Frontotemporal Neurocognitive Disorder is a progressive, neurodegenerative, heterogeneous group of non-Alzheimer dementias disorder characterized by loss of intellectual functions, such as memory problems, impaired abstract thinking, reasoning, behavioral changes, and language deficits with frontal and temporal cortical degeneration and executive function, severe enough to hamper activities of daily living. It requires a multidisciplinary approach to improve patient outcomes. The clinical manifestation includes behavior changes, dietary changes, loss of empathy, apathy, and executive function.
Frontotemporal Disorders /Few people have heard of frontotemporal disorders, which lead to dementias that affect personality, behavior, language, and movement. These disorders are little known outside the circles of researchers, clinicians, patients, and caregivers who study and live with them. Although frontotemporal disorders remain puzzling in many ways, researchers are finding new clues that will help them solve this medical mystery and better understand other common dementias.
Frontotemporal dementia (FTD), or frontotemporal degeneration disease, or frontotemporal neurocognitive disorder, encompasses several types of dementia involving the frontal and temporal lobes.[rx] FTDs are broadly presented as behavioral or language disorders.[rx] The three main subtypes or variant syndromes are a behavioral variant (bvFTD) previously known as Pick’s disease, and two variants of primary progressive aphasia – semantic variant (svPPA), and nonfluent variant (nfvPPA).[rx][rx] Two rare distinct subtypes of FTD are neuronal intermediate filament inclusion disease (NIFID), and basophilic inclusion body disease. Other related disorders include corticobasal syndrome and FTD with amyotrophic lateral sclerosis (ALS) FTD-ALS also called FTD-MND.[rx]
The Basics of Frontotemporal Neurocognitive Disorder
Frontotemporal disorders are the result of damage to neurons (nerve cells) in parts of the brain called the frontal and temporal lobes. As neurons die in the frontal and temporal regions, these lobes atrophy, or shrink. Gradually, this damage causes difficulties in thinking and behaviors normally controlled by these parts of the brain. Many possible symptoms can result, including unusual behaviors, emotional problems, trouble communicating, difficulty with work, or difficulty with walking.
A Form of Dementia
Frontotemporal disorders are forms of dementia caused by a family of brain diseases known as frontotemporal lobar degeneration (FTLD). Dementia is a severe loss of thinking abilities that interferes with a person’s ability to perform daily activities such as working, driving, and preparing meals. Other brain diseases that can cause dementia include Alzheimer’s disease and multiple strokes. Scientists estimate that FTLD may cause up to 10 percent of all cases of dementia and may be about as common as Alzheimer’s among people younger than age 65. Roughly 60 percent of people with FTLD are 45 to 64 years old.
People can live with frontotemporal disorders for up to 10 years, sometimes longer, but it is difficult to predict the time course for an individual patient. The disorders are progressive, meaning symptoms get worse over time. In the early stages, people may have just one type of symptom. As the disease progresses, other types of symptoms appear as more parts of the brain are affected.
No cure or treatments that slow or stop the progression of frontotemporal disorders are available today. However, research is improving awareness and understanding of these challenging conditions. This progress is opening doors to better diagnosis, improved care, and, eventually, new treatments.
FTD? FTLD? Understanding Terms
One of the challenges shared by patients, families, clinicians, and researchers is confusion about how to classify and label frontotemporal disorders. A diagnosis by one doctor may be called something else by a second, and the same condition or syndrome referred to by another name by a pathologist who examines the brain after death.
For many years, scientists and physicians used the term frontotemporal dementia (FTD) to describe this group of illnesses. After further research, FTD is now understood to be just one of several possible variations and is more precisely called behavioral variant frontotemporal dementia, or bvFTD.
This booklet uses the term frontotemporal disorders to refer to changes in behavior and thinking that are caused by underlying brain diseases collectively called frontotemporal lobar degeneration (FTLD). FTLD is not a single brain disease but rather a family of neurodegenerative diseases, any one of which can cause a frontotemporal disorder. Frontotemporal disorders are diagnosed by physicians and psychologists based on a person’s symptoms and results of brain scans and genetic tests. With the exception of known genetic causes, the type of FTLD can be identified definitively only by brain autopsy after death.
