[Show abstract][Hide abstract] ABSTRACT: SUMMARY Objectives: Immunogenic inflammatory myopathies represent the most important group of acquired muscular disorders. Based on clinical as well as histopathological criteria they can be divided into interstitial myositis, focal nodular myositis, and polymyositis. Muscle pain is prominent especially in acute myositis, but is missed in chronic cases and especially inclusion body myositis. Findings: Muscle pain is caused by excitation of intramuscular free nerve endings, so called nociceptors. In skeletal muscle, nociceptors seem to be preferentially localized next to small vessels. The process of nociception is mediated by endogenous substances like bradykinin, serotonin, and histamine, which are released from inflammatory cells and bind to specific receptors in the nociceptor membrane. Furthermore, neuropeptides like substance P, calcitonin-gene related peptide, or nerve growth factor, which are altered in inflammatory myopathies, may be involved in this process. Conclusion: The concept of nociceptor sensitization by chemical stimuli, which are released during inflammation, is supported by numerous studies, and may explain the origin of inflammatory muscle pain especially in dermatomyositis with an local effect on the intramuscular vessels. Nevertheless, the absence of muscle pain in chronic myositis and inclusion body myositis is not yet fully understood.
[Show abstract][Hide abstract] ABSTRACT: SUMMARY Objectives: The clinically most important painful muscle disorders are inflammatory and metabolic myopathies. In the three major groups of autoimmune inflammatory myopathies, dermatomyositis, polymyositis, and sporadic inclusion body myositis, muscle pain is most frequent in dermatomyositis and almost absent in sporadic inclusion body myositis. Findings: The myopathological feature of dermatomyositis is polymyositis of the perifascicular type with pronounced inflammatory reaction of small blood vessels with C5B9 complement deposits and tubuloreticular inclusions as seen by electron microscopy. The last mentioned structures are induced by cytokines. Small free nerve endings are always connected to small blood vessels. In dermatomyositis one can show very clearly that substance P and calcitonine gene related peptide are elevated as signs of an increased nociceptive input. In polymyositis and especially inclusion body myositis there is no such muscular pathology and as far as examined no elevation of substance P and calcitonine gene related peptide in free nerve endings. Many forms of metabolic myopathies, especially glycol[geno]lytic defects, are characterized by symptoms of exercise intolerance [early muscle fatigue, painful contractures with exercise, muscle cramps, myoglobinuria]. The investigation of muscle energy metabolism can be performed non-invasively by phosphorus magnetic resonance spectroscopy. The final diagnosis of the different forms depends on careful morphological and especially enzymatic studies. Pain after exercise is not well understood. Depletion of high-energy phosphates, like phosphocreatine and adenosine triphosphate during exercise, may contribute to the pathogenesis. In the much more frequent local myofascial pain syndrome, caused by trigger points located within the substance of human skeleton muscles, alteration is really difficult. In our understanding, so called contraction discs are the most frequent findings. Often, but not always, these contraction discs are located in a neuromuscular end plate region. Further human studies are ongoing. Conclusions: We conclude that the morphopathogenetic background of muscle pain is still widely unclear. Free nerve endings, substance P and adenosine triphosphate and acidosis seems to be the major player in distinct neuromuscular disorders.
[Show abstract][Hide abstract] ABSTRACT: Objectives: Muscle pain is a frequent concomitant symptom in a variety of neuromuscular disease and the most prominent findings in myofascial pain syndrome, as well as in fibromyalgia syndrome. Findings: Negligible awareness has been focused on pain characteristics in neuromuscular disorders. In the group of inflammatory myopathies, in dermatomyositis, the highest frequency of permanent muscle pain is complained in the shoulder girdle and thigh, and upper arms and legs. Pain quality is reported to be muscle-aching in the majority of patients, but additional different pain characteristics have been documented, including deep, gripping, dull, bright, sharp and superficial. Here small free nerve endings are connected to small blood vessels that show an upregulation of substance P and calcitonine gene related peptide as signs of an increased nociceptive input. Some forms of metabolic myopathies, especially glycogenolytic defects, are characterized by symptoms of stamina, painful contractures with exercise, cramps, and myoglobinuria. Pain expression in McArdle patients with chronic myalgia has frequently the features of functional muscle pain, or fibromyalgia syndrome. Depletion of high-energy phosphates like phosphocreatine and adenosine triphosphate during exercise may contribute to the pathogenesis. In degenerative myopathies, only a few disorders are investigated for pain pattern, but affected patients clearly present with muscle pain in myotonic dystrophies, facioscapulohumeral muscular dystrophy, other rare degenerative myopathies, and the peculiar rippling muscle disease. Most prevalent but still underrecognized as cause of muscle pain is the myofascial pain syndrome. Conclusion: The pathogenetic background of many type of muscle pain is still uncertain. Free nerve endings, substance P and adenosine triphosphate and tissue acidosis seem to be the player in muscle pain.
