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Background Migraine-tic syndrome was first reported in 2004 in a 44-year-old woman who had concomitant symptoms of both typical trigeminal neuralgia and migraine. We report here two further cases of migraine-tic syndrome and speculate on the relevance of this condition to the pathophysiology of headache. Case reports A 43-year-old woman presented with typical trigeminal neuralgia symptoms that preceded the onset of migraine headache; both headache types responded to treatment with sumatriptan. A 35-year-old woman presented with trigeminal neuralgia that consistently followed the onset of migraine headache. The former aspect responded to baclofen, but the migraine headache required treatment with amitriptyline. Discussion These two patients provide further support for the presence of an overlap syndrome of migraine-tic. We suggest that there is a common pathway for trigeminal neuralgia and migraine.

AimTo outline the pathways a cohort of first attendees to our headache clinics had taken over the years in search of explanations and treatment for their headaches. To establish a greater awareness of the shortcomings and failures in their medical journey in the hope that better headache management will emerge in primary care.BackgroundAt first attendance in primary care most headache sufferers will not receive a firm diagnosis. Treatments provided are often ineffective and so many patients embark on a somewhat random self-made journey searching for a remedy. If they reach a Headache Clinic the most common diagnoses are ‘chronic migraine’ and ‘medication overuse headache’. They are either no better or worse than when their headaches first started despite their efforts.MethodWe undertook a prospective questionnaire-based study of over 200 patients on first attendance at each of our headache clinics, three based in District General Hospitals and one in a tertiary referral centre. We documented the patients’ headache characteristics, the ‘burden’ of their headaches, functional handicap and the financial costs incurred seeking help before referral. We also documented what our patients understood about their headache disorder and the treatments previously tried.FindingsMost patients had not been given a formal diagnosis in primary care and many remained unconvinced of the benign nature of their headache problem and wanted further investigations. A few had sought help from headache charities. Many had unrealistic attitudes to their problem and medication overuse was rife. A few patients had been offered triptans in primary care. Key deficiencies in the primary care management of these patients included failure to provide a formal headache diagnosis, inadequate understanding of the nature and mechanism of headaches and failure to follow a resilient management strategy. We provide a more effective management pathway in primary care.

Free radical accumulation and oxidative stress have been proposed as contributing to the progression of amyotrophic lateral sclerosis (motor neuron disease). A range of antioxidant medications is available, and has been studied. We aimed to examine the effects of antioxidant medication in the treatment of people with amyotrophic lateral sclerosis, and searched the Cochrane Neuromuscular Disease Group Trials register (August 2005), MEDLINE (January 1966 to August 2005), EMBASE (January 1980 to August 2005) and other sources. Selection criteria were all randomized or quasi-randomized controlled trials of antioxidant treatment for amyotrophic lateral sclerosis. The authors independently applied the selection criteria, assessed study quality and two authors performed independent data extraction. The search identified 23 studies for consideration but only nine studies met the inclusion criteria. Only two studies used our predetermined primary outcome measure as the primary outcome measure (survival at 12 months treatment). However, sufficient data were available from four studies to allow analysis of this outcome measure, and a meta-analysis was performed. In the individual studies no significant effect was observed for vitamin E 500 mg twice daily; vitamin E 1 g five times daily; acetylcysteine 50 mg/kg daily subcutaneous infusion; or a combination of L-methionine 2 g, vitamin E 400 International Units, and selenium 0.03 mg three times daily (Alsemet). No significant effect on the primary outcome measure was observed in a meta analysis of all antioxidants combined. No significant differences were demonstrated in any of the secondary outcome measures. In the opinion of the reviewers, there is insufficient evidence of efficacy of individual antioxidants, or antioxidants in general, in the treatment of people with amyotrophic lateral sclerosis. One study reported a mild positive effect, but this was not supported by the analysis we used. Generally, the studies were poorly designed, and underpowered, with low numbers of participants and of short duration. Further well-designed trials of medications such as vitamin C and E are unlikely to be performed. If future trials of antioxidant medications are performed, careful attention should be given to sample size, outcome measures, and duration of the trial. The high tolerance and safety, and relatively low cost of vitamins C and E, and other considerations related to the lack of other effective treatments for amyotrophic lateral sclerosis, explain the continuing use of these vitamins by physicians and people with amyotrophic lateral sclerosis. While there is no substantial clinical trial evidence to support their clinical use, there is no clear contraindication.

