Bi-allelic truncating mutations in VWA1 cause neuromyopathy.

The von Willebrand Factor A domain containing 1 protein, encoded by VWA1, is an extracellular matrix protein expressed in muscle and peripheral nerve. It interacts with collagen VI and perlecan, two proteins that are affected in hereditary neuromuscular disorders. Lack of VWA1 is known to compromise peripheral nerves in a Vwa1 knock-out mouse model. Exome sequencing led us to identify bi-allelic loss of function variants in VWA1 as the molecular cause underlying a so far genetically undefined neuromuscular disorder. We detected six different truncating variants in 15 affected individuals from six families of German, Arabic, and Roma descent. Disease manifested in childhood or adulthood with proximal and distal muscle weakness predominantly of the lower limbs. Myopathological and neurophysiological findings were indicative of combined neurogenic and myopathic pathology. Early childhood foot deformity was frequent, but no sensory signs were observed. Our findings establish VWA1 as a new disease gene confidently implicated in this autosomal recessive neuromyopathic condition presenting with child-/adult-onset muscle weakness as a key clinical feature.

[On the Conceptual History of Myotonia Congenita: The Contributions of Julius Thomsen and Adolph Seeligmüller]. / Zur Konzeptgeschichte der Myotonia congenita: Die Beiträge von Julius Thomsen und Adolph Seeligmüller.

Myotonia congenita was first described as an entity in 1876 by Julius Thomsen. Shortly later in the same year it was criticized by Adolph Seeligmüller who extended the clinical findings. Charles Bell, Moritz Benedict and Ernst von Leyden had already partly described the symptoms of the disease before 1876, but did not recognize this as a new entity. A comparison of the publications of Thomsen and Seeligmüller in 1876 and of Seeligmüller's textbook published in 1887, as well as the today's genetically proven disease shows that Seeligmüller correctly criticized two aspects of Thomsen's publication: (i) Thomsen suspected the pathogenesis to be in "one half of the brain's activity, the will" with "seat in the cerebrospinal system" and (ii) he made the assumption of a coordination disorder in the sense of an ataxia [1]. Due to a better understanding of the pathogenesis enabled by Seeligmüller's postulate of a "more difficult mobile muscle substance" [2] without excluding an inborn affection of the lateral cords of the spinal cord, it would have been entirely justified to recognize Seeligmüller's contribution to the conceptual history of Myotonia congenita by including his name in the eponym [3].

Understanding mitochondrial DNA maintenance disorders at the single muscle fibre level.

Clonal expansion of mitochondrial DNA (mtDNA) deletions is an important pathological mechanism in adults with mtDNA maintenance disorders, leading to a mosaic mitochondrial respiratory chain deficiency in skeletal muscle. This study had two aims: (i) to determine if different Mendelian mtDNA maintenance disorders showed similar pattern of mtDNA deletions and respiratory chain deficiency and (ii) to investigate the correlation between the mitochondrial genetic defect and corresponding respiratory chain deficiency. We performed a quantitative analysis of respiratory chain deficiency, at a single cell level, in a cohort of patients with mutations in mtDNA maintenance genes. Using the same tissue section, we performed laser microdissection and single cell genetic analysis to investigate the relationship between mtDNA deletion characteristics and the respiratory chain deficiency. The pattern of respiratory chain deficiency is similar with different genetic defects. We demonstrate a clear correlation between the level of mtDNA deletion and extent of respiratory chain deficiency within a single cell. Long-range and single molecule PCR shows the presence of multiple mtDNA deletions in approximately one-third of all muscle fibres. We did not detect evidence of a replicative advantage for smaller mtDNA molecules in the majority of fibres, but further analysis is needed to provide conclusive evidence.

Cardiolipin Stabilizes and Increases Catalytic Efficiency of Carnitine Palmitoyltransferase II and Its Variants S113L, P50H, and Y479F.