[Show abstract][Hide abstract] ABSTRACT: To describe the clinical and neurophysiological spectrum and prognosis in a large cohort of biochemically and genetically proven late onset Pompe patients. Thirty-eight diagnosed with late onset Pompe disease at our neuromuscular department during 1985 and 2006 are described in detail. The mean delay from onset of symptoms or first medical consultation until diagnosis was 10.4 and 7.1 years, respectively. A different diagnosis was suggested in 11 of 38 patients. Ten patients underwent repeated muscle biopsies before diagnosis of Pompe disease was established. Limb girdle weakness was the most frequent presenting sign. Six patients complained of myalgia. Wolf-Parkinson-White syndrome was found in 3 of 38 patients. Respiratory failure preceded the onset of overt limb muscle weakness in three patients. The course of the patients was progressive in all, but there was a wide variety of progression, which did not correlate with the age of disease onset. In 71% of the patients, neurophysiological investigations revealed a myopathic EMG pattern, half of the patients had spontaneous activity including complex repetitive discharges. A normal EMG was found in 9% of the patients. Nerve conduction studies were normal in all. Pompe disease should be taken into consideration in patients with unexplained limb girdle muscular weakness with respiratory failure. Cardiac manifestations may not be restricted to infantile Pompe disease.
[Show abstract][Hide abstract] ABSTRACT: The need for clinical awareness and diagnostic precision of glycogen storage disease type 2 (GSD2) has increased, as enzyme replacement therapy has become available. So far, only small series have reported the muscle pathology of late-onset GSD2. We reassessed 43 muscle biopsies of 38 GSD2 patients. In all patients the diagnosis of GSD2 has been established by biochemistry and/or mutational analysis of the GAA gene. Additionally to the expected morphological features, ultrastructural analysis revealed a high incidence of autophagic vacuoles, lipofuscin debris, structural Z-line disorganization and histological neurogenic-like pattern that were not thoroughly appreciated, previously. Comparing age at onset and morphology, excessive vacuolar and autophagic myopathy and mitochondrial disorganization of virtually all fibres is common in infants. At juvenile onset, a more moderate vacuolization without significant differences in overall morphology is notable. At late-onset, the spectrum of vacuolar myopathy is more divergent, ranging from almost normal to severe. Here pronounced secondary alterations are observed that include lipofuscin debris, autophagic vacuoles with residual lysosomal bodies and granular inclusions, structural mitochondrial and Z-line texture alterations. Moreover, there is a high incidence of subtle neurogenic-like alteration in all subtypes. Nineteen patients were genetically tested; in 15 patients the common leaky splicing mutation c.-45T>G (or IVS1-13T>G) in intron1 of the GAA gene was found on at least one allele, facilitating genetic screening. In our patients, GAA genotype appears not to be associated with secondary alterations such as autophagic vacuoles, structural alterations or neurogenic-like changes. These findings may have implications for our understanding of the pathogenesis of GSD2 and for assessing therapeutic success of enzyme replacement therapy.
Neuropathology and Applied Neurobiology 11/2007; 33(5):544-59. · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We report on two unrelated patients clinically presenting with late-onset progressive limb girdle weakness; cardiomyopathy was seen in one patient. Muscle biopsy revealed a necrotic myopathy with numerous rimmed vacuoles, ultrastructurally typical paired-helical filaments, and reduced immunohistochemical staining for alpha-dystroglycan. Quadriceps sparing hereditary inclusion body myopathy due to mutations in GNE gene, and OPMD due to PABPN1 mutations were excluded, genetically. We detected a homozygous mutation of the FKRP gene (826C>A) in both patients. Mutations of FKRP have been reported in congenital muscular dystrophies, LGMD2I, cardiomyopathy and hyperCKemia, but not in myopathies with vacuoles and paired-helical filaments. Therefore, our findings further extend the morphological variability of muscular dystrophies due to FKRP mutations.
Acta myologica: myopathies and cardiomyopathies: official journal of the Mediterranean Society of Myology / edited by the Gaetano Conte Academy for the study of striated muscle diseases 10/2006; 25(2):73-6.
[Show abstract][Hide abstract] ABSTRACT: Polymyositis, dermatomyositis, and inclusion body myositis are idiopathic inflammatory myopathies of unknown etiology with autoimmune pathogenesis. For choosing an individual and efficient therapy, diagnostic assignment is an important factor. Therapeutic options in dermatomyositis and polymyositis include corticosteroids and immunosuppressives. Intravenous immunoglobulins are only needed in special cases. In inclusion body myositis, corticosteroids and immunosuppressives are not successful. At the moment intravenous immunoglobulins are the only therapeutic possibility.