Background: Oculopharyngeal muscular dystrophy (OPMD) is caused by expansions of the poly (A) binding protein 2 ( PABP2 ) gene. Previous histological analyses have revealed mitochondrial abnormalities in the muscles of OPMD patients but their significance remains uncertain. Objective: We had the rare opportunity to study monozygotic twins with identical expansions of the PABP2 gene but with markedly different severities of OPMD. Both had histological features of mitochondrial myopathy. We determined whether mitochondrial DNA abnormalities underlay these changes. Methods: Clinical information was obtained by history and examination. Muscle biopsies were obtained from each subject and genetic analysis was performed using long-range PCR and Southern blotting. Results: We demonstrate, for the first time, the presence of mitochondrial DNA (mtDNA) deletions by Southern blotting in individuals with OPMD. This correlates with the presence of mitochondrial myopathy in both twins. Moreover, both twins had different mtDNA deletions, which might explain their phenotypic differences. Conclusion: We hypothesise that mitochondrial dysfunction may occur as a consequence of PABP2 gene mutations, and that this dysfunction may affect the phenotypic manifestations of OPMD.

Summary Background The immune response to an isoform of glutamic acid decarboxylase (GAD), GAD65, is associated with two clinically distinct diseases, stiff-man syndrome (SMS) and type 1 (insulin-dependent) diabetes mellitus. We sought to identify differences in the cellular and humoral immune responses to GAD in these two diseases. Methods We compared T-cell responses in 14 SMS patients with axial disease and 17 patients with type 1 diabetes. Findings Peripheral blood T cells of eight SMS patients recognised different immunodominant epitopes of GAD65 compared with T cells from 17 patients with type 1 diabetes. GAD regions 81–171 and 313–403 induced a dominant T-cell response in six of eight patients with SMS but in only one of 17 patients with type 1 diabetes (p=0·001). No SMS patients responded dominantly to GAD fragments 161–243 and 473–555 compared with ten patients with type 1 diabetes (p=0·008). GAD antibodies were detected in 11 of 14 SMS patients (seven with diabetes) and 11 of 17 patients with type 1 diabetes; IgG1 was dominant in both groups. SMS patients, however, were more likely than patients with diabetes to have isotypes other than IgG1 (p=0·03), in particular, IgG4 or IgE isotypes, which were not detected in patients with type 1 diabetes (p=0·012). Interpretation Our findings indicate differences between patients with SMS and type 1 diabetes in cellular (epitope recognition) and humoral (isotype pattern) responses to GAD65. Thus the same autoantigen can elicit distinct immune responses in patients with SMS, even when associated with diabetes, compared with patients with type 1 diabetes.

Clinical, electrophysiological, and molecular genetic features were investigated in two patients from a family a with dominantly inherited myotonic disease, characterised by painful cramps, stiffness without weakness, fluctuation of symptoms, and cold sensitivity. A reduction in amplitude of the compound muscle action potential was demonstrated on cooling and administration of potassium, although no clinical exacerbation was seen. A heterozygote mutation Val1589Met was identified in the alpha-subunit of the skeletal muscle sodium channel gene in both patients, consistent with the diagnosis of potassium-aggravated myotonia. The phenotype in this family is much milder than that previously described in another family with a mutation at this site.

