ophthalmoplegia even in severely affected patients. We hypothesised that the extraocular muscles sparing in these patients was due to significant expression of cardiac alpha-actin, the alpha-actin isoform expressed in heart and foetal skeletal muscle. We have shown by immunochemistry, Western blotting and a novel MRM-mass spectrometry technique, comparable levels of cardiac alpha-actin in the extraocular muscles of human, pig and sheep to those in the heart. The sparing of extraocular muscles in skeletal muscle alpha-actin disease is thus probably due to greater levels of cardiac alpha-actin, than the negligible amounts in skeletal muscles, diluting out the effects of the mutant skeletal muscle alpha-actin.     

Novel homozygous mutation of the caveolin-3 gene in rippling muscle disease with extraocular muscle paresis

We describe a 39-year-old Japanese man with rippling muscle disease who carried a novel homozygous mutation (Trp70 to a stop codon) in the caveolin-3 gene. The patient also had extraocular muscle paresis showing atrophy of the extraocular muscles on orbital MRI. The involvement of the extraocular muscles of patients with caveolinopathy is discussed.     

Treatment of tardive dystonia with an antispastic agent

Tardive dystonia is a difficult condition to treat. We describe the case of a patient with tardive dystonia that was unresponsive to various pharmacological and electroconvulsive therapies. The patient showed dramatic improvement after the administration of eperisone, a centrally acting muscle relaxant. Eperisone and tolperisone are beta;-aminopropiophenone derivatives which are used clinically as antispastic agents. To date there have been no reports describing the effect of such muscle relaxants on tardive dystonia. The results of our study suggest that these muscle relaxants may be promising therapeutic drugs for the treatment of tardive dystonia.     

Mossy fiber projections to the cerebellar flocculus from the extraocular muscle afferents

Inputs from extraocular muscles to the cerebellar flocculus were studied in anesthetized rabbits by recording neural responses either to electric stimulation to the nerve of the extraocular muscle or to the extraocular muscle stretch. The mossy fiber (mf) origin of the responses was identified by the similarity in the laminal profiles of these responses to those of the mossy fiber responses due to eighth nerve stimulation, the capacity to follow repetitive stimulation and the responses of simple spike discharges of Purkinje cells.The latency of mf responses evoked by electric stimulation of the afferent nerve from the superior oblique muscle was about 4.5–8.0 msec. Ramp displacements applied either to an individual extraocular muscle or to the whole eyeball also produced mf responses.Simple spike discharges of flocculus Purkinje cells were modulated by ramp displacements of extraocular muscles. Forty cells out of 47 cells examined responded with excitation and in 7 cells only inhibition was detected. Phasic, tonic and phasictonic excitations were obatained during ramp displacements. Responses of simple spike discharges were classified as direction-specific plane-specific and non-specific types depending on the convergence of afferent sources of muscles producing excitation.Loci in the flocculus responding to extraocular muscle stimulation were studied histologically and it was revealed that mf responses from extraocular muscles were obtained in extensive parts of the flocculus.     

Brainstem terminations of extraocular muscle primary afferent neurons in the monkey

The central terminations of afferent nerve fibers from the extraocular muscles of the monkey were investigated by means of transganglionic transport of wheat germ agglutinin-conjugated horseradish peroxidase (WGA/HRP). Following injections of selected extraocular muscles with WGA/HRP, terminal labeling was apparent in the ipsilateral trigeminal sensory and cuneate nuclei. The density of trigeminal projections varied markedly from one rostrocaudal level to the next, being heaviest within the ventrolateral portion of pars interpolaris of the spinal trigeminal nucleus. A second extraocular muscle afferent representation was noted in ventrolateral portions of the cuneate nucleus. This projection was restricted to rostral portions of pars triangularis of the cuneate nucleus, partially overlapping the afferent termination from dorsal neck muscles. It is likely that some of the problems encountered in formulating conclusions regarding the functional role of extraocular muscle proprioception are due to a lack of detailed information of the central termination pattern of muscle afferents. Taken together, the present findings should provide a basis for further anatomical and physiological studies designed to elucidate the role played by extraocular muscle proprioceptors in vision and oculomotor control.     

Finger muscle control in children with dystonia

Background: Childhood dystonia is a disorder that involves inappropriate muscle activation during attempts at voluntary movement. Few studies have investigated the muscle activity associated with dystonia in children, and none have done so in the hands. Methods: In this study, we measured surface electromyographic activity in four intrinsic hand muscles while participants attempted to perform an isometric tracking task using one of the muscles. Results: Children with dystonia had greater tracking error with the task‐related muscle and greater overflow to non‐task muscles. Both tracking error and overflow correlated with the Barry‐Albright Dystonia scale of the respective upper limb. Overflow also decreased when participants received visual feedback of non‐task muscle activity. Dicussion: We conclude that two of the motor deficits in childhood dystonia—motor overflow and difficulties in actively controlling muscles—can be seen in the surface electromyographic activity of individual muscles during an isometric task. As expected from results in adults, overflow is an important feature of childhood dystonia. However, overflow may be at least partially dependent on an individual's level of awareness of their muscle activity. Most importantly, poor single‐muscle tracking shows that children with dystonia have deficits of individual muscle control in addition to overflow or co‐contraction. These results provide the first quantitative measures of the muscle activity associated with hand dystonia in children, and they suggest possible directions for control of dystonic symptoms. © 2011 Movement Disorder Society     

