Bergers Disease More Condition_Symptoms

Buerger's disease (also known as thromboangiitis obliterans) is an acute inflammation and thrombosis (clotting) of arteries and veins of the hands and feet. It is strongly associated with use of tobacco products, primarily from smoking, but also from smokeless tobacco.

Features
There is a recurrent acute and chronic inflammation and thrombosis of arteries and veins of the hands and feet. The main symptom is pain in the affected areas. Ulcerations and gangrene in the extremities are common complications, often resulting in the need for amputation of the involved extremity.

Diagnosis
A concrete diagnosis of thromboangiitis obliterans is often difficult as it relies heavily on exclusion of the conditions. The commonly followed diagnostic criteria are below although the criteria tend to differ slightly from author to author. Olin (2000) proposes the following criteria:

Age younger than 45 years
Current (or recent) history of tobacco use
Presence of distal extremity ischemia (indicated by claudication, pain at rest, ischemic ulcers or gangrene) documented by noninvasive vascular testing such as ultrasound
Exclusion of autoimmune diseases, hypercoagulable states, and diabetes mellitus by laboratory tests.
Exclusion of a proximal source of emboli by echocardiography and arteriography
Consistent arteriographic findings in the clinically involved and noninvolved limbs.

Pathophysiology
There are characteristic pathologic findings of acute inflammation and thrombosis (clotting) of arteries and veins of the hands and feet (the lower limbs being more common). The mechanisms underlying Buerger's disease are still largely unknown. It is suspected that immunological reactions play a role.

Treatment
Symptoms are treated as there is no treatment for the disease. Cessation of tobacco use may slow any further progression of the disease. Vascular surgery can sometimes be helpful in treating limbs with poor perfusion secondary to this disease. Use of vascular growth factor and stem cell injections have been showing promise in clinical studies.

Prognosis
Amputation is common and more severe in patients who continue to use tobacco. It often leads to vascular insufficiency. Buerger's is rarely immediately fatal, but rather a life shortening disease.

Prevention
The cause of the disease is unknown but heavily linked to tobacco use. There have also been links to persons with digestive disorders.

Epidemiology
Buerger's is more common among men than women. It is more common in Israel, Japan and India along the "old silk route" than in the United States and Europe. The disease is most common among South Asians, who often smoke cigarettes made of raw tobacco (bidis).

History
Buerger's disease was first reported by Felix Von Winiwater in 1879 in Germany.

It was described in detail by Leo Buerger in 1908 in New York, who called it presenile spontaneous gangrene after studying amputations in 11 patients.

Bergers Disease More Condition_Symptoms

Acohol Withdrawal

Alcoholism is a term with multiple sometimes conflicting definitions, but with no formal recognition of the divergence of meaning. In common and historical usage, alcoholism typically refers to any condition that results in the continued consumption of alcoholic beverages despite negative personal and social consequences. Medical definitions describe alcoholism as a disease which may result in a persistent difficulty in controlling alcohol consumption. Alcoholism may also refer to a preoccupation with or compulsion toward the consumption of alcohol and/or an impaired ability to recognize the negative effects of excessive alcohol consumption. Although not all of these definitions specify current and on-going use of alcohol as a qualifier, some do, as well as remarking on the long-term effects of consistent, heavy alcohol use, including dependence and symptoms of withdrawal.

While the ingestion of alcohol is, by definition, necessary to develop alcoholism, the use of alcohol does not predict the development of alcoholism. The quantity, frequency and regularity of alcohol consumption required to develop alcoholism varies greatly from person to person. In addition, although the biological mechanisms underpinning alcoholism are uncertain, some risk factors, including social environment, emotional health and genetic predisposition, have been identified.

Definitions and Terminology
The definitions of alcoholism and related terminology vary significantly between the medical community, treatment programs, and the general public.


Medical Definitions
The Journal of the American Medical Association defines alcoholism as "a primary, chronic disease characterized by impaired control over drinking, preoccupation with the drug alcohol, use of alcohol despite adverse consequences, and distortions in thinking."

The DSM-IV (the standard for diagnosis in psychiatry and psychology) defines alcohol abuse as repeated use despite recurrent adverse consequences.[2] ; further defining alcohol dependence as alcohol abuse combined with tolerance, withdrawal, and an uncontrollable drive to drink. (See DSM diagnosis below.)

