Stroke Guidelines

Stroke Guidelines
2006 - Internet Stroke Center

link

Cellular and Molecular Methods in Neuroscience Research

Cellular and Molecular Methods in Neuroscience Research

Adalberto Merighi
Giorgio Carmignoto
66 Illustrations

2002 Springer-Verlag New York, Inc.

Download book

Handbook of Psychiatric Drugs

Handbook of Psychiatric Drugs


Title:
Handbook of Psychiatric Drugs
Topic:
The Handbook of Psychiatric Drugs is a comprehensive, clear, concise and quick reference to psychiatric drug therapies, designed to guide the clinician on the selection and implementation of treatment for mental illness.
Each chapter is organised by drug class and follows a standard format for ease of use. Concise sections on pharmacology and indications for use are followed by detailed information on drug selection, initiation and maintenance of treatment and withdrawal. Adverse effects, contraindications and drug interactions are also reviewed in detail, along with issues such as treatment resistance and treatment evaluation.
A handy pocket-sized drug reference, the Handbook of Psychiatric Drugs makes it easy to keep up-to-date with new developments. It is an invaluable resource for all clinicians who use psychiatric drugs to treat medical and psychiatric illness, and an informative read for all those with an interest in the subject.


Editors:
Jeffrey A. Lieberman

Professor and Chair Department of Psychiatry Columbia University, College of Physicians and Surgeons, and Director, New York State PsychiatricInstitute, New York, USA

Allan Tasman
Professor and Chair Department of Psychiatry and Behavioral SciencesUniversity of Louisville School of Medicine, Louisville,Kentucky, USA


Publisher:
John Wiley & Sons Ltd,
Publication Date: 2006-06-05


Download

Acute Medicine: A practical guide to the management of medical emergencies

Acute Medicine: A practical guide to the management of medical emergencies

FOURTH EDITION
By David Sprigings, John B. Chambers
2008 David Sprigings and John B. Chambers
ISBN 978-1-4051-2962-6

Download here

Innere Medizin

Innere Medizin

buch

link

Pain Psychological Perspectives

Title:
Pain Psychological Perspectives
Topic:
This volume provides a comprehensive account of the psychology of pain including both applied and basic topics.
This invaluable new resource presents a state-of-the-art account of the psychology of pain from leading researchers. It features contributions from clinical, social, and biopsychological perspectives, the latest theories of pain, as well as basic processes and applied issues. The book opens with an introduction to the history of pain theory and the epidemiology of pain. It then explores theoretical work, including the gate control theory/neuromatrix model, as well as biopsychosocial, cognitive/behavioral, and psychodynamic perspectives. Issues, such as the link between psychophysiological processes and consciousness and the communication of pain are examined. Pain over the life span, ethno-cultural, and individual differences are the focus of the next three chapters.

Editors:
Thomas Hadjistavropoulos
Kenneth D. Craig


Publisher: Lawrence Erlbaum Associates
Publication Date: 2003-12-01

link

Home Emergency Guide

Home Emergency Guide
Publisher: DK ADULT | ISBN: 0789493462 | edition 2003 | PDF | 260 pages | 15,2 mb
Providing the key to solving a wide range of problems in the home, the Home Emergency Guide features clear, user-friendly symptom charts to help readers determine whether to call an ambulance or a doctor, or to use self-help measures. From resuscitating a victim or making a sling to learning how to snake a toilet or dealing with a stovetop fire, as well as what to do in case of a hurricane, tornado, or earthquake, this all in one emergency guide explains what steps should be taken in order to keep the reader and family safe, before, during, and after the event.

My Links

D

X

U

F

Alzheimer’s Disease Symptoms and Stages

Alzheimer’s disease is the most common form of dementia, a serious brain disorder that impacts daily living through memory loss and cognitive changes. Alzheimer’s is a degenerative disease, progressing from mild forgetfulness to widespread neurological impairment and ultimately death. Chemical and structural changes in the brain gradually destroy the ability to create, remember, learn, reason, and relate to others. As critical cells die, drastic personality loss occurs and body systems fail.

Although not all memory loss indicates Alzheimer’s disease, one in ten people over 65 years of age, and over half of those 85+ have Alzheimer’s disease. Currently, 26 million people worldwide have this dementia, and over 15 million Americans will be affected by the year 2050.
Early-onset Alzheimer’s effects patients under the age of 65. This relatively rare condition is seen more often when parents or grandparents developed Alzheimer’s disease at a young age, and is generally associated with three genetic markers.

Signs and symptoms that may mean Alzheimer’s disease

For many, recognition of memory problems in themselves or a loved one brings fear of Alzheimer’s disease. Age-related brain shrinkage does produce normal changes in processing speed, attention, and short term memory, creating so-called “senior moments.” Understanding significance begins with knowing what is normal.SIGNS OF NORMAL CHANGE VS. EARLY ALZHEIMER’S SYMPTOMS

*Normal
$Early Alzheimer’s disease

*Can’t find your keys 
$Routinely place important items in odd places

*Search for casual names and words 
$Forget names of family and common objects

*Briefly forget conversation details 
$Frequently forget entire conversations

*Can’t find a recipe 
$Can’t follow recipe directions

*Forget to write down a check 
$Can no longer manage checkbook

*Cancel a date with friends 
$Withdraw from usual interests

*Miss an occasional right turn 
$Get lost in familiar places

What else might be causing these symptoms?

Significant cognitive and memory losses are not symptoms of normal aging. Most people over 65 experience a level of forgetfulness that is merely inconvenient and generally involves unimportant information. Terms like eccentric and senile can mask fears of Alzheimer’s disease, while other conditions may actually be causing mental decline.  

