Breaking the cycle of medication overuse headache

When patients who have frequent, disabling migraines take medications to relieve their symptoms, they run the risk that the attacks will increase in frequency to daily or near-daily as a rebound effect comes into play. This pattern, called medication overuse headache, is more likely to happen with butalbital and opioids than with migraine-specific drugs, as partial responses lead to recurrence, repeat dosing, and, eventually, overuse. Breaking the cycle involves weaning the patient from the overused medications, setting up a preventive regimen, and setting strict limits on the use of medications to relieve acute symptoms.
Key pointsMedication overuse headache can occur with as few as 5 days per month of treatment with butalbital or 8 days per month with opioids.The features vary, but the most important is headache on 15 or more days per month, lasting at least 4 hours if untreated, for at least 3 consecutive months. Other common symptoms are morning headaches, neck pain, nonrestorative sleep, and vasomotor instability, all of which tend to improve with weaning from the overused medications.Daily preventive treatment is indicated when patients have 10 or more headaches per month or severe disability from their attacks.With treatment, the prognosis for medication overuse headache is good. However, patients need close followup to prevent recidivism.
Some migraine patients fall into a trap by overusing the medications they take when they get their headaches, ending in a downward spiral of daily or near-daily headaches for which their medications become less and less effective.This condition, called medication overuse headache, makes for a poor quality of life. It is often associated with nonrestorative sleep, neck pain, and vasomotor instability. Comorbid depression and anxiety are common and may complicate treatment. (Depression and anxiety, however, do not cause daily headaches.) Patients can also suffer from the physiologic and psychological consequences of the overused medications.Fortunately, we can break the cycle.1,2 Treatment involves completely weaning the patient from the overused medications and educating her or him to follow a new regimen of prophylaxis and acute treatment with clear limits on frequency of use. Nondrug treatments such as relaxation therapy, biofeedback, and cognitive behavioral therapy can be useful adjuncts.
CROSSING THE LINE: 15 HEADACHE DAYS A MONTHChronic daily headacheWe define chronic daily headache as occurring on at least 15 days per month for at least 3 months in a row and lasting at least 4 hours if untreated.Most patients start with episodic migraine, and many of them remember the period of transformation. Crossing the 15-day-per-month threshold changes the clinical presentation, prognosis, and treatment, all for the worse.In a large population-based study,3 2.5% of patients who began with episodic migraine (headaches on fewer than 15 days per month) had “transformed migraine” (headaches on 15 or more days per month) 1 year later. The prevalence of chronic daily headache is almost 5% of the general population and may account for up to 70% of the initial diagnoses seen in headache centers.The closer a patient is to having 15 headaches per month, the more likely she or he will cross the line.4,5 Katsarava and colleagues5 followed patients for 1 year in a neurology clinic in Germany and found that those starting the year with 6 to 9 headache days per month were 6.2 times more likely to develop chronic daily headache in the next year than those who began the year with 0 to 4 per month—and those starting with 10 to 14 headaches per month were 20 times more likely.Medication overuse headacheMedication overuse headache is a subset of chronic daily headache, also occurring on 15 or more days per month but with the added criterion of medication overuse, ie, regular overuse for more than 3 months of at least one acute treatment drug:Ergotamine, triptans, opioids, or combination analgesic medications on 10 or more days per month on a regular basis for more than 3 months, orSimple analgesics or any combination of ergotamine, triptans, analgesics, or opioids on 15 or more days per month on a regular basis for more than 3 months without overuse of any single class alone.Another criterion is that the patient’s headaches must worsen in some way (usually frequency) as the use of acute medications becomes more frequent.6,7Medication overuse headache is the most common form of secondary chronic daily headache seen in headache practice,8–10 and probably accounts for about half of cases of chronic daily headache.11–13Different terminology confuses the issueMany terms have been used to describe medication overuse headache in the past, such as analgesic-rebound headache (or just rebound headache), transformed migraine with medication overuse, and even chronic migraine. The lack of uniformity in terminology makes for confusion in the literature and difficulty in communicating with patients and colleagues. Some authors mean medication overuse headache when they say chronic daily headache.Complicating this diagnostic confusion is a debate as to whether chronic daily headache in general should be treated as a primary or secondary headache disorder. Some European headache specialists insist on a strict division between primary and secondary daily headaches, and medication overuse headache is one of the latter. Many American specialists believe that chronic daily headache is a collective description or phenotype rather than a diagnostic category, and that it is usually associated with and exacerbated by medication overuse.14,15 The International Classification of Headache Disorders uses the term “chronic migraine” for primary daily headache, and “medication overuse headache” for secondary daily headache or rebound.Many American specialists approach the disorder clinically, treating chronic daily headache in the same way regardless of whether there is medication overuse. They cite randomized controlled trials of topiramate (Topamax) and onabotulinum toxin type A (Botox) that reported comparable benefit with these medications in patients with chronic daily headache with or without medication overuse.16–18
MORE IS LESS: THE PARADOX OF TREATING ACUTE HEADACHEThe clinical paradox and dilemma of treating acute episodic migraine is that more is less: the more days of acute treatment, the less well the migraines are controlled. And thus, the patient is likely to veer out of control.3The compassion that motivates us to prescribe medications for acute episodic migraine must be tempered by the realization that too much of a good thing will result in its malignant transformation to medication overuse headache. Once this develops, preventive and migrainespecific acute medications are less effective, and patients need far more complex interventions.Complicating the dilemma, acute migraine-specific medications such as triptans and dihydroergotamine (Migranal) work better when taken early in migraine attacks, before central sensitization and allodynia develop with attendant photophonophobia and sensitivity to other stimuli. On the other hand, overuse will lead to medication overuse headache.
SYMPTOMS VARYThe symptoms of medication overuse headache vary in frequency, severity, location, quality, and associated features, both among patients and in the same patient. This is because the disease itself varies and also because of differences in the type and frequency of medication intake. Still, some features help to define this problem, and failing to recognize them may account for a widely held clinical feeling that these patients are “difficult.”History of episodic migraine. Generally, medication overuse headache does not occur in nonmigraineurs.Headache on most days of the month. Whenever a migraineur starts having headaches on more days than not, the diagnosis of medication overuse should be considered.Overuse of acute medications. The criteria (see above) allow for combining days of acute medication use. For example, if a patient takes a combination analgesic on 5 days and a triptan on 5 different days, that would still be enough days of acute treatment to trigger medication overuse headache.Variable pain location is a particular characteristic of medication overuse headache. Although the location may differ from day to day (front or back, rostral or caudal, unilateral or bilateral), it is the quantity not the quality or location of the headaches that suggests the diagnosis.A drug-dependent rhythm. Predictably, the headaches come on in the early morning or awaken the patient from sleep. This may be due to variable drug withdrawal.Neck pain. Medication overuse headache frequently involves the neck, and patients often seek and receive treatments such as muscle relaxants or injections to the neck. When patients are weaned from their acute migraine medications, neck pain generally dissipates. The neck pain, however, can recur episodically with their remaining, now-episodic acute migraines. Neck pain associated with medication overuse headache is not usually a sign of a primary neck disorder; rather, it is a symptom of medication overuse headache itself.Concomitant depression and anxiety are comorbid with episodic migraine, but appear to be more common with medication overuse headache. Treating the depression or anxiety does not restore an episodic pattern of migraine; weaning from the overused medications remains the most important intervention. A frequent clinical error is to diagnose and treat the psychiatric issues without recognizing medication overuse as the primary problem.Nonrestorative sleep is almost always reported by patients with medication overuse headache. This is often due to the caffeine contained in combination analgesics or to excessive dietary caffeine intake, but it may also be part of the daily acute drug withdrawal syndrome. The sleep problems are also associated with the concomitant depression. Sleep often improves after weaning from the offending substance or substances. As with neck pain, patients do not have a primary sleep disorder—the sleep disturbance is a symptom of medication overuse headache.Vasomotor instability. Autonomic features are commonly associated with medication overuse headache. Rhinorrhea, nasal stuffiness, and lacrimation are features of medication withdrawal, especially from opioids, and are frequently attributed to sinus disease or “sinus headaches.” Many patients undergo unnecessary sinus procedures or are given antibiotics, decongestants, and other wrong medications for incorrect diagnoses. Decongestants can cause and exacerbate medication overuse headache, so they need to be withdrawn. The sinus features generally remit when the overused migraine medications are eliminated.Preventive medications are less effective or ineffective until the acute medications are withdrawn. Thus, prescribing prevention without weaning is usually futile, and the patients are often dismissed as having a refractory problem. At the same time, migraine-specific acute treatments, ie, triptans and ergots, are usually also less effective. When patients complain that “nothing works,” either preventively or acutely, medication overuse headache should spring to mind.Weaning from overused medications can restore the efficacy of previously ineffective treatments at the same time that a patient is restored to an episodic headache pattern. Thus, complete weaning is the pivotal clinical intervention. Clinically, there is no spontaneous remission from rebound without absolute detoxification, maintained for months.9,19–22
