Summary Cryptogenic (of unknown cause) ischaemic strokes are now thought to comprise about 25% of all ischaemic strokes. Advances in imaging techniques and improved understanding of stroke pathophysiology have prompted a reassessment of cryptogenic stroke. There is persuasive evidence that most cryptogenic strokes are thromboembolic. The thrombus is thought to originate from any of several well established potential embolic sources, including minor-risk or covert cardiac sources, veins via paradoxical embolism, and non-occlusive atherosclerotic plaques in the aortic arch, cervical, or cerebral arteries. Accordingly, we propose that embolic strokes of undetermined source are a therapeutically relevant entity, which are defined as a non-lacunar brain infarct without proximal arterial stenosis or cardioembolic sources, with a clear indication for anticoagulation. Because emboli consist mainly of thrombus, anticoagulants are likely to reduce recurrent brain ischaemia more effectively than are antiplatelet drugs. Randomised trials testing direct-acting oral anticoagulants for secondary prevention of embolic strokes of undetermined source are warranted.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(13)70310-7.pdf

Embolic strokes of undetermined source: the case for a new clinical construct

The aim of the present thesis was to investigate the pathophysiology of chronic tension-type headache with special reference to central mechanisms. Increased tenderness to palpation of pericranial myofascial tissues is the most apparent abnormality in patients with tension-type headache. A new piece of equipment, a so-called palpometer, that makes it possible to control the pressure intensity exerted during palpation, was developed. Thereafter, it was demonstrated that the measurement of tenderness could be compared between two observers if the palpation pressure was controlled, and that the Total Tenderness Scoring system was well suited for the scoring of tenderness during manual palpation. Subsequently, it was found that pressure pain detection and tolerance thresholds were significantly decreased in the finger and tended to be decreased in the temporal region in chronic tension-type headache patients compared with controls. In addition, the electrical pain threshold in the cephalic region was significantly decreased in patients. It was concluded that the central pain sensitivity was increased in the patients probably due to sensitization of supraspinal neurones. The stimulus-response function for palpation pressure vs. pain was found to be qualitatively altered in chronic tension-type headache patients compared with controls. The abnormality was related to the degree of tenderness and not to the diagnosis of tension-type headache. In support of this, the stimulus-response function was found to be qualitatively altered also in patients with fibromyalgia. It was concluded that the qualitatively altered nociception was probably due to central sensitization at the level of the spinal dorsal horn/trigeminal nucleus. Thereafter, the prophylactic effect of amitriptyline, a non-selective serotonin (5-HT) reuptake inhibitor, and of citalopram, a highly selective 5-HT reuptake inhibitor, was examined in patients with chronic tension-type headache. Amitriptyline reduced headache significantly more than placebo, while citalopram had only a slight and insignificant effect. It was concluded that the blockade of 5-HT reuptake could only partly explain the efficacy of amitriptyline in tension-type headache, and that also other actions of amitriptyline, e.g. reduction of central sensitization, were involved. Finally, the plasma 5-HT level, the platelet 5-HT level and the number of platelet 5-HT transporters were found to be normal in chronic tension-type headache. On the basis of the present and previous studies, a pathophysiological model for tension-type headache is presented. According to the model, the main problem in chronic tension-type headache is central sensitization at the level of the spinal dorsal horn/trigeminal nucleus due to prolonged nociceptive inputs from pericranial myofascial tissues. The increased nociceptive input to supraspinal structures may in turn result in supraspinal sensitization. The central neuroplastic changes may affect the regulation of peripheral mechanisms and thereby lead to, for example, increased pericranial muscle activity or release of neurotransmitters in the myofascial tissues. By such mechanisms the central sensitization may be maintained even after the initial eliciting factors have been normalized, resulting in the conversion of episodic into chronic tension-type headache. Future basic and clinical research should aim at identifying the source of peripheral nociception in order to prevent the development of central sensitization and at ways of reducing established sensitization. This may lead to a much needed improvement in the treatment of chronic tension-type headache and other chronic myofascial pain conditions.

Central sensitization in tension-type headache—possible pathophysiological mechanisms

Changes in acetylcholinesterase and butyrylcholinesterase in Alzheimer's disease resemble embryonic development--a study of molecular forms.

Background In 1991, the first world survey of neuromuscular disorders (NMDs) was published in the peer reviewed literature. Since then, diagnostics have been greatly improved through genetic confirmation and consensus on criteria. This prompted us to search the scientific literature since 1990 for the epidemiology of NMDs. Objectives To study occurrence rates, gender and age distribution. Methods Pubmed was searched for 'epidemiology', 'incidence' and 'prevalence' regarding thirty NMDs for peer reviewed literature from 1990-2014. Results We found incidence rates for ten disorders, ranging from 0.05 to 9 per 100,000/yr. Most NMDs showed prevalence rates between 1 and 10 per 100,000 population, except for multifocal motor neuropathy, Lambert-Eaton myasthenic syndrome, Emery-Dreifuss dystrophy, oculopharyngeal muscular dystrophy, and congenital muscular dystrophies, which were l1/100,000. Post-polio syndrome and Charcot-Marie-Tooth disease revealed prevalences g10/100,000. Information regarding incidence, prevalence, age distribution and gender was complete for eight disorders. No data were found for chronic inflammatory demyelinating polyneuropathy, neuralgic amyotrophy, progressive spinal muscular atrophy, McArdle's and Pompe's disease. For the 17 remaining disorders, information was partially available. Conclusions Compared to 1991, prevalence rates of Becker muscular dystrophy, facioscapulohumeral dystrophy, myotonic dystrophy and Charcot-Marie-Tooth disease showed increase, yet with highly overlapping ranges with the exception of myotonic dystrophy. The sum of the available prevalence rates comprises only the tip of the iceberg, but is already in range with the prevalence of Parkinson's disease. Although individual NMDs are rare, as a group they are not.