Symptoms that mimic early Alzheimer’s disease may result from:
Central nervous system and other degenerative disorders-, head injuries, brain tumors, stroke, epilepsy, Pick’s Disease, Parkinson’s disease, Huntington’s disease 
Metabolic ailments- hypothyroidism, hypoglycemia, malnutrition, vitamin deficiencies, dehydration, kidney or liver failure
Substance-induced conditions-drug interactions, medication side-effects, alcohol and drug abuse
Psychological factors- dementia syndrome, depression, emotional trauma, chronic stress, psychosis, chronic sleep deprivation, delirium 
Infections- meningitis, encephalitis, and syphilis
What to do if you notice Alzheimer’s symptoms

Research shows Alzheimer’s disease causes more worry than any other condition for Americans over 55 years of age. If your family history includes Alzheimer’s and you find yourself forgetting things, it doesn’t necessarily mean you have this disease. Even when you fear the worst, it is important to share your concerns and seek expert advice.  
Why not just wait and see?  

When symptoms appear suddenly, it is critical to seek medical attention. Conditions such as stroke, drug interactions, tumors, and seizures should be treated immediately. Timely intervention may also control or eliminate symptoms from other physical and psychological factors. 

If your symptoms are the result of Alzheimer’s disease, medications can delay the onset of more debilitating symptoms. Early diagnosis can prolong independence and is the first step towards treatment, management, and living life fully.
Ten Warning Signs of Alzheimer’s 

According to the Alzheimer’s Association, the ten warning signs are:
Memory loss
Difficulty performing familiar tasks
Problems with language
Disorientation to time and place
Poor or decreased judgment
Problems with abstract thinking
Misplacing things
Changes in mood or behavior
Changes in personality
Loss of initiative
Where should I go if I suspect Alzheimer’s?

Although no single test for Alzheimer’s exists, a skilled general practitioner, neurologist, or geriatrician can make a reasonable diagnosis by excluding other causes of your symptoms. Begin by preparing a list of concerns to discuss with your doctor. Ask a family member or friend to go with you to take notes and help you remember your questions. If your doctor suspects Alzheimer’s disease and recommends further assessment, ask for support and information from your local Alzheimer’s Association while you wait for a diagnosis.
Can I prevent or inhibit Alzheimer’s disease?

With each forgotten name or misplaced item, memory loss can be frightening. Maintaining a brain-healthy lifestyle, understanding controllable risk factors, and participating in research studies, can increase your sense of empowerment and protect your memory. 

Advances in Neuropharmacology

Advances in Neuropharmacology
Academic Press | 2009-08-17 | ISBN: 0123748933 | 600 pages | PDF | 7 MB

Download Link

http://rapidshare.com/files/256805691/0123748933.rar.html

Nature Neuroscience - July 2009

Nature Neuroscience - July 2009
English | 174 pages | PDF | 11.79 MB

Download Link

http://depositfiles.com/files/i7pxpb3ho

Or

http://rapidshare.com/files/248845486/ournutranilujycnecs.rar

limbic system

The term ‘limbic system’ (from Latin limbus: edge) was first used by MacLean in 1952 to describe a set of structurally and functionally related structures of the brain bordering the midline, inner surface of each cerebral hemisphere. These structures were considered to be evolutionarily ancient. MacLean called them the ‘visceral brain’ and suggested they mediate behaviourally ‘primitive’ functions inherited from lower mammals, particularly emotion and motivational behaviour. Although such phylogenetic arguments (based on comparison between species) are now commonly rejected, the concept of the limbic system survives and has since grown to be highly influential yet controversial.

First, there is no consensus over exactly which structures comprise the limbic system. Most schemes, however, consider it to consist of various parts of the cerebral cortex forming a set of ‘rings’ on the inner surface of each hemisphere, linked to a central core of structures lying below the cerebral cortex. The cortical areas include the cingulate cortex, hippocampus, parahippocampal cortex, and rhinal cortex. The various subcortical areas included in the limbic system extend down through the core of the brain to the upper part of the brain stem.

Second, there is considerable debate over what the function of the limbic system is. In addition to early ideas relating the limbic system to emotion and motivation, it has also now been implicated in the processing of sensory (especially olfactory) and cognitive information, learning and memory, sexual function (as part of a reward system serving emotional reactions), and motor functions. Most intriguing is the suggestion that the limbic system is concerned with mental integration of all functions related to personal ‘experience’.

As the number of brain areas said to belong to the limbic system has grown, its proposed functions have, not surprisingly, proliferated. It has been argued that such a heterogeneous collection of structures and functions can no longer be defined by a single general criterion and that the concept of the limbic system has become incoherent, even meaningless. An alternative view is that a quantitative approach (a ‘fuzzy limbic system’), in which different brain regions are described as having a certain degree of ‘limbic-ness’, would avoid the problem of having to define precise boundaries.

Despite controversy, the popularity and universal recognition of the term cannot be denied. This may be due partly to the very vagueness of the concept, which has often been used by authors as a convenience to refer to particularly poorly understood areas of the brain

Anatomy of the Brain

The image on the left is a side view of the outside of the brain, showing the major lobes (frontal, parietal, temporal and occipital) and the brain stem structures (pons, medulla oblongata and cerebellum).

The image on the right is a side view showing the location of the limbic system inside the brain. The limbic system consists of a number of structures, including the fornix, hippocampus, cingulate gyrus, amygdala, the parahippocampal gyrus and parts of the thalamus. The hippocampus is one of the first areas affected by Alzheimer's disease. As the disease progresses, damage extends throughout the lobes.
Glossary of Terms for an Anatomy of the Brain

Amygdala – limbic structure involved in many brain functions, including emotion, learning and memory. It is part of a system that processes "reflexive" emotions like fear and anxiety.

Cerebellum – governs movement.

Cingulate gyrus – plays a role in processing conscious emotional experience.

Fornix – an arch-like structure that connects the hippocampus to other parts of the limbic system.

Frontal lobe – helps control skilled muscle movements, mood, planning for the future, setting goals and judging priorities.

Hippocampus – plays a significant role in the formation of long-term memories.

Medulla oblongata – contains centers for the control of vital processes such as heart rate, respiration, blood pressure, and swallowing.

Limbic system – a group of interconnected structures that mediate emotions, learning and memory.

Occipital lobe – helps process visual information.

Parahippocampal gyrus – an important connecting pathway of the limbic system.

Parietal lobe – receives and processes information about temperature, taste, touch, and movement coming from the rest of the body. Reading and arithmetic are also processed in this region.