Muscle carnitine palmitoyltransferase II (CPT II) deficiency is associated with various mutations in CPT2 gene. In the present study, the impact of the two CPT II variants P50H and Y479F were characterized in terms of stability and activity in vitro in comparison to wildtype (WT) and the well investigated variant S113L. While the initial enzyme activity of all variants showed wild-type-like behavior, the activity half-lives of the variants at different temperatures were severely reduced. This finding was validated by the investigation of thermostability of the enzymes using nano differential scanning fluorimetry (nanoDSF). Further, it was studied whether the protein stabilizing diphosphatidylglycerol cardiolipin (CL) has an effect on the variants. CL indeed had a positive effect on the stability. This effect was strongest for WT and least pronounced for variant P50H. Additionally, CL improved the catalytic efficiency for CPT II WT and the investigated variants by twofold when carnitine was the varied substrate due to a decrease in KM. However, there was no influence detected for the variation of substrate palmitoyl-CoA. The functional consequences of the stabilization by CL in vivo remain open.

Prevalence and characteristics of headache attributed to ingestion or inhalation of a cold stimulus (HICS): A cross-sectional study.

BACKGROUND: Headache attributed to ingestion or inhalation of a cold stimulus (HICS), colloquially called ice-cream headache, is a common form of a primary headache in adults and children. However, previous studies on adults are limited due to the small number of patients. Furthermore, most of the subjects in previous studies had a history of other primary headaches. METHODS: Biographic data, clinical criteria of HICS and prevalence of primary headache were collected by a standardized questionnaire. A total of 1213 questionnaires were distributed; the return rate was 51.9% (n = 629); 618 questionnaires could be analyzed. RESULTS: In a cohort of 618 people aged between 17-63 years (females: n = 426, 68.9%), the prevalence of HICS was 51.3% (317 out of 618). There was no difference between men and women (51.3% vs. 51.6%). The duration of HICS was shorter than 30 sec in 92.7%. In the HICS group, localization of the pain was occipital in 17%. Trigemino-autonomic symptoms occurred in 22%, and visual phenomena (e.g. flickering lights, spots or lines) were reported by 18% of the HICS group. The pain intensity, but not the prevalence of HICS, was higher when tension-type headache and migraine or both were present as co-morbid primary headaches (Numeric Rating Scale (NRS) 4.58 and 6.54, p = 0.006). There was no higher risk of participants with migraine getting HICS than for those who did not have migraine (odds ratio = 1.17, 95% confidence interval (CI) 0.75-1.83; p = 0.496). CONCLUSION: The results of this study modified the current criteria for HICS in the ICHD-3 regarding duration and localization. In addition, accompanying symptoms in about one fifth of the participants are not mentioned in the ICHD-3. Neither migraine nor tension-type headache seems to be a risk factor for HICS. However, accompanying symptoms in HICS are more frequent in subjects with another primary headache than in those without such a headache.

Recurrent Myalgia since Early Infancy-Misleading Clinical Course in a Child with Carnitine Palmitoyltransferase-II Deficiency.

Metabolic myopathies are heterogeneous hereditary diseases affecting skeletal muscle energy supply. Symptoms usually comprise pain, cramps, hypotonia, weakness, and myoglobinuria.We present a boy with recurrent myalgia and weakness after some minutes of exercise or during febrile infections since early infancy. First laboratory workup at the age of 9 years showed no abnormalities, apart from a slightly elevated creatine kinase. After exclusion of common structural and metabolic myopathies, next generation sequencing panel (4 years after the initial diagnostic metabolic workup) revealed two potentially pathogenic missense mutations in the CPT2 gene (c.149C > A (p.P50H) and c.1459G > A (p.E487K)).Our case underscores the clinical variability of muscle carnitine palmitoyltransferase II (CPT II) deficiency and illustrates a pitfall of diagnostic algorithms for metabolic myopathies. Myalgia following exercise of a few minutes duration would have argued for a carbohydrate and against a fatty acid metabolic defect. However, CPT II deficiency is the most common disorder of muscle fatty acid metabolism and should be considered even in atypical scenarios. Analyses of plasma acyl carnitine profile during acute metabolic crises may help to unmask biochemical markers which are often overlooked in dried-blood analyses.