Skeletal muscle abnormalities in two patients with dystonia

We report two patients with dystonia aged 53 and 27 years. One patient was diagnosed as a sporadic case of primary dystonia. The other patient was diagnosed as having secondary dystonia following head injury. Skeletal muscle specimens were obtained by open biopsy from the two patients. The muscle biopsy specimens showed lobulated fibers, ring fibers, and type 1 fiber atrophy. Dystonia comprises involuntary movement and causes abnormal muscle tone. We considered that the abnormal muscle tone caused by dystonia might be involved in the pathogenesis of these histochemical changes in skeletal muscle.     

Measurement of contractile force of skeletal and extraocular muscles: effects of blood supply, muscle size and in situ or in vitro preparation

Contractile forces can be measured in situ and in vitro. To maintain metabolic viability with sufficient diffusion of oxygen, established guidelines for in vitro skeletal muscle preparations recommend use of relatively thin muscles (< or =1.25 mm thick). Nevertheless, forces of thin extraocular muscles vary substantially between studies. Here, we examined parameters that affect force measurements of in situ and in vitro preparations, including blood supply, nerve stimulation, direct muscle stimulation, muscle size, oxygenated or non-oxygenated buffer solutions and the time after interruption of vascular circulation. We found that the absolute forces of extraocular muscle are substantially lower when examined in vitro. In vitro preparation of 0.58 mm thick extraocular muscle from 3-week-old birds underestimated contractile function, but not of thinner (0.33 mm) muscle from 2-day-old birds. Our study shows that the effective criteria for functional viability, tested in vitro, differ between extraocular and other skeletal muscle. We conclude that contractile force of extraocular muscles will be underestimated by between 10 and 80%, when measurements are made after cessation of blood supply (at 5-40 min). The mechanisms responsible for the declining values for force measurements are discussed, and we make specific recommendations for obtaining valid measurements of contractile force.     

Muskelafferenzblockierung in der Behandlung der oromandibulären Dystonie

Oromandibular dystonia is a neuromuscular disorder characterized by tonic or clonic involuntary spasms of the masticatory and lingual muscles. We treated 50 patients with this movement disorder by injection of lidocaine and alcohol into the masticatory or tongue muscles to block muscle afferents from muscle spindle. The patients were divided according to clinical features into four groups: jaw-closing, jaw-opening, jaw-deviation, and tongue dystonias. Objective evaluation of the symptoms before and after therapy was based on a clinical scaling protocol in terms of four parameters (mastication, speech, pain, and discomfort scales). Symptoms improved in all patients without major side effects. The overall objective improvement (60.2+/-29.5%) was significantly (P<0.005, ANOVA) lower in tongue dystonia (14.1%) than in jaw-closing dystonia (67.6%) and jaw-opening dystonia (68.3%). Although the response of the muscle afferent block to tongue dystonia was hardly satisfactory, this treatment is suggested to be effective for oromandibular dystonia.     

Extraocular muscle is spared despite the absence of an intact sarcoglycan complex in gamma- or delta-sarcoglycan-deficient mice

Models of the dystrophin-glycoprotein complex do not reconcile the novel sparing of extraocular muscle in muscular dystrophy. Extraocular muscle sparing in Duchenne muscular dystrophy implies the existence of adaptive properties in these muscles that may extend protection to other neuromuscular diseases. We studied the extraocular muscle morphology and dystrophin-glycoprotein complex organization in murine targeted deletion of the gamma-sarcoglycan (gsg(-/-)) and delta-sarcoglycan (dsg(-/-)) genes, two models of autosomal recessive limb girdle muscular dystrophy. In contrast to limb and diaphragm, the principal extraocular muscles were intact in gsg(-/-) and dsg(-/-) mice. However, central nucleated, presumptive regenerative, fibers were seen in the accessory extraocular muscles (retractor bulbi, levator palpebrae superioris) of both strains. Skeletal muscles of gsg(-/-) mice exhibited in vivo Evans Blue dye permeability, while the principal extraocular muscles did not. Disruption of gamma-sarcoglycan produced secondary displacement of alpha- and beta-sarcoglycans in the extraocular muscles. The intensity of immunofluorescence for dystrophin and alpha- and beta-dystroglycan also appeared to be slightly reduced. Utrophin localization was unchanged. The finding that sarcoglycan disruption was insufficient to elicit alterations in extraocular muscle suggests that loss of mechanical stability and increased sarcolemmal permeability are not inevitable consequences of mutations that disrupt the dystrophin-glycoprotein complex organization and must be accounted for in models of muscular dystrophy.     