Other diagnoses entertained. The more diagnoses suggested for daily headache, and the more treatments tried unsuccessfully, the more likely the diagnosis is actually medication overuse headache. Because this condition is protean, patients and caregivers alike make more and more fanciful diagnoses such as allergies, cervicogenic headache, temperomandibular disorder, occipital neuralgia, chronic Lyme disease, and systemic candidiasis. A useful strategy is to assume that daily headache is likely due to medication overuse. And since medication overuse headache is generally treatable, patients labeled as having refractory headaches often are dramatically improved by appropriate intervention.
WHY ARE MIGRAINEURS SO SUSCEPTIBLE?Medication overuse headache occurs primarily in people with a history of episodic migraine, but the unique susceptibility of migraineurs is not fully understood.Structural changes in the brain?Episodic migraine attacks appear to be generated in the upper brainstem. This region in turn activates a set of peripheral pain mechanisms, ie, meningeal inflammation and vasodilation. The peripheral pain processes turn on afferent circuits that carry the pain signals to the lower brainstem, where these signals are integrated. Finally, the central signals ascend the brainstem, stimulating autonomic nuclei that account for nausea and other vasomotor changes, proceed through the thalamus, and terminate in the cortex where pain is perceived. Thus, migraine without aura consists of three steps—a central generator, a set of peripheral pain mechanisms, and a series of steps culminating in central integration. (Aura involves other steps, not outlined here.)A possible explanation of why migraine becomes chronic is that a yo-yo effect of repeated migrainous pain processes, followed by repeated medication, results in structural changes. These propagate central sensitization with a lowered threshold for activation of all of the central processing of head pain.This set of disturbances may occur due to undertreatment of migraine pain. With inadequate pain control, headaches recur, and the process repeats until damage occurs. Evidence for this is seen in up-regulation of excitatory serotonin receptors when analgesics are repetitively given to laboratory animals.23A pure withdrawal phenomenon?Also possible is that medication overuse headache is just a complex dependence-and-withdrawal phenomenon. Thus, the cyclical use of various medications results in withdrawal headaches and a set of symptoms, including disturbed sleep, morning headache, and vasomotor signs of withdrawal. Arguing against its being a pure withdrawal phenomenon is that daily use of analgesics or opioids generally does not cause daily headache in nonmigraineurs.24
HOW MUCH MEDICATION USE IS TOO MUCH?For an episodic migraine condition to transform into a chronic one, medications need to be taken on only a modest number of days per month: 5 to 10, depending on the type of medication.A pivotal study3 found that butalbital combinations were most likely to cause medication overuse headache, needing to be taken on merely 5 or more days per month to cause it in migraineurs. Opioids caused it if taken 8 or more days per month, and triptans if taken 10 or more days per month. Nonsteroidal anti-inflammatory drugs (NSAIDs) actually protected against transformation to daily headache if used 5 or fewer days per month, but caused medication overuse headache if used 10 or more days per month.Thus, there was a hierarchy of risk, with butalbital being the worst, opioids in the middle, and NSAIDs and triptans the least risky. None of the agents had to be taken daily to trigger medication overuse headache.
PREVENTION IS THE BEST TREATMENTThe best approach to medication overuse headache is to prevent it while the patient still has episodic migraine.Outcomes are better with triptans or ergotsUndertreatment of migraine leads quickly to overuse of symptomatic medications, and from there to medication overuse headache.Outcomes of episodic migraine are better when triptans or ergots (which are migrainespecific) are used first-line in patients with disabling migraine and no vascular contraindications. Patients who start with nonspecific treatment and step up to a more specific treatment when lower-level medications fail have less favorable outcomes in terms of migraine relief and disability time than those treated with triptans from the beginning.25To put this in perspective, if a patient takes an acute medication, gets only partial relief (not a pain-free response) at 2 hours and then takes another pill, or gets a recurrence and takes another pill, the likelihood of prolonging an attack and using more medications goes up. If a patient takes a triptan and gets a sustained pain-free response, the attack is truncated and the medication usage reduced. Therefore, migraine-specific acute treatments are more likely to not be overused.Daily preventive medication, if necessaryAs noted above, if the number of headache days exceeds 10 per month, the likelihood of developing daily headache escalates steeply. Thus, patients with 10 or more days of headache per month should be prescribed preventive medications to be taken daily to reduce the frequency, severity, and duration of attacks. Preventive treatment may also increase the efficacy of the acute treatments.The drugs used for preventive treatment are different than those used for acute treatment and are not likely to cause medication rebound headache. However, they are not very effective. Those that have the best evidence of efficacy are beta-blockers, tricyclic antidepressants, and anticonvulsants; calcium channel blockers and NSAIDs are also popular. This topic has been reviewed in detail elsewhere.26,27
REVERSING MEDICATION OVERUSE HEADACHEIf a patient already has medication overuse headache, the clinician is faced with the problem of weaning her or him from the overused medication while establishing a reasonable regimen of prophylaxis and acute medications with limits.For the most part, these tasks can be accomplished in a series of clinic visits. However, some patients have such severe comorbid medical and psychiatric illnesses that outpatient treatment is impossible. For them, a day hospital or inpatient program with infusion capabilities is often useful.Outpatient treatment of medication overuse headacheOutpatient treatment of medication overuse headache involves:Educating patients about the genesis of the problem and reassuring them that you are not accusing them of being an addict. Most patients who develop medication overuse headache are habituated inadvertently, and this needs to be made clear, along with the overall plan and the likely prognosis.Weaning from the overused medications can be done gradually, tapering the drugs over 4 to 6 weeks, during which preventive medications are introduced. Alternatively, the discontinuation of rebound medications can be done abruptly, with transitional medications (eg, corticosteroids, NSAIDs, dihydroergotamine, or triptans) used as a bridge to blunt withdrawal, during which the prophylaxis is established.Establishing daily preventive medications. The prophylactic regimen can be established either before or during the weaning.Providing acute medications, with limits. At a certain point in the weaning, advise the patient not to treat low-level headaches, and provide a triptan or dihydroergotamine to use for severe attacks, no more than twice weekly and less than 10 days per month. If the patient is in triptan rebound, dihydroergotamine would be the choice.Instructing the patient to keep a headache diary to follow adherence and outcomes.Psychology consultation can be very helpful to teach patients behavioral techniques to deal with anticipatory anxiety during the weaning.Multidisciplinary programs with infusion capabilitySome patients need a more intensive approach to restore an episodic migraine pattern. Examples: those on very high doses of narcotics or barbiturates, those with comorbid medical illnesses that limit both acute and preventive treatments, and those with severe and complicating comorbid psychiatric illnesses.Multidisciplinary programs are available, with specialists in neurology, primary care, psychology, and physical and occupational therapy providing treatment. Patients check into the hospital or a “day hospital,” where they can also receive intravenous infusions to get through the weaning. The goal is to shift the locus of control back to patients as they revert from daily headache to episodic migraine. Patient education is crucial.
OUTCOMES ARE GOODThere is much good news about medication overuse headache.It can be prevented with careful monitoring of acute medication outcomes and number of headache days. Prophylaxis should be used when treating high-frequency or very disabling migraine.Most patients improve when weaned and treated with preventive medications. “Recovery” means at least 3 months off the overused medications. In studies, more than half of patients who underwent treatment for medication overuse headache remained better and had an episodic pattern of headache 5 years later.26Unfortunately, the initial improvement often seen with patients after weaning and being given preventive medication (72%–85% of patients improve) in the first year is often followed by preventable relapse, so it is very important to follow up with patients regularly. 28–32