Cellular Stress in the Pathogenesis of Muscular Disorders-From Cause to Consequence.

Cellular stress has been considered a relevant pathogenetic factor in a variety of human diseases. Due to its primary functions by means of contractility, metabolism, and protein synthesis, the muscle cell is faced with continuous changes of cellular homeostasis that require rapid and coordinated adaptive mechanisms. Hence, a prone susceptibility to cellular stress in muscle is immanent. However, studies focusing on the cellular stress response in muscular disorders are limited. While in recent years there have been emerging indications regarding a relevant role of cellular stress in the pathophysiology of several muscular disorders, the underlying mechanisms are to a great extent incompletely understood. This review aimed to summarize the available evidence regarding a deregulation of the cellular stress response in individual muscle diseases. Potential mechanisms, as well as involved pathways are critically discussed, and respective disease models are addressed. Furthermore, relevant therapeutic approaches that aim to abrogate defects of cellular stress response in muscular disorders are outlined.

Effect of Recanalization on Cerebral Edema, Long-Term Outcome, and Quality of Life in Patients with Large Hemispheric Infarctions.

OBJECTIVES: Space-occupying cerebral edema is the main cause of mortality and poor functional outcome in patients with large cerebral artery occlusion (LVO). We aimed to determine whether recanalization of LVO would augment cerebral edema volume and the impact on functional outcome and quality of life (QoL). MATERIALS AND METHODS: Prospectively, 43 patients with large middle cerebral artery territory infarction or NIHSS ≥ 12 on admission were enrolled. The degree of recanalization (partial and complete versus no recanalization) was assessed by computed tomography (CT)-angiography or Duplex ultrasound more than 24 h after symptom onset. Cerebral edema volume was measured on follow up CTs by computer-based planimetry. Mortality, functional outcome (by modified Ranking Scale (mRS) and Barthel Index (BI)) were assessed at discharge and 12 months, and QoL (by SF-36 and EQ-5D-3L) at 12 months. RESULTS: Mean cerebral edema volume was 333±141 ml without recanalization (n=13, group 1) and 276±140 ml with partial or complete recanalization (n=30, group 2, p= 0.23). There were no significant differences in mortality at discharge (38% versus 23%), at 12 months (58% versus 48%), in functional outcome at discharge (mRS 0-3: 0% both; mRS 4-5: 62% versus 77%) and at 12 months (mRS 0-3: 0% versus 11%; mRS 4-5: 42% versus 41%). The BI improved significantly from discharge to 12 months only in group 2 (p=0.001). Mean physical component score in SF-36 was 25.6±6.4, psychological component score was 41.9±14.1. In the EQ-5D-3L, most patients reported problems with activities of daily living, reduced mobility, and selfcare. CONCLUSIONS: Recanalization of a large cerebral artery occlusion in the anterior circulation territories is not associated with amplification of post-ischemic cerebral edema but may be correlated with better long-term functional outcome. QoL was low and mainly dependent on physical disability. The association between recanalization, collateral status and development of cerebral edema after LVO and the effect on functional outcome and quality of life should be explored in a larger patient population.

Muscle Carnitine Palmitoyltransferase II (CPT II) Deficiency: A Conceptual Approach.