A case of tardive dystonia

Tardive dystonia in a chronic dystonia caused by neuroleptics. A 53-year-old man suffering from a neuroleptic induced dyskinesia began to show an abnormal posture. His abnormal posture was caused by changes of muscle tonus and thought to be a dystonic posture. He had no family history of dystonia. This posture was similar to that of idiopathic dystonia in that the muscle tonus was hypertonic in sitting but was hypotonic in lying, and in that the activity of daily living was not disturbed in spite of hypertonia. But he also showed lingual dyskinesia and hyperreflexia and the electromyographic analysis disclosed the fact that his dystonia was similar to that of secondary dystonia. Brain CT showed the atrophy of the head of caudate nucleus but superconducting MRI disclosed no abnormality in basal ganglia. No effective therapeutics was as yet found in tardive dystonia. So it was proposed that the tardive dystonia was due to irreversible functional damage to the basal ganglia.     

Extraocular muscle activity, rapid eye movements and the development of active and quiet sleep

Rapid eye movements (REMs), traditionally measured using the electrooculogram (EOG), help to characterize active sleep in adults. In early infancy, however, they are not clearly expressed. Here we measured extraocular muscle activity in infant rats at 3 days of age (P3), P8 and P14-15 in order to assess the ontogeny of REMs and their relationship with other forms of sleep-related phasic activity. We found that the causal relationship between extraocular muscle twitches and REMs strengthened during the first two postnatal weeks, reflecting increased control of the extraocular muscles over eye movements. As early as P3, however, phasic bursts of extraocular muscle twitching occurred in synchrony with twitching in other muscle groups, producing waves of phasic activity interspersed with brief periods of quiescence. Surprisingly, the tone of the extraocular muscles, invisible to standard EOG measures, fluctuated in synchrony with the tone of other muscle groups; focal electrical stimulation within the dorsolateral pontine tegmentum, an area that has been shown to contain wake-on neurons in P8 rats, resulted in the simultaneous activation of high tone in both nuchal and extraocular muscles. Finally, when state-dependent neocortical electroencephalographic activity was observed at P14, it had already integrated fully with sleep and wakefulness as defined using electromyographic criteria alone; this finding is not consistent with the notion that active sleep in infants at this age is 'half-activated.' All together, these results indicate exquisite temporal organization of sleep soon after birth and highlight the possible functional implications of homologous activational states in striated muscle and neocortex.     

Checkpoint inhibitor myasthenia-like syndrome and myositis associated with extraocular muscle atrophy

A patient with metastatic melanoma developed myasthenia-like syndrome and paraspinal myositis with subsequent extraocular muscle atrophy associated with immune checkpoint inhibitor treatment. MRI scan of the ocular muscles on admission was normal, however 3 months later revealed significant extraocular muscle atrophy.     

Coexistent Meige's syndrome and myasthenia gravis. A relationship between blinking and extraocular muscle fatigue?

We studied five patients with a combination of Meige's syndrome (blepharospasm-oromandibular dystonia) and myasthenia gravis. The coexistence of two disorders impairing eyelid opening led to diagnostic confusion and delayed appropriate therapy. Detailed oculographic monitoring of one patient indicated that eye position drifting due to myasthenic oculomotor fatigue was corrected by eye blinks, and that blinks tended to occur with slower saccades. Our observations suggest that fatigue of extraocular muscles may lead to synkinetic blinking and perhaps eventually to autonomous blepharospasm.     

大鼠EAMG模型眼外肌下调差异基因的初步筛选

目的 :通过研究大鼠实验性自身免疫性重症肌无力 (EAMG)模型眼外肌存在差异表达的基因 ,探讨重症肌无力患者眼外肌无力的可能机制。方法 :将乙酰胆碱受体单抗mAb3 5和生理盐水分别给予实验组和对照组F3 44大鼠腹腔注射 ,48h后取新鲜眼外肌提取总RNA ,经反转录后获得标记cDNA探针 ,将其与BioStarR 40S表达谱基因芯片杂交 ,结果由扫描仪扫描并用软件进行分析统计。结果 :共筛选出 5 5条表达差异的基因 ,其中 3 0条表达降低。结论 :多种基因参与了重症肌无力眼外肌无力过程 ,差异基因表达的检测结果可为深入研究重症肌无力患者眼外肌无力机制提供新思路。     

Coronoidotomy as treatment for trismus due to jaw-closing oromandibular dystonia.

Oromandibular dystonia is a focal dystonia involving the masticatory and/or tongue muscles. This report describes 2 female patients with jaw-closing dystonia treated by surgical resection of the coronoid process. The patients could not open their mouths due to involuntary jaw-closing muscle contraction. We first treated them by injecting lidocaine and alcohol (muscle afferent block) into the masseter and temporal muscles and then botulinum toxin. However, the trismus improved mildly and transitorily. Therefore, coronoidotomy was done under general anesthesia. The jaw opening increased to 50 mm. Coronoidotomy is useful for patients with jaw-closing dystonia in whom other therapies are ineffective.