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Neuroepidemiology
Neurological disorders as a group are the leading cause of disability worldwide, and their contribution to the overall burden from all health conditions is increasing ( ). Aging of the population, population growth, and the ongoing epidemiological transition are occurring in many countries and regions, and surveillance of the burden of neurological disorders is required to optimize healthcare planning and resource allocation. Epidemiology is the scientific discipline that provides the tools to assess and quantitate the burden of disease.
A useful definition of epidemiology is “the science of the natural history of diseases.” This concept is based on the Greek roots of the word: logos , from legein , “to study”; epi “[what is] on”; demos , “the people.” In epidemiology, the unit of study is a person affected with a disorder of interest. Therefore a definitive diagnosis is the essential prerequisite. This is why the neurologist must be part of any inquiry into the epidemiology of neurological diseases.
After diagnosis, the most important question is the frequency of a disorder. Much of this type of information has been based on case series—that is, the series of cases encountered by individual practitioners, clinics, or hospitals. With such data, however, whether taken as numerator alone (case series) or compared with all admissions (relative frequency), it is difficult to ensure that what has been included is representative of the total population. Accordingly, case material must be referenced to its proper denominator, its true source: the population at risk.
Population-Based Rates
Ratios of cases to population, together with the period to which they refer, constitute the population-based rates. Those commonly measured are the incidence rate, the mortality rate, and the so-called prevalence rate. They ordinarily are expressed in unit-population values. For example, a total of 10 cases among a community of 20,000 represents a rate of 50 per 100,000 population, or 0.5 per 1000.
The incidence or attack rate is the number of new cases over a defined study period divided by the population at risk. This is usually given as an annual incidence rate in cases per 100,000 population per year. The date of onset of clinical symptoms typically dictates the time of accession, although occasionally the date of first diagnosis is used. The (point) prevalence rate is more properly called a ratio , but it refers to the number of those affected, both old and new cases, at one point in time within the community per unit of population. The lifetime prevalence rate refers to the proportion of persons manifesting a disorder of interest during the period of their lives up to the survey date. It is typically reported per 1000 of the population at risk. If no change in case-fatality ratios occurs over time and no change in annual incidence rates (and no migration) occurs, then the average annual incidence rate times the average duration of illness in years equals the point prevalence rate. When numerator and denominator for a rate each refer to an entire community, their quotient is a crude rate for all ages. When both terms of the ratio are delimited by age or sex, these are age- or sex-specific rates, respectively. Such rates for consecutive age groups, from birth to the oldest group of each sex, provide the best description of a disease within a community. In comparing morbidity or mortality rates between two communities for an age-related disorder (such as stroke or epilepsy), differences in crude rates may be observed solely because of differences in the age distributions of the denominator populations. This can be avoided by comparing only the individual age-specific rates between the two, but it rapidly becomes unwieldy. Methods exist for adjusting the crude rates for all ages to permit such comparisons. One such method involves taking community age-specific rates and multiplying them by the proportion of a “standard” population within the same age group. The sum of all such products provides an age-adjusted (to a standard) rate, or a rate for all ages adjusted to a standard population. One common standard in the United States is its population for a given census year. The mortality or death rate is the number of deaths in a population in a period with a particular disease as the underlying cause, such as an annual death rate per 100,000 population. Deaths by cause, based on standard death certificates, are provided by official government agencies. At times, deaths listed as other than underlying cause on the certificate are added to give a count of total deaths for the disease. The standardized mortality ratio (SMR) is the observed number of deaths in the study group of interest divided by the expected number of deaths based on the standard population rates applied to the study group. The great advantage of death rates is their current availability over time and geographical area for many disorders, whereas morbidity rates require specific community surveys. Geographical distributions from death data are especially informative because most population studies available are, of necessity, spot surveys that may tell little about areas that were not investigated. Most often, too, the numbers are larger by orders of magnitude than those that prevalence studies can provide. The principal disadvantage, and it is a major one, is the question of diagnostic accuracy. In clinical practice, the diagnostic code used for morbidity and mortality rates is a three- or four-digit number representing a specific diagnosis in the International Statistical Classification of Diseases, Injuries and Causes of Death (ICD), which is revised periodically. The ICD is the world’s standard tool to code disease. The changes in the 10th revision (ICD-10) were major. ICD-10 was published in 1992 and adopted for use in the United States in 1999 but not fully implemented in most health systems until 2015. It introduced the innovation of an alphanumerical coding scheme of one letter followed by three numbers (e.g., I63.1, cerebral infarction due to thrombosis of precerebral arteries). One drawback of the ICD system of classification is that different diseases are often subserved under the same primary code. To provide a more refined classification for individual diseases, several disciplines have published specialty-related expansions of the primary ICD structure. ICD-10-NA is the expansion of the codes relating to neurological diseases, so that virtually every known neurological disease or condition has a unique alphanumerical identifier ( ). An initial version of ICD-11 was published in 2018; it will undergo translation into national languages ( ). The expectation is that ICD-11 will be available for use in 2022. Lack of space here precludes attention to community survey methods, risk factors and analytic epidemiology, treatment comparisons, and statistical methods—all intrinsic aspects of epidemiology. This chapter highlights the descriptive epidemiological analysis for a few major neurological diseases selected as representative of those most likely to be encountered in clinical neurology.