Changes in the Brain
Frontotemporal disorders affect the frontal and temporal lobes of the brain. They can begin in the frontal lobe, the temporal lobe, or both. Initially, frontotemporal disorders leave other brain regions untouched, including those that control short-term memory.
The frontal lobes, situated above the eyes and behind the forehead both on the right and left sides of the brain, direct executive functioning. This includes planning and sequencing (thinking through which steps come first, second, third, and so on), prioritizing (doing more important activities first and less important activities last), multitasking (shifting from one activity to another as needed), and monitoring and correcting errors.
When functioning well, the frontal lobes also help manage emotional responses. They enable people to avoid inappropriate social behaviors, such as shouting loudly in a library or at a funeral. They help people make decisions that make sense for a given situation. When the frontal lobes are damaged, people may focus on insignificant details and ignore important aspects of a situation or engage in purposeless activities. The frontal lobes are also involved in language, particularly linking words to form sentences, and in motor functions, such as moving the arms, legs, and mouth.
The temporal lobes, located below and to the side of each frontal lobe on the right and left sides of the brain, contain essential areas for memory but also play a major role in language and emotions. They help people understand words, speak, read, write, and connect words with their meanings. They allow people to recognize objects and to relate appropriate emotions to objects and events. When the temporal lobes are dysfunctional, people may have difficulty recognizing emotions and responding appropriately to them.
Which lobe—and part of the lobe—is affected first determines which symptoms appear first. For example, if the disease starts in the part of the frontal lobe responsible for decision-making, then the first symptom might be trouble managing finances. If it begins in the part of the temporal lobe that connects emotions to objects, then the first symptom might be an inability to recognize potentially dangerous objects—a person might reach for a snake or plunge a hand into boiling water, for example.
Types of Frontotemporal Neurocognitive Disorder
Frontotemporal disorders can be grouped into three types, defined by the earliest symptoms physicians identify when they examine patients.
Progressive behavior/personality decline—characterized by changes in personality, behavior, emotions, and judgment (called
behavioral variant frontotemporal dementia).
Progressive language decline—marked by early changes in language ability, including speaking, understanding, reading, and writing (called primary progressive aphasia).
Progressive motor decline—characterized by various difficulties with physical movement, including the use of one or more limbs, shaking, difficulty walking, frequent falls, and poor coordination (called a corticobasal syndrome, supranuclear palsy, or amyotrophic lateral sclerosis).
Based on anatomic, genetic, and neuropathologic categorizations, the six clinical subtypes of FTD or related disorders are
(6) FTD associated with motor neuron disease. Recognition and accurate diagnoses of FTD subtypes will aid the neurologist in the management of patients with FTD.
In the early stages it can be hard to know which of these disorders a person has because symptoms and the order in which they appear can vary widely from one person to the next. Also, the same symptoms can appear later in different disorders. For example, language problems are most typical of primary progressive aphasia but can also appear later in the course of behavioral variant frontotemporal dementia. The table on page 6 summarizes the three types of frontotemporal disorders and lists the various terms that could be used when clinicians diagnose these disorders.
Behavioral Variant Frontotemporal Dementia
The most common frontotemporal disorder, behavioral variant frontotemporal dementia (bvFTD), involves changes in personality, behavior, and judgment. People with this dementia can act strangely around other people, resulting in embarrassing social situations. Often, they don’t know or care that their behavior is unusual and don’t show any consideration for the feelings of others. Over time, language and/or movement problems may occur, and the person needs more care and supervision.
In the past, bvFTD was called Pick’s disease, named after Arnold Pick, the German scientist who first described it in 1892. The term Pick’s disease is now used to describe abnormal collections in the brain of the protein tau, called “Pick bodies.” Some patients with bvFTD have Pick bodies in the brain, and some do not.
