9.10 Public health, epidemiology, and neurological diseases

9.10 Public health, epidemiology, and neurological diseases
Oxford Textbook of Public Health

Public health, epidemiology, and neurological diseases

Walter A. Kukull and James D. Bowen


Clinical overview


Familial and genetic risks

Headache and depression

Stroke and migraine

Costs and public health impact
Traumatic brain injury

Clinical overview

Incidence and prevalence

Risk factors

Implications for public health
Back pain

Clinical overview


Risk factors

Public health importance

Clinical overview

Incidence and prevalence


Infectious causes of epilepsy


Costs and public health burden

Clinical overview

Dementia and Alzheimer’s disease
Peripheral neuropathy

Clinical overview

Carpal tunnel syndrome

Diabetes mellitus

Nutritional neuropathies

HIV infection

Clinical overview

Incidence and prevalence of Parkinson’s disease

Risk factors

Public health impact
Multiple sclerosis

Clinical overview


Case ascertainment


Risk factors
Chapter References

Included in this chapter are brief descriptions of some selected neurological disorders along with a discussion of their general epidemiology. Several themes cut across all of the sections. Case diagnosis is critical to epidemiological study of neurological diseases and disorders. However, diagnosis is difficult for many neurological diseases because specific antemortem biological markers may not exist and clinical diagnosis must be relied on. Variation in clinical criteria can lead to heterogeneity of diagnosed disease. As a case series includes more misclassification of disease diagnoses, the ability to recognize risk factors becomes reduced. Standardization of clinical criteria is one method of limiting the amount of misclassification; in practice, however, standardization is difficult to achieve.
Case ascertainment is a further problem for most epidemiological studies. This addresses the question how were the cases for study detected? If an incidence study must rely on death certificates, it is probably less than optimal for most neurological diseases. The method of identifying and including cases in a case–control study is important because if identification is associated with exposure history, selection bias could result and the findings could then be spurious. Can all identified cases be enrolled in a particular study? Obviously not; many persons decline to participate in studies. Frailty, age, ethnicity, gender, education, and a host of other factors influence participation. An uncontrolled bias may also result if any of these participation factors is systematically related to exposure status. Case-identification methods are critical to cohort studies (and intervention trials) as well. Failure to start with a cohort that is free of the disease of interest will potentially bias results. Lack of sensitivity or specificity in screening or diagnosing disease during follow-up will lead to misestimated incidence and to distorted risk-factor relationships.
Obtaining valid estimates of exposures for analytical risk-factor studies is of great importance. For most neurological diseases exposure determination is complicated by insidious and indeterminate onset of disease, confusing the temporal relationship between exposure and disease. Long-past exposure histories are difficult to construct and validate, especially in diseases that affect memory. Self-report histories and those obtained from proxies are often the basis for risk-factor inference, but may be flawed by distorted recollection or recall bias. Actual records, for example of medication history or occupational exposures, are seldom available. Biological markers of exposure (except for genotype) are difficult to obtain; and some may be affected by disease. Peripheral markers, if available, may not correspond to exposure levels in neuronal tissue. Biopsy may not be feasible or possible and autopsy, while often the gold standard for diagnosis, may reflect cumulative disease processes, leaving the picture additionally confusing.
P>As one leaves major research institutions or attempts to begin epidemiological research studies in less developed countries, the problems grow in magnitude. Differences in available facilities and local practices are likely the easiest to overcome. Addressing political concerns and suspicions to gain co-operation necessary to begin a study may take additional time and preparation. Case detection, acquisition, and exposure measurement still remain critical but the difficulty in obtaining acceptable levels of each is increased by an order of magnitude.
In the following sections we discuss the current descriptive and analytical research for a number of neurological disorders. We also provide a brief appraisal of the public health burden for these conditions.
Clinical overview
The pathogenesis of most headaches is poorly understood. Therefore, the nosology of headaches is based on the cause of headaches in those types where the cause is known, and the clinical picture in those in which the cause is unknown. The International Headache Society classification is currently the most commonly used system of classifying headaches (Table 1). It is important to realize that this system is used to classify individual headaches rather than individuals with headaches. Patients may suffer from more than one type of headache, with each day’s headache fitting into one of the International Headache Society categories. In fact, most headache patients have more than one type of headache. The International Headache Society classification contains a large number of conditions in which the headaches are symptomatic of neurological or systemic diseases. These include trauma, vascular disorders, disorders of cerebrospinal fluid pressure, infection, neoplasms, toxins, withdrawal states, metabolic disorders, and structural lesions of the head, neck, or cranial nerves. Headaches associated with these conditions are comparatively rare. Idiopathic conditions are far more common and include migraine without aura, migraine with aura, tension-type headaches, and cluster headaches. Because these idiopathic headaches are the overwhelming majority, they have the greatest impact on epidemiological studies.

Table 1 International Headache Society (abbreviated classification of headache)