[Show abstract][Hide abstract] ABSTRACT: The diagnosis of mitochondrial myopathy depends upon a constellation of findings, family history, type of muscle involvement, specific laboratory abnormalities, and the results of histological, pathobiochemical and genetic analysis. In the present paper, the authors describe the diagnostic approach to mitochondrial myopathies manifesting as extraocular muscle disease. The most common ocular manifestation of mitochondrial myopathy is progressive external ophthalmoplegia (PEO). To exclude myasthenia gravis, ocular myositis, thyroid associated orbitopathy, oculopharyngeal muscular dystrophy, and congenital fibrosis of the extraocular muscles in patients with an early onset or long-lasting very slowly progressive ptosis and external ophthalmoplegia, almost without any diplopia, and normal to mildly elevated serum creatine kinase and lactate, electromyography, nerve conduction studies and MRI of the orbits should be performed. A PEO phenotype forces one to look comprehensively for other multisystemic mitochondrial features (e.g., exercise induced weakness, encephalopathy, polyneuropathy, diabetes, heart disease). Thereafter, and presently even in familiar PEO, a diagnostic muscle biopsy should be taken. Histological and ultrastructural hallmarks are mitochondrial proliferations and structural abnormalities, lipid storage, ragged-red fibers, or cytochrome-C negative myofibers. In addition, Southern blotting may reveal the common deletion, or molecular analysis may verify specific mutations of distinct mitochondrial or nuclear genes.
[Show abstract][Hide abstract] ABSTRACT: Mutations in CAV3 gene encoding the protein caveolin-3 are associated with autosomal dominant limb girdle muscular dystrophy 1C, rippling muscle disease, hyperCKemia, distal myopathy, hypertrophic cardiomyopathy and rare autosomal recessive limb girdle muscular dystrophy phenotypes. In a 57-year-old patient with asymmetric limb girdle weakness, we detected a novel homozygous intronic mutation (IVS1 + 2T > C) of the CAV3 gene. This is the first splicing mutation reported for CAV3. These findings add to the clinical and genetic variability of CAV3 mutations.
[Show abstract][Hide abstract] ABSTRACT: The distinction between multifocal motor neuropathy, treatable by intravenous immunoglobulins (IVIg), and degenerative motor neurone disorders is often difficult. To find predictive factors for the response to IVIg treatment, 40 consecutive patients with pure lower motor neurone disorders (LMND) were prospectively examined. They all received at least two times IVIg (2 g/kg bodyweight). Prior to the first and before all the following treatments a standardized evaluation was performed including clinical examination, neurophysiological and laboratory evaluation. According to changes in the neurological examination and the Neuromuscular Symptom Score, the patients were divided into responders and non-responders after the second course of treatment. In our study, no single clinical, neurophysiological, or laboratory parameter was sensitive enough to predict response. The only single parameter that highly correlated with a positive response to treatment was an elevated GM1 antibody titre. Lack of response to IVIg treatment is likely in patients with generalization of electromyographic signs of denervation beyond the clinically involved site, proximal localization of the weakness, and an elevated level of the creatinekinase. Conduction blocks do not distinguish between both groups. We propose a scoring system combining clinical, serological and neurophysiological data in order to decide which patients with LMND may receive IVIg.
European Journal of Neurology 03/2006; 13(2):135-40. · 4.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We monitored serum levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) before and during intravenously applied immunoglobulin (IVIG) therapy in 33 patients with chronic immune-mediated neuropathies and myopathies and 15 controls. Baseline MMP-2 and TIMP-2 serum levels were lower and MMP-9 and TIMP-1 serum levels higher in all patients compared to age-matched controls. Eight days after IVIG treatment, MMP-2, TIMP-2, and TIMP-1 serum levels increased, while MMP-9 serum levels decreased, indicating tissue repair. After 60 days, MMP-9 levels increased, MMP-2 approached normal levels, while TIMP-1 and TIMP-2 serum levels were below day 8 levels, indicating relapsing tissue damage. Comparing the MMP/TIMP results with the clinical courses, IVIG treatment tended to change MMP/TIMP levels in a way that paralleled clinical improvement and relapse. In sum, during a distinct time period, IVIG therapy seems to be able to modulate MMP-mediated tissue repair.