According to the APA Dictionary of Psychology, alcoholism is the popular term for alcohol dependence. Note that there is debate whether dependence in this use is physical (characterised by withdrawal), psychological (based on reinforcement), or both.


Terminology
Many terms are applied to a drinker's relationship with alcohol. Use, misuse, heavy use, abuse, addiction, and dependence are all common labels used to describe drinking habits, but the actual meaning of these words can vary greatly depending upon the context in which they are used. Even within the medical field, the definition can vary between areas of specialization. The introduction of politics and religion further muddles the issue.

Use refers to simple use of a substance. An individual who drinks any alcoholic beverage is using alcohol. Misuse, problem use, and heavy use do not have standard definitions, but suggest consumption of alcohol beyond the point where it causes physical, social, or moral harm to the drinker. The definitions of social and moral harm are highly subjective and therefore differ from individual to individual.

Within politics, abuse is often used to refer to the illegal use of any substance. Within the broad field of medicine, abuse sometimes refers to use of prescription medications in excess of the prescribed dosage, sometimes refers to use of a prescription drug without a prescription, and sometimes refers to use that results in long-term health problems. Within religion, abuse can refer to any use of a poorly regarded substance. The term is often avoided because it can cause confusion with audiences that do not necessarily share a single definition.

Remission is often used to refer to a state where an alcoholic is no longer showing symptoms of alcoholism. The American Psychiatric Association considers remission to be a condition where the physical and mental symptoms of alcoholism are no longer evident, regardless of whether or not the person is still drinking. They further subdivide those in remission into early or sustained, and partial or full. Others (most notably Alcoholics Anonymous) use the term recovery to describe those who have completely stopped consumption of alcohol.


Epidemiology
Substance use disorders are a major public health problem facing many countries. "The most common substance of abuse/dependence in patients presenting for treatment is alcohol." In the United Kingdom, the number of 'dependent drinkers' was calculated as over 2.8 million in 2001.

Within the medical community, there is broad consensus regarding alcoholism as a disease state. Outside the medical community, there is considerable debate regarding the Disease Theory of Alcoholism. Proponents argue that any structural or functional disorder having a predictable course, or progression, should be classified as a disease. Opponents cite the inability to pin down the behavioral issues to a physical cause as a reason for avoiding classification.

A 2002 study by the National Institute on Alcohol Abuse and Alcoholism surveyed a group of 4,422 adult alcoholics and found that after one year some were no longer alcoholics, with the breakdown as follows:

25% still dependent
27.3% in partial remission (some symptoms persist)
11.8% asymptomatic drinkers (consumption increases chances of relapse)
35.9% fully recovered — made up of 17.7% low-risk drinkers plus 18.2% abstainers.

Identification and diagnosis
Multiple tools are available to those wishing to conduct screening for alcoholism. Identification of alcoholism may be difficult because there is no detectable physiologic difference between a person who drinks frequently and a person with the condition. Identification involves an objective assessment regarding the damage that imbibing alcohol does to the drinker's life compared to the subjective benefits the drinker perceives from consuming alcohol. While there are many cases where an alcoholic's life has been significantly and obviously damaged, there are always borderline cases that can be difficult to classify.

Addiction Medicine specialists have extensive training with respect to diagnosing and treating patients with alcoholism.

Screening
Several tools may be used to detect a loss of control of alcohol use. These tools are mostly self reports in questionnaire form. Another common theme is a score or tally that sums up the general severity of alcohol use.

The CAGE questionnaire, named for its four questions, is one such example that may be used to screen patients quickly in a doctor's office.
Two "yes" responses indicate that the respondent should be investigated further. The questionnaire asks the following questions:

Have you ever felt you needed to Cut down on your drinking?
Have people Annoyed you by criticizing your drinking?
Have you ever felt Guilty about drinking?
Have you ever felt you needed a drink first thing in the morning (Eye-opener) to steady your nerves or to get rid of a hangover?
The CAGE questionnaire, among others, has been extensively validated for use in identifying alcoholism. It is not valid for diagnosis of other substance use disorders, although somewhat modified versions of the CAGE are frequently implemented for such a purpose.
The Alcohol Dependence Data Questionnaire is a more sensitive diagnostic test than the CAGE test. It helps distinguish a diagnosis of alcohol dependence from one of heavy alcohol use.
The Michigan Alcohol Screening Test (MAST) is a screening tool for alcoholism widely used by courts to determine the appropriate sentencing for people convicted of alcohol-related offenses, driving under the influence being the most common.
The Alcohol Use Disorders Identification Test (AUDIT) is a screening questionnaire developed by the World Health Organization. This test is unique in that it has been validated in six countries and is used internationally. Like the CAGE questionnaire, it uses a simple set of questions - a high score earning a deeper investigation.
The Paddington Alcohol Test (PAT) was designed to screen for alcohol related problems amongst those attending Accident and Emergency departments. It concords well with the AUDIT questionnaire but is administered in a fifth of the time.
A number of free websites provide anonymous self-screening for harmful or hazardous alcohol use, including AlcoholScreening.org and this online version of AUDIT.

