Botulinum toxin treatment improves dysphagia in patients with oculopharyngeal muscular dystrophy and sporadic inclusion body myositis.

OBJECTIVE: Dysphagia can be troublesome in sporadic inclusion body myositis (sIBM) and oculopharyngeal muscular dystrophy (OPMD), but no established treatment exists. Cricopharyngeal muscle botulinum toxin injection has at case level been reported to be effective. We evaluated safety and efficacy of botulinum toxin injections in the cricopharyngeal muscle in patients with dysphagia due to sIBM or OPMD. METHODS: Participants were included from our outpatient clinic. Cricopharyngeal constriction was confirmed by laryngoscopy. After EMG confirmation of needle placement in the cricopharyngeal muscle, botulinum toxin A was injected in awake patients. An individualized dose of 5-10 units of botulinum toxin A was applied initially and titrated up a maximum of 3 times. Outcome measures were change in dysphagia questionnaire, timed cold-water swallow test and subjective dysphagia status (worse, unchanged, improved). Due to the need for individualized dosing and a limited number of available patients, an uncontrolled, un-blinded design was used. RESULTS: Thirteen patients, 3 with OPMD, received at least 1 injection. In the dysphagia questionnaire, all but 2 subjects, none with subjective worsening, improved (p < 0.001). Subjectively, seven felt an improvement, 4 no change and 2 a worsening. No overall change was seen the timed cold-water swallow test. No serious adverse events were observed. CONCLUSION: Botulinum toxin injection of the cricopharyngeal muscle in patients with OPMD and sIBM had a beneficial effect on dysphagia in most of the treated patients. Two of 13 patients experienced a temporary worsening not reflected in dysphagia score. Limitations are the un-blinded and un-randomized design and subjective assessments methods. PROSPECTIVE TRIAL REGISTRATION: EudraCT-number: 2014-002210-23.

MSTO1 mutations cause mtDNA depletion, manifesting as muscular dystrophy with cerebellar involvement.

MSTO1 encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype-phenotype spectrum remains to be explored, pathogenic variants in MSTO1 have recently been reported in a small number of patients presenting with a phenotype of cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic and pigmentary retinopathy. The proposed underlying pathogenic mechanism of MSTO1-related disease is suggestive of impaired mitochondrial fusion secondary to a loss of function of MSTO1. Disorders of mitochondrial fusion and fission have been shown to also lead to mitochondrial DNA (mtDNA) depletion, linking them to the mtDNA depletion syndromes, a clinically and genetically diverse class of mitochondrial diseases characterized by a reduction of cellular mtDNA content. However, the consequences of pathogenic variants in MSTO1 on mtDNA maintenance remain poorly understood. We present extensive phenotypic and genetic data from 12 independent families, including 15 new patients harbouring a broad array of bi-allelic MSTO1 pathogenic variants, and we provide functional characterization from seven MSTO1-related disease patient fibroblasts. Bi-allelic loss-of-function variants in MSTO1 manifest clinically with a remarkably consistent phenotype of childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy. MSTO1 protein was not detectable in the cultured fibroblasts of all seven patients evaluated, suggesting that pathogenic variants result in a loss of protein expression and/or affect protein stability. Consistent with impaired mitochondrial fusion, mitochondrial networks in fibroblasts were found to be fragmented. Furthermore, all fibroblasts were found to have depletion of mtDNA ranging from 30 to 70% along with alterations to mtDNA nucleoids. Our data corroborate the role of MSTO1 as a mitochondrial fusion protein and highlight a previously unrecognized link to mtDNA regulation. As impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with MSTO1 mutations and further define the clinical spectrum and the natural history of MSTO1-related disease.

Phenotype and genotype of muscle ryanodine receptor rhabdomyolysis-myalgia syndrome.