Managing patients with Alzheimer’s disease

• Although there is no treatment that either cures or permanently arrests the disease, there are presently available two types of Alzheimer specific therapies: symptomatic approaches to improve memory based on enhancement of neurotransmitter systems, and neuroprotective strategies using antioxidants.
• Acetylcholinesterase inhibitors reduce the metabolism of the neurotransmitter acetylcholine, and although they probably do not alter the progression of neurodegeneration, possible long term benefits may include delayed institutionalisation, perhaps decreased mortality, and savings in the cost of patient care.
• Optimal management of all medications and any comorbid medical illnesses, including depression, is crucial and may result in significant improvement in cognitive and functional status.
• There is insufficient evidence of efficacy of vitamin E in the treatment of people with Alzheimer’s disease.
• Oestrogens do not benefit cognitive function after the onset of Alzheimer’s, or reduce the risk of its development.
• Alzheimer’s disease results in behavioural problems that can be especially challenging to carers but effectively managed if properly identified.
• In addition to medical therapy, the physician should not overlook the non-pharmacological management interventions that can aid in the care of patients with dementia.
• Patients with more than mild dementia usually have at least one carer and it is important that the clinician recognises his or her vital role in management.

Functional and dissociative neurological symptoms

Most people with functional or dissociative neurological symptoms have a combination of symptoms like "weakness, numbness and fatigue" or "blackouts and sleep problems".
Patients with functional/dissociative symptoms are often concerned that their diagnosis may be wrong. Especially since there is no 'scan' or blood test that can make the diagnosis.