Genetic predisposition testing
Psychiatric geneticists John I. Nurnberger, Jr., and Laura Jean Bierut indicate that alcoholism does not have a single cause—including genetic—but that genes do play an important role "by affecting processes in the body and brain that interact with one another and with an individual's life experiences to produce protection or susceptibility." They also report that less than a dozen alcoholism-related genes have been identified, but that more likely await discovery.

At least one genetic test exists for an allele that is correlated to alcoholism and opiate addiction. Human dopamine receptor genes have a detectable variation referred to as the DRD2 TaqI polymorphism. Those who possess the A1 allele (variation) of this polymorphism have a small but significant tendency towards addiction to opiates and endorphin releasing drugs like alcohol. Although this allele is slightly more common in alcoholics and opiate addicts, it is not by itself an adequate predictor of alcoholism, and some researchers argue that evidence for DRD2 is contradictory.

Some writers posit that alcohol was discovered to be a replacement for polluted drinking water in early urban societies. In these conditions, alcohol's antibacterial properties offset its health risk, and the slow death of cirrhosis of the liver was preferred to an early death from waterborne disease. This caused a selection pressure on the genes of humans who had abandoned the hunter-gatherer lifestyle towards people with genes which were not prone to over consumption and drunkenness. Over generations, the descendants of these first farmers and urban dwellers became dominated by individuals who could drink more beer more often. This theory explains why some groups who continued a predominately hunter-gatherer culture, such as Native Americans or Australian Aborigines, have such high rates of alcoholism today.


DSM diagnosis
The DSM-IV diagnosis of alcohol dependence represents one approach to the definition of alcoholism. In part this is to assist in the development of research protocols in which findings can be compared with one another. According to the DSM-IV, an alcohol dependence diagnosis is:

...maladaptive alcohol use with clinically significant impairment as manifested by at least three of the following within any one-year period: tolerance; withdrawal; taken in greater amounts or over longer time course than intended; desire or unsuccessful attempts to cut down or control use; great deal of time spent obtaining, using, or recovering from use; social, occupational, or recreational activities given up or reduced; continued use despite knowledge of physical or psychological sequelae.


Urine and blood tests
There are reliable tests for the actual use of alcohol, one common test being that of blood alcohol content (BAC). These tests do not differentiate alcoholics from non-alcoholics; however, long-term heavy drinking does have a few recognizable effects on the body, including:

Macrocytosis (enlarged MCV)1
Elevated GGT2
Moderate elevation of AST and ALT and an AST:ALT ratio of 2:1.
High carbohydrate deficient transferrin (CDT)

Effects
The primary effect of alcoholism is to encourage the sufferer to drink at times and in amounts that are damaging. The secondary damage caused by an inability to control one's drinking manifests in many ways.

It is common for a person suffering from alcoholism to drink well after physical health effects start to manifest. The physical health effects associated with alcohol consumption are described in Alcohol consumption and health, but may include cirrhosis of the liver, pancreatitis, polyneuropathy, alcoholic dementia, heart disease, increased chance of cancer, nutritional deficiencies, sexual dysfunction, and death from many sources.


Social effects
The social problems arising from alcoholism can be significant. Being drunk or hung over during work hours can result in loss of employment, which can lead to financial problems including the loss of living quarters. Drinking at inappropriate times, and behavior caused by reduced judgment, can lead to legal consequences, such as criminal charges for drunk driving or public disorder, or civil penalties for tortious behavior. An alcoholic's behavior and mental impairment while drunk can profoundly impact surrounding family and friends, possibly leading to marital conflict and divorce, or contributing to domestic violence. This can contribute to lasting damage to the emotional development of the alcoholic's children, even after they reach adulthood. The alcoholic could suffer from loss of respect from others who may see the problem as self-inflicted and easily avoided.