OBJECTIVES: Rhabdomyolysis and myalgia are common conditions, and mutation in the ryanodine receptor 1 gene (RYR1) is suggested to be a common cause. Due to the large size of RYR1, however, sequencing has not been widely accessible before the recent advent of next-generation sequencing technology and limited phenotypic descriptions are therefore available. MATERIAL & METHODS: We present the medical history, clinical and ancillary findings of patients with RYR1 mutations and rhabdomyolysis and myalgia identified in Denmark, France and The Netherlands. RESULTS: Twenty-two patients with recurrent rhabdomyolysis (CK > 10 000) or myalgia with hyperCKemia (>1.5 × ULN) and a RYR1 mutation were identified. One had mild wasting of the quadriceps muscle, but none had fixed weakness. Symptoms varied from being restricted to intense exercise to limiting ADL function. One patient developed transient kidney failure during rhabdomyolysis. Two received immunosuppressants on suspicion of myositis. None had episodes of malignant hyperthermia. Muscle biopsies were normal, but CT/MRI showed muscle hypertrophy in most. Delay from first symptom to diagnosis was 12 years on average. Fifteen different dominantly inherited mutations were identified. Ten were previously described as pathogenic and 5 were novel, but rare/absent from the background population, and predicted to be pathogenic by in silico analyses. Ten of the mutations were reported to give malignant hyperthermia susceptibility. CONCLUSION: Mutations in RYR1 should be considered as a significant cause of rhabdomyolysis and myalgia syndrome in patients with the characteristic combination of rhabdomyolysis, myalgia and cramps, creatine kinase elevation, no weakness and often muscle hypertrophy.

Frequency and Phenotype of Myotubular Myopathy Amongst Danish Patients with Congenital Myopathy Older than 5 Years.

BACKGROUND: Centronuclear myopathy (CNM) is one of four main subtypes of congenital myopathy. X-linked myotubular myopathy (XLMTM) is considered one of the most severe forms, but survivors past infancy have been described. However, detailed information on XLMTM phenotypes in patients who survive infancy is scarce. OBJECTIVE: The aim of the study was to report the genetic findings in patients with a predominant centronuclear finding on muscle biopsy and describe the prevalence, phenotypes and the course of the disease in patients with XLMTM in a Danish cohort of patients with congenital myopathies older than five years. METHODS: Ninety-four out of 119 invited patients older than five years were included in the study and assessed by muscle tests, functional tests, muscle biopsy, plasma creatine kinase levels and genetic testing. Genes related to CNM were sequenced in patients who had centronuclear findings on muscle histology. In patients with MTM1 mutations, medical records from local hospitals were reviewed to obtain information on birth history and course of disease. RESULTS: Sixteen of 94 patients had CNM on muscle biopsy; three male patients, aged 14-25 years, carried a pathogenic MTM1 mutation, six patients carried a pathogenic DNM2 mutation and two carried pathogenic RYR1 mutations. The mutations have all been described before to cause CNM. The MTM phenotypes ranged from severe (classical) to mild; one patient had always been non-ambulant, one had lost ambulation, and one was still ambulant at 25 years. CONCLUSIONS: Our findings show that CNM caused by DNM2 mutations is the most common form of CNM in Danish patients older than 5 years, but XLMTM is not negligible even past age 5 years, and the phenotype may be much milder than generally described - also in patients with the classically described infantile form of the disease.

Endocrine function over time in patients with myotonic dystrophy type 1.

BACKGROUND AND PURPOSE: Patients with myotonic dystrophy type 1 (DM1) have an increased incidence of endocrine dysfunction. In this study, the temporal evolution of endocrine dysfunction in patients with DM1 was investigated. METHODS: Endocrine function was assessed in 68 patients with DM1, in whom endocrine function had been followed, on average, for 8 years. The endocrine function was assessed by measuring the concentration of hormones and metabolites in blood and by validating libido with questionnaires. RESULTS: At baseline, 30 of the 68 patients presented with at least one hormonal dysfunction. When re-evaluated after 8 years, 57 of 68 patients had endocrine dysfunction. Diabetic patients had increased from one to four. At follow-up, hyperparathyroidism occurred in 25% and abnormal thyroid-stimulating hormone in 21%, compared with 14% and 9% at baseline. Sixteen of 33 men had increased luteinizing hormone levels compared with seven at baseline. CONCLUSIONS: Our findings show that endocrine abnormalities amongst patients with DM1 increase over time. Based on these findings it is suggested that correctable endocrine abnormalities should be monitored periodically in this patient group.

Ocular, bulbar, limb, and cardiopulmonary involvement in oculopharyngeal muscular dystrophy.