Carnitine palmitoyltransferase (CPT) catalyzes the transfer of long- and medium-chain fatty acids from cytoplasm into mitochondria, where oxidation of fatty acids takes place. Deficiency of CPT enzyme is associated with rare diseases of fatty acid metabolism. CPT is present in two subforms: CPT I at the outer mitochondrial membrane and carnitine palmitoyltransferase II (CPT II) inside the mitochondria. Deficiency of CPT II results in the most common inherited disorder of long-chain fatty acid oxidation affecting skeletal muscle. There is a lethal neonatal form, a severe infantile hepato-cardio-muscular form, and a rather mild myopathic form characterized by exercise-induced myalgia, weakness, and myoglobinuria. Total CPT activity (CPT I + CPT II) in muscles of CPT II-deficient patients is generally normal. Nevertheless, in some patients, not detectable to reduced total activities are also reported. CPT II protein is also shown in normal concentration in patients with normal CPT enzymatic activity. However, residual CPT II shows abnormal inhibition sensitivity towards malonyl-CoA, Triton X-100 and fatty acid metabolites in patients. Genetic studies have identified a common p.Ser113Leu mutation in the muscle form along with around 100 different rare mutations. The biochemical consequences of these mutations have been controversial. Hypotheses include lack of enzymatically active protein, partial enzyme deficiency and abnormally regulated enzyme. The recombinant enzyme experiments that we recently conducted have shown that CPT II enzyme is extremely thermoliable and is abnormally inhibited by different emulsifiers and detergents such as malonyl-CoA, palmitoyl-CoA, palmitoylcarnitine, Tween 20 and Triton X-100. Here, we present a conceptual overview on CPT II deficiency based on our own findings and on results from other studies addressing clinical, biochemical, histological, immunohistological and genetic aspects, as well as recent advancements in diagnosis and therapeutic strategies in this disorder.

White matter lesions in treated late onset Pompe disease are not different to matched controls.

INTRODUCTION: Genetic deficiency of α-1,4-glucosidase leads to multi-systemic glycogen storage and causes muscular disorder known as classic infantile Pompe disease (CIOPD) and late onset Pompe disease (LOPD). Treatment with recombinant human alglucosidase alfa is available as enzyme replacement therapy (ERT). Recently progressive white matter lesions (WML) have been observed as a new phenotype in CIOPD patients on treatment with ERT. OBJECTIVE: To investigate the impact of disease and ERT for the development of WML in LOPD. METHODS: WML were analysed in 19 treated LOPD patients and compared with findings of 38 matched controls. RESULTS: Patients median age was 54.4 years (range 19 to 82 years) with median disease duration of 7 years (range 2 to 40 years). Median ERT duration was 63 months (range 9 to 135 months). Grading of WML by Fazekas Score was not different in LOPD patients and controls: Mean of total Fazekas score in LOPD was 2.42 ±â€¯2.40 and in controls 1.60 ±â€¯2.64; p = 0.68. Also volume of WML was similar in patients and controls (mean 5.27 ml ±â€¯5.88 and 7.89 ml ±â€¯11.40 respectively, p = 0.35). Total Fazekas grade correlated directly with the age in LOPD patients (r = 0.60; p = 0.007) and in controls (r = 0.32; p = 0.04). There was a negative correlation of ERT duration and total Fazekas grade (r = -0.41; p = 0.04). CONCLUSION: The study suggests that WML in LOPD mainly result from concomitant cerebrovascular risk factors rather than from the Pompe disease itself.

Myositis in Lewis rats induced by the superantigen Staphylococcal enterotoxin A.

The aetiology of inflammatory myopathies is not clearly known. A predominance of activated Cd8+ T lymphocytes in inflammatory infiltrates has already been detected. Superantigens activate lymphocytes in an oligoclonal manner. In the present investigation, we investigated local effects after injection of the superantigen (Sag) Staphylococcus enterotoxin A (SEA) in the quadriceps femoris muscle of Lewis rats. Histopathology and gene expression profiling was performed after injection of SEA or saline (control group) after one, three and 10 days. Histology revealed focal myositis predominated by Cd8+ T lymphocytes with a perimysial, endomysial and perivascular distribution, peaking 3 days after SEA injection. Using DNA microarray analysis (Affymetrix Rat Genome 230 2.0) genes that were differentially over-expressed at least 15 times at days one, three or ten after SEA injection were further analysed. One day after SEA injection over-expressed genes were related to the immune response (e.g. Fcnb, CD8a) but also to cell proliferation, differentiation and migration (e.g. Mpp2). Three days after SEA injection, differentially overexpressed genes were mainly related to the immune reaction with a clear signature for a Cd8+ T lymphocyte response (e.g. Cd3d, Cd8, Prf1, Gzmb). Ten days after SEA injection, the differentially overexpressed genes were again associated with the immune reaction (e.g. Cd3d, Il2) but also with regenerative processes and wound healing (e.g. Tgfa, Tpm1, Ripply1). The inflammatory response induced by SEA in Lewis rats shares histological and molecular similarities to polymyositis in humans. Therefore, SEA induced myositis can be taken as a new and apt model for polymyositis.