There are many neurological problems. The commonest ones are



• Stroke

• Epilepsy

• Migraine / Headache

• Functional / Dissociative Symptoms

• Multiple Sclerosis

• Brain Tumour

• Parkinsons Disease

• Myasthenia Gravis

• Motor Neuron Disease (also called Amyotrophic Lateral Sclerosis)

• Peripheral Neuropathy

• Nerve Root or Spinal Cord entrapment

• Many hundreds of others.....



On the other hand there are also only a limited number of neurological symptoms.

The commonest ones are:



• Headache

• Weakness

• Sensory Symptoms

• Blackouts

• Memory / Cognitive symptoms

• Speech / Swallowing Symptoms

• Dizziness

• Visual Symptoms – reduced vision, double vision

• Neck, Back and Limb pain

• Tremors, jerks, spasms and contractures

• Bladder symptoms



In fact there are such a limited number of neurological symptoms you can see that its quite understandable for someone with more than one neurological symptom to start to wonder if they have one of the common (or uncommon) neurological diseases.

This website provides a guide to help with this disorders.

Tourette Syndrome

The more alcohol consumed, the smaller the total brain volume: the Framingham Study

Background While adults who drink low to moderate amounts of alcohol have lower rates of cardiovascular disease than other adults, the effect of alcohol on the brain is less clear. There is evidence that drinking large amounts of alcohol is related to brain atrophy. It is uncertain what the effects of low to moderate consumption might be.
Objective To determine whether consumption of smaller amounts of alcohol negatively affects brain volume or is protective in reducing the well-documented age-related decline in brain volume.
Design Total cerebral brain volume (TCBV) was computed, correcting for head size. Multivariate linear regression models were used to evaluate the association between 5 categories of alcohol consumption (abstainers, former drinkers, low, moderate, high) and TCBV, adjusting for age, sex, education, height, body mass index (calculated as weight in kilograms divided by height in meters squared), and the Framingham Stroke Risk Profile. Pairwise comparisons were also conducted between the alcohol consumption groups.
Participants A total of 1839 subjects from the Framingham Offspring Study who had magnetic resonance imaging of the brain between 1999 and 2001.
Results Most participants reported low alcohol consumption, and men were more likely than women to be moderate or heavy drinkers. There was a significant negative linear relationship between alcohol consumption and TCBV (r = –0.25; P < .001). This relationship was modified by sex, with alcohol consumption having a stronger association with TCBV in women than in men (r = –0.29 vs –0.20). Conclusions In contrast to studies on cardiovascular disease, this study found that moderate alcohol consumption was not protective against normal age-related differences in total brain volume. Rather, the more alcohol consumed, the smaller the total brain volume.

Reference:
Carol Ann Paul, MS; Rhoda Au, PhD; Lisa Fredman, PhD; Joseph M. Massaro, PhD; Sudha Seshadri, MD; Charles DeCarli, MD; Philip A. Wolf, MD Association of Alcohol Consumption With Brain Volume in the Framingham Study. Arch Neurol. 2008;65(10):1363-1367 (view)

Alzheimer's disease

The disease course is divided into four stages, with a progressive pattern of cognitive and functional impairment.

Phases

The first symptoms are often mistaken as related to ageing or stress. Detailed neuropsychological testing can reveal mild cognitive difficulties up to eight years before a person fulfills the clinical criteria for diagnosis of AD. These early symptoms can affect the most complex daily living activities. The most noticeable deficit is memory loss, which shows up as difficulty in remembering recently learned facts and inability to acquire new information. Subtle problems with the executive functions of attentiveness, planning, flexibility, and abstract thinking, or impairments in semantic memory (memory of meanings, and concept relationships), can also be symptomatic of the early stages of AD. Apathy can be observed at this stage, and remains the most persistent neuropsychiatric symptom throughout the course of the disease. The preclinical stage of the disease has also been termed mild cognitive impairment, but there is still debate on whether this term corresponds to a different diagnostic entity by itself or just a first step of the disease.

Early dementia

In people with AD, the increasing impairment of learning and memory eventually leads to a definitive diagnosis. In a small proportion of them, difficulties with language, executive functions, perception (agnosia), or execution of movements (apraxia) are more prominent than memory problems. AD does not affect all memory capacities equally. Older memories of the person's life (episodic memory), facts learned (semantic memory), and implicit memory (the memory of the body on how to do things, such as using a fork to eat) are affected to a lesser degree than new facts or memories. Language problems are mainly characterised by a shrinking vocabulary and decreased word fluency, which lead to a general impoverishment of oral and written language. In this stage, the person with Alzheimer's is usually capable of adequately communicating basic ideas. While performing fine motor tasks such as writing, drawing or dressing, certain movement coordination and planning difficulties (apraxia) may be present, making sufferers appear clumsy. As the disease progresses, people with AD can often continue to perform many tasks independently, but may need assistance or supervision with the most cognitively demanding activities.Moderate dementiaProgressive deterioration eventually hinders independence. Speech difficulties become evident due to an inability to recall vocabulary, which leads to frequent incorrect word substitutions (paraphasias). Reading and writing skills are also progressively lost. Complex motor sequences become less coordinated as time passes, reducing the ability to perform most normal daily living activities. During this phase, memory problems worsen, and the person may fail to recognise close relatives. Long-term memory, which was previously intact, becomes impaired, and behavioural changes become more prevalent. Common neuropsychiatric manifestations are wandering, sundowning, irritability and labile affect, leading to crying, outbursts of unpremeditated aggression, or resistance to caregiving. Approximately % of patients also develop illusionary misidentifications and other delusional symptoms. Urinary incontinence can develop. These symptoms create stress for relatives and caretakers, which can be reduced by moving the person from home care to other long-term care facilities.Advanced dementiaDuring this last stage of AD, the patient is completely dependent upon caregivers. Language is reduced to simple phrases or even single words, eventually leading to complete loss of speech. Despite the loss of verbal language abilities, patients can often understand and return emotional signals. Although aggressiveness can still be present, extreme apathy and exhaustion are much more common results. Patients will ultimately not be able to perform even the most simple tasks without assistance. Muscle mass and mobility deteriorate to the point where they are bedridden, and they lose the ability to feed themselves. Finally comes death, usually caused directly by some external factor such as pressure ulcers or pneumonia, not by the disease itself.

Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those afflicted by AD. Plaques are dense, mostly insoluble deposits of amyloid-beta protein and cellular material outside and around neurons. They continue to grow into insoluble twisted fibres within the nerve cell, often called tangles. Although many older individuals develop some plaques and tangles as a consequence of ageing, the brains of AD patients have a greater number of them in specific brain regions such as the temporal lobe.BiochemistryEnzymes act on the APP (amyloid precursor protein) and cut it into fragments. The beta-amyloid fragment is crucial in the formation of senile plaques in AD.Alzheimer's disease has been identified as a protein misfolding disease (proteopathy), caused by accumulation of abnormally folded A-beta and tau proteins in the brain. Plaques are made up of small peptides, – amino acids in length, called beta-amyloid (also written as A-beta or Aβ). Beta-amyloid is a fragment from a larger protein called amyloid precursor protein (APP), a transmembrane protein that penetrates through the neuron's membrane. APP is critical to neuron growth, survival and post-injury repair. In Alzheimer's disease, an unknown process causes APP to be divided into smaller fragments by enzymes through proteolysis. One of these fragments gives rise to fibrils of beta-amyloid, which form clumps that deposit outside neurons in dense formations known as senile plaques. In Alzheimer's disease, changes in tau protein lead to the disintegration of microtubules in brain cells.AD is also considered a tauopathy due to abnormal aggregation of the tau protein. Every neuron has a cytoskeleton, an internal support structure partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the axon and back. A protein called tau stabilises the microtubules when phosphorylated, and is therefore called a microtubule-associated protein. In AD, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport system.Disease mechanismExactly how disturbances of production and aggregation of the beta amyloid peptide gives rise to the pathology of AD has not been elucidated. The amyloid hypothesis traditionally points to the accumulation of beta amyloid peptides as the central event triggering neuron degeneration. Accumulation of aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis, induces programmed cell death (apoptosis). It is also known that Aβ selectively builds up in the mitochondria in the cells of Alzheimer's-affected brains, and it also inhibits certain enzyme functions and the utilisation of glucose by neurons.Various inflammatory processes and cytokines may also have a role in the pathology of Alzheimer's disease. Inflammation is a general marker of tissue damage in any disease, and may be either secondary to tissue damage in AD or a marker of an immunological response.GeneticsWhile the rare, early-onset form of Alzheimer's disease is mainly explained by mutations in three genes, the most common form has yet to be explained by a purely genetic model. The APOE gene is the strongest genetic risk factor for Alzheimer's discovered so far, but its presence is far from explaining all occurrences of the disease.Less than % of AD cases occurring before years of age are due to autosomal dominant (familial) mutations, which therefore represent less than .% of all cases. These mutations have been discovered in three different genes: amyloid precursor protein (APP) and presenilins and . Most mutations in the APP and presenilin genes increase the production of a small protein called Abeta, which is the main component of senile plaques.Most cases of Alzheimer's disease do not exhibit familial inheritance, but genes may act as risk factors. The best known genetic risk factor is the inheritance of the ε allele of the apolipoprotein E (APOE). This gene is implicated in up to % of late-onset sporadic Alzheimer's cases. Geneticists agree that numerous other genes also act as risk factors or have protective effects that influence the development of late onset Alzheimer's disease. Over genes have been tested for association with late-onset sporadic AD. One example is a variant of the reelin gene that may contribute to Alzheimer's risk in women.

Causes

Microscopy image of a neurofibrillary tangle, conformed by hyperphosphorylated tau proteinThree major competing hypotheses exist to explain the cause of the disease. The oldest, on which most currently available drug therapies are based, is the cholinergic hypothesis, which proposes that AD is caused by reduced synthesis of the neurotransmitter acetylcholine. The cholinergic hypothesis has not maintained widespread support, largely because medications intended to treat acetylcholine deficiency have not been very effective. Other cholinergic effects have also been proposed, for example, initiation of large-scale aggregation of amyloid, leading to generalised neuroinflammation.The amyloid hypothesis, currently the most popular, was proposed in . Here amyloid beta (Aβ) deposits are postulated to be the fundamental cause of the disease. It is a compelling theory because the gene for the amyloid beta precursor (APP) is located on chromosome , and people with trisomy (Down Syndrome) who thus have an extra gene copy almost universally exhibit AD by years of age. Also APOE, the major genetic risk factor for AD, leads to excess amyloid buildup in the brain before AD symptoms arise. Thus, Aβ deposition precedes clinical AD. Further evidence comes from the finding that transgenic mice that express a mutant form of the human APP gene develop fibrillar amyloid plaques and Alzheimer's-like brain pathology. An experimental vaccine was found to clear the amyloid plaques in early human trials, but it did not have any significant effect on dementia.Deposition of amyloid plaques does not correlate well with neuron loss. This observation supports the tau hypothesis, the idea that tau protein abnormalities initiate the disease cascade. In this model, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they form neurofibrillary tangles inside nerve cell bodies. When this occurs, the microtubules disintegrate, collapsing the neuron's transport system. This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells.