Cerebrovascular Disease
Stroke (see Chapter 68 ) is the leading cause of disability among major neurological conditions worldwide ( ) and a major cause of disability in the United States ( ). There are approximately 800,000 strokes annually in the United States. Recent epidemiological studies have subdivided stroke into subarachnoid hemorrhage (SAH) or hematoma, intracerebral hemorrhage, and cerebral infarction. Subdural hemorrhage is not included in this category. Cerebral infarction is the most common type of stroke in developed countries, making up more than 70% of cases. Intracerebral hemorrhages account for approximately 10%–15% of strokes, and SAHs make up less than 5%; the remainder are of undetermined etiology.
Mortality Rates
Since the late 1960s, US stroke death rates have declined by 75% overall. The largest declines in stroke mortality were seen in white men and the smallest in black men. Similar decreasing rates in stroke mortality are reported for other countries, including Japan, Australia, New Zealand, Canada, and all of Western Europe.
Quality improvement (QI) programs in hospitals have been shown to improve mortality outcomes. The Florida–Puerto Rico Collaboration to Reduce Stroke Disparities (CreSD) ( ) registry tracks Medicare beneficiaries in hospitals and is part of a national QI initiative by the American Heart Association; its outcomes were compared with those of non-QI hospitals. For the period 2010–2013 in patients treated for a stroke at CreSD hospitals, there were no differences in risk-adjusted in-hospital mortality by race or ethnicity. Blacks had a lower 30-day mortality rate versus Whites (odds ratio, 0.86) but a higher rate of 30-day readmission (hazard ratio, 1.09) and 1-year mortality (odds ratio, 1.13).
In 2016, stroke was the second largest cause of death globally (5.5 million deaths) after ischemic heart disease ( ). The age-standardized stroke mortality rates decreased by 36.2% from 1990 to 2016. These death rates also declined for all but one region from 1990 to 2016, with the greatest decrease in the high-income Asia Pacific region (−66.3%) and no significant change in southern Sub-Saharan Africa (−3.8%).
The geographic differences in stroke mortality within the United States are notable, with the highest rates since the 1940s in the southeastern region. The so-called stroke belt states of Georgia, North Carolina, and South Carolina have consistently demonstrated mortality rates above the US average. The Centers for Disease Control and Prevention (CDC) examined this issue by assessing stroke mortality at the county level between 2014 and 2016 ( Fig. 47.1 ). The concentration of stroke mortality rates in the highest two quintiles within the southeastern region validates the persistence of this trend. The Reasons for Geographic and Racial Difference in Stroke (REGARDS) Study was launched in 2001 to clarify the demographic differences in stroke. Recent data from this project have shown that elevated depressive symptoms in conjunction with high levels of perceived stress were more strongly associated with several parameters of metabolic health than only one of these psychological constructs in a large, diverse cohort of adults ( ).
Morbidity Rates
Like mortality rates, stroke incidence has declined rapidly over the past 50 years in high-income countries. Within the past 20 years, however, the decline in incidence rates in industrialized countries has attenuated ( ). In 2010, an estimated 11.6 million incident ischemic strokes and 5.3 million incident hemorrhagic strokes occurred worldwide, with the majority (63% of ischemic strokes and 80% of hemorrhagic strokes) occurring in low- and middle-income countries ( ). Stroke incidence increases logarithmically with increasing age but with a lesser increase beyond age 74. In recent years, the annual stroke incidence rate in Europe and North America has been between 100 and 350 per 100,000 population, and mostly near 150.
The most recent worldwide trends in stroke incidence were reported from the Global Burden of Disease Group ( ). The highest age-standardized incidence rates for stroke were observed in East Asia (China 354 per 100,000 person-years) and Eastern Europe (Estonia 335 per 100,000 person-years). The lowest incidence rates were in central Latin America (El Salvador: 97 per 100,000 person-years). Regarding stroke subtypes, ischemic stroke incidence rates declined more precipitously in southern Latin America (−38.0%), and the largest increase occurred in East Asia (17.5%). For hemorrhagic stroke, incidence rates decreased in all regions of the world. The largest declines were seen in the high-income Asia Pacific (−32.5%) area, and the smallest in southern Sub-Saharan Africa (−5.1%). In contrast to the 8% global decline in the age-standardized incidence of stroke between 1990 and 2016, rates increased by 0.3%, albeit nonsignificantly, in the group of middle-income countries.
