Thebasic abnormality inMG is a reduction in the acetylcholine receptors (AChRs) at neuromuscular junctions due to the effects of autoantibodies. About 85% of patients with generalizedMGhave antibodies to AChRs, but only approximately 50% of patientswith purely ocularmanifestations (ocularMG) have detectable antibodies.1 Antibodies to another protein at the neuromuscular junction (muscle-specific kinase, or MuSK) are present in approximately 40% of AChR antibody-negative patients with generalized MG.2 Antibodies to another protein, LRP-4 (low-density lipoprotein receptor-4) are present in a small minority of AChR antibody-negative MG patients, and antibodies to agrin are even rarer.3 These antibodies are key to making the diagnosis of MG in most patients. Clinically, MG is manifested by fatigable weakness—weakness that increases withmuscle use and tends to improvewith rest. The particular muscles that are affected vary in different patients. Commonly, extraocular muscles are affected early, giving rise to diplopia andptosis. If weakness remains confined to the extraocular muscles for a period of 3 years, it rarely becomes generalized. However, more often the weakness becomes more generalized and any muscle group can be involved, with weakness of proximal limbmuscles, dysphagia, respiratory insufficiency, and so on. In questioning a patient with suspected or known MG, I ask about diplopia, ptosis, weakness of arms (fixing hair, dressing, lifting half-gallon
Multiple sclerosis (MS) is characterized by chronic inflammation of the central nervous system, and magnetic resonance imaging (MRI) is used as both a diagnostic tool and a parameter in the clinical evaluation. Multiple sclerosis was long regarded as a disease of the white matter (WM) in the brain, which can be visualized by the standard MRI used in daily practice. There is an increasing amount of evidence that grey matter (GM) pathology plays a role from the start of the MS disease and throughout the clinical course. Grey matter atrophy, both cortical and central, is present in the early course of MS and is also related above all to cognitive decline, but also to the development of physical disability as measured by EDSS. In this article, we give an overview of GM atrophy in MS evaluated by MRI and the relation to the clinical course in MS.
Neurogenetics has developed enormously in recent years, and the genetic basis of human disorders is being unravelled rapidly. Many neurological disorders are Mendelian disorders, caused by mutations in genes involved in normal function of the brain, spinal cord, peripheral nerves or muscles. Due to high costs and time-consuming procedures, genetic tests have normally been performed late in the diagnostic process, when clinical examination and other tests have indicated a specific gene as the likely disease cause. Many neurological phenotypes are genetically very heterogeneous, and testing of all possible disease genes has been impossible. As a result, many patients with genetic neurological disorders have remained without a specific diagnosis, even when the disease is caused by mutations in known disease genes. Recent technological advances, in particular next-generation DNA sequencing techniques, have resulted in rapid identification of genes involved in Mendelian disorders and provided new possibilities for diagnostic genetic testing. The development of methods for coupling targeted capture and massively parallel DNA sequencing has made it possible to examine a large number of genes in a single reaction. Diagnostic genetic testing can today be performed by the use of gene panels and exome sequencing. This allows a more precise diagnosis of many neurological disorders, and genetic testing should now be considered earlier in the diagnostic procedure.
OBJECTIVES:The present paper summarizes and compares data from our studies on subjective and objective sleep quality and pain thresholds in tension-type headache (TTH), migraine, and controls.MATERIAL AND METHODS:In a blinded controlled explorative study, we recorded polysomnography (PSG) and pressure, heat, and cold pain thresholds in 34 controls, 20 TTH, and 53 migraine patients. Sleep quality was assessed by questionnaires, sleep diaries, and PSG. Migraineurs who had their recordings more than 2 days from an attack were classified as interictal while the rest were classified as either preictal or postictal. Interictal migraineurs (n=33) were also divided into two groups if their headache onsets mainly were during sleep and awakening (sleep migraine, SM), or during daytime and no regular onset pattern (non-sleep migraine, NSM). TTH patients were divided into a chronic or episodic group according to headache days per month.RESULTS:Compared to controls, all headache groups reported more anxiety and sleep-related symptoms. TTH and NSM patients reported more daytime tiredness and tended to have lower pain thresholds. Despite normal sleep times in diary, TTH and NSM had increased slow-wave sleep as seen after sleep deprivation. Migraineurs in the preictal phase had shorter latency to sleep onset than controls. Except for a slight but significantly increased awakening index SM, patients differed little from controls in objective measurements.CONCLUSIONS:We hypothesize that TTH and NSM patients on the average need more sleep than healthy controls. SM patients seem more susceptible to sleep disturbances. Inadequate rest might be an attack-precipitating- and hyperalgesia-inducing factor.