Alcohol withdrawal
Alcohol withdrawal differs significantly from withdrawal from other drugs in that it can be directly fatal. While it is possible for heroin addicts, for instance, to die from other health problems made worse by the strain of withdrawal, an otherwise healthy alcoholic can die from the direct effects of withdrawal if it is not properly managed. Heavy consumption of alcohol reduces the production of GABA, which is a neuroinhibitor. An abrupt stop of alcohol consumption can induce a condition where neither alcohol nor GABA exists in the system in adequate quantities, causing uncontrolled firing of the synapses. This manifests as hallucinations, shakes, convulsions, seizures, and possible heart failure, all of which are collectively referred to as delirium tremens. All of these withdrawal issues can be safely controlled with a medically supervised detox.


Treatments
Treatments for alcoholism are quite varied because there are multiple perspectives for the condition itself. Those who approach alcoholism as a medical condition or disease recommend differing treatments than, for instance, those who approach the condition as one of social choice.

Most treatments focus on helping people discontinue their alcohol intake, followed up with life training and/or social support in order to help them resist a return to alcohol use. Since alcoholism involves multiple factors which encourage a person to continue drinking, they must all be addressed in order to successfully prevent a relapse. An example of this kind of treatment is detoxification followed by a combination of supportive therapy, attendance at self-help groups, and ongoing development of coping mechanisms. The treatment community for alcoholism typically supports an abstinence-based zero tolerance approach; however, there are some who promote a harm-reduction approach as well.[3]


Effectiveness
The effectiveness of alcoholism treatments varies widely. When considering the effectiveness of treatment options, one must consider the success rate based on those who enter a program, not just those who complete it. Since completion of a program is the qualification for success, success among those who complete a program is generally near 100%. It is also important to consider not just the rate of those reaching treatment goals but the rate of those relapsing. Results should also be compared to the roughly 5% rate at which people will quit on their own.[16] Based on information from Dr. Mark Willenbring of the National Institute on Alcohol Abuse and Alcoholism, the February 2007 issue of Newsweek reported that "A year after completing a rehab program, about a third of alcoholics are sober, an additional 40 percent are substantially improved but still drink heavily on occasion, and a quarter have completely relapsed."[17]


Detoxification
Main article: Alcohol detoxification
Alcohol detoxification or 'detox' for alcoholics is an abrupt stop of alcohol drinking coupled with the substitution of drugs that have similar effects to prevent alcohol withdrawal.

Detoxification treats the physical effects of prolonged use of alcohol, but does not actually treat alcoholism. After detox is complete, relapse is likely without further treatment. These rehabilitations (or 'rehabs') may take place in an inpatient or outpatient setting.


Group therapy and psychotherapy
After detoxification, various forms of group therapy or psychotherapy can be used to deal with underlying psychological issues that are related to alcohol addiction, as well as provide relapse prevention skills.

The mutual-help group-counseling approach is one of the most common ways of helping alcoholics maintain sobriety. Many organizations have been formed to provide this service, including Alcoholics Anonymous, LifeRing Secular Recovery, Rational Recovery, Smart Recovery, Al-Anon/Alateen, and Women For Sobriety.


Rationing and moderation
Rationing and moderation programs such as Moderation Management do not mandate complete abstinence. While most alcoholics are unable to limit their drinking in this way, some return to moderate drinking. A 2002 U.S. study by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) showed that 17.7% of individuals diagnosed as alcohol dependent more than one year prior returned to low-risk drinking.[5]


Medications
Although not necessary for treatment of alcoholism, a variety of medications may be prescribed as part of treatment. Some may ease the transition to sobriety, while others cause physical hardship to result from the use of alcohol. In most cases the desired effect is to have an alcoholic abstain from drinking.

