Ten-year follow-up in a case series of integrative botulinum toxin intervention in adolescents with chronic daily headache and associated muscle pain.

INTRODUCTION: A total of 83% of children report headache during a 6-month period. The estimated 1-year prevalence of chronic daily headache (CDH) in children is at least 1 to 2%. Muscle pain is associated with headache severity and chronicity. Muscle pain can be associated with active muscular trigger points, a functional concept still remaining a controversy. An integrated approach including bio-behavioral management is accepted as standard treatment but does not provide sufficient pain relief in all patients. OBJECTIVE: We report the individual clinical course of five adolescents with treatment-refractory CDH associated with focal muscle pain. We describe a concept of short-term integrative intervention including botulinum toxin (StiBo) in a personalized "follow the referred pain pattern" injection regimen with the focus on long-term follow-up. RESULTS: StiBo showed short-term efficacy on headache frequency and severity. In the long-term follow-up, CDH was not existent in any of the patients. CONCLUSION: The treatment may have enabled the patients to draw attention away from a repeated circle of muscle-triggered pain and withdrawal of daily activities toward self-driven activities, thereby potentially preventing the development of further chronification. To prove this hypothesis, a prospective, placebo-controlled study in young adolescents with CDH should be initiated including objective outcome parameters on muscular level.

Scapuloperoneal syndrome type Kaeser and a wide phenotypic spectrum of adult-onset, dominant myopathies are associated with the desmin mutation R350P.

In 1965, an adult-onset, autosomal dominant disorder with a peculiar scapuloperoneal distribution of weakness and atrophy was described in a large, multi-generation kindred and named 'scapuloperoneal syndrome type Kaeser' (OMIM #181400). By genetic analysis of the original kindred, we discovered a heterozygous missense mutation of the desmin gene (R350P) cosegregating with the disorder. Moreover, we detected DES R350P in four unrelated German families allowing for genotype-phenotype correlations in a total of 15 patients carrying the same mutation. Large clinical variability was recognized, even within the same family, ranging from scapuloperoneal (n = 2, 12%), limb girdle (n = 10, 60%) and distal phenotypes (n = 3, 18%) with variable cardiac (n = 7, 41%) or respiratory involvement (n = 7, 41%). Facial weakness, dysphagia and gynaecomastia were frequent additional symptoms. Overall and within each family, affected men seemingly bear a higher risk of sudden, cardiac death as compared to affected women. Moreover, histological and immunohistochemical examination of muscle biopsy specimens revealed a wide spectrum of findings ranging from near normal or unspecific pathology to typical, myofibrillar changes with accumulation of desmin. This study reveals that the clinical and pathological variability generally observed in desminopathies may not be attributed to the nature of the DES mutation alone, but may be influenced by additional genetic and epigenetic factors such as gender. In addition, mutations of the desmin gene should be considered early in the diagnostic work-up of any adult-onset, dominant myopathy, even if specific myofibrillar pathology is absent.

Brain imaging and neuropsychology in late-onset dementia due to a novel mutation (R93C) of valosin-containing protein.

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD, MIM 167320) is a recently identified autosomal dominant disorder due to mutations in the valosin-containing protein (VCP) that affects muscle, bone and brain. Brain involvement and neuropsychological findings of IBMPFD have not been described in detail. A patient carried a novel heterozygous base pair change, 47832C>T, in the VCP gene that resulted in substitution of an arginine residue by cysteine at position 93 (R93C). He presented first with myopathy while bone involvement remained subclinical. The patient developed behavioral abnormalities in his 60s and showed frank personality change with fluent empty speech at the age of 74 years. This syndrome was best classified as semantic dementia. Magnetic resonance imaging disclosed slight but progressive cerebral atrophy with prominent callosal and frontal white matter loss. Positron emission tomography demonstrated glucose hypometabolism of the frontal and temporal lobes disproportionate to their structural involvement. This first comprehensive clinical and neuroimaging study in IBMPFD may raise the awareness among clinicians as well as basic scientists for this exemplary genetic model of dementia.

LGMD 2I due to the common mutation 826C>A in the FKRP gene presenting as myopathy with vacuoles and paired-helical filaments.

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.

Alterations in the trapezius muscle in young patients with migraine--a pilot case series with MRI.

BACKGROUND/PURPOSE: Migraine is frequent in young adults and adolescents and often associated with neck muscle tension and pain. Common pathophysiological pathways, such as reciprocal cervico-trigeminal activation, are assumed. Tense areas within the neck muscles can be clinically observed many patients with migraine. The aim of this pilot case study was to visualize these tense areas via magnet resonance imaging (MRI). METHODS: Three young patients with migraine were examined by an experienced investigator. In all three patients tense areas in the trapezius muscles were palpated. These areas were marked by nitroglycerin capsules on the adjacent skin surface. RESULTS: The MRI showed focal signal alterations at the marked locations within the trapezius muscles. CONCLUSION: Visualization of palpable tense areas by MRI may be usefully applied in the future to help elucidate the underlying pathophysiological processes of migraine.