The Greater Cincinnati and Northern Kentucky Stroke Study was the first large metropolitan-based study of stroke trends among a racially diverse population ( ). The incidence for stroke between 1993 and 2010 in the study population was assessed to identify temporal trends. Incidence rates for all strokes decreased in men over the time interval but were stable for women. Incidence rates for intracerebral hemorrhage and SAH were stable in both men and women. Overall decreases in stroke incidence over time are driven by a decrease in ischemic stroke in men. In the United States, the age-adjusted prevalence of stroke was 2.7% in 2006 and remained relatively stable at 2.5% between 2013 and 2016 ( ). Breakdown by race revealed the highest rates among Native American/Alaska Native people (5.9%), followed by Black people (3.9%); the lowest rates were found in Asian/Native Hawaiian/Other Pacific Island people (1.5%). Between 2006 and 2010, the age group above 65 years of age had stroke prevalence rates 10-fold greater than those in the 18- to 44-year-old group.
Transient Ischemic Attacks
Although clearly a subset of cerebrovascular disease, transient ischemic attacks (TIAs) have generally been excluded from most morbidity and mortality surveys of stroke. As with incidence and prevalence rates for stroke, a marked increase in TIA rates occurs with age. To better elucidate time trends in TIA, an analysis of incident TIAs from 1998 to 2000 and 2009 to 2011 in northern Portugal was assessed ( ). Crude annual TIA incidence rates had a nonsignificant increase from 67 to 74 per 100,000 between periods; however, men below age 65 showed a significantly increased risk for TIA (incident relative risk: 1.79). A higher TIA risk in men has been demonstrated in other studies as well. Recent population-based incidence studies for TIA have reported slightly lower rates from 0.26 per 1000 person-years in China to 40 per 100,000 in New Zealand ( ).
The new tissue-based definition of TIA takes into account recent neuroimaging findings and also provides a much shorter duration for the diagnosis ( ). Studies that have used this new definition have shown a heterogeneous response in the frequency of diffusion-weighted magnetic resonance imaging (DW-MRI) signal in patients presenting with TIA symptoms ( ). This calls into question the utility of using MRI in population-based studies until the variability in responses can be understood. If the new definition were to be used in epidemiological studies, the estimated annual incidence of TIA would be lowered by 33% and the incidence of ischemic stroke increased by 7% ( ). However, a major underascertainment of TIA is probable in all surveys unless one directly questions the entirety of the subject population. This may also give spuriously high frequencies for completed stroke after TIA because only a retrospective history of TIA occurrence is given in many studies of stroke.
Primary Neoplasms
Three large centralized US databases that provide descriptive epidemiological data on primary brain tumors have been created (see Chapter 71 ). These databases are the Central Brain Tumor Registry of the United States (CBTRUS); the Surveillance, Epidemiology, and End Results (SEER) database; and the National Cancer Database (NCDB). According to the CBTRUS database, an estimated 86,970 new cases of primary malignant and nonmalignant brain and other central nervous system (CNS) tumors are expected to be diagnosed in the United States in 2019 ( ). The lifetime risk of developing a CNS tumor is estimated to be 0.62% in the United States ( ). Little is known of the causes of most primary brain tumors, but their epidemiological features may provide clues for more definitive studies.
Within the CNS, approximately 85% of primary tumors have been intracranial and 15% intraspinal. For the brain, the major groupings are the gliomas (40%–50%, of which approximately half are glioblastomas) and the meningiomas (15%–20%). Pituitary adenomas plus schwannomas, especially acoustic, add another 15%–20%. The most common spinal cord tumors are neurofibroma and meningioma, followed by ependymoma and angioma.
Mortality Rates and Survival
Between 2011 and 2015, the average annual mortality rate in the United States was 4.37 per 100,000, with 77,375 deaths attributed to primary brain malignancies and other CNS tumors. The 5-year relative survival rate in the United States following diagnosis of a primary brain malignancy or other CNS tumor (including lymphomas and leukemias, tumors of the pituitary and pineal glands, and olfactory tumors of the nasal cavity) is 33.8% for males and 36.4% for females ( ).
Reported 5-year survival ratios for the period 1995–2008 have been 69% for clinically diagnosed meningioma. The relative 5-year survival rate for children younger than 15 years of age with brain and other CNS tumors is now 70.9%, compared with 35% some 30 years ago ( ). The 5-year survival for oligodendrogliomas between 2000 and 2013 was 77.1 years for males and 81.1 years for females. The more aggressive anaplastic oligodendroglioma had corresponding 5-year survival estimates of 55.5 years for males and 54.7 years for females ( ).