Primary Progressive Aphasia
Primary progressive aphasia (PPA) involves changes in the ability to communicate—to use language to speak, read, write, and understand what others are saying. Problems with memory, reasoning, and judgment are not apparent at first but can develop over time. In addition, some people with PPA may experience significant behavioral changes, similar to those seen in bvFTD, as the disease progresses.
There are three types of PPA, categorized by the kind of language problems seen at first. Researchers do not fully understand the biological basis of the different types of PPA. But they hope one day to link specific language problems with the abnormalities in the brain that cause them.
In semantic PPA, also called semantic dementia, a person slowly loses the ability to understand single words and sometimes to recognize the faces of familiar people and common objects.
In agrammatic PPA, also called progressive nonfluent aphasia, a person has more and more trouble producing speech. Eventually, the person may no longer be able to speak at all. He or she may eventually develop movement symptoms similar to those seen in corticobasal syndrome.
In logopenic PPA, a person has trouble finding the right words during the conversation but can understand words and sentences. The person does not have problems with grammar.
Movement Disorders
Two rare neurological disorders associated with FTLD, corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP), occur when the parts of the brain that control movement is affected. The disorders may affect thinking and language abilities, too.
CBS can be caused by corticobasal degeneration—gradual atrophy and loss of nerve cells in specific parts of the brain. This degeneration causes progressive loss of the ability to control movement, typically beginning around age 60. The most prominent symptom may be the inability to use the hands or arms to perform a movement despite normal strength (called apraxia). Symptoms may appear first on one side of the body, but eventually, both sides are affected. Occasionally, a person with CBS first has language problems or trouble orienting objects in space and later develops movement symptoms.
PSP causes problems with balance and walking. People with the disorder typically move slowly, experience unexplained falls, lose facial expression, and have body stiffness, especially in the neck and upper body—symptoms similar to those of Parkinson’s disease. A hallmark sign of PSP is trouble with eye movements, particularly looking down. These symptoms may give the face a fixed stare. Behavior problems can also develop.
Other movement-related frontotemporal disorders include frontotemporal dementia with parkinsonism and frontotemporal dementia with amyotrophic lateral sclerosis (FTD-ALS).
Frontotemporal dementia with parkinsonism can be an inherited disease caused by a genetic tau mutation. Symptoms include movement problems similar to those of Parkinson’s disease, such as slowed movement, stiffness, and balance problems, and changes in behavior or language.
FTD-ALS is a combination of bvFTD and ALS, commonly called Lou Gehrig’s disease. Symptoms include the behavioral and/or language changes seen in bvFTD as well as the progressive muscle weakness seen in ALS. Symptoms of either disease may appear first, with other symptoms developing over time. Mutations in certain genes have been found in some patients with FTD-ALS.
Causes of Frontotemporal Neurocognitive Disorder
Frontotemporal lobar degeneration (FTLD) is not a single brain disease but rather a family of brain diseases that share some common molecular features. Scientists are beginning to understand the biological and genetic basis for the changes observed in brain cells that lead to FTLD.
Scientists describe FTLD in terms of patterns of change in the brain seen in an autopsy after death. These changes include loss of neurons and abnormal amounts or forms of proteins called tau and TDP-43. These proteins occur naturally in the body and help cells function properly. When the proteins don’t work properly and accumulate in cells, for reasons not yet fully understood, neurons in specific brain regions are damaged.
In most cases, the cause of a frontotemporal disorder is unknown. In about 15 to 40 percent of people, a genetic (hereditary) cause can be identified. Individuals with a family history of frontotemporal disorders are more likely to have a genetic form of the disease than those without such a history.
Familial and inherited forms of frontotemporal disorders are often related to mutations (permanent changes) in certain genes. Genes are basic units of heredity that tell cells how to make the proteins the body needs to function. Even small changes in a gene may produce an abnormal protein, which can lead to changes in the brain and, eventually, disease.