BACKGROUND:The Global Burden of Disease study (GBD) is a large international initiative to collect and systematize data on disease burden expressed in non-economic terms, to allow comparisons across different disease conditions and countries.OBJECTIVES:To use data from the large GBD 2010 database to determine the importance of neurological disorders in Norway, and to compare it with global data on the same disorders.MATERIALS AND METHODS:Relevant data were extracted from the Lancet publication from December 2012, and from the interactive website of the Institute of Health Metrics and Evaluation on GBD.RESULTS:Neurological disorders (Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy, migraine and tension-type headache, other neurological disorders) account for 5-6% of the disease burden in Norway, which is more than it does globally. When also stroke, low back pain and neck pain are included, 10% of the disease burden in Norway is represented by neurological disorders.CONCLUSIONS:Neurological disorders are of great public health importance. This knowledge is useful in dimensioning and organizing healthcare systems and necessary when planning education of health personnel on all levels.
OBJECTIVES:There is increasing knowledge about an association between migraine and ischaemic stroke. Cortical spreading depression (CSD) is the probable biological substrate of migrainous aura. To investigate the influence of CSD on the apparent stroke - migraine association, we hypothesized that magnetic resonance (MR) diffusion weighted images of acute ischaemic stroke patients would reveal an association between small cortical infarctions and migraine.METHODS:We included all patients admitted to the Bergen stroke unit between 2006 and 2012 with verified acute ischaemic stroke by MR imaging. Patients were grouped in a migraine and a no-migraine group. Baseline data and clinical characteristics were analysed between the groups. Imaging data were analysed with respect to infarct location and size. Multivariate analyses were performed to adjust for confounders and provide risk estimates for observed associations.RESULTS:A total of 1703 subjects were enrolled, 787 subjects were excluded due to uncertain or unobtainable migraine diagnosis, leaving 196 and 720 subjects in the migraine and no-migraine group, respectively. The migraine group was younger and included a higher proportion of females. There were more infarctions due to cardio-embolism (P=0.015) and fewer due to small vessel disease (P=0.018) in the migraine group. A higher rate of patients in the migraine group presented symptoms from the posterior circulation (P=0.008). Migraine was associated with cortical infarctions (OR 1.8 CI: 1.3-2.5, P=0.001). Migraine was also associated with small infarctions (OR 1.9 CI: 1.04-3.5, P=0.038).CONCLUSIONS:Migraine was associated with small cortical infarctions. This association may be due to cortical spreading depression.
Objectives Sepiapterin reductase deficiency is a rare, but treatable inherited disorder of tetrahydrobiopterin and neurotransmitter metabolism. This disorder is most probably underdiagnosed. To date, only 44 cases have been described in the literature. We present the clinical and genetic investigations in a family with a complex movement disorder. Materials and methods We examined two affected sisters and three healthy family members. The cerebrospinal fluid was analyzed for neurotransmitter and pterins, and the sepiapterin reductase gene (SPR) was sequenced. Results The sisters had a complex movement disorders with dystonia and diurnal fluctuations. Both had oculogyric crises, and the older sister also hypersomnia. Both sisters had raised prolactin levels twice above the reference level. One sister had a dramatic response to levodopa, the other responded, but developed dyskinesia despite low doses. Both patients improved dramatically over time with levodopa (2.3 and 1.5 mg/kg/day). Very low levels of homovanillic acid and 5-hydroxyindoleacetic acid and increased levels of sepiapterin and dihydrobiopterin were measured in the cerebrospinal fluid before treatment. DNA analyses revealed a novel homozygous mutation in exon 2 in the SPR gene, c.364A >G/p.(Tyr123Cys), located in a highly conserved region in the gene. Both parents and the healthy sister were carriers for the same mutation. Conclusions A new homozygous mutation in the SPR gene was found in two sisters with dopa-responsive dystonia. This important and treatable neurotransmitter disorder must be considered in patients with a complex movement disorder with diurnal fluctuations with or without intellectual impairment. Patients with these symptoms should undergo levodopa trial, cerebrospinal fluid investigations, and genetic analyses.