Antabuse (disulfiram) prevents the elimination of acetaldehyde, a chemical the body produces when breaking down ethanol. Acetaldehyde itself is the cause of many hang over symptoms from alcohol use. The overall effect is severe discomfort when alcohol is ingested: an extremely fast acting and long lasting uncomfortable hang over. This discourages an alcoholic from drinking in significant amounts while they take the medicine. Heavy drinking while on antabuse can cause severe illness and death.
Naltrexone is a competitive antagonist for opioid receptors, effectively blocking our ability to use endorphins and opiates. Naltrexone is used in two very different forms of treatment. The first treatment uses naltrexone to decrease cravings for alcohol and encourage abstinence. The other treatment, called pharmacological extinction, combines naltrexone with normal drinking habits in order to reverse the endorphin conditioning that causes alcohol addiction. Naltrexone comes in two forms. Oral naltrexone, originally but no longer available as the brand ReVia, is a pill form and must be taken daily to be effective. Vivitrol is a time-release formulation that is injected in the buttocks once a month.
Piracetam appears to be effective in treating alcoholism or its symptoms in clinical studies.[18][19][20][21][22][23]. Piracetam appears to reduce levels of lipofuscin in the rat brain. [24] (Lipofuscin accumulation is common symptom of aging and alcoholism).
Acamprosate (also known as Campral) is thought to stabilize the chemical balance of the brain that would otherwise be disrupted by alcoholism. The Food and Drug Administration (FDA) approved this drug in 2004, saying "While its mechanism of action is not fully understood, Campral is thought to act on the brain pathways related to alcohol abuse...Campral proved superior to placebo in maintaining abstinence for a short period of time...[25]" While effective alone,[26] it is often paired with other medication treatments like naltrexone with great success.[27] Acamprosate reduces glutamate release. The COMBINE study was unable to determine the presence of efficacy for Acamprosate.
Sodium oxybate is the sodium salt of gamma-hydroxybutyric acid (GHB). It is used for both acute alcohol withdrawal and medium to long-term detoxification. This drug enhances GABA neurotransmission and reduces glutamate levels. It is used in Italy in small amounts under the trade name Alcover.
Baclofen has been shown in animal studies and in small human studies to enhance detoxification.This drug acts as a GABA B receptor agonist and this may be beneficial.

Pharmacological extinction
See also: Sinclair Method
Pharmacological extinction is the use of opioid antagonists like naltrexone combined with normal drinking habits to eliminate the craving for alcohol. The simple description is that the use of opioid antagonists reverses the effect that alcohol consumption has on alcohol addiction. When consuming alcohol with a proper dose of opioid antagonist in the drinker's system, the drinker will become less addicted to alcohol instead of more. This technique has been used to successfully treat tens of thousands of alcoholics in Finland, Pennsylvania, and Florida, and is sometimes referred to as the Sinclair Method.

While standard naltrexone treatment uses the drug to curb craving and enforce abstinence, pharmacological extinction targets the endorphin-based neurological conditioning. Our behaviors become conditioned when our neurons are bathed in endorphins following that action. Conversely, we receive negative reinforcement when we perform that action and yet do not get our endorphins. By having the alcoholic go about their normal drinking habits (limited only by safety concerns), and while preventing the endorphins from being released by the alcohol, the pull to drink is eliminated over a period of about three months. This allows an alcoholic to give up drinking as being sensibly unbeneficial. The effects persist after the drug is discontinued, but the addiction can return if the person drinks without first taking the drug. This treatment is also highly unusual in that it works better if the patient does not go through detoxification before starting it. Clinical studies have shown this treatment to allow 78-87% of inductees to reduce their drinking below levels dangerous to health, and allow 25% of inductees to achieve complete abstinence. Follow-up studies indicate an overall 50% relapse rate over five years, and 2% relapse rate for those who continue to take naltrexone before drinking.

There is a lot of professional resistance to this treatment for two reasons. Studies have demonstrated that controlled drinking for alcoholics was not a useful treatment technique. Other studies have also shown naltrexone to be of questionable value in supporting abstinence alone. The individual failure of these two separate treatments is inappropriately presumed to indicate that their use in combination is equally ineffective.


Nutritional therapy
Preventative treatment of alcohol complications includes long-term use of a multivitamin as well as such specific vitamins as B12 and folate.

While nutritional therapy is not a treatment of alcoholism itself, it treats the difficulties that can arise after years of heavy alcohol use. Many alcohol dependents have insulin resistance syndrome, a metabolic disorder where the body's difficulty in processing sugars causes an unsteady supply to the blood stream. While the disorder can be diminished by a hypoglycemic diet, this can affect behavior and emotions, side-effects often seen among alcohol dependents in treatment. The metabolic aspects of such dependence are often overlooked, causing poor treatment outcomes.