OBJECTIVES: To assess skeletal muscle weakness and progression as well as the cardiopulmonary involvement in oculopharyngeal muscular dystrophy (OPMD). MATERIALS AND METHODS: Cross-sectional study including symptomatic patients with genetically confirmed OPMD. Patients were assessed by medical history, ptosis, ophthalmoplegia, facial and limb strength, and swallowing capability. Cardiopulmonary function was evaluated using forced expiratory capacity in 1 s (FEV1), electrocardiogram (ECG), Holter monitoring, and echocardiography. RESULTS: We included 13 symptomatic patients (six males, mean age; 64 years (41-80) from 8 families. Ptosis was the first symptom in 8/13 patients followed by limb weakness in the remaining 5 patients Dysphagia was never the presenting symptom. At the time of examination, all affected patients had ptosis or had previously been operated for ptosis, while ophthalmoplegia was found in 9 patients. Dysphagia, tested by cold-water swallowing test, was abnormal in 9 patients (17-116 s, ref <8 s). Six patients could not climb stairs of whom two were wheelchair bound and one used a rollator. Six patients had reduced FEV1 (range 23%-59%). No cardiac involvement was identified. CONCLUSIONS: Limiting limb weakness is common in OPMD and can even be the presenting symptom of the disease. In contrast, dysphagia was not the initial symptom in any of our patients, although it was obligatory for diagnosing OPMD before genetic testing became available. Mild respiratory dysfunction, but no cardiac involvement, was detected.

Becker muscular dystrophy with widespread muscle hypertrophy and a non-sense mutation of exon 2.

Becker muscular dystrophy features progressive proximal weakness, wasting and often focal hypertrophy. We present a patient with pain and cramps from adolescence. Widespread muscle hypertrophy, preserved muscle strength and a 10-20-fold raised CPK were noted. Muscle biopsy was dystrophic, and Western blot showed a 95% reduction of dystrophin levels. Genetic analyses revealed a non-sense mutation in exon 2 of the dystrophin gene. This mutation is predicted to result in a Duchenne phenotype, but resulted in a mild Becker muscular dystrophy with widespread muscle hypertrophy. We suggest that this unusual phenotype is caused by translation re-initiation downstream from the mutation site.

Experimental brush-evoked allodynia activates posterior parietal cortex.

OBJECTIVE: To study the brain activation pattern of coexisting experimental ongoing pain and brush-evoked allodynia (pain evoked by innocuous brush) with the use of PET. BACKGROUND: Neuropathic pain usually has two essential phenomena: ongoing pain and brush-evoked allodynia, which coexist and may influence each other. Capsaicin induces both ongoing pain and brush-evoked allodynia. METHODS: Eight healthy right-handed volunteers participated in eight H2(15)O PET scans with two blocks of four randomized conditions: 1) rest, 2) brush, 3) capsaicin pain, and 4) capsaicin pain + brush (brush-evoked allodynia). Capsaicin was injected intradermally on the nondominant forearm and the subjects rated pain intensity and unpleasantness on 100-mm visual analogue scales. RESULTS: Pain intensity and unpleasantness were significantly higher during brush-evoked allodynia (74 +/- 4 and 67 +/- 4 mm) compared with capsaicin pain alone (60 +/- 4 and 51 +/- 5 mm). Brush-evoked allodynia, but not capsaicin pain alone, increased blood flow significantly in the contralateral right sensory association cortex Brodmann area (BA) 5/7, and in bilateral prefrontal cortex BA 9/10/47 and insula. No significant activity was seen in thalamus or primary somatosensory cortex (SI). Direct comparison between capsaicin pain and brush-evoked allodynia revealed significant increase in contralateral BA 5/7 only. CONCLUSIONS: The specific activation of contralateral BA 5/7 indicates that this brain region is important to the processing of brush-evoked allodynia. The involvement of BA 5/7 in brush-evoked allodynia is claimed to reflect multisensory input to this region, its role in conscious pain perception, and its neuroplastic properties.

Has basic research contributed to chronic pain treatment?

Our understanding of nociceptive processing and of plastic changes after persistent noxious input has increased immensely within the last two decades. It is now clear that long-lasting noxious stimulation or damage to the nervous system give rise to a neuronal hyperexcitability and that this sensitisation of the nervous system plays an important role for development and maintenance of chronic pain. The manifestations of such hyperexcitability are numerous and include among others: increased neuronal response to a suprathreshold stimulus, expansion of the peripheral areas from where a central neurone can be activated and the recruitment of previous non-responding nociceptive neurones. Furthermore, it has been possible to modulate this neuronal hyperexcitability by the discovery of molecular targets for pain, by sequencing DNA of ion channels and receptors and by development of new molecules that exert their effects on these molecular targets. The changes in responsiveness appear to be partly time and intensity dependent and partly dependent on the cause of injury. Whereas relatively short-lasting and moderate noxious input leads to reversible plastic changes, more intense and long-lasting noxious stimulation implies a risk for persistent and more profound alterations in transmitters, receptors, ion channels and in neuronal connectivity. Despite the explosion of new knowledge in pain processing and in molecular background for neuroplasticity, this progress has unfortunately not resulted in a corresponding improvement of our ability to treat chronic pain. The number of patients with chronic unrelieved pain is still high and newer types of treatment have so far not resulted in a substantially better treatment. Nevertheless, there is now an ongoing systematic research in which chronic pain conditions are assessed in a fashion so that mechanisms underlying pain can be dissected. Moreover, controlled clinical trials together with systematic reviews are carried out which in the future should permit formulation of treatment algorithms for chronic pain. Finally, it is likely that the development of new specific types of treatment will show efficacy if they are evaluated and analysed not on the global pain experience, but more specifically on those targets and elements of the pain experience they are aimed to deal with.