Pons – contains centers for the control of vital processes, including respiration and cardiovascular functions. It also is involved in the coordination of eye movements and balance.

Temporal lobe – processes hearing, memory and language functions.

Thalamus – a major relay station between the senses and the cortex (the outer layer of the brain consisting of the parietal, occipital, frontal and temporal lobes).

When to seek medical advice in Neck pain

Neck pain doesn't always require medical care. Rarely, it can be a sign of an emergency.

When to try home care
Neck pain caused by muscle irritations is usually easy to self-diagnose, and it usually gets better on its own within a few of days. This type of neck pain typically develops after excessive activity, a period of overuse or prolonged postures that put excessive strain on your neck muscles. If your neck pain doesn't let up within a week or two, see your doctor.

When to seek immediate medical care
See your doctor if the following signs and symptoms occur in conjunction with neck pain:

• Severe pain from an injury. After head or neck trauma, such as whiplash or a blow to your head, see your doctor immediately. Severe pain over a bone might indicate a fracture or an injury to a ligament.
• Shooting pain. Pain radiating to your shoulder, through your shoulder blades or down your arm, with or without numbness or tingling in your fingers, may indicate nerve irritation. Neck pain from nerve irritation can last from weeks to six months or longer. More sophisticated tests and treatments are available for this type of continued nerve irritation, so see your doctor.
• Loss of strength. Weakness in an arm or a leg, walking with a stiff leg, or shuffling your feet indicates a possible neurological problem and needs immediate evaluation.
• Change in bladder or bowel habits. Any significant change, especially a sudden onset of incontinence, could indicate a neurological problem.

brain and nervous system

in Nervous System Center

Locate information about the nervous system and disorders that can affect the human brain and other parts of the central nervous system.

What is the brain and nervous system?

How your nervous system works and how brain and central nervous system disorders are diagnosed and treated.
http://www.mayoclinic.com/health/nervous-system/BN00034
http://www.mayoclinic.com/health/nervous-system/BN00035
http://www.mayoclinic.com/health/nervous-system/BN00036
http://www.mayoclinic.com/health/nervous-system/BN00037

Brain and nervous system disorders:
A-Z

From epilepsy to stroke — information to help you understand your nervous system condition.
http://www.mayoclinic.com/health/stroke/BN00039
http://www.mayoclinic.com/health/brain-disorders/BN00040
http://www.mayoclinic.com/health/nervous-system/BN00041
http://www.mayoclinic.com/health/seizures/BN00042
http://www.mayoclinic.com/health/back-pain/BN00045

http://www.mayoclinic.com/

Deep Brain Stimulation Bests Medical Therapy for Advanced Parkinson's Disease

January 8, 2009 — Results of a randomized trial show that compared with best medical therapy (BMT), deep brain stimulation (DBS) increased "on" time without dyskinesias and improved motor function as well as quality of life at 6 months in patients with moderate to severe Parkinson's disease (PD), but at the cost of increased serious adverse events (SAEs).

"What we saw is that deep brain stimulation has the ability to shift these patients from the 'off' state to the 'on' state, and that was reflected in the quality-of-life measures," study author Kenneth Follett, MD, PhD, from the department of neurosurgery at the University of Nebraska Medical Center, in Omaha, told Medscape Neurology & Neurosurgery.

SAEs occurred in about 40% of DBS patients, including 1 death from cerebral hemorrhage, about a 4-fold increase over medical therapy, he noted. However, he noted, "by 6 months, almost all serious adverse events had resolved, and the incidence of permanent complication was very low."

The results are published in the January 7 issue of the Journal of the American Medical Association.

Widespread Use, Little Randomized Evidence

Widespread use of DBS for Parkinson's disease began during the 1990s, and acceptance has increased over the past 15 years, the authors write. Despite the increased use, there have been few randomized trials comparing surgery with best medical therapy. Recent reports outlining unexpected behavioral effects of DBS have highlighted this lack of randomized evidence, they note.

Only 1 other randomized trial has been done comparing these approaches, reported in 2006 (Deuschl G et al. N Engl J Med. 2006;355:896-908). It showed significant improvement in patient outcomes after DBS of the subthalamic nucleus "but also pointed out that not all patients who received deep brain stimulation improved," the authors note.

The current study compared 6-month outcomes among 255 patients with advanced PD (Hoehn & Yahr stage > 2 without medication) randomized to receive either DBS or BMT. Dr. Follett emphasized that BMT was also active management, with every patient followed by a movement-disorders specialist to provide optimal medical care.

Patients were stratified by age (<> 70 years) and by study site (7 Veterans Affairs and 6 university hospitals). Older patients were included in this study to more closely resemble the general population of patients with advanced PD, the authors note; 25% of patients were aged 70 years or older.

Patients randomized to DBS underwent a second randomization to receive bilateral stimulation of either the globus pallidus or the subthalamic nucleus. The best target for stimulation remains 1 of the "key clinical questions" in this area, Dr. Follett noted, and this second phase of the study will help to answer that question. For the purposes of this analysis, though, outcomes for all DBS patients represent pooled data. The data on this question are still blinded and are expected to be reported later in 2009, he said.

"The bottom line is that even with pooled data, those patients who underwent DBS had substantial and very statistically significant improvements in Parkinson's symptoms compared with those patients who continued on best medical therapy," Dr. Follett said.

On time without dyskinesia increased a mean of 4.6 hours per day in those receiving DBS vs no change (0 hours) in those on BMT. "So they went from about 6.5 hours per day in on time prior to surgery to almost 11 hours per day following surgery," Dr. Follett said. "That's most of the waking day; the hours when they need to be out and be active."

Time in the on state came from time previously spent in the off state, which decreased in the DBS groups from 6 hours prior to surgery to 3.4 hours after surgery, again vs no change in the medical-therapy group. Sleep time did not change significantly in either group.