Migraine without aura was previously named common migraine. It is an episodic headache that, as its name suggests, has no aura. Some patients experience a vague prodrome for a day or so prior to the onset of the headache. The headache may be unilateral or bilateral. It may change locations during the course of the headache. Some have throbbing pain while others have constant non-throbbing pain. Patients are often overly sensitive to sound (phonophobia) and light (photophobia) or smells. Nausea, vomiting, or diarrhoea may occur. The pain often builds over a few hours. Most last for several hours before slowly subsiding, though some may last for a few days.
Migraine with aura was previously named classic migraine. The identifying feature of this type of headache is the aura. This consists of an alteration of neurological function that usually precedes the headache. The aura most commonly consists of changes in vision with a central area of visual loss surrounded by a rim of shimmering light (the scintillating scotoma). The shimmering may look like flashing or twinkling lights, heat waves, or zigzag lines (fortification spectra). The area of visual abnormality gradually increases in size as the headache attack progresses. Non-visual auras may also occur, including paraesthesias, numbness, weakness, aphasia, or vertigo. Auras usually precede the headache by about 20 min, though the timing may vary. The headache resembles that seen in migraine without aura. It is most commonly, though not always, unilateral. It is most often throbbing and often associated with nausea and vomiting. It typically lasts a few hours. It is episodic and may have a prodrome preceding the headache.
Tension-type headaches are usually bilateral and have a sensation of pressure or a tight band around the head. They are less likely to have a prodrome and less likely to have nausea or vomiting. They do not have auras. They usually last longer than migraine headaches, typically an entire day or even several days. They build up more slowly than migraine headaches.
Cluster headaches are named after their tendency to occur in clusters lasting 2 to 6 months. However, other types of headaches may also occur in clusters and the diagnosis is made based on the characteristics of the headache rather than the clustering. The headache develops abruptly. It usually occurs daily during a cluster and often occurs at the same time of day. The pain is more short-lived than that of other idiopathic headaches and generally subsides within 2 h. It is unilateral and often associated with autonomic changes on the affected side. These include vasodilatation with unilateral flushing, conjunctival injection, nasal drainage, and sweating. Sympathetic dysfunction in the ipsilateral eye (Horner’s syndrome) may occur. The pain is more severe than that seen with migraine and patients are often agitated during the attack.
As noted patients often suffer from more than one type of headache. In a single patient, less severe headaches tend to resemble tension-type while more severe ones resemble migraine. There is also a tendency for a patient’s headaches to change over time with the headache pattern being classic migraine in youth but more closely matching that of tension-type headaches with time. These headaches may increase in frequency with age and become chronic daily headaches. Some term these headaches transitioned migraine.
Recent studies have assessed the prevalence of headache and migraine in many countries. Most of these studies have used the International Headache Society criteria in some fashion to determine probable diagnosis. Characteristics of the samples selected and analytical designs have differed, sometimes substantially, raising questions of comparability.
Gobel et al. (1994) selected a representative sample of 5000 persons from among 30 000 households in Germany. Using International Headache Society criteria, Gobel et al. determined that approximately 71 per cent of the subjects reported a history of headache. The lifetime prevalence of migraine was 27.5 per cent. This survey did not rely on use of medical care and so may estimate the underlying lifetime prevalence of both treated and untreated migraine. Lavados and Tenhamm (1997) selected a population sample of approximately 1400 persons in Santiago, Chile, but asked subjects about prevalence of headache within the last year rather than lifetime occurrence. The prevalence of migraine was reported as 7.3 per cent but with a marked gender difference: 2 per cent in males and 12 per cent in females. Merikangas et al. (1994) studied the prevalence of headache in persons aged 29 to 30 in Zurich, Switzerland, again using the International Headache Society criteria. Migraine with aura had a 1-year prevalence of 3.3 per cent and migraine without aura showed a 1-year prevalence of 21.3 per cent. These figures are roughly consistent, though somewhat higher than the previous citation; however, some of the increased prevalence may be due to the young adult age group. Francheschi et al. (1997) studied an elderly population (mean age 73 years) in Italy to determine whether increasing age would affect reported prevalence. Francheschi et al. report that although 18 per cent of subjects admitted to ‘troublesome’ headaches in the past, only 6 per cent were currently bothered by headache and 1 per cent met criteria for current migraine (per International Headache Society criteria). These results leave the impression that headache problems in young adulthood may not persist into old age. However, in order to evaluate adequately the change in frequency of headache events with age would require a cohort study design instead of a cross-sectional one. O’Brien et al. (1994) drew a stratified sample in Canada selecting 2922 subjects for study and conducted a telephone interview based on International Headache Society criteria. The prevalence of migraine was 7.8 per cent in males and 24.9 per cent in females; only about 46 per cent of those with migraine were reported to have ever contacted a physician for their problem. Within women the peak prevalence was seen in the 40- to 44-year age group. Thus, despite the variation in design and case ascertainment methods there may be a gender difference and age-related differences that appear with some consistency in a number of countries.
Osuntokun et al. (1992) applied a screening questionnaire to more than 18 000 persons in Nigeria. The questionnaire was not strictly according to the International Headache Society criteria but reportedly showed high sensitivity and specificity when compared to the gold standard neurologist examination for headache. Much lower lifetime prevalence of migraine, 5.3 per cent, was reported in this study than in those primarily comprised of Caucasians. No gender difference was noted, also in contrast to the studies reported above. Stewart et al. (1996a) compared migraine prevalence in Caucasians, African Americans, and Asian Americans living in the United States. The study involved about 12 000 persons aged 18 to 65 selected from Baltimore County, Maryland, selected by random digit dialling, and interviewed by telephone. Observed prevalence of migraine in Caucasians was 20.4 per cent for women and 8.6 per cent for men; among African Americans, 6.2 per cent in women and 7.2 per cent in men; and among Asian Americans, 9.2 per cent in women and 4.2 per cent in men. Despite obvious geographical and sociodemographic differences, as well as methodological differences between the two studies (Osuntokun et al. 1992; Stewart et al. 1996a), there appears to be a suggestion that susceptibility to migraine may be affected by ethnicity.
Stewart et al. (1992) also conducted a large, earlier study of migraine prevalence in about 15 000 persons. Prevalence of migraine was reported as 5.7 per cent for men and 17.6 per cent for women (using standard criteria); lower income was also associated with increased prevalence. These estimates compare favourably with other studies cited above which also included both treated and untreated, self-reported headache. Stewart et al. (1995) also conducted a meta-analysis that included 24 population-based studies of migraine. Most of the variation in prevalence estimates, among the studies included, was accounted for by age and gender differences along with case definition. Stewart concluded that after accounting for age, gender, and case definition, migraine prevalence estimates were stable across the studies included in the meta-analysis.
Familial and genetic risks
The influence of genetic constitution on the occurrence of migraine has been investigated principally by studies of familial aggregation and by twin studies. While these classic methods provide general clues concerning whether a genetic component to the disease may exist, their lenses are generally not of sufficient resolution to identify specific genes or linked markers. Progress in molecular genetics is providing remarkable discoveries for many diseases. Preliminary reports of rare mutations in the mitochondrial genome and associations with polymorphic forms of serotonergic and dopaminergic genes and migraine are as yet unsubstantiated, but may be more carefully evaluated and tested in the future (Peroutka 1998).
Two recent twin studies based in the Danish Twin Registry (Gervil et al. 1999; Ulrich et al. 1999) compared concordance rates of migraine without aura and migraine with aura. Twin pairs with one member affected by a specific type of migraine were selected from the registry. Both monozygotic and dizygotic twins (same sex) were selected for study and the occurrence of migraine was determined by interview and/or examination. The overall lifetime prevalence of migraine with aura for monozygotic and dizygotic twins was 7 per cent, similar to population surveys. The concordance in monozygotic twins was 34 per cent compared to 12 per cent for dizygotic twins. For migraine without aura the pairwise concordance for monozygotic twins was 28 per cent, compared with 18 per cent for dizygotic. This indicates a potential genetic contribution to migraine. But, because there is substantially less than 100 per cent concordance among monozygotic twins, the modifying influence of environmental factors may also be important in migraine aetiology. Ziegler et al. (1998) studied monozygotic and dizygotic, female twin pairs, raised together (n = 154) and raised apart (n = 43). This classical twin-study design aimed to tease out the relative contributions of genetic constitution and environmental exposures. Results showed that concordance was higher for monozygotic than dizygotic twins, whether raised together or raised apart. Zeigler et al. concluded that about 50 per cent of the variance was explained by genetic factors and the remaining half was due to ‘nonshared environmental factors’, and measurement error.
Stewart et al. (1997b) examined familial aggregation in first-degree relatives of migraine probands and first-degree relatives of unaffected control subjects. While some excess of migraine was noted in the relatives of migraine probands, the most pronounced increase was in the relatives of those probands with ‘disabling migraine’. Thus, severity appears to be associated with familial risk. Stewart et al. concluded that familial factors may account for less than half of migraine cases, but that familial factors, as examined, include both genetic and environmental influences.
Evidence for linkage to a specific susceptibility locus was recently published (Nyholt et al. 1998). The analysis was based on three large multigenerational families and it shows linkage on the X-chromosome (Xq). As a potential X-linked dominant, the authors conclude that it may explain an observed excess of migraine in relatives of male probands and that it may also be related to the higher observed prevalence of migraine in females. Nyholt et al. acknowledge that much genetic heterogeneity is still likely to exist.
Headache and depression
Breslau and colleagues (Breslau and Davis 1993; Breslau et al. 1994) conducted a longitudinal study in 1007 young adults to observe the association between migraine and major depression. They reported a significant threefold increased risk of major depression among those with a history of migraine and also a threefold increased risk for migraine among those with prior depression. This finding raised the possibility that the two disorders may have mechanisms in common. Pine et al. (1996) reported a similar longitudinal study that followed 776 persons aged 9 to 18 (in 1983) for up to 9 years. They reported that in subjects with no history of ‘chronic impairing headache’, those with major depression at baseline had a 10-fold risk of developing such headaches during follow-up. Breslau et al. (2000) conducted another study to clarify the association between severe headache or migraine and depression. In this longitudinal study, persons with severe headache experienced approximately a threefold increased risk of first-onset depression but those with major depression at baseline experienced no significantly increased risk of severe headache. However, the previously reported ‘bi-directional’ association between migraine and depression was replicated.
Stroke and migraine
Data from the Physicians Health Study (Buring et al. 1995) and from the National Health and Nutrition Examination Survey (Merikangas et al. 1997) support a significantly increased risk of stroke in persons with a history of migraine. Because of the relatively high prevalence of migraine among young women the occurrence of stroke in that population is of some concern. In a World Health Organization case–control study sample Chang et al. (1999) reported approximately a threefold increased odds ratio for history of migraine in young women with ischaemic stroke as compared to controls. Tzourio et al. (1995) reported a similar level of association in a smaller French study and Mitchell et al. (1998) reported a slightly more modest level of association in a study conducted in Australia. Tietjen (2000) cautions that the relationship between migraine and stroke may be complicated by the contribution of additional risk factors, such as cigarette smoking and oral contraceptives, and possibly by genetic factors, as well. Thus, additional study may be needed to describe adequately the true relationship between migraine and stroke.
Costs and public health impact
The estimated 23 million persons with migraines in the United States may miss 150 million work days each year with an associated cost of up to $17 billion (Cady 1999; Hu et al. 1999). Many more persons suffer with decreased effectiveness at work than actually miss work days; this results in additional hidden loss of productivity due to migraine (Stewart et al. 1996b; Schwartz et al. 1997). New treatments are relatively effective but only a minority of persons consult physicians for their problem or receive the effective medications (Lipton 1998). Early recognition and treatment of migraine may significantly limit societal and personal costs (Cady 1999).
Traumatic brain injury
Clinical overview
A variety of traumas may afflict the nervous system, including brain, spinal cord, and peripheral nerves. Trauma to the brain is of greatest epidemiological importance. Traumas to the brain may be divided into penetrating or closed head injuries. The damage inflicted by penetrating head injuries varies with the velocity of the penetrating object. Low-velocity injuries such as knives produce less injury than high-velocity objects. High-velocity penetrations like bullets produce more widespread injury since the shock wave of the object projects far beyond the immediate track of the missile. Closed head injuries can lead to brain damage through a variety of mechanisms. Bleeding from tearing of blood vessels may lead to epidural or subdural haematomas with resulting mass effects. The brain may be contused due to the impact, particularly in the inferior frontal and temporal areas which overlie bony protuberances. Cerebral oedema may occur through a number of mechanisms, including injury to blood vessels (vasogenic oedema), injury to cell membranes (cytotoxic oedema), or metabolic changes. Hydrocephalus may develop due to blockage of the routes of normal cerebrospinal fluid flow. Finally, closed head injuries may lead to pathological changes in the brain named diffuse axonal injury. The pathological finding in diffuse axonal injury is the axonal retraction ball. These balls of axonal material occur at the site of axon transection or sites of altered axonal flow which are seen with torsional forces.
The symptoms of focal head injuries are determined by the site of injury. More diffuse injuries lead to altered consciousness or cognitive changes. Altered consciousness ranges from a momentary stun to brief unconsciousness, coma, or persistent vegetative state. Cognitive alterations may be profound but are often mild and difficult to recognize. In subtle cases, neuropsychological testing may be needed to demonstrate the abnormality. Such testing may identify focal changes associated with focal brain injury, but more commonly they find difficulties with attention, concentration, short-term memory, and tasks requiring rapid processing of information.
For mild head injuries, the severity of the injury is usually measured by the degree of post-traumatic amnesia. Amnesia lasting less than 5 min is very mild, less than 1 h is mild, 1 to 24 h is moderate, 1 to 7 days is severe, more than 7 days is very severe, and more than 4 weeks is extremely severe. More severe head injuries are usually classified by the Glasgow Coma Scale. Scores of 13 to 15 are minor, 9 to 12 are moderate, 5 to 8 are severe, and 4 or less are very severe.
Incidence and prevalence
The National Institutes of Health consensus statement (1998) estimated the annual incidence of traumatic brain injury to be 100 per 100 000 persons (in the United States). The prevalence of persons living with impairment resulting from traumatic brain injury may be between 2.5 million and 6.5 million in the United States (National Institutes of Health 1998). Traumatic brain injury accounts for approximately 52 000 deaths each year. The majority of traumatic brain injury incidence is due to vehicular accidents (auto, bicycle, motorcycle) or pedestrian versus vehicle accidents. Violence and assault also contribute substantially. Sports injuries may account for about 3 per cent of traumatic brain injury, but because they tend to be less severe than other types may also be significantly under-reported (National Institutes of Health 1998). Earlier estimates of incidence for the United States, 1970 to 1975, are relatively consistent (Caveness 1979). Ingebrigtsen et al. (1998) studied hospital-referred head injury in Norway and reported an annual incidence of 229 per 100 000 population, seemingly greater then the United States estimates. Hillier et al. (1997) report an even higher incidence in South Australia of 322 per 100 000. Young adult males predominate as cases in both of these studies and it is estimated that potentially 25 per cent of the annual incidence may require continuing care because of impairment resulting from the injury (Hillier et al. 1997). A British study (Moles et al. 1999) suggests that ethnicity may modify the risk of traumatic brain injury due to assault, with black males experiencing a two- to threefold predominance in admissions. Of course, findings related to ethnicity may be country specific and associated with a variety of other social and political factors.
The potential for lifelong impact on social and occupational functioning, and years of life lost, is great for traumatic brain injury because the peak incidence occurs among people aged 15 to 24. Traumatic brain injury is about twice as common in males as in females. In this age group, vehicle accidents and violence are the principal causes of traumatic brain injury. Two other age-incidence peaks occur, one among the elderly (75 years and older) and the other among the very young. In these age groups, falls predominate as the immediate cause. Among the very young, a relatively substantial proportion of traumatic brain injury is attributed to assault (National Institutes of Health 1998).
Risk factors
Vehicle accidents