Dystonia is a heterogeneous movement disorder and has been defined as 'a syndrome of sustained muscle contractions, frequently causing twisted and repetitive movements, or abnormal postures'. The classification of dystonia has developed along with increasing knowledge, and different schemes have been suggested, including age at onset, body distribution, and etiology as the main differentiating factors. A revised definition and a new classification of dystonia have now been proposed by a group of leading dystonia experts and will be referred here. The discovery of the first two gene mutations causing primary generalized dystonia (DYT1-TOR1A and DYT6-THAP1) has facilitated studies on pathogenesis and pathophysiology of primary dystonias, by comparing neurophysiology between manifesting and non-manifesting carriers, and by studying the molecular biology of the mutant gene products. During recent years, several other gene mutations causing primary dystonia, dystonia-plus, and paroxysmal dystonia disorders have been discovered. Only during the last year, by the use of whole-exome sequencing techniques, mutations in three different genes in families with predominantly cervical dystonia were found, which may lead to improved insight into the pathogenesis also of the more frequent focal dystonias. Botulinum neurotoxin (BoNT) and deep brain stimulation (DBS) have revolutionized the symptomatic treatment for dystonia during the last two decades and continue to be refined to improve efficacy and expand their indications. Unfortunately, no progress has been made in the oral medication of dystonia. Current and future new insights into pathogenetic and pathophysiological mechanisms of dystonia will hopefully lead to improvement also in this area soon.
OBJECTIVES:There is a wide variation in reported prevalence and incidence of myasthenia gravis (MG). In this study, we aimed to evaluate the validity of two nationwide databases by comparing prevalence and incidence rates reported from three recent studies using the two databases as case-finding method.MATERIALS AND METHODS:Two different Norwegian nationwide databases were used: the acetylcholine receptor antibody database (reference cohort) and the Norwegian Prescription Database (NorPD) (study cohort). Presence of acetylcholine receptor antibodies (AChR) is specific for MG. Up to 85% of MG patients are AChR antibody-positive. All samples from the whole country were tested at one laboratory. NorPD contains patient information on all prescriptions of pyridostigmine.RESULTS:Prevalence was 131 per million in the study cohort and 145 per million estimated from the reference cohort (Jan 1, 2008). No significant difference in prevalence between the study cohort and the reference cohort was found (SIR 1.1, 95% CI 1.0-1.2). The annual incidence rate was 16.0 per million in the study cohort and 8.8 per million estimated from the reference cohort, twofold more new MG patients were found in the study cohort compared to estimated figures from the reference cohort (SIR 1.8; 1.4-2.3).CONCLUSIONS:This study confirms an optimal and unbiased case finding in both databases. Our calculated prevalence and incidence rates are in line with previous population-based studies. There was good agreement in prevalence reported from the two databases. The discrepancy in incidence is expected to diminish as years of study are increasing in NorPD.
OBJECTIVES:The aim of this study was to compare the short-term clinical outcome of patients with acute cerebral ischemia and mild symptoms receiving rt-PA with that of patients with acute cerebral ischemia and mild symptoms not treated with rt-PA, and to investigate the frequency of symptomatic intracranial hemorrhage (sICH) in these patients.MATERIALS AND METHODS:All patients with confirmed ischemic stroke/TIA and mild symptoms were included. Mild symptoms were defined as NIHSS score≤5 on admission. Functional outcome was assessed with modified Rankin Scale (mRS) at day 7 or at earlier discharge. Excellent outcome was defined as mRS=0. sICH was defined according to both NINDS and ECASS III criteria.RESULTS:Of 2753 patients with confirmed ischemic stroke/TIA admitted between February 2006 and February 2013, 966 (35.3%) were excluded because of having admission NIHSS>5. A total of 1791 patients presented with mild symptoms on admission (NIHSS≤5), of which 158 (8.8%) patients received rt-PA. Treatment with rt-PA and early admission were independently associated with excellent outcome. Higher NIHSS score on admission and prior ischemic stroke were independently associated with poor outcome. Three (1.9%) sICH were diagnosed in rt-PA-treated patients and one (0.1%) in patients not receiving rt-PA.CONCLUSIONS:This study highlights the efficacy of rt-PA in patients with acute cerebral ischemia presenting with mild symptoms and confirms the low-risk profile of this treatment.