Societal impact
The various health problems associated with long-term alcohol consumption are generally perceived as detrimental to society, for example, money due to lost labor-hours, medical costs, and secondary treatment costs. Alcohol use is a major contributing factor for head injuries, motor vehicle accidents, violence, and assaults. Beyond money, there is also the pain and suffering of the all individuals besides the alcoholic affected. For instance, alcohol consumption by a pregnant woman can lead to Fetal alcohol syndrome, an incurable and damaging condition.

Estimates of the economic costs of alcohol abuse, collected by the World Health Organization, vary from one to six per cent of a country's GDP. One Australian estimate pegged alcohol's social costs at 24 per cent of all drug abuse costs; a similar Canadian study concluded alcohol's share was 41 per cent.
A study quantified the cost to the UK of all forms of alcohol misuse as £18.5–20 billion annually (2001 figures).

Stereotypes

Depiction of a wino or town drunkStereotypes of alcoholics are often found in fiction and popular culture. Common examples include the 'town drunk' or the portrayal of certain nationalities as alcoholics. In modern times, the recovery movement has led to more realistic depictions of problems that stem from heavy alcohol use. Authors such as Charles R. Jackson and Charles Bukowski describe their own alcohol addiction in their writings. Films like Days of Wine and Roses, My Name is Bill W., Arthur, Leaving Las Vegas chronicle similar stories of alcoholism.


Politics and public health
Because alcohol use disorders are perceived as impacting society as a whole, governments and parliaments have formed alcohol policies in order to reduce the harm of alcoholism. The World Health Organization, the European Union and other regional bodies are working on alcohol action plans and programs.

Organizations working with those suffering from alcoholism include:

Alcoholics Anonymous (AA)
International Organisation of Good Templars (IOGT)
LDS Family Services
LifeRing Secular Recovery (LifeRing)
Moderation Management (MM)
Narcotics Anonymous (NA), Alcohol is a drug, although not a narcotic.
Rational Recovery (RR)
Secular Organizations for Sobriety (SOS)
Smart Recovery (Self Management And Recovery Training - SMART)
Women For Sobriety (WFS)
Online Addiction Recovery

Acohol Withdrawal

Acoustic Nueroma

The myelodysplastic syndromes (MDS, formerly known as "preleukemia") are a diverse collection of hematological conditions united by ineffective production of blood cells and varying risks of transformation to acute myelogenous leukemia. Anemia requiring chronic blood transfusion is frequently present. Although not truly malignant, MDS is nevertheless classified within the haematological neoplasms.

Signs and symptoms
Abnormalities include:

neutropenia, anemia and thrombocytopenia (low cell counts of white and red blood cells, and platelets, respectively)
abnormal granules in cells, abnormal nuclear shape and size
chromosomal abnormalities, including chromosomal translocations and abnormal chromosome number.
Symptoms of myelodysplastic conditions:

Anemia—chronic tiredness, shortness of breath, chilled sensation, sometimes chest pain
Neutropenia (low neutrophil count) —increased susceptibility to infection
Thrombocytopenia (low platelet count) —increased susceptibility to bleeding
Although there is some risk for developing acute myelogenous leukemia, about 50% of deaths occur as a result of bleeding or infection. Leukemia that occurs as a result of myelodysplasia is notoriously resistant to treatment.

Diagnosis
Investigation:

Full blood count and examination of blood film
Bone marrow examination by an experienced hematopathologist
Cytogenetics or chromosomal studies. This is performed on the bone marrow aspirate.

Pathophysiology
MDS is thought to arise from mutations in the multi-potent bone marrow stem cell, but the specific defects responsible for these diseases remain poorly understood. Differentiation of blood precursor cells is impaired, and there is a significant increase in levels of cell death apoptosis in bone marrow cells. Clonal expansion of the abnormal cells results in the production of cells which have lost the ability to differentiate. If the overall percentage of bone marrow blasts rises over a particular cutoff (20% for WHO and 30% for FAB) then transformation to leukemia (specifically acute myelogenous leukemia or AML) is said to have occurred. The progression of MDS to leukemia is a good example of the multi-step theory of carcinogenesis in which a series of mutations occur in an initially normal cell and transform it into a cancer cell.

While recognition of leukemic transformation was historically important (see History), a significant proportion of the morbidity and mortality attributable to MDS results not from transformation to AML but rather from the cytopenias seen in all MDS patients. While anemia is the most common cytopenia in MDS patients, given the ready availability of blood transfusion MDS patients rarely suffer injury from severe anemia. However, if an MDS patient is fortunate enough to suffer nothing more than anemia over several years, they then risk iron overload. The two most serious complications in MDS patients resulting from their cytopenias are bleeding (due to lack of platelets) or infection (due to lack of white blood cells).