As mentioned above vehicle accidents may account for half of the traumatic brain injury observed in the United States (National Institutes of Health 1998). There are approximately 3 million motor vehicle accidents each year which result in death or severe injury (in the United States) (Murphy et al. 2000). For these accidents, well-known risk factors appear to prevail. Consistent with the risk of traumatic brain injury, persons aged 15 to 24 predominate. Alcohol use is an important determinant of motor vehicle accidents and therefore also of traumatic brain injury (National Institutes of Health 1998). Young children typically tend to suffer low-energy type head injury (Berney et al. 1994) in household accidents, leading to a more favourable outcome. However, motor vehicle accidents generally result in high-energy accidents and greater morbidity and mortality. Car safety seats for younger children may afford some degree of protection.
Helmets for bicyclists may afford some degree of protection against traumatic brain injury (Rivara et al. 1997; Linn et al. 1998). A study conducted in British Columbia, Canada (Linn et al. 1998), found a fourfold increase in risk of concussion among non-helmet users and a twofold increase in risk of hospital admission. A study in New York found a similar proportion of head injuries among helmeted and non-helmeted child bicyclists (Shafi et al. 1998). However, children with helmets were more likely to experience only concussion compared to an excess of skull fractures among non-helmeted children. Rivara et al. (1997) studied over 3000 bicycle injuries; roughly half of the bicyclists were wearing helmets at the time of the accident. Overall, about 22 per cent of the cases involved a head injury. Comparing ‘serious’ injury (injury severity score greater than 8) to less than serious injury, Rivara et al. found that younger age and speed increased the risk of a serious injury somewhat, but a fourfold increase in risk was seen if a motor vehicle was involved in the crash. However, risk of ‘serious’ injury, as defined, was not associated with helmet use. Subjects who experienced neck injury were substantially more likely to die but helmet use did not decrease the risk of neck injury. While this study sounds somewhat negative for helmet use, this may not be the correct interpretation. Collisions involving motor vehicles and bicycles are likely to result in very serious injuries; helmets alone obviously cannot protect against those injuries. In the situation where a bicyclist loses control and crashes, some degree of protection against concussion is likely to be afforded. Among teenagers helmet use may be lower, even when required by law (Puder et al. 1999). Thompson and Patterson (1998) summarized studies of bicycle helmets, recommending that they be worn by all competitive and non-competitive riders: ‘Helmet use reduces the risk of head injury by 85 per cent, brain injury by 88 per cent and severe brain injury by at least 75 per cent.’
Among the elderly, falls are one of the more important causes of traumatic brain injury (National Institutes of Health 1998; Luukinen et al. 1999). Other neurological conditions such as movement disorders and/or dementia, may make a person more likely to experience falling. Weakness, unsteadiness, certain medications, and other medical conditions may also increase the likelihood of falling. Vision deficits are common in the elderly, due to loss of acuity, glaucoma, macular degeneration, and other causes; poor vision can contribute to falling. Mechanically speaking, elders may be more likely to fall and be injured when surfaces are uneven or slippery, or when they must use a cane or walker. Thus, elders require additional care and help to avoid the serious injury that may result from falls.
The very young are also at increased risk of traumatic brain injury due to falls (National Institutes of Health 1998). They, like the very old, may tend to be unsteady or to use mechanical devices such as walkers or strollers. Unlike their older counterparts, however, 3-year-olds are seldom content to remain still for extended periods: climbing from a shopping cart to visit a toy, exploring a new flight of stairs, or escaping from a crib before nap time is over.
As much as 20 per cent of traumatic brain injury may be the result of violence, roughly half being due to firearms (National Institutes of Health 1998). The age group at highest risk is 15 to 24 years. While males appear to be more likely to sustain an injury due to violence, women may be more likely to die as a result (Gilthorpe et al. 1999). Generally, community violence indicates an increased risk that traumatic brain injury will be involved. Durkin et al. (1996) describe the incidence of paediatric, severe non-fatal assault in North Manhattan (New York City) as approximately 60 per 100 000 (about 30 per 100 000 due to firearms). Among adolescents, firearms were the most common method of serious assault and carried more than a 10-fold increased fatality risk. A similar study of general trauma was conducted in Los Angeles County (Demetriades et al. 1998). In that study homicides accounted for 45 per cent of traumatic deaths compared to 32 per cent resulting from traffic accidents. The incidence of firearm-related injury or death was 42 per 100 000. The homicide rate varied dramatically by age and ethnic group. Overall it was about 14 per 100 000, but rose to 73 per 100 000 in African-American males and further to 164.2 per 100 000 among 15- to 34-year-old African-American males. While this study speaks to trauma and homicide generally, Lam and MacKersie (1999) states that among children admitted to hospitals 75 per cent are admitted because of trauma and as many as 70 per cent of paediatric trauma deaths are due to head injury. Also, firearms may be involved in a substantial proportion of traumatic brain injury, hence the relevance of these statistics.
Abuse and domestic violence are important causes of traumatic brain injury among women and among children (Jenny et al. 1999; Monahan and O’Leary 1999). Monahan and O’Leary estimate that about 35 per cent of the 2 to 3 million women battered each year by their domestic partner sustain traumatic brain injury as a result. The sequelae of these injuries may be difficult to document because they may include behavioural and cognitive deficits as well as the acute physical problems. Abusive head trauma may also be an under-recognized problem among very young children (Jenny et al. 1999). So-called ‘shaken baby syndrome’ and other forms of physical abuse may result in traumatic brain injury as well as in spinal cord injury (1998).
Sports injuries account for a relatively small proportion of serious traumatic brain injury (National Institutes of Health 1998). However, many mild head injuries may go unreported and it is unclear what the long-term risk of such injuries may be. Ferguson et al. (1999) suggest that study of mild head injury resulting in postconcussive syndrome may be additionally difficult because of a form of recall bias among the cases based on their expectations of recovery.
Implications for public health
While the actual case fatality rate for traumatic brain injury may be high, that in itself does not describe the major cost. The National Institutes of Health Consensus Statement (1998) estimates that nearly $10 billion are spent annually in the United States for acute and rehabilitative care for new cases. Furthermore, they estimate that lifetime care costs may range from $600 000 to nearly $2 million per person. Personal costs experienced by victims of traumatic brain injury cannot be estimated realistically; lost opportunities for education and employment, changed or foregone personal relationships, and psychological distress may all result from traumatic brain injury (Colantonio et al. 1998). Also, as Annegers et al. (1998) point out, the risk of seizures following traumatic brain injury is increased up to 17-fold in patients with severe injuries.
The causes of traumatic brain injury are well specified and observable. The challenge remains, however: how can the occurrence of motor vehicle accidents and violence be reduced, thereby dramatically reducing the occurrence of traumatic brain injury?
Back pain
Clinical overview
The many causes of low back pain can be divided according to the anatomical structures involved. Nerve roots may be impinged leading to sciatica. The lumbar plexus or more peripheral nerves may be diseased. The subarachnoid space or meningeal structures may be involved with infection or tumour. Vertebral bodies may be involved with tumours, infections, or fractures. Joints may be affected by a number of diseases, including osteoarthritis, ankylosing spondylitis, or inflammatory diseases. Muscles may be injured or affected by diseases such as myositis. These anatomically based diseases often garner the bulk of medical attention, perhaps because they are more readily defined on testing or because they have treatments which are more frequently successful. However, they constitute a very small portion of back pain cases. By far, the most common cause of low back pain is idiopathic.
The medical history is useful in differentiating some of the types of low back pain. Pain that begins in the low back and radiates in the distribution of a neurological structure is likely due to impingement on that structure. For example, pain radiating down the leg in the distribution of the L5 nerve root is often due to a disk impinging on the nerve root. Back pain following trauma suggests bony disease. Fever or weight loss suggest infectious or neoplastic causes. The physical examination concentrates on focal points of pain, and the examination of relevant neurological pathways.
Tests extend the physical examination. Plain spine radiographs are used to evaluate bone diseases such as trauma, neoplasm, or infection. Better definition may be seen with CT scanning. Scanning with MRI provides the best definition of neurological structures. All of these techniques have a high false-positive rate for identifying causes of low back pain. Electromyography and nerve conduction velocities are used to determine whether damage has occurred to parts of the peripheral nervous system.
Low back pain is one of the most common diseases encountered in general practice, with up to 2 per cent of the population seeking medical care for it each year (Dillane et al. 1966). The lifetime prevalence of back pain is very high, ranging from 49 to 70 per cent (Shelerud 1998; Andersson 1999). Prevalence rates vary depending on the manner in which the question is framed. Asking for any history of back pain results in higher rates than asking about pain of specific duration, location, or severity. Only 14 per cent of patients report an episode of back pain lasting at least 2 weeks (Deyo and Twui-Wu 1987).
The point prevalence of low back pain ranges from 12 to 30 per cent (Shelerud 1998; Andersson 1999). In a review of a wide range of neurological disorders, Kurtzke found an annual point prevalence for low back pain of approximately 0.5 per cent with lumbosacral herniated disk disease representing another 0.3 per cent (Kurtzke 1982). The annual incidence of low back pain was approximately 1.5 per cent with lumbosacral herniated disk disease representing another 1.5 per cent (Kurtzke 1982). Surveys more directed towards back pain have higher prevalence rates. Elliott et al. (1999), using a community mail survey, found the point prevalence of back pain to be 6 per cent, while Reigo et al. (1999) noted an 11 per cent point prevalence for back pain in a population based study. Croft et al. (1999) found a 1-year prevalence rate of 34 per cent in men and 37 per cent in women in a prospective study of a population without prior back pain. Again, the rates of back pain vary depending on the duration, location, and severity of the pain.
Many studies of the prevalence of low back pain concentrate on the workforce rather than the general population because of the economic impact of back pain on industry. In a general population sample, Picavet et al. (1999) found that the 12-month period prevalence of low back problems for working and non-working men was 44.4 per cent and 45.8 per cent respectively, and for women was 48.2 per cent and 55.0 per cent respectively. Frymoyer et al. (1983) reported that about 2 per cent of employees seek medical care each year for low back pain. Behrens et al. (1994) noted that back pain related to the work environment (such as repetitive activities, and so on) occurred in 4.5 per cent and that back pain due to a work-related injury occurred in 2.5 per cent of workers. Guo et al. (1999) found that 4.6 per cent of workers had back pain for at least 1 week within the past year. Back pain accounts for 20 per cent of compensatable injuries (Klein et al. 1984).
Risk factors
There are several demographic and anthropomorphic features associated with low back pain. Those who are 35 to 55 years of age are most commonly affected (Shelerud 1998) but most of these first developed pain in earlier life. In the general population, age has only a modest effect on the 1-year prevalence of back pain, with rates varying from 7.6 to 9.4 per cent across various age ranges in adults (Andersson 1999). In the workforce, however, back pain increases with age (Rossignol et al. 1988; van Doorn 1995). Rossignol et al. (1988) found that the odds for developing back pain doubled with an increase in age of 23 years. Older workers have longer duration of back pain and more time off from work compared to younger workers (Shelerud 1998). Back pain in the elderly has received relatively less attention, making estimates of prevalence in this age group difficult (Bressler et al. 1999). Children also suffer back pain with a lifetime prevalence of 10 per cent in 10-year-olds, 53 per cent in 13-year-olds, and 71 per cent in 15-year-olds (Duggleby and Kumar 1997). In the general population, men and women are equally susceptible to back pain (Shelerud 1998). In the workforce, men predominate, perhaps because more men are in the workforce. There have not been strong associations found between body build, weight, or mild leg length inequality and the development of low back pain (Deyo and Bass 1987; Shelerud 1998). However, some studies suggest that tallness may increase the risk (Shelerud 1998). Those in the highest 20 per cent of body mass index may also be at risk, especially in women (Shelerud 1998; Croft et al. 1999). Physical fitness and high levels of physical activity are generally believed to be protective (Cady et al. 1979; Shelerud 1998). Lumbar mobility has historically been believed to be protective for back pain, but recent studies have suggested that this is not the case (Shelerud 1998). The association of posture to back pain is also uncertain (Shelerud 1998). An increase in strength was associated with less back pain in some studies, but not in others (Shelerud 1998). Back pain has long been attributed to changes seen on spine radiographs as well as MRI scans. These include degenerative changes, spondylolisthesis, and lumbar stenosis. However, the ability of these changes to predict the development of back pain is poor, in large part because of the high prevalence of these conditions in the asymptomatic population (Shelerud 1998). A family history of back pain carries a relative risk of 2.1 (Rozenberg et al. 1998).
Smoking increases the risk of developing low back pain (Deyo and Bass 1987; Frymoyer 1988), but this increase is rather modest (Leboeuf-Yde 1999). Odds ratios in large studies have ranged from insignificant to 3.12, with the majority of studies showing odds ratios of less than 2 (Leboeuf-Yde 1999). Some studies have shown a dose effect (Leboeuf-Yde 1999). Eriksen et al. (1999) found that work environment was associated with back pain in smokers but not in non-smokers. It is uncertain whether the association between smoking and back pain reflects a causal relationship or whether smoking serves as a marker for another underlying cause. Previous pregnancy is a risk factor for back pain (Shelerud 1998). Patients with a prior episode of low back pain are at greatly increased risk of recurrence, with the lifetime recurrence reaching as high as 85 per cent (Valkenburg and Haanen 1982).
Patients who are chronically ill with back pain often have emotional factors that interplay with it. Psychological factors such as anxiety, depression, alcoholism, somatization, stress, type A personality, job dissatisfaction, negative body image, a weak ego, and poor drive have been associated with back pain (Anderson 1981; Rozenberg et al. 1998; Shelerud 1998). However, it is unknown whether these emotional factors precede the onset of illness or whether they develop as part of the response to the pain (Anderson 1981; Frymoyer et al. 1983; Bigos et al. 1991). The data regarding psychological factors associated with the work environment and personality profiles such as the Minnesota Multiphasic Personality Inventory are also conflicting (Shelerud 1998). A recent prospective study of transit workers found that psychosocial job factors and physical workload increased the risk of back pain, suggesting that some of the psychosocial factors are contributors to, rather than results of, the condition. The odds ratios were increased for psychological job demands (1.5), job dissatisfaction (1.56), job problems (1.52), and physical labour (3.04) (Krause et al. 1998).
Factors associated with employment are often linked with back pain (Devereux et al. 1999; Hoogendoorn et al. 1999). About two-thirds of back pain cases are related to employment, with one-third occurring in the setting of lifting/twisting and one-third related to falls (Brown 1975). Lifting heavy objects, lifting with twisting movements (Kelsey 1975), and frequent lifting seem to increase injury rates (Kelsey et al. 1979). The relative risk of repeated improper lifting may be as high as 7.2 (Rozenberg et al. 1998). Driving and jobs that require prolonged sitting also increase the risk of back pain (Kelsey 1975).
Physically demanding work increased the risk of back pain in a number of studies (Shelerud 1998) These studies are difficult to interpret, however, because of the difficulty in accurately quantifying the physical demands of various jobs.
Static work postures such as prolonged sitting, standing, or bending increase the risk of developing back pain (Shelerud 1998). The weight of objects requiring lifting, the frequency of lifting, object bulk, the position from which the object must be lifted, bending, and twisting all increase the risk of occupational back pain (Shelerud 1998).
Vibration, especially in the seated position, seems to increase the risk of back pain (Shelerud 1998). However, most of these jobs also involve prolonged sitting during the operation of motor vehicles.
Public health importance
Back pain is one of the most frequently encountered disorders. The cause of the pain in most cases remains unknown. Though many factors have been associated with back pain, most study designs have been inadequate in determining whether they are a cause or result of the chronic pain. Population-based prospective studies will be needed to determine whether premorbid conditions predict future back pain. The occurrence of back pain, as indicated by the prevalence discussed above, makes it a significant public health concern as well as an important cause of disability.
Clinical overview
The International League Against Epilepsy classification system for epilepsy (Table 2) (International League Against Epilepsy 1997) is currently the most prominent. Seizures may be classified according to the characteristics of the individual seizure. Location-related seizures (formerly named partial or local seizures) begin in a part of one cerebral hemisphere. The areas of brain initially involved determine the symptoms of location-related seizures. Seizures involving the motor cortex lead to jerking (clonic) movements or stiffening (tonic) movements. Head turning, eye turning, speech arrest, or unusual arm posturing may occur with frontal-lobe seizures. Seizures originating in the parietal region are associated with sensory symptoms including numbness or tingling. Occipital lobe seizures may lead to visual loss, visual hallucinations, or seeing light flashes or colours. Temporal lobe seizures may cause auditory or olfactory hallucinations. The olfactory hallucinations are often unpleasant smells. Unusual abdominal sensations such as risings or tightness may be noted. Repetitive movements or activities may occasionally be seen with temporal lobe seizures. Déjà vu and jamais vu may occur. Location-related seizures may (simple partial) or may not (complex partial seizures) be associated with altered consciousness. They may secondarily generalize after a focal onset.