Diagnosis

PET scan of the brain of a person with AD showing a loss of function in the temporal lobeAlzheimer's disease is usually diagnosed clinically from the patient history, collateral history from relatives, and clinical observations, based on the presence of characteristic neurological and neuropsychological features and the absence of alternative conditions. Advanced medical imaging with computed tomography (CT) or magnetic resonance imaging (MRI), and with single photon emission computed tomography (SPECT) or positron emission tomography (PET) can be used to help exclude other cerebral pathology or subtypes of dementia. Assessment of intellectual functioning including memory testing can further characterise the state of the disease. Medical organisations have created diagnostic criteria to ease and standardise the diagnostic process for practicing physicians. Sometimes the diagnosis can be confirmed or made at post-mortem when brain material is available and can be examined histologically.Diagnostic criteriaThe National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (now known as the Alzheimer's Association) established the most commonly used diagnostic criteria for Alzheimer's disease. These criteria require that the presence of cognitive impairment, and a suspected dementia syndrome, be confirmed by neuropsychological testing for a clinical diagnosis of possible or probable AD. A histopathologic confirmation including a microscopic examination of brain tissue is required for a definitive diagnosis. Good statistical reliability and validity have been shown between the diagnostic criteria and definitive histopathological confirmation. Eight cognitive domains are most commonly impaired in AD—memory, language, perceptual skills, attention, constructive abilities, orientation, problem solving and functional abilities. These domains are equivalent to the NINCDS-ADRDA Alzheimer's Criteria as listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) published by the American Psychiatric Association.Diagnostic toolsNeuropsychological screening tests can help in the diagnosis of AD. In them patients have to copy drawings similar to the one shown in the picture, remember words, read or sum.Neuropsychological screening tests, such as the mini-mental state examination (MMSE), are widely used to evaluate the cognitive impairments needed for diagnosis. More comprehensive test arrays are necessary for high reliability of results, particularly in the earliest stages of the disease. Neurological examination in early AD will usually provide normal results, except for obvious cognitive impairment, which may not differ from standard dementia. Further neurological examinations are crucial in the differential diagnosis of AD and other diseases. Interviews with family members are also utilised in the assessment of the disease. Caregivers can supply important information on the daily living abilities, as well as on the decrease, over time, of the person's mental function. A caregiver's viewpoint is particularly important, since a person with AD is commonly unaware of his own deficits. Many times, families also have difficulties in the detection of initial dementia symptoms and may not communicate accurate information to a physician. Supplemental testing provides extra information on some features of the disease or is used to rule out other diagnoses. Blood tests can identify other causes for dementia than AD—causes which may, in rare cases, be reversible. Psychological tests for depression are employed, since depression can either be concurrent with AD or be the cause of cognitive impairment.When available as a diagnostic tool, SPECT and PET neuroimaging are used to confirm a diagnosis of Alzheimer's in conjunction with evaluations involving mental status examination. The ability of SPECT to differentiate Alzheimer's disease from other possible causes in somebody already known to be suffering from dementia, appears to be superior to attempts to diagnose by mental testing and history. A new technique known as PiB PET has been developed for directly and clearly imaging beta-amyloid deposits in vivo using a tracer that binds selectively to the Abeta deposits. Another recent objective marker of the disease is the analysis of cerebrospinal fluid for amyloid beta or tau proteins. Both advances have led to the proposal of new diagnostic criteria.PreventionIntellectual activities such as playing chess or regular social interaction have been linked to a reduced risk of AD in epidemiological studies, although no causal relationship has been found.Global studies of measures to prevent or delay the onset of AD have often produced inconsistent results. At present, there appears to be no definitive evidence to support the belief that any particular measure is effective in preventing AD. However, epidemiological studies have proposed relationships between certain modifiable factors, such as diet, cardiovascular risk, pharmaceutical products, or intellectual activities among others, and a population's likelihood of developing AD. Only further research, including clinical trials, will reveal whether, in fact, these factors can help to prevent AD.The components of a Mediterranean diet, which include fruit and vegetables, bread, wheat and other cereals, olive oil, fish, and red wine, may all individually or together reduce the risk and course of Alzheimer's disease. Several vitamins such as B, B, C or folic acid have been found in some studies to be related to a reduced risk of AD but other studies indicate that they do not have any significant effect on the onset or course of the disease and may have important secondary effects. Curcumin from the curry spice turmeric has shown some effectiveness in preventing brain damage in mouse models. The prevalence of AD among the elderly in India has been reported to be about one quarter of that in the U.S., and curry intake has been reported to correlate positively with cognitive function in elderly Asians.Although cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes, and smoking, are associated with a higher risk of onset and course of AD, statins, which are cholesterol lowering drugs, have not been effective in preventing or improving the course of the disease. However long-term usage of non-steroidal anti-inflammatory drug (NSAIDs), is associated with a reduced likelihood of developing AD in some individuals. Other pharmaceutical therapies such as female hormone replacement therapy are no longer thought to prevent dementia, and a systematic review concluded that there was inconsistent and unconvincing evidence that ginkgo has any positive effect on cognitive impairment.Intellectual activities such as reading, playing board games, completing crossword puzzles, playing musical instruments, or regular social interaction may also delay the onset or reduce the severity of Alzheimer's disease. Bilingualism is also related to a later onset of Alzheimer's.Some studies have shown an increased risk of developing AD with occupational exposure to magnetic fields, intake of metals, particularly aluminium, or exposure to solvents. The quality of some of these studies has been criticised, and other studies have concluded that there is no relationship between these environmental factors and the development of AD.

