Summary Background Comparable data on the global and country-specific burden of neurological disorders and their trends are crucial for health-care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study provides such information but does not routinely aggregate results that are of interest to clinicians specialising in neurological conditions. In this systematic analysis, we quantified the global disease burden due to neurological disorders in 2015 and its relationship with country development level. Methods We estimated global and country-specific prevalence, mortality, disability-adjusted life-years (DALYs), years of life lost (YLLs), and years lived with disability (YLDs) for various neurological disorders that in the GBD classification have been previously spread across multiple disease groupings. The more inclusive grouping of neurological disorders included stroke, meningitis, encephalitis, tetanus, Alzheimer's disease and other dementias, Parkinson's disease, epilepsy, multiple sclerosis, motor neuron disease, migraine, tension-type headache, medication overuse headache, brain and nervous system cancers, and a residual category of other neurological disorders. We also analysed results based on the Socio-demographic Index (SDI), a compound measure of income per capita, education, and fertility, to identify patterns associated with development and how countries fare against expected outcomes relative to their level of development. Findings Neurological disorders ranked as the leading cause group of DALYs in 2015 (250·7 [95% uncertainty interval (UI) 229·1 to 274·7] million, comprising 10·2% of global DALYs) and the second-leading cause group of deaths (9·4 [9·1 to 9·7] million], comprising 16·8% of global deaths). The most prevalent neurological disorders were tension-type headache (1505·9 [UI 1337·3 to 1681·6 million cases]), migraine (958·8 [872·1 to 1055·6] million), medication overuse headache (58·5 [50·8 to 67·4 million]), and Alzheimer's disease and other dementias (46·0 [40·2 to 52·7 million]). Between 1990 and 2015, the number of deaths from neurological disorders increased by 36·7%, and the number of DALYs by 7·4%. These increases occurred despite decreases in age-standardised rates of death and DALYs of 26·1% and 29·7%, respectively; stroke and communicable neurological disorders were responsible for most of these decreases. Communicable neurological disorders were the largest cause of DALYs in countries with low SDI. Stroke rates were highest at middle levels of SDI and lowest at the highest SDI. Most of the changes in DALY rates of neurological disorders with development were driven by changes in YLLs. Interpretation Neurological disorders are an important cause of disability and death worldwide. Globally, the burden of neurological disorders has increased substantially over the past 25 years because of expanding population numbers and ageing, despite substantial decreases in mortality rates from stroke and communicable neurological disorders. The number of patients who will need care by clinicians with expertise in neurological conditions will continue to grow in coming decades. Policy makers and health-care providers should be aware of these trends to provide adequate services. Funding Bill & Melinda Gates Foundation.

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Global, regional, and national burden of neurological disorders, 1990-2016: A systematic analysis for the Global Burden of Disease Study 2016

Epilepsy is the third most common chronic brain disorder, and is characterized by an enduring predisposition to generate seizures. Despite progress in pharmacological and surgical treatments of epilepsy, relatively little is known about the processes leading to the generation of individual seizures, and about the mechanisms whereby a healthy brain is rendered epileptic. These gaps in our knowledge hamper the development of better preventive treatments and cures for the approximately 30% of epilepsy cases that prove resistant to current therapies. Here, we focus on the rapidly growing body of evidence that supports the involvement of inflammatory mediators-released by brain cells and peripheral immune cells-in both the origin of individual seizures and the epileptogenic process. We first describe aspects of brain inflammation and immunity, before exploring the evidence from clinical and experimental studies for a relationship between inflammation and epilepsy. Subsequently, we discuss how seizures cause inflammation, and whether such inflammation, in turn, influences the occurrence and severity of seizures, and seizure-related neuronal death. Further insight into the complex role of inflammation in the generation and exacerbation of epilepsy should yield new molecular targets for the design of antiepileptic drugs, which might not only inhibit the symptoms of this disorder, but also prevent or abrogate disease pathogenesis.