Normal FGF-21-Serum Levels in Patients with Carnitine Palmitoyltransferase II (CPT II) Deficiency.

Fibroblast growth factor 21 (FGF-21) is known to be a biomarker for mitochondrial disorders. An upregulation of FGF-21 in serum and muscle of carnitine palmitoyltransferase I (CPT I) and carnitine palmitoyltransferase II (CPT II) knock-out mice has been reported. In human CPT II deficiency, enzyme activity and protein content are normal, but the enzyme is abnormally regulated by malonyl-CoA and is abnormally thermolabile. Citrate synthase (CS) activity is increased in patients with CPT II deficiency. This may indicate a compensatory response to an impaired function of CPT II. In this study, FGF-21 serum levels in patients with CPT II deficiency during attack free intervals and in healthy controls were measured by enzyme linked immunosorbent assay (ELISA). The data showed no significant difference between FGF-21 concentration in the serum of patients with CPT II deficiency and that in the healthy controls. The results of the present work support the hypothesis that in muscle CPT II deficiency, in contrast to the mouse knockout model, mitochondrial fatty acid utilization is not persistently reduced. Thus, FGF-21 does not seem to be a useful biomarker in the diagnosis of CPT II deficiency.

Lack of activation of the S113L variant of carnitine palmitoyltransfersase II by cardiolipin.

The phospholipid environment of the mitochondrial inner membrane, which contains large amounts of cardiolipin, could play a key role in transport of the long chain fatty acids. In the present study, the pre-incubation of cardiolipin with the wild type carnitine palmitoyltransferase (CPT) II led to a more than 1.5-fold increase of enzyme activity at physiological temperatures. At higher temperatures, however, there was a pronounced loss of activity. The most frequent variant S113L showed even at 37 °C a great activity loss. Pre-incubation of the wild type with both malonyl-CoA and cardiolipin counteracted the positive effect of cardiolipin. Malonyl-CoA, however, showed no inhibition effect on the variant in presence of cardiolipin. The activity loss in presence of cardiolipin at fever simulating situations was more pronounced for the variant comparing to the wild type. The reason might be a disturbed membrane association or a blockage of the active center of the mutated enzyme.

"Thoracic migraine" as a new manifestation of migraine: Case report.

Background and objectives Abdominal pain is a well-known headache-associated symptom in migraine in children, but rarely in adults. We describe a case of a female patient with typical accompanying migraine symptoms without headache but with thoracic pain. Case report The present case of a 41 year-old-woman shows recurrent attacks with thoracic pain and typical accompanying migraine symptoms but without headache. Symptoms resolved upon treatment with triptans and beta blockers. Discussion This case might be interpreted as "thoracic migraine", and extends the spectrum of migraine forms. Conclusion In patients with facial pain secondary to lung cancer, an anatomical connection between the vagal nerve, the nucleus tractus solitarii, the jugular ganglion and trigeminal system has been suggested. The present case might be an analogy to this explanation.

Prevalence of Headache in Patients With Mitochondrial Disease: A Cross-Sectional Study.