Management

There is no cure for Alzheimer's disease; available treatments offer relatively small symptomatic benefit but remain palliative in nature. Current treatments can be divided into pharmaceutical, psychosocial and caregiving.PharmaceuticalThree-dimensional molecular model of donepezil, an acetylcholinesterase inhibitor used in the treatment of AD symptomsMolecular structure of memantine, a medication approved for advanced AD symptomsFour medications are currently approved by regulatory agencies such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) to treat the cognitive manifestations of AD: three are acetylcholinesterase inhibitors and the other is memantine, an NMDA receptor antagonist. No drug has an indication for delaying or halting the progression of the disease.Reduction in the activity of the cholinergic neurons is a well-known feature of Alzheimer's disease. Acetylcholinesterase inhibitors are employed to reduce the rate at which acetylcholine (ACh) is broken down, thereby increasing the concentration of ACh in the brain and combating the loss of ACh caused by the death of cholinergic neurons. As of , the cholinesterase inhibitors approved for the management of AD symptoms are donepezil (brand name Aricept), galantamine (Razadyne), and rivastigmine (branded as Exelon and Exelon Patch). There is evidence for the efficacy of these medications in mild to moderate Alzheimer’s disease, and some evidence for their use in the advanced stage. Only donepezil is approved for treatment of advanced AD dementia. The use of these drugs in mild cognitive impairment has not shown any effect in a delay of the onset of AD. The most common side effects are nausea and vomiting, both of which are linked to cholinergic excess. These side effects arise in approximately ten to twenty percent of users and are mild to moderate in severity. Less common secondary effects include muscle cramps, decreased heart rate (bradycardia), decreased appetite and weight, and increased gastric acid production. Glutamate is a useful excitatory neurotransmitter of the nervous system, although excessive amounts in the brain can lead to cell death through a process called excitotoxicity which consists of the overstimulation of glutamate receptors. Excitotoxicity occurs not only in Alzheimer's disease, but also in other neurological diseases such as Parkinson's disease and multiple sclerosis. Memantine (brand names Akatinol, Axura, Ebixa/Abixa, Memox and Namenda), is a noncompetitive NMDA receptor antagonist first used as an anti-influenza agent. It acts on the glutamatergic system by blocking NMDA receptors and inhibiting their overstimulation by glutamate. Memantine has been shown to be moderately efficacious in the treatment of moderate to severe Alzheimer’s disease. Its effects in the initial stages of AD are unknown. Reported adverse events with memantine are infrequent and mild, including hallucinations, confusion, dizziness, headache and fatigue. The combination of memantine and donepezil has been shown to be "of statistically significant but clinically marginal effectiveness".Antipsychotic drugs are modestly useful in reducing aggression and psychosis in Alzheimer's patients with behavioural problems, but are associated with serious adverse effects, such as cerebrovascular events, movement difficulties or cognitive decline, that do not permit their routine use.Psychosocial interventionA specifically designed room for sensory integration therapy, also called snoezelen; an emotion-oriented psychosocial intervention for people with dementiaPsychosocial interventions are used as an adjunct to pharmaceutical treatment and can be classified within behaviour-, emotion-, cognition- or stimulation-oriented approaches. Research on efficacy is unavailable and rarely specific to AD, focusing instead on dementia in general.Behavioural interventions attempt to identify and reduce the antecedents and consequences of problem behaviours. This approach has not shown success in improving overall functioning, but can help to reduce some specific problem behaviours, such as incontinence. There is a lack of high quality data on the effectiveness of these techniques in other behaviour problems such as wandering.Emotion-oriented interventions include reminiscence therapy, validation therapy, supportive psychotherapy, sensory integration, also called snoezelen, and simulated presence therapy. Supportive psychotherapy has received little or no formal scientific study, but some clinicians find it useful in helping mildly impaired patients adjust to their illness. Reminiscence therapy (RT) involves the discussion of past experiences individually or in group, many times with the aid of photographs, household items, music and sound recordings, or other familiar items from the past. Although there are few quality studies on the effectiveness of RT, it may be beneficial for cognition and mood. Simulated presence therapy (SPT) is based on attachment theories and involves playing a recording with voices of the closest relatives of the person with Alzheimer's disease. There is preliminary evidence indicating that SPT may reduce anxiety and challenging behaviours. Finally, validation therapy is based on acceptance of the reality and personal truth of another's experience, while sensory integration is based on exercises aimed to stimulate senses. There is little evidence to support the usefulness of these therapies.The aim of cognition-oriented treatments, which include reality orientation and cognitive retraining, is the reduction of cognitive deficits. Reality orientation consists in the presentation of information about time, place or person in order to ease the understanding of the person about its surroundings and his or her place in them. On the other hand cognitive retraining tries to improve impaired capacities by exercitation of mental abilities. Both have shown some efficacy improving cognitive capacities, although in some studies these effects were transient and negative effects, such as frustration, have also been reported.Stimulation-oriented treatments include art, music and pet therapies, exercise, and any other kind of recreational activities. Stimulation has modest support for improving behaviour, mood, and, to a lesser extent, function. Nevertheless, as important as these effects are, the main support for the use of stimulation therapies is the improvement in the person's daily life routines.CaregivingFurther information: Caregiving and dementiaSince Alzheimer's has no cure and it gradually renders people incapable of tending for their own needs, caregiving essentially is the treatment and must be carefully managed over the course of the disease.During the early and moderate stages, modifications to the living environment and lifestyle can increase patient safety and reduce caretaker burden. Examples of such modifications are the adherence to simplified routines, the placing of safety locks, the labelling of household items to cue the person with the disease or the use of modified daily life objects. The patient may also become incapable of feeding themselves, so they require food in smaller pieces or pureed. When swallowing difficulties arise, the use of feeding tubes may be required. In such cases, the medical efficacy and ethics of continuing feeding is an important consideration of the caregivers and family members. The use of physical restraints is rarely indicated in any stage of the disease, although there are situations when they are necessary to prevent harm to the person with AD or their caregivers.As the disease progresses, different medical issues can appear, such as oral and dental disease, pressure ulcers, malnutrition, hygiene problems, or respiratory, skin, or eye infections. Careful management can prevent them, while professional treatment is needed when they do arise. During the final stages of the disease, treatment is centred on relieving discomfort until death.PrognosisThe early stages of Alzheimer's disease are difficult to diagnose. A definitive diagnosis is usually made once cognitive impairment compromises daily living activities, although the person may still be living independently. He will progress from mild cognitive problems, such as memory loss through increasing stages of cognitive and non-cognitive disturbances, eliminating any possibility of independent living.Life expectancy of the population with the disease is reduced. The mean life expectancy following diagnosis is approximately seven years. Fewer than % of patients live more than fourteen years. Disease features significantly associated with reduced survival are an increased severity of cognitive impairment, decreased functional level, history of falls, and disturbances in the neurological examination. Other coincident diseases such as heart problems, diabetes or history of alcohol abuse are also related with shortened survival. While the earlier the age at onset the higher the total survival years, life expectancy is particularly reduced when compared to the healthy population among those who are younger. Men have a less favourable survival prognosis than women.The disease is the underlying cause of death in % of all cases. Pneumonia and dehydration are the most frequent immediate causes of death, while cancer is a less frequent cause of death than in the general population.