Table 2 The International League Against Epilepsy classification of epileptic seizures

Generalized seizures are those that begin in widespread areas of the brain. The most common type of generalized seizure is noted for muscle stiffening followed by jerking (tonic–clonic). Generalized seizures were formerly called grand mal seizures. Absence seizures (formerly petit mal) consist of brief episodes of staring and lack of responsiveness. Myoclonic seizures involve brief jerks of muscles rather than repetitive clonic movements. Tonic seizures involve a generalized muscle stiffening. Atonic seizures involve sudden loss of muscle tone.
In addition to the individual types of seizures already noted, there are a number of epileptic syndromes recognized by the International League Against Epilepsy classification. These are distinguished by their age of onset, clinical features, electroencephalographic patterns, and clinical course.
Incidence and prevalence
Aspects of epilepsy epidemiology have been reviewed by a number of contemporary authors, among them: Grunewald and Panayiotopoulos (1993), Senanayake and Roman (1993), Annegers (1994), Gordon (1994), Berg et al. (1996), de Bittencourt et al. (1996), Duchowny and Harvey (1996), Anderson et al. (1997, 1999), Ottman (1997), and Kramer (1999). Below we present several studies that focus on the incidence and prevalence of epilepsy.
Hauser et al. (1996) reported the age-adjusted incidence of epilepsy as 44 per 100 000 person-years, based on data from the Rochester Epidemiology Project spanning approximately a 50-year period up to 1980. Reassessment in that same population for 1980 to 1984 yielded a consistent though slightly higher estimate of epilepsy incidence (Zarrelli et al. 1999). Importantly, Hauser et al. noted that the incidence and prevalence of epilepsy and unprovoked seizures decreased with calendar time among children and increased among the elderly. The prevalence of active epilepsy among those aged 75 or older was reported as 1.5 per cent (as of January 1980). About 1 per cent of persons under age 20 experienced epilepsy; Hauser et al. (1996) noted that their prognosis was generally favourable with most achieving control within 2 years. Kramer et al. (1998) reported the distribution of different seizure types, among 440 children with two or more unprovoked seizures, attending the paediatric neurology clinic in Tel Aviv. Partial seizures accounted for 52 per cent and primary generalized seizures 33 per cent among children.
Olafsson and Hauser (1999) conducted a survey in rural Iceland determining the prevalence of recurrent unprovoked seizures. Records of primary care physicians and neurologists were used for case identification. The crude age-adjusted prevalence was observed to be 4.8 per 1000 population. Similarly, Beilmann et al. (1999) reported on epilepsy in Estonia. The prevalence of ‘active epilepsy’, as of December 1997, among persons aged 1 month to 19 years was 3.6 per 1000. Beilmann et al. concluded that the prevalence of childhood epilepsy in Estonia was similar to that found in other developed countries. However, Beilmann et al. included as ‘active epilepsy’ all those with ‘at least one seizure during the last 5 years, regardless of treatment’. Case definition causes concern about the comparability of prevalence proportions obtained. Another example of case definition was presented by Wallace et al. (1998), who counted only treated epilepsy for the incidence and prevalence numerators. Treated epilepsy implied specifically that identified cases must be taking antiepileptic medication. Despite this restriction, Wallace et al. reported a 1995 prevalence of 5.15 per 1000 persons, rather consistent with other overall estimates. Prevalence increased with age from 3.6 per 1000 in 5- to 9-year-olds to 7.54 per 1000 among those aged 80 to 84. These estimates are considerably higher than those reported by Hauser et al. (1996).
Another method of case ascertainment was used by Nicoletti et al. (1998, 1999), to study epilepsy and other neurological conditions in Bolivia. For this study a ‘door-to-door survey’ was conducted; 10 000 persons were screened, approximately 1000 were referred to neurologists, and of those, 112 were determined to have active epilepsy, leading to a prevalence estimate of 11.1 per 1000. In contrast to studies reported above (Hauser et al. 1996; Wallace et al. 1998), the highest prevalence occurred in the age group 15 to 24 (20.4 per 1000). Regardless of the shift in peak occurrence the prevalence appears dramatically higher than in other studies. Part of the difference may be due to methods; population screening versus clinic-based surveillance. However, the difference between more and less ‘developed’ countries may also contribute to the disparity.
Persons with epilepsy may experience two to three times the risk of death compared to their unaffected counterparts (Cockerell 1996). Sperling et al. (1999) examined the relationship between recurrent seizure and risk of death; they compared persons whose seizures had been eliminated by surgery to those with recurrent seizures. The standardized mortality ratio for persons with recurrent seizure was approximately fourfold higher than expected. A longitudinal study conducted in The Netherlands (Shackleton et al. 1999) enrolled newly diagnosed epilepsy patients (n = 1355) who were followed for a mean of 28 years. Overall, they observed a threefold excess in all cause mortality, and a sevenfold increase among those under age 20. A substantial part of the increased mortality was said to be due to the epilepsy itself. Loiseau et al. (1999) studied short-term mortality after first afebrile, provoked, or unprovoked seizure (n = 804). After 1 year of follow-up no deaths had occurred among patients with idiopathic seizures. Increased standardized mortality ratios were observed for those with provoked seizures or seizures related to other central nervous system disorders.
Sudden unexplained death in persons with epilepsy (SUDEP) (Annegers and Coan 1999) is a substantial risk in younger-aged persons as compared to individuals without epilepsy. Much of the excess risk may be associated with seizure severity, with greater severity leading to greater risk of death (Annegers and Coan 1999). Careful definition of SUDEP is necessary as is attention to methodological detail; early findings may have been the result of selection bias and similar problems (Ficker et al. 1998). In a population-based study in Rochester, Minnesota, all persons diagnosed with epilepsy between 1935 and 1994 were followed to determine cause of death. SUDEP rates were compared to the rate of sudden unexplained death in the general population for ages 20 to 40. Although the SUDEP death rate exceeded the expected by 23.7 times, it was still a rare cause of death accounting for only 1.7 per cent of the deaths in the epilepsy cohort. Nilsson et al. (1999) investigated SUDEP in Sweden, focusing on risk factors. They found that patients with 50 seizures per year were about 10 times more likely to succumb to SUDEP than patients with two or fewer seizures. Risk of SUDEP was also substantially increased with the number of concomitant antiepileptic drugs, and among those who had frequent medication changes. Compared to the general population the cohort of epilepsy patients experienced an all-cause mortality approximately 3.6 times greater than the general population, with the majority of the excess mortality due to malignant neoplasms; diseases of the circulatory, respiratory, and digestive systems; injury; and poisoning (Nilsson et al. 1997). McGugan (1999) provides a current review of SUDEP and notes that young male epileptics with generalized seizures are at greatest risk. The mechanism of death in cases is of course, ‘unexplained’; however, many persons have ischaemic damage to the heart even though coronary arteries appear normal (McGugan 1999).
Infectious causes of epilepsy
In developing countries infections are a much more important cause of epilepsy than in the United States and Europe (Senanayake and Roman 1993); overall prevalence of epilepsy may approach 57 per 1000 population. Parasitic, bacterial, and viral infections contribute substantially to this, but hereditary factors, perinatal damage, head trauma, and toxic exposures also play important aetiological roles. From a public health view, the excess risk attributable to many of these exposures is potentially preventable (Senanayake and Roman 1993).
An example of an important infectious risk factor is Taenia solium cysticercosis (from pork tapeworm) which can lead to neurocysticercosis. Palacio et al. (1998) examined a series of 643 epilepsy patients in Columbia, of whom 376 had serological tests for cysticercus. The prevalence of antibody was 17.5 per cent among late-onset epilepsy patients. Among patients with no CT scan evidence of neurocysticercosis, only 2.7 per cent had antibody. However, a similar study conducted in Honduras (Sanchez et al. 1999) raises questions as to the validity of the serology antibody tests in predicting neurocysticercosis. Sanchez et al. conclude CT scan findings of neurocycticercosis are necessary for diagnosis. Even though the population is frequently exposed to T. solium, as indicated by serology, neurocysticercosis is not always the result. A different view is presented by Bern et al. (1999). They combined data from 12 population-based community studies in Peru and showed a seroprevalence of 6 to 24 per cent. The high seroprevalence was presented as evidence for the prevalence of neurocysticercosis. Bern et al. estimated a burden of 23 000 to 39 000 symptomatic neurocysticercosis cases in Peru. Extrapolating from these data, Bern et al. concluded that cysticercosis is a formidable cause of neurological disease in Latin America. Whether seropositivity is synonymous with neurocysticercosis appears controversial. The common occurrence of the T. solium cyst may account for an important fraction of epilepsy in Latin American countries.
The rapid progress in mapping the human genome has led to many important findings and will likely continue to do so. The potential contribution of genes to the aetiology of epilepsy has been recently reviewed or commented on by a number of authors, including Berkovic (1997), Ottman (1997), Leppert and Singh (1999), Noebels (1999), Steinlein (1999), and Weissbecker et al. (1999).
The gene story in epilepsy is far from complete or clear at this time. There appears to be substantial genetic heterogeneity, and not all findings of association or linkage have been confirmed. There is some degree of consensus, however, that idiopathic generalized epilepsies are likely to have a genetic aetiology (Steinlein 1999). Delgado-Escueta et al. (1999) points out that approximately half of the prevalent epilepsies in the United States are generalized epilepsies and that, of those cases, juvenile myoclonus epilepsy and childhood absence epilepsy may account for 15 to 45 per cent. Potential gene sites for these two types of epilepsy have been identified on chromosomes 1p, 3p, 6p, 8q, and 15q. Phillips et al. (1998) report similar genetic heterogeneity for autosomal dominant frontal-lobe epilepsy with possible sites on 15q and 20q. Plaster et al. (1999) report identification of a locus for familial adult myoclonic epilepsy, another idiopathic generalized epilepsy, on chromosome 8q. Xiong et al. (1999) conducted a linkage study in two large French-Canadian families with familial partial epilepsy syndrome with variable foci, identifying a locus on 22q. However, they acknowledge that an Australian family with similar phenotype showed no linkage to chromosome 22—again indicating genetic heterogeneity. Lopes-Cendes et al. (2000) conducted a genome-wide search for linkage to generalized epilepsy with febrile seizures, and located a linked marker on 2q. However, recognizing that there are multiple phenotypes within the kindred, they also suggest that genetic or environmental factors may modify the effect of the 2q to generalized epilepsy with febrile seizures gene.
Because of the observed phenotypic and genetic heterogeneity, environmental factors may play a role in the expression of disease. Larger epidemiological studies may provide a mechanism for observing that interaction (Ottman and Susser 1992; Ottman et al. 1996). Furthermore, genetic epidemiology has been developing rapidly over the past decade, undoubtedly helping to address and clarify the complexities of gene–gene and gene–environment interactions.
Costs and public health burden
The costs of epilepsy are often categorized as direct and indirect (Begley et al. 1999, 2000; Beghi et al. 2000). The direct costs refer to those specifically involved with epilepsy treatment; the indirect costs include lost work days and unrealized earnings. Begley et al. (2000) estimate that the 181 000 new cases of epilepsy in the United States in 1995 will result in a lifetime cost of $11.1 billion. The 2.3 million prevalent cases, in 1995, resulted in an annual cost of $12.5 billion. Begley et al. (1999, 2000) estimate that indirect costs may account for 85 per cent of the total and that the largest share of direct costs is attributable to patients with intractable epilepsy. Annegers et al. (1999) caution that cost figures for the United States and Europe may derive from different methodologies, thus methods may influence the degree of comparability. With regard to the quality of life reported by persons with epilepsy, Leidy et al. (1999) report that seizure frequency is inversely associated with health-related quality of life. Seizure-free individuals report a quality of life similar to the general population; however, more seizures lead to a poorer quality of life, regardless of additional comorbidity and irrespective of gender. Effective seizure control appears to be important in reducing costs as well as increasing patient quality of life.
Clinical overview
Dementia presents with a slowly progressive loss of cognitive function. This often begins with trivial forgetfulness, but progresses to more serious cognitive impairment. Behavioural changes may be prominent, including agitation, wandering, personality change, or depression. In late stages, patients may be completely dependent on others. Various definitions of dementia have been used in past research studies, but the Diagnostic and Statistical Manual of Mental Disorders, edition IV (DSM-IV) is the most commonly used (American Psychiatric Association Task Force 1994). The DSM-IV criteria for dementia require memory impairment and one or more additional cognitive disturbance. These include aphasia (language disturbance), apraxia (impaired ability to carry out motor activities despite intact motor function), agnosia (failure to recognize or identify objects despite intact sensory function), and disturbances in executive functioning (i.e. planning, organizing, sequencing, abstracting). The cognitive deficits must be severe enough to cause significant impairment in social or occupational functioning and represent a significant decline from a previous level of functioning. Dementia must be differentiated from delirium. The causes of dementia are listed in Table 3.