DBS patients also had significant and clinically meaningful improvements of motor function: 71% of DBS patients had improvements of 5 or more points on the United Parkinson's Disease Rating Score motor subscale, vs 32% of those on BMT (P < .001). Significant improvements were also seen in a summary measure of quality of life and on 7 of 8 PD quality-of-life scores, they add. Interestingly, outcomes among those 70 years of age and older were similar to those younger than 70 years, including both motor improvements and the incidence of SAEs. "Although sometimes we're a little leery about offering this surgery to older people, the study tells us in fact that age alone should not be a contraindication to surgery," Dr. Follett said. Increased Serious Adverse Events However, the improvements were not without some cost. At least 1 SAE occurred in 49 DBS patients compared with 15 medical-therapy patients (P < .001). Of SAEs in the surgical patients, 39 were related to the surgical procedure, most commonly infections, and there was 1 death secondary to cerebral hemorrhage. Other events included nervous system disorders, psychiatric disorders, and device-related complications. The incidence of SAEs was greater than that seen in the study by Deuschl et al, the authors note. "The greater number of serious adverse events in our trial is likely attributable to inclusion of an older cohort of patients and the fact that the trial was rigorously monitored for identification of all adverse events." Also of some concern were statistically significant treatment differences between baseline and follow-up in neurocognitive measures, including composite measures of working memory, processing speed, phonemic fluency, and delayed recall on the Brief Visuospatial Memory Test. Those on best medical therapy actually showed improvements of 1 to 2 points on some of these measures, while those in the DBS group showed 1- to 3.5-point decrements. The clinical significance of these cognitive changes and SAEs and the risk/benefit ratio in light of the motor-function and quality-of-life improvements remain to be seen, the authors conclude. "Caution should be exercised, however, against overstating or understating the risks of deep brain stimulation in patients with PD," they write. "Physicians must continue to weigh the potential short-term and long-term risks with the benefits of deep brain stimulation in each patient." Questions Remain Günther Deuschl, MD, PhD, from the department of neurology at the Universitätsklinikum Schleswig-Holstein, in Kiel, Germany, first author of the only other randomized trial comparing these modalities, wrote an editorial accompanying the article. He noted that these results are similar to their findings in terms of efficacy but underlined the higher incidence of SAEs seen in this trial, with at least 1 event occurring in 49 DBS patients vs 15 patients in the medical-therapy group. The cumulative risk for device-related problems was 10% at 6 months, and stimulation-related problems, which can mostly be corrected, were even more frequent, he writes. While, similar to other prospective studies, psychiatric adverse effects were not seen in this study to be more common with DBS than BMT, "cumulative data from 55 centers have shown that the suicide rate following deep brain stimulation was 13 times higher in the first postoperative year . . . and doubled after 4 years. Risk factors have been identified, but prevention algorithms still need to be developed." A variety of questions remain to be answered about this treatment, Dr. Deuschl writes, including the optimal timing to undertake surgery, replication of the finding of similar results in older and younger PD populations that is at odds with previous findings, and the best target for stimulation, insight on which will be provided by follow-up data from this study. "Overall, the results of this important study by Weaver et al have convincingly confirmed the 6-month efficacy of deep brain stimulation for advanced PD with the largest patient group studied thus far," Dr. Deuschl concludes. "However, this study, along with previous research on this therapy, shows that such progress cannot be made without costs in terms of adverse effects."

Restless Legs Syndrome: A Unique Case and Essentials of Diagnosis and Treatment

Abstract

Restless legs syndrome (RLS) is a common, poorly understood movement disorder that can cause significant sleep disruption. RLS is characterized by uncomfortable sensations deep in the legs, relieved only by voluntary movement. Differential diagnosis includes peripheral neuropathy, leg cramps, and akathesia. Although RLS is familial in 50% of cases, secondary etiologies can be medically important, such as iron deficiency anemia and renal failure. We report a rare case of RLS associated with hyperparathyroidism. To our knowledge, only 1 other case of hyperparathyroid-related RLS has been described.

Genetics and Natural History of Multiple Sclerosis

Abstract

Recent studies have better defined the association between the human leukocyte antigen (HLA)-DR, cytotoxic T-lymphocyte antigen-4, interleukin-7 receptor, and interferon-gamma polymorphisms and susceptibility to multiple sclerosis (MS), while many more studies have been added to the controversial pool of likely false-positive and false-negative genetic association and linkage studies. Apolipoprotein E alleles may yet play an important role in disease course and cognitive impairment, although largely refuted as being directly associated with ambulatory measures of disease severity. Natural history studies have started to better define the clinical phenotypic heterogeneity of idiopathic inflammatory diseases of the central nervous system, fueling new hypotheses about immunopathogenesis of MS. Our understanding of phenotype measurement tools is improving. However, despite all the ongoing effort, the cause of MS and the determinants of heterogeneity in the clinical phenotype of MS remain largely unknown. As advances in our understanding of the immunobiology of MS start to bridge the gap between pathological and clinical natural history of the disease, biologically relevant phenotypes of MS will hopefully emerge to allow more specific treatment modalities to be developed and brought to practice.
Introduction

Multiple sclerosis (MS) belongs to a heterogenous spectrum of idiopathic inflammatory demyelinating diseases of the central nervous system (CNS) that vary from each other by pathology, lesion characteristics (extent, location, size, and number), time course of disease evolution, and clinical outcome ( Table 1 , Fig. 1). Pathological differences of individual idiopathic inflammatory demyelinating diseases have recently been reviewed.[1]


The dynamic natural history of idiopathic inflammatory demyelinating diseases of the central nervous system (CNS) in relation to disease severity as defined by the EDSS score. Idiopathic inflammatory demyelinating diseases are defined in two axes of disease severity: (1) as a function of pathological extent ranging from limited-restricted CNS involvement to multifocal or diffuse disease and pathological severity ranging from inflammation to necrosis (Y axis); and (2) as a function of time-dependent balance between predominant demyelination, extent of remyelination, and axonal loss (X axis).