Epidemiology

Two main measures are used in epidemiological studies: incidence and prevalence. Incidence is the number of new cases per unit of person–time at risk (usually number of new cases per thousand person–years); while prevalence is the total number of cases of the disease in the population at a given time.Regarding incidence, cohort longitudinal studies (studies where a disease-free population is followed over the years) provide rates between – per thousand person–years for all dementias and – for AD, which means that half of new dementia cases each year are AD. Advancing age is a primary risk factor for the disease and incidence rates are not equal for all ages: every five years after the age of , the risk of acquiring the disease approximately doubles, increasing from to as much as per thousand person years. There are also sex differences in the incidence rates, women having a higher risk of developing AD particularly in the population older than .Prevalence of AD in populations is dependent upon different factors including incidence and survival. Since the incidence of AD increases with age, it is particularly important to include the mean age of the population of interest. In the United States, Alzheimer prevalence was estimated to be .% in the year both overall and in the – age group, with the rate increasing to % in the – group and to % in the greater than group. Prevalence rates in less developed regions are lower. The World Health Organization estimated that in , .% of people worldwide had dementia, and that the prevalence would increase to .% in and to .% in . Other studies have reached similar conclusions. Another study estimated that in , .% of the world population (range .–.%; absolute number . million, range .–. million) were afflicted by AD, and that the prevalence rate would triple and the absolute number would quadruple by the year .HistoryAuguste D, first described patient with AD by Alois Alzheimer in The ancient Greek and Roman philosophers and physicians associated old age with increasing dementia. It was not until that German psychiatrist Alois Alzheimer identified the first case of what became known as Alzheimer's disease in a fifty-year-old woman he called Auguste D. Alzheimer followed her until she died in , when he first reported the case publicly. During the next five years, eleven similar cases were reported in the medical literature, some of them already using the term Alzheimer's disease. The disease was first described as a distinctive disease by Emil Kraepelin, who included Alzheimer’s disease, also named presenile dementia by Kraepelin, as a subtype of senile dementia in the eighth edition of his Textbook of Psychiatry, published in .For most of the twentieth century, the diagnosis of Alzheimer's disease was reserved for individuals between the ages of and who developed symptoms of dementia. The terminology changed after when a conference on AD concluded that the clinical and pathological manifestations of presenile and senile dementia were almost identical, although the authors also added that this did not rule out the possibility of different aetiologies. This eventually led to the diagnosis of Alzheimer's disease independently of age. The term senile dementia of the Alzheimer type (SDAT) was used for a time to describe the condition in those over , with classical Alzheimer's disease being used for those younger. Eventually, the term Alzheimer's disease was formally adopted in medical nomenclature to describe individuals of all ages with a characteristic common symptom pattern, disease course, and neuropathology.

Social costs

Dementia, and specifically Alzheimer's disease, may be among the most costly diseases for society in the developed countries, while their cost in developing countries such as Argentina, or Korea, is also high and rising. These costs will probably increase with the ageing of society, becoming an important social problem. AD associated costs include direct medical costs such as nursing home care, direct nonmedical costs such as in-home day care, and indirect costs such as lost productivity of both patient and caregiver. Numbers vary between studies but dementia costs worldwide have been calculated around $ billion, while costs of Alzheimer in the United States may be $ billion each year.The greatest origin of costs for society is the long-term care by health care professionals and particularly institutionalisation, which corresponds to / of the total costs for society. The cost of living at home is also very high, specially when informal costs for the family, such as caregiving time and caregiver's lost earnings, are taken into account.Costs increase with dementia severity and the presence of behavioural disturbances, and are related to the increased caregiving time required for the provision of physical care. Therefore any treatment that slows cognitive decline, delays institutionalisation or reduces caregivers' hours will have economic benefits. Economic evaluations of current treatments have shown positive results.The role of the main caregiver is often taken by the spouse or a close relative. Alzheimer's disease is known for placing a great burden on caregivers which includes social, psychological, physical or economic aspects. Home care is usually preferred by patients and families. This option also delays or eliminates the need for more professional and costly levels of care. Nevertheless two-thirds of nursing home residents have dementias.Dementia caregivers are subject to high rates of physical and mental disorders. Factors associated with greater psychosocial problems of the primary caregivers include having an affected person at home, the carer being a spouse, demanding behaviours of the cared person such as depression, behavioural disturbances, hallucinations, sleep problems or walking disruptions and social isolation. Regarding economic problems, family caregivers often give up time from work to spend hours per week on average with the person with AD, while the costs of caring for them are high. Direct and indirect costs of caring for an Alzheimer's patient average between $, and $, per year in the United States, depending on the study.Cognitive behavioural therapy and the teaching of coping strategies either individually or in group have demonstrated their efficacy in improving caregivers' psychological health.Research directionsAs of , the safety and efficacy of more than pharmaceutical treatments are being investigated in clinical trials worldwide, and approximately one-fourth of these compounds are in Phase III trials, which is the last step prior to review by regulatory agencies.One area of clinical research is focused on treating the underlying disease pathology. Reduction of amyloid beta levels is a common target of compounds under investigation. Immunotherapy or vaccination for the amyloid protein is one treatment modality under study. Unlike preventative vaccination, the putative therapy would be used to treat people already diagnosed. It is based upon the concept of training the immune system to recognise, attack, and reverse deposition of amyloid, thereby altering the course of the disease. An example of such a vaccine under investigation was ACC-, although the trials were suspended in . Similar agents are bapineuzumab, an antibody designed as identical to the naturally-induced anti-amyloid antibody, and MPC-, a selective amyloid beta- lowering agent. Other approaches are neuroprotective agents, such as AL-, and metal-protein interaction attenuation agents, such as PBT. A TNFα receptor fusion protein, etanercept has showed encouraging results.In , two separate clinical trials showed positive results in modifying the course of disease in mild to moderate AD with methylthioninium chloride (trade name rember), a drug that inhibits tau aggregation, and dimebon, an antihistamine.

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