Repetitive intradermal capsaicin: differential effect on pain and areas of allodynia and punctate hyperalgesia.

This study examined the effect of repeated intradermal capsaicin injections on capsaicin pain intensity and areas of allodynia and punctate hyperalgesia. Seventeen healthy volunteers participated in four sessions separated by at least 5 days. Each session included four intradermal injections of 10 microg of capsaicin. In one session injections were given with 0.5 cm and 6 min intervals, in a second with 0.5 cm and 15 min intervals, in a third with 0.5 cm and 24 min intervals, and in a fourth session with 4 cm and 15 min intervals. Following each injection capsaicin pain intensity was measured in the first 5 min, the area of allodynia at 5 min and area of punctate hyperalgesia at 10 min. With 6 min and 0.5 cm between repeated injections, capsaicin pain intensity decreased significantly whereas areas of allodynia and punctate hyperalgesia increased. In contrast, both capsaicin pain intensity and areas of allodynia and punctate hyperalgesia increased when the interval between injections was 24 min and 0.5 cm or 15 min and 4 cm. With 15 min and 0.5 cm between injections, capsaicin pain intensity did not change, whereas areas of allodynia and punctate hyperalgesia increased. There were no significant relations between capsaicin pain intensity and areas of allodynia and punctate hyperalgesia after first injections. The findings indicate that the response to intradermal injection of capsaicin is dependent on the time and distance between injections. The lack of significant relation between capsaicin pain intensity and area of allodynia and punctate hyperalgesia suggests that the two phenomena are mediated by different central mechanisms.

Intramuscular and intradermal injection of capsaicin: a comparison of local and referred pain.

The present study compared capsaicin-induced muscle and skin pain in humans. Twelve healthy subjects received, in a randomised, balanced order, 3 intramuscular (i.m.) injections into the brachioradial muscle: capsaicin 100 microg/1 ml, capsaicin 100 microg/20 microl or 1 ml solvent (Tween 80), and one intradermal injection (i.d.): capsaicin 100 microg/20 microl. Local and referred pain intensities and areas were assessed from 0 to 60 min after injection. Intradermal capsaicin produced more intense local pain than i.m. capsaicin in the first min (skin: 68+/-6, muscle: 51+/-6 mm VASxmin, P<0.05). In contrast, the local pain offset was later (muscle: 38+/-5, skin: 23+/-5 min, P<0.05) and referred pain was more frequent (muscle: 9/12, skin: 1/12 subjects, P<0.01) following i.m. capsaicin compared with i.d. capsaicin. Capsaicin (1 ml) produced significantly more pain than 20 microl i.m. (pain in the first min: 1 ml: 71+/-6, 20 microl: 51+/-6 VASxmin, P<0.05, offset: 1 ml: 50+/-4, 20 microl: 38+/-5 min, P<0.05). The different local and referred pain following identical noxious stimulation of muscle and skin indicates that the neurophysiological mechanisms underlying skin and muscle pain differs. The model with identical noxious stimulation of muscle and skin may be suitable for the study of differences in deep and superficial pain as seen in the clinic.

Differential effect of painful heterotopic stimulation on capsaicin-induced pain and allodynia.

Painful heterotopic stimulation (HTS) may inhibit experimental and clinical pain, an effect known as diffuse noxious inhibitory control (DNIC). This study examined the effect of painful HTS on capsaicin-induced pain intensity, brush-evoked pain intensity and area of brush-evoked pain in humans. Immersion of the foot into painful cold water significantly reduced capsaicin-induced pain intensity and brush-evoked pain intensity in the contralateral forearm, but did not change area of brush-evoked pain. The observed differential effect on the magnitude of pain and hyperalgesia on the one hand and area of hyperalgesia on the other suggests that the DNIC effect on spinal activity is selective and not general.