BACKGROUND: Mitochondrial diseases are a heterogeneous group of diseases with different phenotypes and genotypes. Headache and, particularly migraine, seems to occur often in patients with MELAS and in patients with CPEO phenotypes. The International Classification of Headache Disorders (ICHD-3 beta) has classified headache as a secondary entity only in MELAS patients. Other headache phenotypes in mitochondrial diseases are not considered in ICHD-3beta. In this study, we analyzed headache phenomenology in a large group of patients with mitochondrial disorders. METHODS: A cross-sectional questionnaire-based study on 85 patients with mitochondrial disease with different genotypes and phenotypes was conducted between 2010 and 2011. A structured headache questionnaire according to ICHD-2 was used followed by a telephone interview by a headache expert. Prevalence and characteristics of headache could be analyzed in 42 patients. Headache diagnosis was correlated with genotypes and phenotypes. In addition, the mtDNA haplotype H was analyzed. RESULTS: Headache was reported in 29/42 (70%; 95% CI, from 55.1 to 83.0%) of the patients. Tension-type headache (TTH) showed the highest prevalence in 16/42 (38%; 95% CI, from 23.4 to 52.8%) patients, followed by migraine and probable migraine in 12/42 (29%; 95% CI, from 14.9 to 42.2%) patients. Nine of the 42 (21%; 95% CI, from 9 to 33.8%) patients reported two different headache types. Patients with the mtDNA mutation m.3243A > G (n = 8) and MELAS (n = 7) showed the highest prevalence of headaches (88% and 85%, respectively). In patients with the CPEO phenotype (n = 32), headache occurred in 14/18 (78%; 95% CI, from 58.6 to 97%) of patients with single deletions, and in 7/13 (54%; 95% CI, from 26.7 to 80.9%) patients with multiple mtDNA deletions. There were no association between the mtDNA haplotype Hand the headache-diagnosis. CONCLUSIONS: The prevalence of headache was higher in patients with mitochondrial diseases than reported in the general population. In all phenotype and genotype groups, TTH was more frequent than migraine. The data also show that the current ICHD-3 beta exclusively focused on MELAS syndrome as vasculopathy does not consider the broader spectrum of headache phenotypes in mitochondrial disorders.

Malony-CoA inhibits the S113L variant of carnitine-palmitoyltransferase II.

Carnitine palmitoyltransferases (CPT), located both in the outer (CPT I) and inner membrane (CPT II) of mitochondria, are the key players for an efficient transport of long chain fatty acids into this cell compartment. The metabolite malonyl-CoA is known to inhibit CPT I, but not CPT II. His6-N-hCPT2 (wild type) and His6-N-hCPT2/ S113L (variant) were produced recombinantly in prokaryotic host, purified and characterized according to their functional and regulatory properties. The wild type and the variant showed the same enzymatic activity and were both inhibited by malonyl-CoA and malonate in a time-dependent manner. The inhibition was, however, significantly more pronounced in the mutated enzyme. The residual activities were 40% and 5% at temperatures of 4 °C and 30 °C, respectively. The inhibitory effect proceeded irreversibly with no recovery after postincubation of palmitoyl-CoA (Pal-CoA) as native substrate. A model of malonyl-CoA and malonate binding to human CPT II was suggested by docking studies to explain the action of the inhibitors regarding to the effect of the mutation on the protein conformation. Results indicated that not only CPT I, but also CPT II can be inhibited by malonyl-CoA. Thus, the complete inhibition of total CPT (i.e. CPT I and CPT II) in muscle homogenates by an established assay is not due to a lack of enzymatically active CPT II, but rather due to an abnormal regulation of the enzyme.

Assessment of physical fatigability and fatigue perception in myasthenia gravis.

INTRODUCTION: Fatigue includes both performance fatigability and fatigue perception. METHODS: In 32 stable patients with generalized myasthenia gravis (MG) and 17 controls, time-dependent physical performance was assessed by the arm movement test (AMT) and 6-minute walk test (6MWT). MG patients presented with low quantitative MG scores (mean 0.5, SD 0.5) and without pathologic decrement. Fatigability was based on calculation of linear trend (LT) reflecting dynamic performance within subsequent constant time intervals. Perception of physical fatigue was analyzed using fatigue questionnaires. RESULTS: MG patients showed a negative LT in both AMT and 6MWT, significantly differing from stable performance in controls. LT inversely correlated with elevation of acetylcholine receptor antibodies (r = -0.59, P < 0.005) but not with quantitative MG score and fatigue perception. CONCLUSIONS: LT allows quantification of fatigability as an objective measurement of decline in individual performance, even in patients without obvious neuromuscular deficits in routine testing. The missing correlation of experienced fatigue supports the multidimensional fatigue model. Muscle Nerve 55: 657-663, 2017.