Scientists have discovered several different genes that, when mutated, can lead to frontotemporal disorders:
Tau gene (also called the MAPT gene)—A mutation in this gene causes abnormalities in a protein called tau, which forms tangles inside neurons and ultimately leads to the destruction of brain cells. Inheriting a mutation in this gene means a person will almost surely develop a frontotemporal disorder, usually the bvFTD form, but the exact age of onset and symptoms cannot be predicted.
PGRN gene— A mutation in this gene can lead to lower production of the protein progranulin, which in turn causes TDP-43, a cellular protein, to go awry in brain cells. Many frontotemporal disorders can result, though bvFTD is the most common. The PRGRN gene can cause different symptoms in different family members and cause the disease to begin at different ages.
VCP, CHMP2B, TARDBP, and FUS genes— Mutations in these genes lead to very rare familial types of frontotemporal disorders. TARDBP and FUS gene mutations are more often associated with hereditary ALS.
C9ORF72 gene— An unusual mutation in this gene appears to be the most common genetic abnormality in familial frontotemporal disorders and familial ALS. It also occurs in some cases of sporadic ALS. This mutation can cause a frontotemporal disorder, ALS, or both conditions in a person.
Scientists are continuing to study these genes and to search for other genes and proteins, as well as nongenetic risk factors, that may play a role in frontotemporal disorders. They are trying to understand, for example, how mutations in a single gene lead to different frontotemporal disorders in members of the same family. Environmental factors that may influence the risk for developing the disorders are also being examined.
Families affected by inherited and familial forms of frontotemporal disorders can help scientists further research by participating in clinical studies and trials. For more information, talk with a health care professional, contact any of the research centers listed at the end of this booklet or search www.clinicaltrials.gov.
Symptoms of Frontotemporal Neurocognitive Disorder
Symptoms of frontotemporal disorders vary from person to person and from one stage of the disease to the next as different parts of the frontal and temporal lobes are affected. In general, changes in the frontal lobe are associated with behavioral symptoms, while changes in the temporal lobe lead to language and emotional disorders.
Symptoms are often misunderstood. Family members and friends may think that a person is misbehaving, leading to anger and conflict. For example, a person with bvFTD may neglect personal hygiene or start shoplifting. It is important to understand that people with these disorders cannot control their behaviors and other symptoms. Moreover, they lack any awareness of their illness, making it difficult to get help.
Behavioral Symptoms
Problems with executive functioning—Problems with planning and sequencing (thinking through which steps come first, second, third, and so on), prioritizing (doing more important activities first and less important activities last), multitasking (shifting from one activity to another as needed), and self-monitoring and correcting behavior.
Perseveration—A tendency to repeat the same activity or to say the same word over and over, even when it no longer makes sense.
Social disinhibition—Acting impulsively without considering how others perceive the behavior. For example, a person might hum at a business meeting or laugh at a funeral.
Compulsive eating—Gorging on food, especially starchy foods like bread and cookies, or taking food from other people’s plates.
Utilization behavior—Difficulty resisting impulses to use or touch objects that one can see and reach. For example, a person picks up the telephone receiver while walking past it when the phone is not ringing and the person does not intend to place a call.
Inappropriate social behavior and lack of social tact/manners. Examples include touching or kissing strangers, urinating in public, making rude or offensive comments, arguing, rashly overspending, and/or doing or saying things that others would find embarrassing or disgusting.
Lack of empathy (interest in, or understanding of, what others feel), loss of interest in other people or activities, reduced affection, neglect of personal grooming and hygiene. People with FTD are not aware of the changes that are happening and do not know how hurtful they are to close family members.
Changes in food preferences, overstuffing mouth with food, binge eating, eating food quickly, attempting to eat non-food items.
Becoming very obsessive or developing rituals, repeating things, collecting/hoarding items.
Language Symptoms
Aphasia—A language disorder in which the ability to use or understand words is impaired but the physical ability to speak properly is normal.
Dysarthria—A language disorder in which the physical ability to speak properly is impaired (e.g., slurring) but the message is normal. People with PPA may have only problems using and understanding words or also problems with the physical ability to speak. People with both kinds of problems have trouble speaking and writing. They may become mute, or unable to speak. Language problems usually get worse, while other thinking and social skills may remain normal for longer before deteriorating.