European Neurology 02/2006; 55(4):204-8. · 1.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Three unrelated, sporadic patients with muscle coenzyme Q10 (CoQ10) deficiency presented at 32, 29, and 6 years of age with proximal muscle weakness and elevated serum creatine kinase (CK) and lactate levels, but without myoglobinuria, ataxia, or seizures. Muscle biopsy showed lipid storage myopathy, combined deficiency of respiratory chain complexes I and III, and CoQ10 levels below 50% of normal. Oral high-dose CoQ10 supplementation improved muscle strength dramatically and normalized serum CK.
[Show abstract][Hide abstract] ABSTRACT: A growing number of therapeutic agents and exogenous toxins are harmful to structure and function of human skeletal muscle. The clinical syndrome encompasses asymptomatic creatine kinase elevation, myalgia, exercise intolerance, muscle paresis and atrophy, and lastly acute rhabdomyolysis. Toxic myopathies are potentially reversible, hence a prompt recognition is particularly helpful for the early diagnosis and in conclusion elimination of a myopathy inducing toxin. Toxic myopathies may be classified as acute or chronic accordingly to the exposition time to a toxin. Main source of an exogenous induced toxic myopathy is chronic alcohol abuse. Alcohol excess induces acute and/or chronic neuropathy and myopathy, consequently muscle wasting and weakness occurs. Drug-induced myopathies are most frequently seen due to amplified utilization of corticosteroids or lipid lowering agents.
Der Internist 12/2005; 46(11):1198-206. · 0.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Involvement of the interleukin-6 receptor complex (IL-6RC) in neuroregulatory and immunological processes of the brain and particularly in Alzheimer's disease (AD) has been hypothesized. The functionally active IL-6RC consists of the cytokine IL-6, which acts through the ligand binding IL-6R and the signal transducing gp130. Using a new immunocytochemical protocol on rapid autopsy cryostat brain sections we studied the expression of the IL-6RC in Braak IV-V staged AD patients compared to normal age-matched controls (HC) across five different cortical regions. Inter-rater reliability of the method was high. The "baseline" expression in normal human brain was determined for IL-6,IL-6R and gp130 in all cortical regions. In normal tissue IL-6 expression was lower in parietal cortex. Higher IL-6R expression was shown in frontal, occipital and parietal cortex, lower expression in temporal cortex and cerebellum. In AD IL-6 expression levels were generally increased in parietal cortex and decreased in occipital cortex compared to controls. IL-6R expression levels were strongly increased in AD frontal and occipital cortex and decreased in temporal cortex and cerebellum. Our findings indicate an altered cortical immunoreactivity pattern of the functional IL-6RC in AD supporting the hypothesis of a disease-related role of IL-6 in AD pathophysiology.
European Archives of Psychiatry and Clinical Neuroscience 09/2005; 255(4):269-78. · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Zeitschrift für Rheumatologie 06/2005; 64(4):274-6. · 0.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Die Myotoxizitt von Chloroquin und Hydroxychloroquin ist langjhrig bekannt. blicherweise kann es dosisabhngig in den ersten 24 Monaten der Medikation zur Entwicklung einer Gliedergrtelschwche im Rahmen einer vakuolren Myopathie kommen. Wir berichten ber einen Fall mit Ausbildung einer Muskelschwche nach siebenjhriger Einnahme von tglich 250 mg Chloroquinphosphat (=155 mg Chloroquinbase). Auch nach langjhriger, scheinbar gut vertragener Chloroquinmedikation muss auf die Ausbildung relevanter Nebenwirkungen geachtet werden.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.
Zeitschrift für Rheumatologie 04/2005; 64(4):274-276. · 0.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Deficiencies of different proteins involved in copper metabolism have been reported to cause human diseases. Well-known syndromes, for example, are Menkes and Wilson diseases. Here we report a patient presenting with congenital cataract, severe muscular hypotonia, developmental delay, sensorineural hearing loss and cytochrome-c oxidase deficiency with repeatedly low copper and ceruloplasmin levels. These findings were suggestive of a copper metabolism disorder. In support of this, the patient's fibroblasts showed an increased copper uptake with normal retention. Detailed follow-up examinations were performed. Immunoblotting for several proteins including ATP7A (MNK or Menkes protein), ATP7B (Wilson protein) and SOD1 showed normal results, implying a copper metabolism defect other than Wilson or Menkes disease. Sequence analysis of ATOX1 and genes coding for proteins that are known to play a role in the mitochondrial copper metabolism (COI-III, SCO1, SCO2, COX11, COX17, COX19) revealed no mutations. Additional disease genes that have been associated with cytochrome-c oxidase deficiency were negative for mutations as well. As beneficial effects of copper histidinate supplementation have been reported in selected disorders of copper metabolism presenting with low serum copper and ceruloplasmin levels, we initiated a copper histidinate supplementation. Remarkable improvement of clinical symptoms was observed, with complete restoration of cytochrome-c oxidase activity in skeletal muscle.