Cognitive fatigue in patients with myasthenia gravis.

INTRODUCTION: Cognitive fatigue has frequently been reported in myasthenia gravis (MG). However, objective assessment of cognitive fatigability has never been evaluated. METHODS: Thirty-three MG patients with stable generalized disease and 17 healthy controls underwent a test battery including repeated testing of attention and concentration (d2-R) and Paced Auditory Serial Addition Test. Fatigability was based on calculation of linear trend (LT) reflecting dynamic performance within subsequent constant time intervals. Additionally, fatigue questionnaires were used. RESULTS: MG patients showed a negative LT in second d2-R testing, indicating cognitive fatigability. This finding significantly differed from stable cognitive performance in controls (P < 0.05). Results of Paced Auditory Serial Addition Test testing did not differ between groups. Self-assessed fatigue was significantly higher in MG patients compared with controls (P < 0.001), but did not correlate with LT. CONCLUSIONS: LT quantifies cognitive fatigability as an objective measurement of performance decline in MG patients. Self-assessed cognitive fatigue is not correlated with objective findings. Muscle Nerve 56: 449-457, 2017.

Experimental provocation of 'ice-cream headache' by ice cubes and ice water.

Background There are various studies on experimentally provoked 'ice-cream headache' or 'headache attributed to ingestion or inhalation of a cold stimulus' (HICS) using different provocation protocols. The aim of this study was to compare two provocation protocols. Methods Ice cubes pressed to the palate and fast ingestion of ice water were used to provoke HICS and clinical features were compared. Results The ice-water stimulus provoked HICS significantly more often than the ice-cube stimulus (9/77 vs. 39/77). Ice-water-provoked HICS had a significantly shorter latency (median 15 s, range 4-97 s vs. median 68 s, range 27-96 s). There was no difference in pain localisation. Character after ice-cube stimulation was predominantly described as pressing and after ice-water stimulation as stabbing. A second HICS followed in 10/39 (26%) of the headaches provoked by ice water. Lacrimation occurred significantly more often in volunteers with than in those without HICS. Discussion HICS provoked by ice water was more frequent, had a shorter latency, different pain character and higher pain intensity than HICS provoked by ice cubes. The finding of two subsequent HICS attacks in the same volunteers supports the notion that two types of HICS exist. Lacrimation during HICS indicates involvement of the trigeminal-autonomic reflex.

The concept and diagnostic criteria of primary lateral sclerosis.

OBJECTIVES: Primary lateral sclerosis (PLS) is commonly considered as a motor neuron disease (MND) variant which almost exclusively affects upper motor neurons (UMN). There is still no consensus whether PLS should be regarded as an independent disease entity separate from amyotrophic lateral sclerosis (ALS) or as a comparatively slowly progressive variant of ALS. Given these different views, clinical diagnosis of PLS is a challenge. In this multicenter study, we analyzed clinical features of patients diagnosed with PLS in four specialized MND centers. MATERIAL AND METHODS: We retrospectively analyzed clinical, laboratory, imaging, and electrophysiological data of 76 patients with PLS diagnosed in four specialized ALS centers. We analyzed the concept of the disease based on our findings and an extensive review of the literature. RESULTS: We found that 79% of patients showed asymmetrical symptoms, 60% showed clinical or electrophysiological signs of lower motor neuron (LMN) involvement after a mean of 8.4 ± 5.0 years, and extrapyramidal and/or non-motoric symptoms were frequently observed. Interestingly, none of the patients diagnosed with PLS fulfilled the diagnostic criteria proposed by Pringle et al. in 1992. CONCLUSIONS: Our data show that PLS as a disease entity is still not well enough defined and that there are different concepts about its clinical presentation. We believe that further prospective longitudinal studies are needed in order to refine diagnostic criteria to reflect current clinical practice. Furthermore, neuropathological and neuroimaging approaches might help to arrange PLS in the MND spectrum and its classification.