Types and classification

French-American-British (FAB) classification
In 1974 and 1975 a group of pathologists from France, the United States, and Britain met and deliberated and derived the first widely used classification of these diseases. This French-American-British (FAB) classification was published in 1976 and revised in 1982. Cases were classified into 5 categories: (ICD-O codes are provided where available)

(M9980/3) Refractory anemia (RA) - characterized by less than 5% primitive blood cells (myeloblasts) in the bone marrow and pathological abnormalities primarily seen in red cell precursors;
(M9982/3) Refractory anemia with ringed sideroblasts (RARS) - also characterized by less than 5% myeloblasts in the bone marrow, but distinguished by the presence of 15% or greater red cell precursors in the marrow being abnormal iron-stuffed cells called "ringed sideroblasts";
(M9983/3) Refractory anemia with excess blasts (RAEB) - characterized by 5-19% myeloblasts in the marrow;
(M9984/3) Refractory anemia with excess blasts in transformation (RAEB-T) - characterized by 20-29% myeloblasts in the marrow (30% blasts is defined as acute myeloid leukemia);
(M9945/3) Chronic myelomonocytic leukemia (CMML) - not to be confused with chronic myelogenous leukemia or CML - characterized by less than 20% myeloblasts in the bone marrow and greater than 1000 * 109/uL monocytes (a type of white blood cell) circulating in the peripheral blood.
A table comparing these is available from the Cleveland Clinic.

The best prognosis is seen with refractory anemia with ringed sideroblasts and refractory anemia, where some non-transplant patients live more than a decade (the average is on the order of 3-5 years, although long term remission is possible if a bone marrow transplant is successful); the worst outlook is with RAEB-T, where the mean life expectancy is less than 1 year. About 1/4 of patients develop overt leukemia. The others die of complications of low blood count or unrelated disease. The International Prognostic Scoring System is another tool for determining the prognosis of MDS, published in Blood in 1997.[1] This system takes into account the percentage of blasts in the marrow, cytogenetics, and number of cytopenias.

The FAB classification was used by pathologists and clinicians for almost 20 years.

WHO classification
In the late 1990s a group of pathologists and clinicians working under the World Health Organization (WHO) modified this classification, introducing several new disease categories and eliminating others.

One new category was refractory cytopenia with multilineage dysplasia (RCMD), which includes patients with pathological changes not restricted to red cells (i.e., prominent white cell precursor and platelet precursor (megakaryocyte) dysplasia. See below for morphologic definitions of dysplasia.

The list of dysplastic syndromes under the new WHO system includes:

Refractory anemia (RA)
Refractory anemia with ringed sideroblasts (RARS)
Refractory cytopenia with multilineage dysplasia (RCMD)
Refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS)
Refractory anemia with excess blasts I and II
5q- syndrome
Myelodysplasia unclassifiable (seen in those cases of megakaryocyte dysplasia with fibrosis and others)
RAEB was divided into *RAEB-I (5-10% blasts) and RAEB-II (11-19%) blasts, which has a poorer prognosis than RAEB-I. Auer rods may be seen in RAEB-II which may be difficult to distinguish from acute myeloid leukemia.

The category of RAEB-T was eliminated; such patients are now considered to have acute leukemia. 5q- syndrome, typically seen in older women with normal or high platelet counts and isolated deletions of the long arm of chromosome 5 in bone marrow cells, was added to the classification.

CMML was removed from the myelodysplastic syndromes and put in a new category of myelodysplastic-myeloproliferative overlap syndromes. Not all physicians concur with this reclassification. This is because the underlying pathology of the diseases is not well understood. It is difficult to classify things that are not well understood.

Diagnosis
The average age at diagnosis for MDS is about 65 years, but pediatric cases have been reported. Some patients have a history of exposure to chemotherapy (especially alkylating agents such as melphalan, mustard, cyclophosphamide, busulfan, and chlorambucil) or radiation (therapeutic or accidental), or both (e.g., at the time of stem cell transplantation for another disease). Workers in some industries with heavy exposure to hydrocarbons such as the petroleum industry have a slightly higher risk of contracting the disease than the general population. Males are slightly more frequently affected than females. Xylene and benzene exposure has been associated with myelodysplasia. Vietnam Veterans that were exposed to Agent Orange are at risk of developing MDS.