Natural history defines the study of clinical evolution and outcome of individual syndromes in the absence of any disease-modifying treatment modalities. Being able to diagnose these syndromes separately constitutes probably the most important aspect of being able to predict the natural history because there is considerable variation in clinical outcome and response to treatment modalities by syndrome alone. Some of the individual idiopathic inflammatory demyelinating diseases, including acute disseminated encephalomyelitis (ADEM), acute transverse myelitis (ATM), and neuromyelitis optica (NMO), are extensively discussed in subsequent articles in this issue of Seminars of Neurology. Following the initial presentation, these syndromes may evolve (e.g., isolated ATM versus recurrent ATM or progressive myelopathy); however, surrogate markers are not always available to predict such an evolution.[2]

Diagnosis of MS is based on currently accepted consensus clinical and magnetic resonance imaging (MRI) criteria (McDonald criteria) requiring documentation of white matter disease disseminated in time and space ( Table 2 ).[3] However, some of the earlier studies referenced in this review have used the previous consensus criteria (Poser's criteria) for diagnosis of MS.[4] Although diagnostic criteria are essential for clinical trials, they do not necessarily encompass the full biological spectrum of MS. Furthermore, other idiopathic inflammatory demyelinating diseases (e.g., NMO) may fulfill the criteria for MS but represent a different disease process. Additionally, once a MS diagnosis is established, subsequent clinical manifestations and temporal course are heterogenous. This phenotypic heterogeneity likely results from complex interactions of multiple genetic, environmental, physiological, and pathological factors.[5,6]

This review discusses the current state of our understanding of genetic epidemiology of MS susceptibility and outcome, and the natural history of clinically isolated idiopathic inflammatory demyelinating diseases and MS in the context of predictors of disease outcome and disease course.

Dementia

Introduction

Perhaps the most important challenge in treating dementia is identifying cases (albeit uncommon) of reversible dementia such as chronic drug intoxication, vitamin deficiencies (B-12 and folate), subdural hematoma(s), major depression (causing forgetfulness), normal pressure hydrocephalus (NPH), and hypothyroidism. The management of such causes is aimed at treating the underlying disease process.

However, most causes of dementia, including degenerative brain diseases (ie, Alzheimer disease) and multi-infarct states, are incurable. This does not mean that symptoms cannot be treated. The pharmacotherapy of dementia is tailored to the specific problems confronted, although these are influenced by the underlying diagnosis.

Six clinical categories associated with dementia are amenable to pharmacotherapeutic intervention, as follows:

• Prevention of neurodegeneration
• Intellectual decline
• Behavioral disorders
• Sleep disorders
• Common medical complications
• Abrupt worsening of dementia

These categories are applicable to almost all cases of irreversible dementia, although some are more frequently problematic depending on the specific disease involved. Nonetheless, this basic framework can be applied, with some fine-tuning, to most patients with dementia.

Prevention of Neurodegeneration

There are ongoing efforts to study drugs that may have an effect on the progression of neurodegeneration. These data are available primarily for Alzheimer disease (AD), although such effects, if ultimately proven to be significant, might be applicable to the broader family of neurodegenerative diseases. Some of the more popular agents are estrogen replacement therapy (in women only), vitamins (E and C), and nonsteroidal anti-inflammatory drugs (NSAIDs).

A few clinical studies seem to suggest that estrogen replacement therapy (ERT) is associated with a lower incidence of AD in women.

• However, based on results from the Women's Health Initiative Memory Study (WHIMS), daily conjugated equine estrogens (CEE) with or without medroxyprogesterone acetate (MPA) should not be used to either prevent dementia or improve cognitive function in women older than 65 years.
• 
  
• The WHIMS trial revealed that there was actually an increased risk of dementia with CEE and MPA compared with placebo. While, this conclusion can be drawn from WHIMS, it does not mean that estrogen treatment has no effect on dementia. The WHIMS is an ancillary study portion of the Women's Health Initiative (WHI). This large study was discontinued early because of increased risks of coronary disease, stroke, thromboembolism, and breast cancer.

Vitamin E has been available as a nutritional supplement for many years without prescription in doses ranging from 30 international units (IU) to 1000 IU.

• A recent study suggested that 2000 IU daily delayed the need for institutionalization of patients with AD.
• 
  
• Minor bleeding (subcutaneous) was a potential adverse effect.
• 
  
• The same study showed a similar benefit for selegiline. However, no additional benefit for combination therapy (ie, vitamin E and selegiline) was found.
• 
  
• Concerns have been raised regarding the statistical methods used in this study, as well as its true biological validity. Thus, it cannot yet be recommended that high doses of vitamin E (1000-2000 mg) be taken solely to prevent dementia.
• 
  
• A recent study seemed to indicate that the incidence and prevalence of AD may be lower in those that use vitamin E and C in combination. However, again, there awaits larger controlled trials to be able to make clear recommendations in favor of vitamins for dementia.

NSAIDs are thought to retard neurodegenerative progression because of biochemical inflammatory markers found in the microscopic lesions of the brain (particularly neuritic plaques) in AD.

• Small clinical and large epidemiological studies support the hypothesis that patients who take NSAIDs have reduced risks of dementia onset and rate of progression.
• 
  
• However, dose and specific agent remain unclear.
• 
  
• Given the risk of serious upper gastrointestinal bleeding associated with NSAIDs, caution must be exercised.
• 
  
• Data are conflicting regarding the potential prophylactic efficacy of low-dose aspirin (81-325 mg daily) in dementia. Aspirin already is used for stroke and myocardial infarction prophylaxis.
• 
  
• A recent meta-analysis of NSAID use and risk of dementia studies was undertaken. The studies found that bias in the studies (recall, prescription, and publication bias) could account for the conclusion that NSAIDs are beneficial. Hence, it cannot be recommended that NSAIDs be used solely in an effort to prophylaxis against dementia.

Limited data suggest that Ginkgo biloba, a plant extract, may have a modest neuroprotective effect.

• Whether it has an additive effect with any other neuroprotective agent is unknown.
• 
  
• Limited case reports have been published of hemorrhagic conditions such as intracranial and intraocular bleeding in patients taking ginkgo, but these reports are rare and not unique to ginkgo.
• 
  
• Additionally, a recent randomized, double-blind, placebo-controlled trial of two doses of ginkgo biloba extract in dementia of the Alzheimer type did not find a difference in efficacy. However, the authors noted a study limitation due to similar result with placebo.
• 
  
• Given the concern of ginkgo's interaction with some medications used in the elderly and lack of clear benefit, recommending ginkgo solely for dementia cannot be given at this point.