Table 3 Causes of dementia

Although Alzheimer’s disease is the most common form of dementia, many other disorders must be considered, including drug-induced conditions, alcoholism, stroke, Parkinson’s disease, Huntington’s disease, subdural haematoma, brain tumours, hydrocephalus, vitamin B12 deficiency, hypothyroidism, neurosyphilis, and HIV infection. Criteria for the diagnosis of Alzheimer’s disease have been proposed (McKhann et al. 1984; American Psychiatric Association Task Force 1994).
Vascular dementia is difficult to differentiate from Alzheimer’s disease because of the common association of stroke and Alzheimer’s disease in the elderly. The more sophisticated the search for stroke, the more likely strokes will be found. The clinical identification of stroke is surpassed by CT, which is surpassed by MRI. However, the false-positive identification of stroke also increases. Many different criteria have been developed to diagnose vascular dementia (Chui et al. 1992; Roman et al. 1993; American Psychiatric Association Task Force 1994). Much of the pioneering work in the definition and recognition of vascular dementia can be attributed to Hachinski and colleagues (Hachinski 1983, 1990, 1991, 1994; Wade and Hachinski 1986; Larson et al. 1989; Pantoni and Inzitari 1993; Rockwood et al. 1999; Rockwood et al. 2000).
Recently two additional types of dementia, Lewy body disease (McKeith et al. 1992) and frontotemporal dementia (Anonymous 1994), have been separated from Alzheimer’s disease based on their clinical presentations and pathology. Lewy body disease presents with cognitive losses. In addition fluctuating cognitive performance, visual hallucinations, and parkinsonism are suggestive of this disease. Memory impairment may not necessarily be prominent in the early stages. Deficits in attention, frontal subcortical skills, and visuospatial ability predominate.
In frontotemporal dementia, changes in behaviour dominate the early course of the disease. These include loss of personal awareness, loss of social graces, disinhibition, overactivity, restlessness, impulsivity, distractibility, hyperorality, withdrawal from social contact, apathy or inertia, and stereotyped or perseverative behaviours. Speech-output changes occur, including progressive reduction of speech, stereotypy of speech, perseveration, and echolalia. Physical signs include early or prominent primitive or ‘frontal’ reflexes, early incontinence, late akinesia, rigidity, and tremor. Deficits in social comportment, behaviour, judgement, or language are out of proportion to the memory deficit. The memory loss is variable and often appears to be due to lack of concern or effort. Frontal-lobe impairments are notable, including those in abstraction, planning, and self-regulation of behaviour. There are several pathologies that may lead to frontotemporal dementia, including some with dominantly inherited mutations related to the protein tau.
Dementia and Alzheimer’s disease
Prevalence and incidence
Evans et al. (1989) reported the results of a community study in East Boston. The prevalence estimates for dementia and Alzheimer’s disease were based on a complex community-sampling scheme (Beckett and Evans 1994). The results of this study remain controversial but are also widely cited to place an upper bound on potential prevalence of dementia in communities in the United States. Prevalence rose from 3 per cent among those aged 65 to 74 years to 47 per cent in those over 85. Over 80 per cent of the observed dementia cases were classified as Alzheimer’s disease. Evans et al. later applied the observed rates to census data, projecting that 10.3 million people would have Alzheimer’s disease in the year 2050. Recently, a meta-analysis of prevalence studies, worldwide, was conducted (Fratiglioni et al. 1999); it was noted that prevalence and incidence rates were geographically consistent except for variation due to methodological differences. Prevalence rose from 0.3 to 1.0 per cent in those aged 60 to 64, to between 43 and 68 per cent in persons aged 95 or older. As a summary figure, prevalence is often reported as 6 to 10 per cent among persons aged 65 or older in North America (Hendrie 1998). Brookmeyer et al. (1998) have estimated that in 1997 there were approximately 2.32 million persons with Alzheimer’s disease in the United States; if disease onset could be delayed 2 years there would be 2 million fewer cases in the future.
The substantial burden of dementia prevalence is a function of disease incidence and subsequent survival. Jorm and Jolley (1998) gathered data from 23 studies and produced a meta-analysis of dementia incidence. Incidence was estimated for Europe, the United States, and East Asia; dementia, Alzheimer’s disease, and vascular dementia rates were computed. Incidence rates for the United States and Europe were quite similar: ‘moderate’ dementia incidence rose from 3.6 per 1000 person-years (ages 65 to 69) to 37.7 per 1000 person-years (ages 85 to 89) in Europe, and from 2.4 to 27.5 per 1000 person-years for the same age groups in the United States. The incidence of ‘mild’ Alzheimer’s disease was also computed, and ranged from 2.5 per 1000 person-years (ages 65 to 69) to 46.1 per 1000 person-years (ages 85 to 89), for Europe, compared with 6.1 to 74.5 for the United States, and, 0.7 to 39.7 for East Asia.
Rocca et al. (1998) reanalysed dementia and Alzheimer’s disease incidence data for 1975 through 1984, based on charted data from the Rochester Epidemiology Project at Mayo Clinic. The results showed dementia incidence overall as 2.2 per 1000 person-years in those aged 65 to 69, rising to 40.8 per 1000 person-years in those aged 90 or more. Similarly for Alzheimer’s disease, rates rose from 1.2 to 33.9 per 1000 person-years. Rocca et al. noted that annual incidence appeared to stay rather stable during the 1975 to 1984 time interval. After disaggregating the data for the oldest old, Rocca also reported that rates appeared to continue to rise with age after age 84; they also noted that rates were similar for men and women.
The combined analysis of four large ongoing European cohort studies of dementia and Alzheimer’s disease was recently reported by Launer et al. (1999). Cohorts enrolled in Denmark, France, The Netherlands, and the United Kingdom summed to more than 16 000 members aged 65 or older at enrolment. After a mean follow-up of 2.2 years (comprising approximately 28 600 person-years) the overall incidence of dementia was 14.6 per 1000 person-years, with about two-thirds of these cases due to Alzheimer’s disease. Incidence of dementia was 2.5 per 1000 person-years at ages 65 to 69, and rose to 85.6 per 1000 person-years in those aged 90 and older. Similarly Alzheimer’s disease rose from 1.2 per 1000 person-years to 63.5 per 1000 person-years across the same age groups. Launer et al.’s report is one of the first using data from large cohort studies which are now underway in Europe and in the United States. As more cohort studies begin to report incidence, consistent estimates are likely to emerge.
Although, presumably, the majority of the difference between the rates of dementia and Alzheimer’s disease reported above reflect vascular dementia, this cannot be stated with certainty. Despite diagnostic criteria for vascular dementia (Chui et al. 1992; Roman et al. 1993), this syndrome remains an area of controversy and uncertainty (Nyenhuis and Gorelick 1998; Chui and Gonthier 1999; Gorelick et al. 1999; Leys et al. 1999; Roman 1999a,b). Application of the diagnostic criteria has been shown to be difficult and unreliable in practice, even by experienced research investigators (Chui et al. 2000). Many of the reliability and validity problems experienced by investigators in classifying a case as ‘vascular’ or Alzheimer’s disease may stem from the mutual exclusion of the two conditions, imposed by the diagnostic criteria. There is growing interest concerning a potential vascular component contributing to dementia in Alzheimer’s disease (Brayne et al. 1998; Breteler et al. 1998; Copeland et al. 1999; Di Iorio et al. 1999; Goulding et al. 1999; Leys et al. 1999; Meyer et al. 2000).
Because identification of late-stage dementia and Alzheimer’s disease holds little hope for treatment applications or for identification of consistent risk factors, interest has begun to focus on early identification of disease. Early forms of pre-Alzheimer’s disease or dementia are difficult to distinguish from relatively benign cognitive decline associated with ageing. However, when mild cognitive decline can be identified it appears that perhaps 50 per cent may progress to become dementia (Almkvist et al. 1998; Wolf et al. 1998; Almkvist and Winblad 1999; Petersen et al. 1999; Celsis 2000). Distinguishing between normal persons, those with mild cognitive impairment, and those with incipient dementia/Alzheimer’s disease may provide important clues about risk factors and critical periods of exposure prior to disease onset. Reliable and valid distinction may also help to determine whether mild cognitive impairment is a treatable and reversible phenomenon.
Risk (and protective) factors for Alzheimer’s disease
Until the mid-1990s most analytical observational studies of Alzheimer’s disease were based on a case–control design. In this design, cases of disease were identified and their exposure histories were compared to those of persons without the disease. The design itself is well accepted as a method of study. However, in the case of Alzheimer’s disease (and dementia) problems with case ascertainment, case selection, and exposure measurement may have caused at least some results to be biased or spurious. Now, as cohort studies of Alzheimer’s disease and dementia are beginning to emerge, findings which were viewed as consistent in case–control studies are being questioned or refuted. One example of this concerns the observation of a potential protective effect for Alzheimer’s disease associated with cigarette smoking. A meta-analysis of smoking–Alzheimer’s disease studies showed a consistent decreased risk associated with smoking (Lee 1994). The majority of these studies were of the case–control design. When case–control studies rely on cross-sectional samples to obtain cases, they are most likely to encounter those cases with the longest survival after diagnosis (Gordis 1996; MacMahon and Trichopoulos 1996; Rothman and Greenland 1998). Also, when decreased postdiagnosis survival among cases is associated with the exposure of interest (e.g. smoking), a potential spurious excess of exposure among controls may be observed. Wang et al. (1999) conducted a cross-sectional and a longitudinal study to observe the smoking–Alzheimer’s disease relationship. They found that while mortality between smoking and non-smoking control subjects was rather similar, Alzheimer’s disease case smokers had a threefold increase in risk of death as compared to Alzheimer’s disease non-smokers. Therefore, because of mortality, smoking would be less common in a cross-sectional sample of Alzheimer’s disease cases than among controls. Cohort studies (Launer et al. 1999; Merchant et al. 1999; Wang et al. 1999; Doll et al. 2000) where this selection bias is eliminated (essentially) now report either ‘no association’ or a potential increased risk of Alzheimer’s disease associated with smoking.
Head trauma (Brayne 1991) has also been shown to be a relatively consistent risk factor for Alzheimer’s disease, primarily based on case–control studies. Here, selective recall or recall bias may be more important than the effect of survival, even though risk of death and/or continued cognitive impairment immediately resulting from the injury is substantial (Anonymous 1998). Several recent longitudinal studies now show negligible risk of Alzheimer’s disease associated with head injury (Launer et al. 1999; Mehta et al. 1999; Nee and Lippa 1999), although others still find some potentially increased risk (Tang et al. 1996; Schofield et al. 1997).
Higher educational level has been proposed as influencing decreased risk of Alzheimer’s disease, but the relationship between education and Alzheimer’s disease may be quite complex (Gainotti et al. 1998 ; Hendrie 1998; Ott et al. 1998; Geerlings et al. 1999a,b; Muller-Spahn and Hock 1999; Stern et al. 1999; Hall et al. 2000; Munoz et al. 2000; Riley et al. 2000). Educational level influences a subject’s likelihood of participation in epidemiological studies. Educational level influences the diagnostic process, at least in the early stages of disease, because of the individual’s ability to respond correctly in testing situations. Education may influence health-care usage and may result in greater income or higher occupational level. The idea that higher education confers greater ‘cognitive reserve’ to be accessed when disease strikes is tantalizing, though biologically unsubstantiated. Recently an important idea was raised concerning the importance of early life development as increasing susceptibility to Alzheimer’s disease (Moceri et al. 2000). The biological plausibility for that association has been recently discussed by Alzheimer’s disease neuropathologists (Braak et al. 1999).