Summary We have identified the first stop-codon point mutation in mtDNA to be reported in association with human disease. A 36-year-old woman experienced episodes of encephalopathy accompanied by lactic acidemia and had exercise intolerance and proximal myopathy. Histochemical analysis showed that 90% of muscle fibers exhibited decreased or absent cytochrome c oxidase (COX) activity. Biochemical studies confirmed a severe isolated reduction in COX activity. Muscle immunocytochemistry revealed a pattern suggestive of a primary mtDNA defect in the COX-deficient fibers and was consistent with either reduced stability or impaired assembly of the holoenzyme. Sequence analysis of mtDNA identified a novel heteroplasmic G→A point mutation at position 9952 in the patient's skeletal muscle, which was not detected in her leukocyte mtDNA or in that of 120 healthy controls or 60 additional patients with mitochondrial disease. This point mutation is located in the 3′ end of the gene for subunit III of COX and is predicted to result in the loss of the last 13 amino acids of the highly conserved C-terminal region of this subunit. It was not detected in mtDNA extracted from leukocytes, skeletal muscle, or myoblasts of the patient's mother or her two sons, indicating that this mutation is not maternally transmitted. Single-fiber PCR studies provided direct evidence for an association between this point mutation and COX deficiency and indicated that the proportion of mutant mtDNA required to induce COX deficiency is lower than that reported for tRNA-gene point mutations. The findings reported here represent only the second case of isolated COX deficiency to be defined at the molecular genetic level and reveal a new mutational mechanism in mitochondrial disease.

Amyotrophic lateral sclerosis (ALS) is found in a familial form in around 5-10% of cases. Of these familial cases around 20% are associated with mutations of SOD-1. The genetic basis of the disease in the remaining familial cases, and genetic risk factors in sporadic cases, are unknown. Recently, the common forms of spinal muscular atrophy (SMA) have been associated with mutations of the SMN and NAIP genes on chromosome 5, in the region q11.2-13.3. Some patients with both familial and sporadic motor neuron disease show only lower motor neuron signs, in common with SMA patients, and families containing individuals with phenotypes of both childhood SMA and adult motor neuron disease have been reported. We therefore examined the SMA locus as a candidate for ALS, in 54 patients with sporadic motor neuron disease, and 10 single-generation familial patients (with no evidence of SOD-1 mutations), and in a single patient with Brown-Vialetto-Van Laere syndrome. No mutations of the SMN or NAIP genes were detected. The difficulties of classification of lower motor neuron presentations of motor neuron diseases are discussed. The demonstration that mutations diagnostic of SMA are not found in ALS patients helps distinguish these conditions.

We present a new approach to constrain and validate atomic oxygen (O) concentrations in the mesopause region (∼ 80 to ∼ 100 km). In a prior companion paper [Mlynczak et al., ], we presented O-atom concentrations in the mesopause region inferred from measurements of day ozone and night hydroxyl emission rates made by the Sounding of the Atmosphere using Broadband Emission Radiometry (SABER) instrument. The approach presented here uses the constraint of global, annual mean energy balance to derive atomic oxygen concentrations, consistent with rates of radiative cooling by carbon dioxide (CO2) and solar heating due to molecular oxygen (O2). The mathematical difference between these cooling and heating rates, on a global annual mean basis, effectively constrains the maximum heating rate for the sum of all other processes. The remaining terms, solar heating due to ozone plus a series of exothermic chemical reactions can be expressed as functions of O. This new approach enables a simple mathematical expression that yields the vertical profile of global annual mean >radiatively constrained> atomic oxygen in the mesopause region. The radiatively constrained atomic oxygen depends only on the CO2 cooling rates, O2 solar heating rates, and standard reaction rate coefficients and enthalpies. Radiative cooling and solar heating rates used in these analyses are derived from measurements made by the SABER instrument on the NASA Thermosphere Ionosphere Mesosphere Energetics and Dynamics satellite. There is excellent agreement between the SABER radiatively constrained atomic oxygen and that derived from the SABER ozone and OH emission measurements over most of the mesopause region. Radiatively constrained atomic oxygen represents an upper limit on the global average O-atom concentration in the mesopause region. © 2013. American Geophysical Union. All Rights Reserved.

We describe two women with acquired partial lipodystrophy, one with significant myopathic symptoms and signs. Muscle biopsy of deltoid and quadriceps was performed in each case. The light microscopy findings were of type 1 and type 2 fibre hypertrophy, with an increase in intracytoplasmic fat in both cases. Electron microscopy showed normal fibres, with accumulations of electron-lucent fat droplets between the myofibrils. The cause of the lipodystrophies is uncertain, but myopathy may be a feature, and muscle biopsy studies may help in further defining the syndrome.