Intellectual Decline

Intellectual decline is intrinsic to the definition of dementia. One of the prominent pathophysiological changes is a loss of cholinergic neurons (especially in the basal forebrain). In an attempt to ameliorate this cerebral cholinergic deficiency state, centrally acting acetylcholinesterase inhibitors have been developed that are modestly effective in enhancing intellectual skills such as memory in patients with AD.

The first such medication, tacrine (Cognex), has a high incidence of adverse effects, especially gastrointestinal (nausea, diarrhea, hepatotoxicity). These occurred at higher dosages (40 mg qid), which tend to be the therapeutically effective doses. Thus, many patients are not able to tolerate potentially effective doses.

The second drug, donepezil (Aricept), released in the United States in January 1997, is similar to tacrine in efficacy but has a low incidence of dose-limiting adverse effects.

Two more cholinesterase inhibitors have become available since donepezil. They are rivastigmine (Exelon) and galantamine (Razadyne). In addition to oral administration, rivastigmine is also available as transdermal patch. All 3 drugs represent different classes of cholinesterase inhibitors and are all approved by the FDA for use in Alzheimer disease. Additionally, rivatigmine is indicated for dementia associated with Parkinson disease. They differ primarily in their pharmacologic properties rather than in efficacy. As such, when the initial drug fails in efficacy or tolerability, then a different cholinesterase inhibitor can be tried. Combining two cholinesterase inhibitors is not recommended.

Generally, it is recommended to start treatment early in the course of illness to maximize longer-term benefits. Limited data exist on use of cholinesterase inhibitors in other dementias (multi-infarct, Pick disease, dementia with Lewy bodies). However, it may be considered given some of the pathological similarities to Alzheimer disease and lack of FDA approved medicines for other dementias. However, third party payers may or may not provide coverage when use is outside of product labeling.

Side effects of cholinesterase inhibitors, in a minority of patients, can include nausea, vomiting, diarrhea, and anorexia. These side effects are more common in the initiation phase of the drug rather than during maintenance.

Some studies have suggested that the cholinesterase inhibitors may also improve secondary symptoms of dementia such as behavior/psychiatric. Therefore, it is prudent to avoid starting another medication to address additional dementia symptoms till the effect of the cholinesterase inhibitor is determined.

Recently, an analysis of clinical trials published in the British Medical Journal online concluded that, due to methodological concerns and modest benefit, the scientific basis of the true efficacy of donepezil, rivastigmine, and galantamine is questionable. However, in the US, the FDA requires rigorous controlled trials to approve medications.

More recently, another medication memantine, an uncompetitive N -methyl-D-aspartate (NMDA) antagonist, has received FDA approval for Alzheimer disease. Additionally, some studies suggest that improvement in primary and secondary symptoms in Alzheimer disease may be greater when memantine is used in combination with a cholinesterase inhibitor.

Side effects of memantine include somnolence, dizziness, headache, and constipation.

Behavioral Disorders

Three categories of behavioral or psychiatric disturbances are common in patients with dementia: psychosis, anxiety, and depression. Although dementia is defined by intellectual decline, its course is complicated by behavioral changes. Behavioral problems correlate more strongly with the need for nursing home placement than intellectual decline alone.

Psychosis

Psychosis in dementia, while variable in its features, typically involves paranoid delusions and formed visual hallucinations.

• Typical paranoid themes involve infidelity and money/theft.
• These sentiments can interfere with a well-intentioned caregiver and may make it impractical for the patient to remain at home.
• Fortunately, psychotic symptoms respond to neuroleptic management in most patients.

A seemingly endless number of neuroleptic medications are available, but a working familiarity with the following 4 can be useful. Two are "typical" neuroleptic agents and 2 are "atypical" neuroleptic agents. The main difference between the 2 types is that the typical agents produce extrapyramidal adverse effects (ie, parkinsonism) at a higher frequency, although in general they are quite effective in ameliorating psychosis. The atypical agents are less likely to cause extrapyramidal side effects, but efficacy is less predictable, especially in cases of acute severe agitation.

• Two commonly used typical neuroleptics are haloperidol (Haldol) and risperidone (Risperdal). They share a similar dosing schedule.
  • The 2 most frequent errors in their use are overdosing and delaying treatment until a mild problem escalates into a crisis.
  • Most patients can be treated with a low maintenance dose without undue parkinsonism.
  • Typical maintenance doses for haloperidol and risperidone are between 0.5 and 2 mg daily.
  • Extrapyramidal adverse effects can develop gradually despite a stable low dose, and the patient must be monitored carefully for these effects.
  • Risperidone is more selective neurochemically than haloperidol, and extrapyramidal effects are milder at low doses. This is variable, however, and risperidone can cause severe parkinsonism despite its greater selectivity. At the doses described, the adverse effects do not differ greatly, and haloperidol is much less expensive.
• Two relatively new atypical neuroleptic agents are quetiapine (Seroquel) and olanzapine (Zyprexa). Both can be quite effective, although they are better used in less acute settings.
  • Starting doses for quetiapine are 25 mg once or twice daily, and for olanzapine 2.5 mg once or twice daily.
  • These agents are more expensive than haloperidol, and cost can be a limiting factor.
  • They are most useful in patients in whom dementia is associated with parkinsonism (particularly Parkinson-dementia complex, diffuse Lewy body disease, and related disorders).

Acute psychotic crises require more aggressive (and sometimes inpatient) management. These crises often occur in the hospitalized patient with dementia.

• Initial doses of 5-10 mg of haloperidol parenterally are often necessary, with rapid tapering of the dose as the agitated psychosis abates.
• In a hospitalized patient, regularly scheduled doses are more effective than "as needed" doses.
• For example, rather than giving 5 mg of haloperidol intramuscularly for acute agitation, a maintenance dose of 1 mg twice a day orally may prevent such episodes.
• The course of acute agitation/psychosis is much more variable than that of chronic (and generally milder) psychosis, and psychiatric consultation is advisable if the initial measures are inadequate.