Several ‘protective’ factors for Alzheimer’s disease have been proposed in the past 10 years. These include: anti-inflammatory medications (Breitner 1996; McGeer et al. 1996; Stewart et al. 1997a; Stratman et al. 1997; Hendrie 1998; in ‘t Veld et al. 1998; Mortimer 1998; Combs et al. 2000), oestrogen replacement therapy (Brenner et al. 1994; Haskell et al. 1997; Henderson 1997a,b; Kawas et al. 1997; Baldereschi et al. 1998; Birge 1998; Yaffe et al. 1998; Costa et al. 1999; McEwen and Alves 1999; Waring et al. 1999; Henderson et al. 2000; Mulnard et al. 2000; Nourhashemi et al. 2000; Slooter et al. 1999), and antioxidants such as vitamin C and vitamin E (e.g. Morris et al. 1998). While the initial associations appear relatively consistent across studies, designs differ and conclusions are still tentative. Randomized trials for some are either proposed or underway. Results have given no indication that oestrogen replacement therapy is an effective treatment for Alzheimer’s disease (Henderson et al. 2000; Mulnard et al. 2000). That result, however, does not address oestrogen as a preventive measure.
Alzheimer’s disease is likely to be heterogeneous both diagnostically and aetiologically. What results in the Alzheimer’s disease phenotype may be the sum or product of ageing, environmental factors, genetic constitution, and sociodemographic experiences. Aside from the observable effect of ageing dramatically increasing the risk of dementia and Alzheimer’s disease, success in finding environmental risk factors has been limited and potentially related to design and selection factors.
Genetics and Alzheimer’s disease
Great progress has been made in the genetics of Alzheimer’s disease. However, most of the strict genetic ’causes’ of disease have been limited to so-called ‘familial’ Alzheimer’s disease. Familial Alzheimer’s disease behaves similarly to an autosomal dominant genetic pattern and tends to affect predominantly persons under 60. Familial Alzheimer’s disease, so defined, appears to account for less than 5 per cent of all Alzheimer’s disease, but important clues may be gleaned from the study of familial disease that will apply to the more common form (often called sporadic—but it, too, may have undiscovered genetic causes). Several current reviews of Alzheimer’s disease genetics include Tanzi et al. (1996), Hardy et al. (1998), Levy-Lahad et al. (1998), Price et al. (1998), Tilley et al. (1998), Shastry and Giblin (1999), Sisodia (1999), Steiner et al. (1999), Tanzi (1999), and St George-Hyslop (2000).
The largest proportion of familial Alzheimer’s disease is attributed to mutations in the presenilin 1 gene (chromosome 14) and the next largest known contribution is due to mutations in a homologous gene on chromosome 1, presenilin 2. A very small proportion of cases is due to specific mutations in the amyloid precursor protein gene (chromosome 21). It is abnormal cleavage of the amyloid precursor protein, which results in the formation of amyloid b (1-42) protein. Amyloid b protein aggregates in the brain, forming the characteristic plaques of Alzheimer’s disease. Recently very important work has been published concerning identification of enzymes, which cleave the precursor protein abnormally forming the amyloid b 1-42 protein. This work may ultimately help to identify sites for drug intervention, not only for familial but also for non-familial Alzheimer’s disease (Hussain et al. 1999; Sinha et al. 1999; Steiner et al. 1999; Vassar et al. 1999; Yan et al. 1999; Octave et al. 2000; Phimister 2000). Perhaps one-quarter to one-half of familial Alzheimer’s disease is still of unknown genetic cause (Levy-Lahad et al. 1998; Price et al. 1998; Shastry and Giblin 1999; Sisodia 1999).
Arguably the strongest and most consistent risk factor for non-familial Alzheimer’s disease (other than age) is apolipoprotein E genotype. The association was first described from Allen Roses’ laboratory (Corder et al. 1993; Saunders et al. 1993a,b; Strittmatter et al. 1993; Roses 1994; Roses and Saunders 1994). Apolipoprotein E naturally occurs as three different alleles (e2, e3, and e4) which pair to form one of six genotypes for each individual. Genotypes containing the e4 allele are associated with increased risk of Alzheimer’s disease; homozygous e4 greatly increased risk (e.g. more than eightfold). Since the initial description of increased risk associated with the e4 allele, many investigators have observed the association. Discussion of apolipoprotein E genotype is now included in most risk-factor studies of Alzheimer’s disease, either as a focus or as a potential confounder/effect-modifier of an association. Farrer et al. (1997) provided a meta-analysis of the age and gender effects, and Mayeux et al. (1998) later described caveats for the potential value of apolipoprotein E genotype in Alzheimer’s disease diagnosis. Despite the huge number of studies including apolipoprotein E genotype relatively little is known concerning how the e2, e3, and e4 alleles actually work to influence the risk of Alzheimer’s disease.
Evidence for the effects of other genes on Alzheimer’s disease has also been raised. Alpha-2 macroglobulin was first shown as a potential risk factor by Blacker et al. (1998), but then a number of other investigators failed to replicate the association (Liao et al. 1998; Alvarez et al. 1999; Dodel et al. 2000; Gibson et al. 2000). This association remains controversial. Other genetic associations have been studied but with limited impact to date (Hirano et al. 1997; Hutchin et al. 1997; Pericak-Vance et al. 1997; Ghetti et al. 1999; Lilius et al. 1999; Meier-Ruge and Bertoni-Freddari 1999; Perry 1999; Roks et al. 1999; Shastry and Giblin 1999; Small et al. 1999; Bullido et al. 2000; Nicoll et al. 2000). Progress continues, and there is considerable hope that important genes will be discovered which may provide indications for prevention or therapy.
Peripheral neuropathy
Clinical overview
Though the term peripheral neuropathy may refer to any disease of the peripheral nerves, it is generally used to describe a group of systemic diseases that affect the peripheral nerves rather than focal diseases affecting an isolated nerve. Most of these diseases initially affect longer nerves, with symptoms developing first in the feet and progressing up the legs. There are a few peripheral neuropathies that affect the shorter proximal nerves first. By the time the symptoms have reached the knees, the hands become symptomatic, followed by the anterior trunk and crown of the head. The symptoms that develop depend on the type of nerve fibre involved. Involvement of motor fibres leads to weakness, muscle wasting, and hyporeflexia. If longstanding, motor neuropathies may lead to high arches (pes cavus) or hammer toes. Sensory nerve involvement leads to loss of sensation, distorted sensation (dysaesthesias), or spontaneous unpleasant sensations (paraesthesias). Autonomic neuropathies most commonly lead to postural hypotension but may also include sexual dysfunction, bowel dysfunction, bladder dysfunction, sweating dysfunction, or gastroparesis. The size of the affected nerve fibre can often be suggested by the history, with disease of large fibre causing reflex loss, vibration loss, and joint position loss. Small fibre disease often leads to autonomic dysfunction, dysaesthesias, loss of pain sensation, and loss of temperature sensation.
Electrodiagnostic testing is often performed to diagnose and further classify peripheral neuropathies. Nerve conduction velocities can be used to classify peripheral neuropathies into those that are demyelinating and those that are axonal. Demyelinating neuropathies lead to disproportionate slowing of nerve conduction speeds and increases in latency of responses. Axonal diseases cause disproportional loss of amplitude with relative preservation of conduction speed. Nerve conduction studies measure only the fast-conducting large-diameter fibres. Electromyography measures the electrical activity of muscle fibres. It is useful in diagnosing a number of muscle and myoneural junction diseases. The use of electromyography in the diagnosis of peripheral neuropathy is primarily in recognizing the loss of innervation of muscle fibres by large myelinated neurones. Loss of innervation leads to increased insertional activity, positive waves, fibrillation potentials, polyphasic motor unit potentials, and decreased recruitment patterns.
Generally, polyneuropathies are the result of lesions involving many peripheral nerves and result in autonomic neuropathies, sensory loss, or weakness. Mononeuropathies, as the name implies, involve a single nerve injury or entrapment. Carpal tunnel syndrome and Bell’s palsy are common examples of mononeuropathies. Peripheral nerve disorders are also often classified as either hereditary or acquired. Charcot–Marie–Tooth syndrome is perhaps the most well-known hereditary form. Acquired nerve disorders are commonly associated with trauma or compression, diabetes, alcoholism, and other nutritional and metabolic problems. They may also be related to infectious causes such as Guillain–Barré syndrome, leprosy, Lyme disease, or HIV infection; or, they may be caused by toxic exposures to metals (e.g. lead, mercury) or industrial chemicals, or even by therapeutic drugs (e.g. antineoplastic agents) (Rowland and Merritt 1995).
Carpal tunnel syndrome
First characterized in 1880 by James J. Putnam, carpal tunnel syndrome is probably the most common neuropathy (Sternbach 1999). Carpal tunnel release surgery is also one of the most common hand surgeries performed in the United States (Rayan 1999). Franklin et al. (1991) reported that ‘occupational’ carpal tunnel syndrome resulting from repetitive, higher-impact actions may differ from carpal tunnel syndrome occurring in a non-occupational setting. Specifically, occupational carpal tunnel syndrome appeared to occur nearly equally among men and women and at a substantially lower mean age than had been reported for non-occupational carpal tunnel syndrome (37 versus 51 years). Based on workmen’s compensation records over the period 1984 to 1988, an incidence of 1.74 per 1000 full-time equivalent jobs was observed (Franklin et al. 1991). Abbas et al. (1998) conducted a meta-analysis of work-related carpal tunnel syndrome. They showed that force and repetitive motion were important predictors of carpal tunnel syndrome after adjusting for study population and country of origin.
A general population estimate of carpal tunnel syndrome incidence was reported by Nordstrom et al. (1998). Medical records of all cases occurring in 2 years in a defined population were reviewed and classified as definite or probable carpal tunnel syndrome. In contrast to the occupational carpal tunnel syndrome incidence observed by Franklin et al. (1991), as well as other previous incidence estimates, Nordstrom et al. reported a carpal tunnel syndrome incidence of 3.46 per 1000 person-years. The apparent secular increase in incidence may reflect a true change in incidence or may be partially due to popular knowledge of the condition and diagnostic suspicion. Prevalence of symptoms in relation to true disease prevalence is also an important consideration (Atroshi et al. 1999). Reported carpal tunnel syndrome symptoms of tingling, pain, and numbness have shown a prevalence of about 14 per cent, whereas carpal tunnel syndrome was clinically and electrophysiologically confirmed in less than 3 per cent. Atroshi et al. (1999) conclude that symptoms of carpal tunnel syndrome are common but only about 1 in 5 of the persons complaining of symptoms is likely to actually have confirmed carpal tunnel syndrome.
Studying carpal tunnel syndrome patients recruited from physicians’ offices, Katz et al. (1998) attempted to describe predictors of work absence. Approximately 70 per cent of the 315 patients had undergone surgery, the majority women. After 30 months of follow-up, those who began with worse functional status were more likely to have missed work. The other major predictor of work absence was reported to be having a ‘contested Worker’s Compensation claim’.
Non-occupational factors related to the occurrence and treatment of carpal tunnel syndrome were studied by Solomon et al. (1999) and Stallings et al. (1997). Solomon et al. found that carpal tunnel syndrome patients with inflammatory arthritis were about three times more likely to undergo carpal tunnel release surgery; patients with diabetes and hypothyroidism were also significantly more likely to receive surgery. Obesity has been reported as a risk factor for the occurrence of carpal tunnel syndrome, an association that was addressed in a case–control study by Stallings et al. (1997). Results indicated that obesity, as determined by body mass index, was significantly more common among cases than among control subjects.
Diabetes mellitus
Diabetes is a common, yet complex, cause of both mono- and polyneuropathies (Rowland and Merritt 1995). Peripheral neuropathy may affect more than 30 per cent of diabetes patients. More effective glucose control could reduce the risk to some extent (Boulton 1998a, b). Patients with diabetes have a higher hospital admission rate, length of stay, and mortality than non-diabetics (Currie et al. 1998), indicating the potential human and economic cost of the disease.