Perampanel [2‐(2‐oxo‐1‐phenyl‐5‐pyridin‐2‐yl‐1,2‐dihydropyridin‐3‐yl)benzonitrile; E2007] is a potent, selective, orally active non‐competitive AMPA receptor antagonist developed for the treatment of epilepsy. Perampanel has a 2,3′‐bipyridin‐6′‐one core structure, distinguishing it chemically from other AMPA receptor antagonist classes. Studies in various physiological systems indicate that perampanel selectively inhibits AMPA receptor‐mediated synaptic excitation without affecting NMDA receptor responses. Blocking of AMPA receptors occurs at an allosteric site that is distinct from the glutamate recognition site. Radioligand‐binding studies suggest that the blocking site coincides with that of the non‐competitive antagonist GYKI 52466, believed to be on linker peptide segments of AMPA receptor subunits that transduce agonist binding into channel opening. As is typical for AMPA receptor antagonists, perampanel exhibits broad‐spectrum antiseizure activity in diverse animal seizure models. Perampanel has high oral bioavailability, dose‐proportional kinetics, and undergoes oxidative metabolism, primarily via CYP3A4, followed by glucuronidation. The terminal half‐life (t½) in humans is 105 h; however, in the presence of a strong CYP3A4 inducer (such as carbamazepine), the t½ can be reduced. In sum, perampanel is a selective, centrally acting, negative allosteric modulator of AMPA receptors with good oral bioavailability and favorable pharmacokinetic properties.
Epileptic seizures occur as a result of episodic abnormal synchronous discharges in cerebral neuronal networks. Although a variety of non-conventional mechanisms may play a role in epileptic synchronization, cascading excitation within networks of synaptically connected excitatory glutamatergic neurons is a classical mechanism. As is the case throughout the central nervous system, fast synaptic excitation within and between brain regions relevant to epilepsy is mediated predominantly by AMPA receptors. By inhibiting glutamate-mediated excitation, AMPA receptor antagonists markedly reduce or abolish epileptiform activity in in vitro preparations and confer seizure protection in a broad range of animal seizure models. NMDA receptors may also contribute to epileptiform activity, but NMDA receptor blockade is not sufficient to eliminate epileptiform discharges. AMPA receptors move into and out of the synapse in a dynamic fashion in forms of synaptic plasticity, underlying learning and memory. Often, the trigger for these dynamic movements is the activation of NMDA receptors. While NMDA receptor antagonists inhibit these forms of synaptic plasticity, AMPA receptor antagonists do not impair synaptic plasticity and do not inhibit memory formation or retrieval. The demonstrated clinical efficacy of perampanel, a high-potency, orally active non-competitive AMPA receptor antagonist, supports the concept that AMPA receptors are critical to epileptic synchronization and the generation and spread of epileptic discharges in human epilepsy.
The Phase II and Phase III clinical development program of perampanel is providing a wealth of data on the safety and tolerability of this alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist as an adjuvant treatment for refractory partial-onset seizures. In Phase II dose-finding studies, perampanel was associated with an acceptable tolerability profile up to the maximum evaluated dose of 12 mg/day. Subsequent multinational, multicenter, randomized, double-blind, placebo-controlled Phase III registration studies further supported the tolerability of perampanel across the dose range 2-12 mg/day, with interim data from ongoing extension studies indicating that safety outcomes may be maintained over several years. An analysis of the pooled Phase III data indicated that the frequency of adverse events reported with perampanel generally increased in a dose-dependent manner, and the most common adverse events were dizziness and somnolence. Overall, perampanel has been associated with an acceptable and consistent safety profile that is maintained over long-term settings.
OBJECTIVES:The aim of the study was to investigate immunoglobulin levels in patients with epilepsy using the antiepileptic drugs (AED) levetiracetam (LEV), carbamazepine (CBZ), or lamotrigine (LTG).METHODS:A total of 211 patients and 80 controls (age: 18-45 years) of both genders were included. The patients had been treated with either LEV (n = 47), CBZ (n = 90), or LTG (n = 74) monotherapy for at least 6 months. Total concentrations of immunoglobulin G (IgG), IgG subclasses (IgG1, IgG2, IgG3, and IgG4), immunoglobulin A (IgA), and immunoglobulin M (IgM) were measured. Smoking, drinking habits, and physical activity were recorded, and body mass index (BMI) was calculated.RESULTS:A significantly lower total IgG and IgG1 was found in both men and women treated with LTG and in men on CBZ. IgG2 and IgG4 were also lower in LTG-treated women, and IgA and IgM were lower in LTG-treated men. Patients treated with LEV did not differ from the control group.CONCLUSIONS:Low levels of immunoglobulins were found in patients with epilepsy treated with LTG or CBZ. As our group of patients consisted of otherwise healthy young adults, one should be especially aware of a possible effect of AEDs on immunoglobulin levels when treating selected patient groups, for example immunocompromised patients. Immunoglobulin concentrations should be measured in patients treated with LTG or CBZ who experience recurrent infections, and a change in medication should be considered.