Creatine monohydrate in muscular dystrophies: A double-blind, placebo-controlled clinical study.

The authors assessed the safety and efficacy of creatine monohydrate (Cr) in various types of muscular dystrophies in a double-blind, crossover trial. Thirty-six patients (12 patients with facioscapulohumeral dystrophy, 10 patients with Becker dystrophy, 8 patients with Duchenne dystrophy, and 6 patients with sarcoglycan-deficient limb girdle muscular dystrophy) were randomized to receive Cr or placebo for 8 weeks. There was mild but significant improvement in muscle strength and daily-life activities by Medical Research Council scales and the Neuromuscular Symptom Score. Cr was well tolerated throughout the study period.

De novo missense mutation in a constitutively expressed exon of the slow alpha-tropomyosin gene TPM3 associated with an atypical, sporadic case of nemaline myopathy.

We describe an atypical case of nemaline myopathy with an unusual distribution of muscle weakness who presented at 14 years of age with kyphoscoliosis. In this patient, we demonstrate heterozygosity for a de novo CGT-CAT (Arg167His) mutation in a constitutively expressed exon (exon 5) of slow alpha-tropomyosin (TPM3). This is the first mutation identified in a constitutively expressed exon of TPM3 in a nemaline myopathy patient, but is similar to recently described mutations in beta-tropomyosin (TPM2) associated with nemaline myopathy and mutations in fast alpha-tropomyosin (TPM1) which cause hypertrophic cardiomyopathy.

High-dose immunoglobulin therapy in sporadic inclusion body myositis: a double-blind, placebo-controlled study.

Sporadic inclusion body myositis (s-IBM) is an acquired inflammatory muscle disease of unknown cause. In general, s-IBM presents with slowly progressive, asymmetric weakness, and atrophy of skeletal muscle. There is a mild transitory or nil responsiveness to standard immunosuppressive treatment. A controlled cross-over study of 22 s-IBM patients over 3 months showed a partial improvement in those treated with high-dose intravenous immunoglobulin therapy (IVIG) versus placebo. The present study included 22 patients aged 32-75 years and with a mean duration of disease of 5.2+/-3.6 years. They were randomized by a double-blind, placebo-controlled, cross-over design to monthly infusions of 2 g/kg bodyweight IVIG or to placebo for 6 months each, followed by the alternative treatment. After 6 and 12 months the response to treatment was evaluated, using a modified Medical Research Council scale, Neuromuscular Symptom Score (NSS), the patient's own assessment of improvement, arm outstretched time, and electromyography. No serious side effects were seen, in particular no viral infection and no major cardiac or neurological complications. Overall there was no progression of the disease in 90% of patients, unlike that which might have been expected in untreated patients. A mild and significant improvement (11%) in clinical symptoms was found using NSS, but not with other test procedures. There was a trend to mild improvement in treated patients when using other tests. Individual responses to treatment was heterogeneous. The validity of this study may be reduced by mismatch of groups with regard to age at onset and variability in disease expression. The findings of this study largely confirm those of a previous IVIG trial. Treatment with IVIG may be mildly effective in s-IBM by preventing disease progression or inducing mild improvement. Long-term studies are needed to evaluate further the benefit of IVIG therapy in s-IBM.

Respiratory insufficiency as a presenting symptom of LGMD2D in adulthood.

Several forms of recessive limb girdle muscular dystrophy (LGMD2C-F) are due to mutations in genes coding for sarcoglycans. Clinically, most sarcoglycanopathies present in childhood with skeletal muscle wasting and early loss of ambulation; respiratory insufficiency is rare. However, some cases of LGMD2D with a late onset and a milder course have been reported. In this study, two adult brothers, compound heterozygous for two missense mutations of the SGCA gene (Arg77Cys, Val247Met), presented with respiratory insufficiency while they were still ambulatory.

[New insights in pathogenesis and therapy of sporadic inclusion body myositis (s-IBM)]. / Neue Gesichtspunkte zur Pathogenese und Therapie der sporadischen Einschlusskörpermyositis (s-IBM).

Sporadic inclusion body myositis (s-IBM) is a chronic progressive inflammatory myopathy which occurs preferentially in older patients. Histologic hallmarks are rimmed vacuoles and eosinophilic cytoplasmatic inclusions. The etiology is still unknown, but different pathogenetic mechanisms such as slow virus infection, autoimmunopathogenesis, myonuclear alterations, and mitochondrial defects have been implicated. A relation to neurodegenerative disorders and prion diseases has also been suggested. There is a poor response if any to immunosuppressive therapy. Stabilization of disease progression was shown only by intravenous immunoglobulin (IVIG) therapy. Future findings in the field of s-IBM pathogenesis may result in better therapeutic options.