Dyck et al. (1997, 1999) developed a composite score for assessing the degree of diabetic polyneuropathy, then conducted a longitudinal study of 264 diabetics to determine how hyperglycaemia related to diabetic polyneuropathy. Microvessel disease, chronic hyperglycaemia, and type of diabetes were the most important predictors of polyneuropathy. Orchard et al. (1996) have also shown that among insulin-dependent diabetes mellitus patients diabetic autonomic neuropathy is strongly influenced by chronic hyperglycaemia and is associated with increased mortality. A study of diabetic peripheral neuropathy in 16 European countries identified several additional risk factors: elevated diastolic blood pressure, ketoacidosis, elevated fasting triglyceride level, and microabuminuria (Tesfaye et al. 1996).
Nutritional neuropathies
An epidemic of peripheral neuropathy was reported in Cuba during 1992 and 1993 (Roman 1994). That epidemic was said to affect over 50 000 Cubans and achieved a cumulative incidence rate of 461 per 100 000. An optic form and a peripheral form of the disease were observed. Extensive search for toxic exposures and a variety of other risk factors eventually lead to nutritional deficiency as the principal explanation for the outbreak. (Roman 1994; Hedges et al. 1997). Intervention and treatment with multivitamins, in particular B vitamins, acted to stop the outbreak.
HIV infection
Because of the prevalence of HIV in many countries, it is important to consider the prevalence of peripheral neuropathy among HIV-infected cases. This reached 44 per cent in one African study (Parry et al. 1997). Distal symmetrical polyneuropathy was predominant in persons with frank AIDS. One potential cause of that neuropathy is the AIDS therapy itself (Moyle and Sadler 1998). Specifically, nucleoside analogue reverse transcriptase inhibitors may act, in about 10 per cent of patients, to promote neuropathy. The severity of the neuropathy may then cause patients to discontinue the needed therapy.
Clinical overview
There are four cardinal features of parkinsonism: tremor, rigidity, bradykinesia, and postural gait changes. Though there are no established criteria, the diagnosis of parkinsonism usually requires two or more of these symptoms. The tremor of parkinsonism may take many forms. The most common form of tremor in parkinsonism has a frequency of 4 to 6 Hz. It is most prominent at rest, lessening with volitional movements. It has a somewhat rotary component with the ‘pill rolling’ tremor of the hands classically described. The hands are most prominently affected but the head, trunk, and legs may also be involved. Emotional stress may aggravate the tremor. The rigidity of parkinsonism is often described as ‘lead pipe rigidity’. This rigidity is approximately equal in flexor and extensor muscles in contrast to the rigidity seen in spasticity, which is not equal. The rigidity is present throughout the full range of motion and is not dependent on speed of movement. The combination of rigidity with superimposed tremor constitutes ‘cogwheeling’, two of the four cardinal features of parkinsonism. Bradykinesia may take a number of forms, including the masked face with loss of blinking, wide-eyed staring, and loss of facial expression. Speech may be hypophonic, rapid, and without the usual modulations of pitch, enunciation, or emotion. Bodily movements become slowed with fewer spontaneous movements of the limbs. Rapid repetitive movements of the limbs are slowed. There may be a marked latency before planned movements are begun. Postural gait changes lead to a stooped posture with kyphosis, flexed arms, flexed legs, and loss of arm swing. The gait becomes unstable with patients being unable to reflexively recover from minor imbalances. The centre of balance may get progressively ahead of the patient as they walk leading to a ‘festinating gait’. In severe cases, patients may be unable to move (freezing) when they encounter minor obstacles such as doorways or cracks (Rowland and Merritt 1995). While movement disorder specialists make the diagnosis of parkinsonism with some degree of confidence, Parkinson’s disease usually requires histopathological confirmation. In an attempt to increase the accuracy and validity of clinical diagnosis, improvements in clinical diagnostic criteria have been proposed (Gelb et al. 1999; Jankovic et al. 2000).
Parkinsonism includes several major subclasses: idiopathic parkinsonism (Parkinson’s disease), symptomatic parkinsonism (drug-induced, toxin-induced, and other specific causes), ‘Parkinson-plus’ syndromes (multiple system atrophy, progressive supranuclear palsy), and hereditary degenerative diseases (Hallervorden–Spatz disease, Huntington’s disease). Parkinson’s disease, or idiopathic parkinsonism comprises approximately 80 per cent of parkinsonism (Rowland and Merritt 1995).
Multiple system atrophy is sometimes misdiagnosed as Parkinson’s disease; it is a relatively rare and very debilitating condition, usually involving progressive autonomic failure plus poor responsiveness to levodopa or cerebellar ataxia (Gilman et al. 1998; Kaufmann 1998; Lantos 1998; Austin et al. 1999; Oertel and Bandmann 1999; Siemers 1999; Swan and Dupont 1999). There is some speculation that multiple system atrophy may be a synucleinopathy (Goedert and Spillantini 1998; Wakabayashi et al. 1998; Dickson et al. 1999). The role of environmental toxins in the pathogenesis of multiple system atrophy has also been discussed but little evidence for such an association has been established to date (Hanna et al. 1999).
Incidence and prevalence of Parkinson’s disease
Prevalence has been reported with dramatic inconsistency. Case ascertainment, age structure of the population, and study design may account for some part of the variability. Certainly door-to-door screening may find more disease than relying on medical records or death certificates. Decisions regarding the inclusion of institutionalized subjects in a screening effort may also impact obtained prevalence.
Consider that Parkinson’s disease prevalence typically has been reported in the range of about 50 to 200 per 100 000 population, with a maximum of about 350 per 100 000. Examples in this range include 117.9 per 100 000 in Japan (Kusumi et al. 1996), 115 per 100 000 in Sweden (Fall et al. 1996), and 168 to 196 per 100 000 in Italy (Chio et al. 1998). Morgante et al. (1992) conducted a study in Sicily and found 63 Parkinson’s disease cases among 24 496 persons in the population base, which results in a prevalence proportion of 257.2 per 100 000 (or 0.257 per cent). The Rotterdam Study (de Rijk et al. 1995) reported identifying a total of 97 Parkinson’s disease cases from among 6969 enrolled subjects age 55 or older, for a crude prevalence of 1.39 per cent or 1392 per 100 000. Recently, the combined results of five European studies were published (de Rijk et al. 1997). These included 14 636 persons age 65 or older; after age-adjusting to the European 1991 standard population the prevalence of Parkinson’s disease was reported as 1.6 per 100 population (presumably age 65 or older). This translates to about 1600 per 100 000. In addition, the age-specific prevalence of Parkinson’s disease was reported to increase from 0.6 per cent in 65- to 69-year-olds to 3.5 per cent in 85- to 89-year-olds (or 600 to 3500 per 100 000) (de Rijk et al. 1997).
The example above is instructive. Not only must the reader attend to differences in case ascertainment when evaluating reported prevalence estimates, but also attention should be directed to the base from which the prevalence proportion is calculated. Limiting the base to only those subjects above a particular age can have dramatic effects on the reported proportion with disease. Furthermore, when restricted base figures are reported along with, perhaps, more conventional total population prevalence proportions, it may be easy for the reader to misinterpret findings.
Incidence rates for Parkinson’s disease and parkinsonism carry many of the same caveats raised for prevalence. In addition, confusion is added by choosing to report incidence in terms of person-years, or per population per year, or perhaps as projected cumulative lifetime incidence. With some effort, or with some assumptions, conversions can be made, but this may not be obvious to the reader. For example, Kusumi et al. (1996) reported Parkinson’s disease incidence in a Japanese city as 15.0 per 100 000 population per year (1989 to 1992); Fall et al. (1996) reported Parkinson’s disease incidence in Sweden (age adjusted) as 7.9 per 100 000 person-years; and Hofman reported Parkinson’s disease incidence in The Netherlands as 11 per 100 000 person-years. Bower et al. (1999) studied the incidence of parkinsonism and Parkinson’s disease in Rochester, Minnesota, 1976 to 1990. The overall figures for Parkinson’s disease showed an incidence rate of 10.8 per 100 000 person-years (i.e. based on the entire age distribution population). The age-specific incidence for ages 50 to 59 was 17.4 per 100 000 person-years, rising to 52.5 for ages 60 to 69, and peaking at 93.1 for ages 70 to 79 and 79.1 for ages 80 to 99. Parkinsonism showed an overall incidence rate of 25.6 per 100 000 person-years and rose from 26.5 at ages 50 to 59 to 304.8 per 100 000 person-years in those aged 80 to 99.
Age-specific incidence rates provide critical information not available from summary rates. The strong influence of age on the disease process is evident from the Rochester data: the incidence among those aged 0 to 29 is practically nil, while the incidence triples from 50 to 59 to 60 to 69, then nearly doubles again in the 70 to 79 age group (Bower et al. 1999). How ageing contributes to the degenerative process of Parkinson’s disease or how aging increases susceptibility to genetic and environmental risk factors is important in describing the epidemiology of parkinsonism and Parkinson’s disease.
Risk factors
A number of excellent reviews are available that discuss the epidemiology and risk factors for Parkinson’s disease, for example Schoenberg (1987), Ben-Shlomo (1997), Langston (1998), Checkoway and Nelson (1999), and Tanner and Ben-Shlomo (1999).
The controversy over environmental and genetic causes of Parkinson’s disease provides the current focus. Clear and consistent evidence of specific, strong, environmental risk factors has not been found. However, the possibility of environmental causes was increased by the observation that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a ‘designer’ street drug, was observed to cause acute Parkinson’s disease shortly after ingestion. Because the structure of this drug and its metabolism products are somewhat similar to some pesticides and herbicides, there was and is great interest in exploring the potential for those types of exposures as risk factors or causes of Parkinson’s disease. Similarly, observations focusing on family history and familial cases, along with the rapid increase in information available on the human genome, has led to new interest in describing the genetics of Parkinson’s disease.
Rural living, well-water consumption, and pesticide/herbicide exposure are reported relatively frequently as potential risk factors for Parkinson’s disease, although neither critical time periods and duration for these exposures to influence onset, nor specific mechanisms have been identified. For example, a case–control study conducted by Gorell et al. (1998) found about a fourfold increase in risk of Parkinson’s disease for exposure to herbicides and insecticides and nearly a threefold increase in risk of Parkinson’s disease for those who had a farming occupation (but no increase for rural or farm residence, nor well-water use). Marder et al. (1998) found an association between farming, rural living, and well water in a multiethnic case–control study, but that association held only for African Americans and not for Hispanics. Kuopio et al. (1999) conducted a population-based case–control study in Finland and found no association between farming, drinking water, pesticide/herbicide use, and Parkinson’s disease, but they did show that cases had a history of fewer domestic animals at home.
An association between exposure to metals and Parkinson’s disease has been described by Gorell et al. (1999a, b). An association was noted with manganese exposure and with copper, also with combinations of lead and iron or copper. While interesting, it raises the question of whether the manganese association represented manganism rather than Parkinson’s disease.
Smoking has been rather consistently associated with decreased risk of Parkinson’s disease in reported reviews (Ben-Shlomo 1997; Langston 1998; Checkoway and Nelson 1999; Tanner and Ben-Shlomo 1999) and in individual studies (Tzourio et al. 1997; Rybicki et al. 1999; Taylor et al. 1999; Werneck and Alvarenga 1999). Reasons for the plausibility of such an association revolve around the potential action of nicotine on neurones. Although this is one of the more consistent findings it is not completely without alternative explanations. Most epidemiological studies of Parkinson’s disease use ‘prevalent’ or existing cases in their studies. The low incidence of Parkinson’s disease effectively precludes concentrating on only newly diagnosed cases in all but the largest of studies (or in very large cohort studies). When attempting to identify a cross-sectional sample of cases for enrolment into a case–control study, it can be shown that those patients who have had the disease the longest are the most likely to be included. The most severe, short duration, or rapidly declining cases tend to be missed. If Parkinson’s disease cases who had a history of smoking were much more likely to die than non-smoking Parkinson’s disease cases, and if, at the same time, the smoking–non-smoking mortality differential was somewhat less among the controls, the cross-sectional sampling of cases and controls could give the spurious impression of an excess of smoking among controls. The excess numbers of smokers among controls might then be misinterpreted as a causal protective effect.