Dysplasia can affect all three lineages seen in the bone marrow. The best way to diagnose dysplasia is by morphology and special stains (PAS) used on the bone marrow aspirate and peripheral blood smear. Dysplasia in the myeloid series is defined by:

Granulocytic series
Hypersegmented neutrophils (also seen in Vit B12/Folate deficiency)
Hyposegmented neutrophils (Pseudo-Pelger Huet)
Hypogranular neutrophils or pseudo Chediak Higashi large granules
Dimorphic granules (basophilic and eosinophilic granules) within eosinophils
Erythroid series
Binucleated erythroid percursors and karyorrhexis
Erythroid nuclear budding
Erythroid nuclear strings or internuclear bridging (also seen in congenital dyserythropoietic anemias)
PAS (globular in vacuoles or diffuse cytoplasmic staining) within erythroid precursors in the bone marrow aspirate (has no bearing on paraffin fixed bone marrow biopsy). Note: One can see PAS vacuolar positivity in L1 and L2 blasts (AFB classification; the L1 and L2 nomenclature is not used in the WHO classification)
Ringed sideroblasts seen on Prussian blue iron stain (10 or more iron granules encircling 1/3 or more of the nucleus and >15% ringed sideroblasts when counted amongst red cell precursors)
Megakaryocytic series (can be the most subjective)
Hyposegmented nuclear features in platelet producing megakaryocytes (lack of lobation)
Hypersegmented (osteoclastic appearing) megakaryocytes
Ballooning of the platelets (seen with interference contrast microscopy)
Other stains can help in special cases (PAS and napthol ASD chloroacetate esterase positivity) in eosinophils is a marker of abnormality seen in chronic eosinophilic leukemia and is a sign of aberrancy.

On the bone marrow biopsy high grade dysplasia (RAEB-I and RAEB-II) may show atypical localization of immature precursors (ALIPs) which are islands of immature cells clustering together. This morphology can be difficult to recognize from treated leukemia and recovering immature normal marrow elements. Also topographic alteration of the nucleated erythroid cells can be seen in early myelodysplasia (RA and RARS), where normoblasts are seen next to bony trabeculae instead of forming normal interstitially placed erythroid islands.

Myelodysplasia is a diagnosis of exclusion and must be made after proper determination of iron stores, vitamin deficiencies, and nutrient deficiencies are ruled out. Also congenital diseases such as congenital dyserthropoietic anemia (CDA I through IV) has been recognized, Pearson's syndrome (sideroblastic anemia), Jacobson's syndrome, ALA (aminolevulinic acid) enzyme deficiency, and other more esoteric enzyme deficiencies are known to give a pseudomyelodysplastic picture in one of the cell lines, however, all three cell lines are never morphologically dysplastic in these entities with the exception of chloramphenicol, arsenic toxicity and other poisons.

All of these conditions are characterized by abnormalities in the production of one or more of the cellular components of blood (red cells, white cells other than lymphocytes and platelets or their progenitor cells, megakaryocytes).

Epidemiology
The exact number of people with MDS is not known because it can go undiagnosed and there is no mandated tracking of the syndrome. Some estimates are on the order of 10,000 to 20,000 new cases each year in the United States alone. The incidence is probably increasing as the age of the population increases

Therapy
The goals of therapy are to control symptoms, improve quality of life, improve overall survival, and decrease progression to acute myelogenous leukemia.

The IPSS scoring system can help triage patients for more aggressive treatment (i.e. bone marrow transplant) as well as help determine the best timing of this therapy. Supportive care with blood product support and hematopoeitic growth factors (e.g. erythropoietin) is the mainstay of therapy.

Three agents have been approved by the US FDA for the treatment of MDS: 5-azacytidine, decitabine, and lenalidomide. Chemotherapy with the hypomethylating agents 5-azacytidine and decitabine has been shown to decrease blood transfusion requirements and to retard the progression of MDS to AML. Lenalidomide was approved by the FDA in December 2005 only for use in the 5q- syndrome.

Bone marrow transplant, particularly in younger patients (ie less than 40 years of age), more severely affected patients, offers the potential for curative therapy. Success of bone marrow transplantation has been found to correlate with severity of MDS as determined by the IPSS score, with patients having a more favorable IPSS score tending to have a more favorable outcome with transplantation.

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