The skeletal muscle ryanodine receptor plays a crucial role in excitation-contraction (EC) coupling and is implicated in various congenital myopathies. The periodic paralyses are a heterogeneous, dominantly inherited group of conditions mainly associated with mutations in the SCN4A and the CACNA1S genes. The interaction between RyR1 and DHPR proteins underlies depolarization-induced Ca(2+) release during EC coupling in skeletal muscle. We report a 35-year-old woman presenting with signs and symptoms of a congenital myopathy at birth and repeated episodes of generalized, atypical normokalaemic paralysis in her late teens. Genetic studies of this patient revealed three heterozygous RYR1 substitutions (p.Arg2241X, p.Asp708Asn and p.Arg2939Lys) associated with marked reduction of the RyR1 protein and abnormal DHPR distribution. We conclude that RYR1 mutations may give rise to both myopathies and atypical periodic paralysis, and RYR1 mutations may underlie other unresolved cases of periodic paralysis with unusual features.

External climate forcings-such as long-term changes in solar insolation-generate different climate responses in tropical and high latitude regions. Documenting the spatial and temporal variability of past climates is therefore critical for understanding how such forcings are translated into regional climate variability. In contrast to the data-rich middle and high latitudes, high-quality climate-proxy records from equatorial regions are relatively few, especially from regions experiencing the bimodal seasonal rainfall distribution associated with twice-annual passage of the Intertropical Convergence Zone. Here we present a continuous and well-resolved climate-proxy record of hydrological variability during the past 25,000 years from equatorial East Africa. Our results, based on complementary evidence from seismic-reflection stratigraphy and organic biomarker molecules in the sediment record of Lake Challa near Mount Kilimanjaro, reveal that monsoon rainfall in this region varied at half-precessional ( approximately 11,500-year) intervals in phase with orbitally controlled insolation forcing. The southeasterly and northeasterly monsoons that advect moisture from the western Indian Ocean were strengthened in alternation when the inter-hemispheric insolation gradient was at a maximum; dry conditions prevailed when neither monsoon was intensified and modest local March or September insolation weakened the rain season that followed. On sub-millennial timescales, the temporal pattern of hydrological change on the East African Equator bears clear high-northern-latitude signatures, but on the orbital timescale it mainly responded to low-latitude insolation forcing. Predominance of low-latitude climate processes in this monsoon region can be attributed to the low-latitude position of its continental regions of surface air flow convergence, and its relative isolation from the Atlantic Ocean, where prominent meridional overturning circulation more tightly couples low-latitude climate regimes to high-latitude boundary conditions.

Mutations of the copper/zinc superoxide dismutase (SOD-1) gene are present in around 20% of patients with a family history of amyotrophic lateral sclerosis. The finding of these mutations in patients with sporadic amyotrophic lateral sclerosis is rare. We describe a family with amyotrophic lateral sclerosis associated with the SOD-1 mutation Asp 101 Asn. This mutation was previously described as occurring in a patient with sporadic disease. We discuss the difficulties in defining truly sporadic amyotrophic lateral sclerosis, and the consequent implications on the neurogenetic advice given to other family members.

Autosomal recessive spinal muscular atrophy (SMA) shows substantial phenotypic variability, presenting at a variety of ages from infancy to adult life. Diagnostic difficulties may arise because SMA sometimes produces a dystrophic or myopathic phenotype rather than classical neurogenic abnormalities. Two brothers are described who illustrate this principle and highlight the increasing importance of molecular genetics in investigating patients with neuromuscular diseases. The findings are discussed in the light of recent observations in a mouse model of SMA.