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The role of inflammation in epilepsy

Background Few longitudinal studies of dementia in Parkinson disease (PD) have been reported, and the proportion of patients with PD who eventually develop dementia is unknown. Objective To examine the 8-year prevalence, characteristics, and risk factors of dementia in patients with PD. Methods Patients were recruited from an epidemiological study of PD in the county of Rogaland, Norway, using explicit criteria for PD. Subjects with cognitive impairment at disease onset were excluded. A semistructured caregiver-based interview, cognitive rating scales, and neuropsychological tests were used to diagnose dementia according to criteria from the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition at baseline and 4 and 8 years later. A population-based sample of 3295 subjects in the municipality of Odense, Denmark, was used as a comparison group and examined at baseline and after 2 and 5 years. Results We included 224 patients with PD (116 women). At baseline, 51 patients (26%) had dementia. Fifty-five patients died, and 10 refused follow-up without their dementia status known. Forty-three and 28 new cases of dementia were identified at the 4- and 8-year evaluations, respectively. The 4-year prevalence of dementia in PD was nearly 3 times higher than in the non-PD group. The 8-year prevalence in PD was 78.2% (95% confidence interval [CI], 71.1-84.0). Risk factors for dementia were hallucinations before baseline (odds ratio [OR] = 3.1; 95% CI, 1.6-6.2) and akinetic-dominant or mixed tremor/akinetic PD (OR = 3.3; 95% CI, 1.2-8.5). Conclusions More than three quarters of this representative PD cohort developed dementia during the 8-year study period. Early hallucinations and akinetic-dominant PD were associated with an increased risk of dementia.

https://jamanetwork.com/journals/jamaneurology/articlepdf/783882/NOC20205.pdf

Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study.

Objective To estimate the current incidence and prevalence in the United States of 12 neurologic disorders. Methods We summarize the strongest evidence available, using data from the United States or from other developed countries when US data were insufficient. Results For some disorders, prevalence is a better descriptor of impact; for others, incidence is preferable. Per 1,000 children, estimated prevalence was 5.8 for autism spectrum disorder and 2.4 for cerebral palsy; for Tourette syndrome, the data were insufficient. In the general population, per 1,000, the 1-year prevalence for migraine was 121, 7.1 for epilepsy, and 0.9 for multiple sclerosis. Among the elderly, the prevalence of Alzheimer disease was 67 and that of Parkinson disease was 9.5. For diseases best described by annual incidence per 100,000, the rate for stroke was 183, 101 for major traumatic brain injury, 4.5 for spinal cord injury, and 1.6 for ALS. Conclusions Using the best available data, our survey of a limited number of disorders shows that the burden of neurologic illness affects many millions of people in the United States.

How common are the “common” neurologic disorders?

Dose-ranging study of riluzole in amyotrophic lateral sclerosis

The objective of this investigation was to clarify the epidemiology of idiopathic Parkinson's disease (PD) in the county of Rogaland, Norway Total case ascertainment and a high diagnostic accuracy were attempted through a detailed community study and the use of a new clinical diagnostic classification The study population comprised 220,858 inhabitants, and a total of nearly 400 patients was interviewed and examined by a neurologist On prevalence day, January 1, 1993, 245 patients were included in the study The diagnostic classification revealed 135 patients with clinically definite, 74 with probable, and 36 with possible PD The crude prevalence rate was shown to be 1109 per 100,000 inhabitants The total age-adjusted prevalence was calculated to be 1024 per 100,000 and to 1209 per 100,000 men and 898 per 100,000 women Among the 245 patients, 28 patients had a tremor-dominant disease, 50 patients an akinetic-dominant disease, and 167 patients a mixed clinical pattern of PD Age-adjusted prevalence figures were slightly higher for rural compared to urban areas About 50% of the PD patients were in need of public help, 15% had complaints about pain related to their parkinsonism, and after approximately 6 years of levodopa treatment, 20% were suffering from clinical fluctuations The study showed that 40% of the patients had some degree of thought disorder The prevalence figures for PD in this study are slightly lower than those reported from most previous prevalence studies with a comparable study design for case finding This may be due to a careful diagnostic evaluation with the use of specified diagnostic criteria, excluding patients with other parkinsonian syndromes