Glioblastoma is the most common primary brain tumor in adults, with a uniformly poor prognosis. Median survival for glioblastoma remains approximately 1 year after diagnosis. Overall 5-year survival from SEER registries for glioblastoma between 1995 and 2008 was 4.7 years. Several studies from cancer registries have indicated that the 5-year survival rate, typically reported at 4%–10% over the past 30 years, may be too optimistic ( ). Series from Canada, Sweden, and the United States that reviewed clinical and histological data from registries found that in half of all reported cases of glioblastoma, the tumor had been misclassified and on close inspection was found to be a less aggressive tumor ( ). Corrected 5-year survival rates are more likely to be in the range of 2%–3%. Recent treatment trials for glioblastoma using temozolomide and radiation have shown some promise in improving survival ( ).
The Global Burden of Disease 2016 collaborators evaluated brain and CNS cancer mortality in regions around the globe (GBD 2016 Brain and Other CNS Cancer Collaborators, 2019). Age-standardized death rates for brain and other CNS cancers were the highest in central Europe, tropical Latin America, and Australasia. Country-level age-standardized death rates were highest for Palestine (8.3 per 100,000 person-years) and Albania (7.2 per 100,000 person-years). The countries with the most brain and CNS cancer deaths overall were China, India, and the United States.
Morbidity Rates
In the United States between 2011 and 2015, brain and other CNS tumors (malignant and nonmalignant) were the most common cancers in persons aged 0–14 years, with an average annual age-adjusted incidence rate of 5.65 per 100,000 population. Moving up to the group aged 15–39 years, brain and other CNS tumors constituted the second leading cancer group, with an average annual age-adjusted incidence of 11.20 per 100,000 population. Finally, brain and other CNS tumors were the eighth most common cancers among persons above 40 years of age, with an average annual age-adjusted incidence of 44.5 per 100,000 population. The most recent overall incidence estimate for all primary brain tumors in the United States is 19.9 per 100,000 population for 2004–2008 ( ). For children 0–19 years of age, the rate was 4.9 per 100,000 person-years and for adults above 20 years of age it was 25.9 per 100,000 population. Fig. 47.2 , A displays the overall primary brain tumor incidence rates by age group and histological behavior. The distribution of CNS tumors by site is presented in Fig. 47.2 , B . The meninges, at 34%, are the most frequent site for tumors. As a group, the major lobes of the brain (frontal, temporal, parietal, and occipital) account for 22% of brain tumors. The pituitary is the location for nearly 15% of tumors and the pineal for 0.5%. The spinal cord and cauda equina account for 3% of tumors in the CNS.
The GBD collaborators have shown that the number of incident cases of brain cancer and CNS tumors has increased across all geographical regions between 1990 and 2016 with the exception of Eastern Europe, where incident cases are stable (GBD 2016 Brain and Other CNS Cancer Collaborators, 2019). Age-standardized incidence rates were highest in Western Europe, East Asia, and Central Europe. They were lowest in Oceania and Sub-Saharan Africa. Specific countries with the highest age-standardized incidence rates included the Nordic countries (Finland’s 13.2 per 100,000 person-years to Iceland’s 20.8 per 100,000 person-years) and Luxembourg (16.2 per 100,000 person-years). In this study, the mortality-to-incidence ratio decreased in countries with higher levels of economic development, which is likely related to the specialized imaging and therapy required to diagnose and treat brain tumors. Overall there is great heterogeneity in incidence rates worldwide; this requires further study.
Although some CNS tumors have a clear genetic character, less than 5% can be attributed to inheritance. Many risk factors have been implicated in human brain tumors, the vast majority of which are unsubstantiated by scientific evidence. High-dose irradiation leads to an increased incidence of primary brain tumors, but the association of higher brain tumor risk with low doses of radiation is more controversial.
Convulsive Disorders
Epilepsy is defined as recurrent seizures (i.e., two or more distinct seizure episodes) that are unprovoked by any immediate cause or diagnosis of an epilepsy syndrome (see Chapter 101 ). In 2017, the International League Against Epilepsy (ILAE) updated the classification system for seizures; they are divided into those of (1) focal, (2) generalized, and (3) unknown onset, with subcategories of motor and nonmotor and with retained or impaired awareness for focal seizures ( ). Within the localization-related and generalized groups, further subdivisions into symptomatic (known cause), idiopathic (presumed genetic origin), and cryptogenic (no clear cause) are recognized. The major clinical types of seizures within the localization groups include tonic-clonic, clonic, myoclonic, epileptic spasms, and nonmotor (absence) seizures. Status epilepticus is defined as any seizure lasting for 30 minutes or longer, or recurrent seizures for more than 30 minutes during which the patient does not regain consciousness.
Epidemiological studies of epilepsy have often suffered from lack of agreement on definitions and classifications. Consensus guidelines have been published to assist in the standardization of such studies, but a new, simplified, etiology-oriented classification system will likely be needed in light of new genetic and imaging developments.
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