Approximately 30% of all stroke patients suffer from post-stroke visual impairment. Hemianopia is the most common symptom, but also neglect, diplopia, reduced visual acuity, ptosis, anisocoria, and nystagmus are frequent. Partial or complete recovery of visual disorders can occur, but many patients suffer permanent disability. This disability is often less evident than impairment of motor and speech functions, but is negatively correlated with rehabilitation outcome and can lead to a significant reduction in day-to-day functioning. To be visually impaired after stroke reduces quality of life and causes social isolation because of difficulties in navigating/orientating in the surroundings. A thorough diagnosis including targeted examination and later follow-up with eye examination and perimetry is essential in order to establish the extent of the visual impairment and to select the best rehabilitation strategy. Patients seem to profit from visual rehabilitation focused on coping strategies.
Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors play a key role in mediating glutamatergic transmission in the cortex. Perampanel (2-[2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl] benzonitrile) is a potent, orally active, highly selective, non-competitive AMPA-type glutamate receptor antagonist, identified via a focused discovery program at Eisai Research Laboratories. Development of perampanel as adjunctive therapy for the treatment of partial-onset seizures was planned in keeping with regulatory guidance and guidelines on antiepileptic drug (AED) development. This is the first AED with a specific action on glutamate-mediated excitatory neurotransmission to show evidence of efficacy and tolerability in reducing treatment-refractory partial-onset seizures in Phase III clinical trials. Perampanel (Fycompa(®)) has been approved in the EU and the United States for adjunctive treatment of partial-onset seizures.
The efficacy of adjunctive perampanel has been investigated in an extensive clinical development program across a broad, multinational population of patients with refractory partial-onset seizures. Further to the results of two Phase II dose-finding studies, perampanel was evaluated in three large Phase III registration studies at the predicted no-effect dose of 2 mg/day and the predicted effective doses of 4, 8, and 12 mg/day. In all three studies, perampanel 4, 8, and 12 mg/day consistently provided significant reductions in the frequency of partial-onset seizures compared with placebo. Improvements in responder rates and seizure freedom rates were also observed. In addition, data from recent interim analyses of extension studies have indicated that these efficacy outcomes may be maintained with long-term treatment. Overall, these studies form a solid evidence base to support the efficacy of adjunctive perampanel in the treatment of refractory partial-onset seizures.
To evaluate the efficacy of adjunctive, once-daily perampanel against secondarily generalized (SG) seizures in three Phase III trials (studies 304, 305, and 306) and their extension (study 307). The Phase III studies enrolled patients (≥ 12 years) with uncontrolled partial-onset seizures despite treatment with 1-3 concomitant antiepileptic drugs. Patients completing the core Phase III studies were eligible for the extension study. Endpoints included median percent change in SG seizure frequency, 50% responder (proportion of patients achieving a ≥ 50% reduction in SG seizure frequency), 75% response, and seizure-freedom rates. In total, 1480 patients were randomized and treated in the three perampanel Phase III trials. At baseline, 71.9% of placebo-treated and 68.4% of perampanel-treated patients had a history of SG seizures. In the individual core Phase III studies, perampanel (4-12 mg) reduced seizure frequency and improved responder rates. Consistent with this, in pooled analyses of the Phase III data, the median percent change in SG seizure frequency was -48.6%, -62.9%, and -53.3% with perampanel 4, 8, and 12 mg, respectively, vs -19.4% with placebo; 50% responder rates were 49.3%, 60.5%, and 53.7% vs 37.0% with placebo. More perampanel-treated patients had ≥ 75% reductions in SG seizure frequency, and seizure-freedom rates improved, compared with placebo. Improvements in seizure frequency and responder rate were maintained during the extension study. Perampanel consistently demonstrated efficacy against SG seizures when assessed using various endpoints. Furthermore, reductions in seizure frequency and improvements in responder rate were sustained with long-term perampanel treatment.