Interest in pesticide exposure as a potential cause led to a new approach for evaluating the occurrence of susceptible persons. Specifically, some persons may be more, or less, able to metabolize environmental toxins because of polymorphic genes involved in metabolism. One of the family of cytochrome P-450 biotransformation genes, CYP2D6, is involved in metabolism of debrisoquine (structurally similar to pesticides); some polymorphic forms are ‘poor’ metabolizers and others are normal or rapid metabolizers of debrisoquine. Initial studies appeared to show that poor metabolizers were at increased risk of Parkinson’s disease but later studies and meta-analyses fail to support this conclusion (Christensen et al. 1998; Joost et al. 1999; Sabbagh et al. 1999).
A similar approach has been taken to identify susceptibles focusing on polymorphic forms of glutathione transferases, which are involved in the metabolism of pesticides and other xenobiotics. Menegon et al. (1998) tested four different glutathione transferases classes and found the distribution of glutathione transferases (p) genotypes differed between cases and controls who had been exposed to pesticides. Another example of this ecogenetic approach was applied to the association between smoking and Parkinson’s disease by testing the modifying effect of monoamine oxidase-B genotype (Costa et al. 1997; Checkoway et al. 1998a,b). Checkoway et al. (1998b) reported that smokers with one form of the monoamine oxidase-B gene appeared to have lowered risk of Parkinson’s disease but that those with the other form did not. Recently, Mellick reported a different polymorphism of the monoamine oxidase-B gene as a relatively strong marker for Parkinson’s disease in an Australian cohort. Monoamine oxidase-A genotype, on the other hand, has been shown to be not significantly associated with Parkinson’s disease (Costa-Mallen et al. 2000). Continued efforts to identify gene–environment interaction in this way may eventually prove fruitful, but success is rather limited to date.
A relatively small subset of Parkinson’s disease appears to be due to autosomal dominant (or recessive) gene or genes (Jones et al. 1998; Payami and Zareparsi 1998; Veldman et al. 1998; Wood 1998; Zareparsi et al. 1998). The a-synuclein gene on 4q and another autosomal dominant gene on 2q appear to be sufficient to cause a particular subtype of Parkinson’s disease, but the familial form of the disease is quite rare (Vaughan et al. 1998). Similarly, 6q contains a recessive gene for ‘juvenile parkinsonism’. Additional work is ongoing to describe the influence of mutations in the tau gene (17q) (Hardy et al. 1998; D’Souza et al. 1999; Hulette et al. 1999; Sperfeld et al. 1999). Genetic heterogeneity appears to be common in Parkinson’s disease. With the increased progress in genetic research generally it is quite likely that additional genes will be found which may explain parts of parkinsonism and Parkinson’s disease.
Public health impact
Parkinson’s disease is progressive and debilitating. While initial treatments with levodopa and similar medications effectively quell most motor symptoms, their effectiveness begins to subside in about 50 per cent of patients after 3 to 5 years. With increasing motor problem comes increased health care cost and decreased quality of life (Chrischilles et al. 1998; Dodel et al. 1998; de Boer et al. 1999). For many patients, dementia also ensues as Parkinson’s disease progresses (Marder and Mayeux 1991; Oertel 1995; Marder et al. 1999).
Multiple sclerosis
Clinical overview
Although multiple sclerosis is not as common as most of the neurological diseases previously discussed, it is an important cause of disability in young adults in developed countries, and is thus worthy of at least brief discussion here. The impact of this disease on society is disproportionately large because it strikes people 20 to 50 years of age. The impact of multiple sclerosis on wage earning is also notable, with only 21 per cent of multiple sclerosis patients having no work limitations and only 29 per cent remaining in the work force (Minden et al. 1993). In addition to the stresses the disease places on home life and employment, multiple sclerosis patients have substantial increases in medical costs compared to the general population (Minden et al. 1993). Because of lost earnings and increased health-care costs, multiple sclerosis is the third leading cause of significant disability in the 20 to 50 age range (Cobble et al. 1993).
Clinically, multiple sclerosis is characterized by demyelination of central nervous system white matter tracts including motor, sensory, cerebellar, visual, brainstem, autonomic, and spinal cord pathways. The symptoms may be episodic, with exacerbations and remissions, with symptoms remaining stable between exacerbations (relapsing/remitting disease). Alternatively, symptoms may slowly progress in the absence of exacerbations (primary progressive disease). Relapsing/remitting cases may change to include slow deterioration of the baseline in between attacks (secondary progressive disease). When the disease results in death, the immediate cause is usually infection, secondary to urinary tract involvement or pneumonia.
At present, corticosteroids are used to shorten the length of acute relapses. Interferon-b1a, interferon-b1b, glateramer acetate, and mitoxantrone have all been shown to slow the progression of the disease. In addition to disease-modifying therapy, symptomatic treatments are often required. New immunosuppressive treatments are being tested, and may prove to be efficacious in the future.
The criteria developed by Schumacher et al. (1965) and revised by Poser et al. (1991) are generally used for diagnosis. The criteria for clinically definite multiple sclerosis include two or more episodes of neurological deficit and evidence on neurological examination, MRI, or evoked potential of more than one site of involvement in the central nervous system.
Case ascertainment
Because of the necessity for neurological expertise and special studies to make reliable diagnoses, reported worldwide prevalences may not be completely comparable, especially where differences in the availability and quality of health care exist. The requirement for repeated attacks before a diagnosis is made leads to difficulties in determining exact incidence figures in a timely manner.
Disease prevalence—the number of cases present (alive) at a given time within a circumscribed population—is easier to determine than incidence. This is because all cases are included, regardless of disease duration, which can vary from as little as 1 year to more than 40 years, especially with treatment. The reported prevalence of multiple sclerosis varies widely with latitude, from 1 per 100 000 or less near the equator, to over 150 per 100 000 in some high-latitude areas. In the southern hemisphere less data are available, but studies in Australia and New Zealand support a similar gradient in prevalence (Skegg et al. 1987). Persons who migrate in childhood from high-risk to lower-risk areas seem to lower their risk of multiple sclerosis, while migrants over age 15 retain the risk associated with their areas of origin (Alter et al. 1966; Dean 1967; Detels et al. 1977).
Risk factors
Genetic susceptibility
There are several types of evidence for genetic influences on susceptibility. Asian, African, and aboriginal groups seem to have lower prevalence than Caucasians, regardless of latitude of residence. Because more research has been done on Caucasians, it has been shown in this group that some alleles of the HLA complex are associated with multiple sclerosis susceptibility (Multiple Sclerosis Genetics Group 1996). In addition, other groups of genes that influence the immune response or myelin structure have been investigated (Sadovnick et al. 1991). The extremely high rate of concordance in monozygotic twins also supports a genetic contribution to the disease (Xian-hao and McFarlin 1984). The higher rate of multiple sclerosis in females compared to males also supports involvement of the immune system.
Environmental factors
In the presence of inherent susceptibility, some external factors seem to be associated with multiple sclerosis. The lack of complete concordance in monozygotic twins supports an environmental factor. People with multiple sclerosis have a later age of exposure to common childhood exanthematous diseases, and lower birth orders (Allen and Brankin 1993). There have been reports of clusters of disease, thought to have been related to environmental exposures, but on investigation these supposed clusters have generally not been beyond expected variability. An apparent epidemic of multiple sclerosis following the British invasion of the Faeroe Islands has not yet been fully explained.
These genetic and environmental factors may result in an autoimmune destruction of myelin corresponding to the attacks that occur in multiple sclerosis. The positive effect of immunomodulating treatments supports this view of pathogenesis. However, much remains to be clarified about the mechanisms of the disease process.
Presenting current and useful research information on a number of neurological conditions is a difficult task. This chapter has addressed that challenge, for some selected neurological conditions. Conditions such as headache and back pain have substantial public health impact because of the age groups affected, their prevalence, and the lost productivity (or economic loss) related to them. Multiple sclerosis, a relatively uncommon neurological disease, can affect individuals in young adulthood, decrease their productivity, and ultimately make them dependent on others. Traumatic brain injury occurring in youth or young adulthood can cause years of extra medical care in addition to lost productivity among those who survive the immediate event. Epilepsy may have onset throughout life; it may result from trauma or may be caused by specific genes, among other causes. While there are intractable forms of epilepsy, great strides have been made in seizure control enabling patients to lead relatively full and normal lives. Neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease, rob older individuals of productivity, functional ability, and independence; they also force huge increases in health-care costs. Without question neurological diseases have substantial public health effects.
Determining the incidence and prevalence for most of the diseases and conditions in this chapter is quite an inexact science. The conditions are often difficult to define and detect in the population and for the most part they are not regarded as ‘reportable’ conditions. Therefore we gain insight as to disease occurrence primarily from limited but (hopefully) well-designed and conducted studies. As mentioned in the introduction to this chapter, the epidemiological study of neurological conditions is a complicated matter. Problems with diagnostic inaccuracy and insidious disease onset influence our ability to observe risk-factor associations; factors related to survival may be mistaken for risk/protective factors.
The recent identification of the code for the human genome foretells the increasing promise of genetic research. The contribution of genes that in and of themselves cause disease may be smaller than that of genes which act to metabolize or potentiate environmental exposures. The interaction between genes and environment will be increasingly well studied in the future. Descriptions of gene products and function may lead to specific drug therapies never before possible. The genetic information presented in this chapter, while relatively current, may become obsolete quickly. The fields of genetics and molecular biology are moving rapidly. It is also a challenge for epidemiologists to apply the knowledge gained by genetic researchers to the design and analysis of epidemiological studies. The diagnosis of neurological conditions may be made more accurately and earlier with genetic information. Science and the public health will benefit beyond even our current expectations, from the Human Genome Project.
Epidemiology must take advantage of these molecular advances. Many scholars have written on the advantages and disadvantages of reductionism in science. Much of epidemiology lies in its public health context, and the same is likely to be true for genetic influences on neurological diseases. Arrays of genes may identify susceptible individuals; however, those individuals may avoid disease unless met with specific environmental or behavioural exposures. The tasks of public health and epidemiology will still involve prevention, the non-random occurrence of disease, and its environmental context—in addition to heredity. The tools to address those tasks will continue to be refined.
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