Neurotrophic factors, such as ciliary neurotrophic factor (CNTF), have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), a human neurodegenerative disease primarily of upper and lower motor neurones. A null mutation of the CNTF gene has recently been described. The mutation is an intronic point mutation (G to A) which generates a new splice acceptor site and a 4 bp insertion within the CNTF coding region, and prevents the expression of the normal protein. We investigated this as a candidate gene in 49 families with ALS, where the genetic component may be expected to be strongest. 65% were normal homozygotes, and 35% were heterozygotes for the mutation. No mutant homozygotes were detected. The absence of CNTF protein expression associated with the homozygote mutation does not appear to be of major significance in the development of ALS.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder, primarily affecting both upper and lower motor neurons. The median age of onset is around 68 years, and median survival approximately 2 years, although with significant variability1. The pathogenesis is unknown, but the recognition of mutations in the gene for copper/zinc Superoxide dismutase (SOD-1)2 in a proportion of patients (around 1–2% of all cases), almost all of whom have a family history of the condition, has provided fruitful avenues of research3. Nevertheless, the mechanism by which these mutations lead to the expression of the disease is not yet established4,5.

Immune mediated inflammatory myopathies are a heterogeneous group of acquired diseases characterised by inflammation of skeletal muscle. In recent years, this group of conditions has become better characterised by the detection of autoantibodies to a number of intracellular proteins. The authors have identified three patients with a novel, progressive inflammatory myopathy, associated with circulating IgG antibodies to γ/δ-sarcoglycan, two proteins which form part of the sarcolemmal dystrophin-glycoprotein complex. All three patients responded to steroids initially, with a rapid decrease in CK levels to normal levels, and plasma exchange undertaken in two also produced additional temporary improvement. The patients presented with proximal weakness in the upper and lower limbs, with high CK levels (>2000 IU/L). Patient 3 also had mild facial and neck weakness and dysphagia. With disease progression, distal weakness developed in the upper limbs in a pattern consistent with inclusion body myositis (IBM) but the quadriceps, normally markedly affected in IBM, remained spared. Muscle biopsies showed inflammation, with rimmed vacuoles and dystrophic changes similar to those seen in IBM, but the inflammation included prominent accumulations of CD4+T lymphocytes and plasma cells, together with membrane attack complex deposition on muscle fibres and endothelium. Analysis of myositis specific and associated antibodies (Jo-1, PL-7, PL-12, EJ, OJ, SRP, PM-Scl (75Kd and 100Kd), Ku, Mi-2β, U1-RNP) was negative. Immunohistochemistry using patients9 sera on healthy control muscle revealed uniform immunoglobulin binding to sarcolemma. Western blot of sarcolemmal fractions against patients9 sera demonstrated a distinct band of 35 kDa. This antibody was subsequently shown to react with recombinant γ- and δ-sarcoglycan, two proteins of the muscle cell membrane with >80% homology. These three patients have a novel inflammatory myopathy associated with anti-γ/δ-sarcoglycan autoantibodies. This myopathy appears to be responsive to steroids and plasma exchange. The potential pathogenic role of the autoantibodies in this condition will require further elucidation.

In 1952, Wildervanck described the first case of what he styled the cervico-oculo-acoustic (COA) syndrome. This comprises Klippel Feil's (KF) anomaly (congenitally fused cervical vertebrae), congenital sensorineural deafness and Duane's retraction syndrome (deficient abduction with retraction on adduction). Since that original paper, there have been further reports describing this triad, either completely or incompletely. A further case of this syndrome is reported and the first report of MRI head scan findings in this condition is presented. In addition, the origin of mirror movements observed as part of the KF syndrome are discussed.

Transient global amnesia (TGA) is a well defined and not uncommon clinical entity, comprising the sudden development of a dense anterograde amnesia, usually accompanied by repetitive questioning, without alteration in consciousness or other epileptic phenomena, or the development of focal neurological features. Behaviour during the episode may otherwise appear normal and recovery is complete within 24 hours, except for an amnesic gap for the duration of the attack together with a short and variable period of retrograde amnesia.1 The cause of TGA is not known, but it seems to be strongly associated with migraine, although …

A tumour which on CT is clearly intrinsic, irregular, exhibits patchy enhancement with contrast, and invades periventricular tissues, especially the corpus callosum, is very likely to be a glioma and may not be biopsied. A case is presented with these radiological features in which the tumour proved to be a tuberculoma, with complete clinical and radiological resolution after antituberculous chemotherapy.