/pdf/the-epidemiology-of-neuromuscular-disorders-a-comprehensive-2fmaypnniq.pdf

The Epidemiology of Neuromuscular Disorders: A Comprehensive Overview of the Literature.

Background: Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy. CMT is classified into 2 main subgroups: CMT type 1 (CMT1; demyelinating fo

/pdf/epidemiologic-study-of-charcot-marie-tooth-disease-a-3ytpxlq2xr.pdf

Epidemiologic Study of Charcot-Marie-Tooth Disease: A Systematic Review

We identify the prevalence and genetic features of Charcot-Marie-Tooth disease (CMT) in Yonago and Sakaiminato, western Japan. From information in registered records and questionnaires, definite or candidate CMT patients were examined. Eleven families with 19 patients (7 female and 12 male) were identified and the prevalence was 10.8 per 100,000 in April 2000. Eleven patients in 6 families showed a Thr124Met mutation of the MPZ gene, in 2 families duplication of the PMP22 gene was suggested and no abnormalities were found in 2 families. To identify the occurrence of mildly affected CMT, the exhaustive region-matched and family study was necessary.

An epidemiological genetic study of Charcot-Marie-Tooth disease in Western Japan.

Seventy-eight patients with tension-type headache (TH) were treated with tizanidine hydrochloride (tizanidine). Plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) and serum free fatty acids (FFA) levels in these patients were determined before the treatment with tizanidine. Eighteen healthy volunteers composed the control group. Four weeks after the treatment with tizanidine 24 (31%) of 78 patients showed excellent improvement (excellent group); 28 (35%) showed moderate improvement (moderate group); 18 (23%) showed mild improvement (mild group); 7 (10%) showed no improvement and one (1%) showed worsening of her headache (no change and worsened group). The plasma MHPG levels in the excellent group were significantly higher than in the other groups, including the control group. The serum FFA levels in the excellent group were significantly higher than in the controls. In this study, 66% of the patients reported improvement in their headaches. Some patients with TH had high plasma MHPG levels and these patients in particular showed excellent improvement after the administration of tizanidine. Though there may be a placebo response to some extent, the clinical usefulness of tizanidine for TH seems to be excellent. Further study is necessary concerning the pharmacological effect of tizanidine and plasma MHPG levels in patients with TH.

Treatment of tension-type headache with tizanidine hydrochloride: its efficacy and relationship to the plasma MHPG concentration.

To evaluate the change of the neurotransmitter function in migraine, a neuroendocrinological study was performed in eleven female migraineurs and nine female controls. Thyrotropin releasing hormone, luteinizing hormone releasing hormone, and insulin were simultaneously loaded (the Triple test). Before and after loading, serum glucose, prolactin (PRL), thyroid stimulating hormone (TSH), luteinizing hormone, follicle stimulating hormone, adrenocorticotropic hormone, cortisol, human growth hormone and beta-endorphin were measured. The Triple test produced an increase of PRL in both migraine and control groups, but in migraineurs the increase was significantly larger than in controls. TSH also increased in response to the test, but the TSH response in patients was less than in controls, although not significantly so. The responses of other substances showed no significant differences between the two groups. Although dopaminergic hypofunction in migraine has been proposed by some authors, the present findings rather suggest a serotonergic hyperfunction.

A neuroendocrinological study in female migraineurs: prolactin and thyroid stimulating hormone responses.

Aim: We assessed the long-term prognosis of patients with large subcortical infarctions (LSCI). Methods: We defined LSCI as lesions ≥15 mm confined to deep penetrating arteries without a cardioembolic or atherothrombotic source. Patients with acute ischemic strokes were consecutively registered and followed for 751 ± 441 days. The clinical characteristics and long-term prognoses of patients with LSCI were compared to those of patients with lacunar (LACI), atherothrombotic (ATI) and cardioembolic infarctions (CEI). Results: At discharge from the hospital, the proportion of good outcomes (modified Rankin Scale ≤2) for patients with LSCI (52.1%) was similar to that for ATIs (47.2%), but worse than that for LACIs (73.2%). After a 3-year follow-up period, the mortality rates from LSCI, LACIs, ATIs and CEIs were 8.4, 8.2, 22.3 and 41.1%, respectively; the recurrence rates were 9.3, 14.1, 16.6 and 23.8%, respectively. Conclusions: The short-term prognosis of functional outcomes for LSCI was worse than that for LACIs, but similar to acute-phase ATI outcomes. The long-term prognosis after a LSCI is good, and recurrence tends to be lower than for LACIs.

Long-term prognosis of patients with large subcortical infarctions.

Through an epidemiological survey, we observed 3 types of clinical courses among patients with senile dementia of the Alzheimer type (SDAT). The mental ability of the patients declined rapidly (Group A; n = 11), gradually (Group B; n = 6), or showed extremely slow changes (Group C; n = 9). The acetylcholinesterase (AChE) activity and somatostatin (SRIF) concentration of the cerebrospinal fluid (CSF) were measured in patients with Alzheimer's disease (AD) and 3 types of SDAT. Both AChE activity and SRIF concentration of CSF were significantly lower in Group A and among patients with AD compared with age-matched control subjects. Both AChE activity and SRIF concentration of CSF were not significantly different in Groups B and C. This biochemical study confirmed our epidemiological finding that only the patients in Group A with SDAT closely resembled the clinical course of AD and may belong to the category of neurodegenerative disorders.

Characterization of the course of senile dementia of the Alzheimer type using cerebrospinal fluid levels of acetylcholinesterase and somatostatin.

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