In patients with dementia who are undergoing scheduled surgery, initiation of a neuroleptic several days before the surgery may be helpful in reducing the incidence and severity of postoperative confusion and agitation. An example might be to begin haloperidol 1 mg bid 3 days before scheduled hip replacement in a patient with mild to moderately severe AD. If the patient does well postoperatively, the dose can be tapered.

Once a patient's behavior has improved in any of these circumstances, tapering and discontinuation of the neuroleptic should be considered.

Anxiety

Many patients with dementia are anxious, often clinging to their caregiver.

• Benzodiazepines, while often effective, have 2 potential drawbacks: They run the risk of causing paradoxical agitation and, even when effective, they are often sedating. They generally should not be considered first-line agents in this setting.
• Buspirone (BuSpar) generally is tolerated better than benzodiazepines and rarely causes paradoxical agitation, so it is a first-line agent in this setting. A typical starting dose in mild cases is 5 mg twice daily, with gradual titration of the dose according to symptoms and adverse effects (which are typically few).
• When anxiety is more severe, trazodone 50 mg at bedtime can be helpful, and in more severe cases, neuroleptic therapy may be necessary.

Depression

A comprehensive discussion of the pharmacotherapy of depression in the elderly and demented patient is beyond the scope of this article, but a few practical principles are worth mentioning.

• Tricyclic antidepressants should be avoided in the population of patients with dementia.
  • These agents are associated with a high incidence of increased confusion and daytime sedation related to the anticholinergic adverse effects. They should not be used as sleeping pills.
  • Much preferred in elderly patients with dementia are the selective serotonin reuptake inhibitors (SSRIs).
• Sertraline (Zoloft) is a good example of the SSRIs but is only one of several that can be considered in this context.
  • It has a neurochemically selective profile, is generally well tolerated and, in addition to its antidepressant effects, may have a mild antipsychotic effect as well.
  • Typical doses of sertraline range from 25-50 mg each morning.
• Paroxetine (Paxil) is another good choice (among others), generally in doses of 10-20 mg daily.

These medications are sometimes helpful even in nondepressed patients with dementia who have significant fatigue or abulia, 2 other common problems in this context (especially in the frontotemporal dementia syndromes).

Patients with severe depression should be referred for psychiatric consultation for more definitive and aggressive management.

Sleep Disturbances

The disturbed and reversed sleep-wake cycle is a notorious problem not only for the patient with dementia, but also for the caregiver. Restoration of the sleep-wake cycle is therefore of major importance. Short-acting sedative-hypnotic medications are preferred over long-acting agents to facilitate sleep onset and to avoid daytime somnolence. These agents include diphenhydramine (Benadryl), chloral hydrate, and zolpidem, and the newer drugs eszopiclone, zaleplon, and ramelteon.

• Diphenhydramine (25-50 mg at bedtime) is inexpensive, available without prescription, and has few adverse effects. Unfortunately, it is often ineffective, and thus many patients with significant sleep disorders require a stronger agent such as chloral hydrate or zolpidem.
• Chloral hydrate (500-1000 mg at bedtime) is an old medication, has few adverse effects, and is used by electroencephalography (EEG) laboratories to obtain sleep EEGs.
  • It has no effect on EEG patterns and is well tolerated, in addition to being relatively inexpensive.
  • Unfortunately, it is becoming more difficult to obtain as it is replaced by newer generation drugs like zolpidem.
• Zolpidem (5-10 mg at bedtime) has positive qualities similar to those of chloral hydrate, but it is more expensive than chloral hydrate. Zolpidem now is available in extended-release formulations (CR) to minimize nighttime awakenings. Zolpidem is FDA approved for short-term use.
• Like zolpidem, zaleplon is approved for short-term use to help with sleep onset.
• Eszopiclone has indication to help sleep onset and maintenance and longer-term use.
• Ramelteon works at the MT1 and MT2 receptors in the suprachiasmatic nucleus, which are involved in the sleep wake cycle. Additionally, it does not act on the GABA-benzodiazepine receptor complex. It has an FDA approval for longer-term use.
• Trazodone 50 mg at bedtime may help patients sleep through the night and may be given in conjunction with the shorter-acting sedative-hypnotic agents.

As in the treatment of any associated symptoms in elderly persons, drug interactions need to be considered because of the multiple medications that elderly persons may already be taking.

Associated Symptoms

Several problems are encountered frequently in the patient with dementia, either as a direct result of the dementing illness or as an unrelated problem.