Creatine, phosphocreatine, ATP and phosphate concentrations were measured in extracts of tibialis anterior and gastrocnemius muscles from 42 normal and 39 dystrophic mice from 1 to 16 weeks of age. No differences were observed at 1 week, prior to the onset of histological abnormalities in dystrophic animals. Creatine and phosphocreatine concentrations were significantly reduced in older dystrophic mice, and phosphate levels were higher, while ATP levels generally did not differ. Tenotomy of gastrocnemius at 1 week prevented the development of dystrophy in this muscle but this was not associated with an increase in phosphogen concentrations. Serum creatine kinase levels were significantly higher in dystrophic mice than normal mice but only during the first two weeks of life; levels in older mice were not significantly different. This study shows that the reported deficits in phosphogen concentrations in dystrophic muscles are likely to reflect the results, rather than the cause, of the dystrophic process.

There are a number of methods available for the measurement of phosphate ion concentration, which may be used when moderately labile phosphate esters such as ATP are present in low concentration. However, the highly acidic conditions usually employed make these unsuitable when very labile esters such as phosphocreatine are present. A method in which the phosphomolybdate complex is developed under mildly acidic conditions, using high molybdate concentrations to counteract the reduced assay sensitivity at high pH, is described. The assay is linear in the range 5-300 microM phosphate, and micromolar concentrations of phosphate can be reliably measured in the presence of millimolar phosphocreatine.

We have examined the variation of creatine kinase (CK) levels with age in 206 unrelated normal females. The subjects included 75 adult women aged 15-50, 11 post-menopausal women aged 50-70 and 120 girls under 15 years of age, comprising 84 girls with idiopathic epilepsy (65 pre-menarchal and 19 post-menarchal), well controlled on various anticonvulsant combinations, and 36 normal schoolgirl volunteers (28 pre-menarchal and 8 post-menarchal). Comparison of mean and variance values showed no significant difference between the CK levels in normal and epileptic girls and the data were subsequently combined. Creatine kinase levels were significantly higher in the pre-menarchal girls than in the post-menarchal girls and normal adult women. Levels were high in the first few months of life, fell during infancy and early childhood, rose rapidly in later childhood and then fell abruptly around the time of menarche. The levels then fell slowly throughout adult life but rose again after age 40. This phasic variation with age may be related to hormonal status. The use of age-specific CK ranges may have a significant effect on the carrier detection rate in Duchenne dystrophy.

Muscle biopsy extracts from a series of 6 patients with McArdle's disease were investigated by analytical SDS-polyacrylamide gel electrophoresis, to establish the presence or absence of the myophosphorylase protein subunit. In 4 cases, the band corresponding to the myophosphorylase subunit was totally absent from the electrophoretic staining pattern, and in 2 cases was present, but with a greatly reduced staining intensity compared with control normal patients; thus in none of the cases of McArdle's disease investigated was there evidence for a myophosphorylase subunit band of comparable staining intensity to that found in control normal patients. This result contrasts with previously reported findings (Feit and Brooke 1976) which suggested that McArdle's disease exists in biochemically heterogeneous forms; in one form of the disease myophosphorylase being totally absent and in a second form present to a similar extent as normal, but in an inactive form. On the basis of the results reported in this paper, we would suggest that myophosphorylase deficiency is a single gene disorder characterized by the absence or marked reduction of the myophosphorylase protein.

SUMMARY:A case of neonatal myasthenia gravis is reported in the infant of an asymptomatic thymectomized mother with comparably elevated acetylcholine receptor (AChR) antibody titers. The mother remained asymptomatic despite elevated antibody titers while the infant became asymptomatic in association with the disappearance of the AChR antibody. It is suggested that the AChR antibody plays an essential role in the development of neonatal myasthenia gravis. It is also suggested that a thymic factor is necessary for the development of clinical symptomatology accounting for the lack of correlation between the clinical state of the mother and infant.

Cyclosporin toxicity may produce a wide range of neurological disorders. We report three patients whose neurological problems developed while taking cyclosporin following cardiac transplantation, but resolved rapidly when the drug was discontinued. In two cases, MRI revealed abnormalities which disappeared with clinical recovery. Blood cyclosporin concentrations were not markedly increased, and it is possible that the neurotoxic effects of cyclosporin are mediated by metabolites, through an effect on the blood-brain barrier.