The epidemiology of Parkinson's disease in the county of Rogaland, Norway

Patients with myasthenia gravis (MG) and thymoma have in their sera antibodies which react with non-receptor antigens from striated muscle. The purpose of this investigation was to characterize the antigen(s). Polypeptides in homogenates from rat skeletal muscle were separated by SDS-PAGE and trans-blotted to nitrocellulose. Sera from six patients with MG and thymoma stained a large (molecular weight greater than 500 kD) polypeptide, while no staining was observed with sera from 20 non-thymoma MG patients. Titin is one of the large (greater than 500 kD) polypeptides of striated muscle and the antibody containing MG sera have antibodies that bind to titin in a preparation of myofibrillary proteins from rabbit skeletal muscle. The staining pattern is identical to that obtained with antiserum to titin, showing that the antigen has the same electrophoretic mobility as titin. Antibodies from the sera of the patients with MG and thymoma, affinity-purified on the large polypeptide, reacted with skeletal muscle sections in a cross-striational pattern, near the A/I band junction but within the I band, corresponding to the localization of one of the epitopes of titin. Our findings therefore indicate that the muscle antibodies found in the sera from some MG patients with thymoma are directed against titin.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2249.1990.tb05440.x

Patients with myasthenia gravis and thymoma have in their sera IgG autoantibodies against titin

Approximately 15% of patients with myasthenia gravis (MG) have thymus neoplasia. These MG with thymoma (MGT) patients show autoantibodies to striated muscle as well as autoantibodies to acetylcholine receptor. To characterize these thymoma-associated muscle antigens, we cloned a number of immunopositive cDNAs by immunoscreening muscle cDNA libraries with sera from MGT patients. Analysis of the isolated cDNAs show that all share a common sequence encoding a distinct region of the titin gene. We expressed this main immunogenic region (MIR) of titin in Escherichia coli, and determined autoantibody serum titers directed against the obtained recombinant antigen in a variety of patients. We could detect titin MIR autoantibodies in 97% of sera from MGT patients but not in control sera from healthy blood donors. Therefore, expressed titin from the MIR of the molecule is a sensitive marker antigen for evaluating the presence of thymoma in MG.

Titin antibodies in myasthenia gravis Identification of a major immunogenic region of titin

Myasthenia gravis is an autoimmune disease caused, in most cases, by antibodies attaching to the acetylcholine receptor. Some myasthenia gravis patients have antibodies that bind in a cross-striational pattern to skeletal and heart muscle tissue sections (striational antibodies). These antibodies react with epitopes on the muscle proteins titin and ryanodine receptor, are found mainly in sera of patients with thymoma and late-onset myasthenia gravis, and may correlate with myasthenia gravis severity. Their presence may predict an unsatisfactory outcome after thymectomy. The detection of titin and ryanodine receptor antibodies provides more specific clinical information than the immunofluorescent demonstration of striational antibodies.

https://jamanetwork.com/journals/jamaneurology/articlepdf/788016/noc40129.pdf

Striational antibodies in myasthenia gravis: reactivity and possible clinical significance.

Sera from 23 patients with acute Guillain Barre syndrome (GBS), 15 patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and from 40 age-matched blood donors were analysed for antibodies to acidic glycosphingolipids from human brain and peripheral nerve. Antibodies to ganglioside LM1, the major ganglioside of peripheral nerve myelin. were found in 43% of GBS and in 67% of CIDP patients' sera, and in 20% of the blood donors. However, antisulphatide antibodies were detected in 65% and 87% of the sera from GBS and CIDP patients, respectively, but only in 15% of the control sera. Sulphatide is the major acidic glycosphingolipid in myelin and its concentration in peripheral nerve myelin is 100 times higher than that of LM1. The high frequency of LM1 and, in particular of sulphatide antibodies, might thus be relevant to the pathogenesis of the GBS and CIDP.

Antibodies in sera from patients with inflammatory demyelinating polyradiculoneuropathy react with ganglioside LM1 and sulphatide of peripheral nerve myelin.

Johan A. Aarli

Papers

The epidemiology of Parkinson's disease in the county of Rogaland, Norway

Patients with myasthenia gravis and thymoma have in their sera IgG autoantibodies against titin

Titin antibodies in myasthenia gravis Identification of a major immunogenic region of titin

Striational antibodies in myasthenia gravis: reactivity and possible clinical significance.

Antibodies in sera from patients with inflammatory demyelinating polyradiculoneuropathy react with ganglioside LM1 and sulphatide of peripheral nerve myelin.