• Incontinence
  • Pharmacotherapy consists of oxybutynin (Ditropan) or tolterodine (Detrol).
    • These are predominantly peripherally acting anticholinergic drugs, but they carry some risk of exacerbating confusion.
    • Small doses (eg, 2.5-5 mg oxybutynin bid, or 2 mg tolterodine bid) should be used if necessary, with careful monitoring and forewarning of caregivers.
  • Despite the small risk of increased confusion, both are generally well tolerated.
• Parkinsonism
  • Whether due to the underlying disease or a complication of neuroleptic therapy, parkinsonism is a common problem in the population of patients with dementia.
  • An important question to be considered is whether the parkinsonism is disabling to the patient.
  • The principle of therapy for parkinsonism is to increase dopamine levels in the brain. This is accomplished either by stopping dopaminergic antagonists (neuroleptics) or by administering a dopamine agonist (typically levodopa/carbidopa).
  • Increasing dopamine levels in the brain of a patient with dementia can cause or aggravate confusion and/or worsen hallucinations.
  • Hence, the only reason to treat parkinsonism is that it is disabling to the patient (particularly if associated with increased risk of falls, which can cause hip fracture).
  • If a medication change is made, it should be gradual, and the possibility of behavioral deterioration should be monitored.
  • In patients with parkinsonism due to their underlying disease, initial levodopa doses should be low (50 mg in the morning) and be titrated carefully upward according to symptoms and side effects.
  • Some diseases, including corticobasal ganglionic degeneration, small-vessel multi-infarct dementia, and progressive supranuclear palsy, are not responsive to levodopa (though an empirical therapeutic trial still may be reasonable in some patients).
  • Other Parkinson-dementia complex diseases such as Parkinson disease with dementia and diffuse Lewy body disease often are responsive to levodopa, but higher doses may increase confusion and hallucinations.
• Pain
  • Causes of pain in an elderly patient with or without dementia are innumerable and include vertebral compression fracture, low back pain, neck pain, and arthritis.
  • In the patient with dementia, pain can cause behavioral deterioration and should be considered in this context. The offending problem may not be clinically obvious, but treatment is warranted.
  • Acetaminophen, NSAIDs, and if necessary, propoxyphene are the most commonly used agents.
  • Severe pain from a serious problem, such as a hip fracture, must be treated more aggressively and may require narcotic analgesia.
  • Concomitant prophylactic neuroleptic use should be considered in this setting.
• Dysphagia
  • This is a common problem in the later stages of most neurodegenerative diseases, and generally it occurs earlier in those that impair motor function, such as those associated with parkinsonism or motor neuron disease.
  • A formal swallowing study is useful to determine if the patient is actually aspirating (ie, food and/or liquid getting into the windpipe and lungs).
  • Aspirating is a potentially serious situation that can be handled initially by altering the consistency of the food (ie, smaller pieces, mechanically soft food), changing the position of the patient when swallowing, and other swallowing strategies. Consultation with speech pathology and/or occupational therapy can be helpful in this situation.
  • If aspiration is severe, an invasive procedure may be required.
    • Feeding tubes (such as a nasogastric tube) are uncomfortable and temporary.
    • A percutaneous gastrostomy in a patient with an advanced degenerative brain disease is a more definitive step, but one that may not always be appropriate. Quality-of-life issues are of paramount importance in this context.
  • A different type of "swallowing disorder" occurs in some patients with frontotemporal dementia, who can swallow but hold the food in their mouth for long periods of time and may eventually swallow or spit it out.
    • This is not a true swallowing problem and does not jeopardize the airway, though it may interfere with nutrition.
    • It generally is handled best through behavioral measures rather than a feeding tube.
• Driving
  • Patients with clinically obvious visuospatial impairment occurring within the context of a degenerative brain disease should not drive. This may be particularly apparent in patients with progressive visual syndromes (also termed "the visual variant of Alzheimer disease" and "posterior cortical atrophy") or corticobasal ganglionic degeneration.
  • Driving within the context of clinically typical AD, in which visual cortices and visual function typically are preserved, is a more challenging, but very important, issue confronting the patient, family, and physician.
    • Caregiver surveys reveal that a significant proportion of patients with AD continue to drive despite driving difficulties.
    • Although one survey of moving violation and police accident reports from a state motor vehicle authority failed to disclose an increased number of reports for a sample of 143 licensed drivers with AD, this was thought to reflect the far fewer number of miles driven by the study patients than by the average driver due to the active intervention of family and physicians to reduce patient road exposure.
    • In contrast, multiple road test–based studies of driving skills in patients with AD uniformly report poorer driving safety records compared to age-matched controls, even in mild stages of AD.
    • These and more recent studies employing driving simulators have shown that neuropsychological measures of attention and spatial skills in particular correlate well with driving performance.
  • Roughly 50% of patients with AD do not stop driving for at least 3 years after initial diagnosis, yet 41-63% of patients with mild AD fail a road test.
  • Clearly, the spatially challenging task of driving represents a clinically important concern, even in the absence of obvious, severe visuospatial impairment in patients with AD.

Abrupt Decline

In a patient with a known slowly progressive degenerative dementia, sudden changes in cognitive, behavioral, or health status sometimes occur. Mental status is often a barometer of health in the patient with dementia, and abrupt changes necessitate searching for a superimposed problem. Treatment then is directed at the superimposed problem. Four categories of common superimposed problems are the following:

• Intercurrent illness
  • The most common intercurrent illnesses in all patients with dementia are infections, especially urinary tract infections and pneumonia.
  • Many other serious illnesses need to be considered, including subdural hematoma and stroke and nonneurological problems such as pulmonary embolism and myocardial infarction.
  • Essentially, any serious illness should be considered.
• Catastrophic reaction
  • Behavioral outbursts can be precipitated by sudden psychosocial stressors such as an unfamiliar environment (especially when traveling), crowds, and confrontation with others.
  • Disturbed sleep-wake cycles can lead to further deterioration in behavior.
  • Confusion is typically worse in the evening ("sundowning"), and if a patient is up much of the night, he or she may be even more confused the following day.
• Pain
  • As previously noted, patients with severe dementia who are unable to articulate their discomfort may exhibit a decline in their behavior, with agitation and combativeness, as the consequence of a painful condition.
  • Osteoporotic vertebral compression, pelvic, and even hip fractures are common in such a setting.
• Medications
  • Medication errors, side effects, and interactions are important causes of rapid behavioral decline. Patients with dementia should have their medication administration supervised because both missed doses and overdosage can occur.
  • Thyroid and diabetes medications, as well as psychotropic medications, commonly cause problems.
  • Sedative-hypnotics and benzodiazepines may cause paradoxical agitation rather than sedation owing to behavioral disinhibition, even when properly administered.
  • Neuroleptics cause parkinsonism in a dose-related fashion, which can be mild (eg, lethargy, drooling).
  • Patients with psychiatric disorders on long-term psychotropic medications (eg, lithium) can develop signs of toxicity at previously therapeutic doses and blood levels.

Summary

The syndrome of dementia is a multifaceted symptom complex, and no single medication adequately addresses all possible complications. A systematic analysis of each patient's clinical situation leads to an appropriately tailored treatment plan. This plan is influenced by the primary dementing illness as well as coexistent problems. The outline provided in this article is a framework to be adapted to the specific needs of the individual patient. It is not a comprehensive listing of all possible medications, but rather a deliberately abbreviated, practically oriented list of examples.

Finally, clinicians must remember that not all patients respond equally well to any one drug, and alternate strategies must be considered in patients in whom a recommended agent fails to help or has adverse side effects. Psychiatric consultation may be helpful in patients who are not responding to first-line pharmacotherapeutic efforts, but the neurologist must have a working plan to address the problems presented by this common neurological syndrome.