Emotional Symptoms
Apathy—A lack of interest, drive, or initiative. Apathy is often confused with depression, but people with apathy may not be sad. They often have trouble starting activities but can participate if others do the planning.
Compulsive eating—Gorging on food, especially starchy foods like bread and cookies, or taking food from other people’s plates.
Emotional changes—Emotions are flat, exaggerated, or improper. Emotions may seem completely disconnected from a situation or are expressed at the wrong times or in the wrong circumstances. For example, a person may laugh at sad news.
Social-interpersonal changes—Difficulty “reading” social signals, such as facial expressions, and understanding personal relationships. People may lack empathy—the ability to understand how others are feeling—making them seem indifferent, uncaring, or selfish. For example, the person may show no emotional reaction to illnesses or accidents that occur to family members.
Movement Symptoms
Dystonia—Abnormal postures of body parts such as the hands or feet. A limb may be bent stiffly or not used when performing activities that are normally done with two hands.
Gait disorder—Abnormalities in walking, such as walking with a shuffle, sometimes with frequent falls.
Tremor—Shakiness, usually of the hands.
Clumsiness—Dropping of small objects or difficulty manipulating small items like buttons or screws.
Apraxia—Loss of ability to make common motions, such as combing one’s hair or using a knife and fork, despite normal strength.
Neuromuscular weakness—Severe weakness, cramps, and rippling movements in the muscles.
Diagnosis of Frontotemporal Neurocognitive Disorder
Consensus criteria for FTD
Core diagnostic features
A. Insidious onset and gradual progression
B. Early decline in social interpersonal conduct
C. Early impairment in regulation of personal conduct
D. Early emotional blunting
E. Early loss of insight
Supportive diagnostic features
A. Behavioral disorder
1. Decline in personal hygiene and grooming
2. Mental rigidity and inflexibility
3. Distractibility and impersistence
4. Hyperorality and dietary changes
5. Perseverative and stereotyped behavior
6. Utilization behavior
B. Speech and language
1. Altered speech output
a. Aspontaneity and economy of speech
b. Pressure of speech
2. Stereotypy of speech
3. Echolalia
4. Perseveration
5. Mutism
C. Physical signs
1. Primitive reflexes
2. Incontinence
3. Akinesia, rigidity, and tremor
4. Low and labile blood pressure
D. Investigations
1. Neuropsychology: impairment on frontal lobe tests without severe amnesia, aphasia, or perceptuospatial disorder
2. Electroencephalography: normal on conventional EEG despite clinically evident dementia
No single test, such as a blood test, can be used to diagnose a frontotemporal disorder. A definitive diagnosis can be confirmed only by a genetic test in familial cases or a brain autopsy after a person dies. To diagnose a probable frontotemporal disorder in a living person, a doctor— usually a neurologist, psychiatrist, or psychologist—will:
record a person’s symptoms, often with the help of family members or friends
compile a personal and family medical history
perform a physical exam and order blood tests to help rule out other similar conditions
if appropriate, order testing to uncover genetic mutations
conduct a neuropsychological evaluation to assess behavior, language, memory, and other cognitive functions
use brain imaging to look for changes in the frontal and temporal lobes.
In all forms of FTD, functional ability and activities of daily living are compromised.[rx][rx][rx]
Behavior variant type FTD (bvFTD) – It is the most common phenotype. Patients suffering from bvFTD may present with a cluster of altered behavior and personality changes earlier in the disease process, which include disinhibition, loss of emotional reactivity and disease insight, apathy, impaired abstract thinking and executive function that gradually worsens over time. Additionally, it may demonstrate a change in dietary behavior and loss of fundamental emotions and empathy but with intact memory until late in the disease.[rx][rx]
Semantic variant FTD – In this form of FTD, patients manifest language difficulties characterized by paraphasia (impaired word-finding ability or loss of vocabulary), difficulty in understanding the meaning of words, impaired comprehension, and difficulty in recognizing unfamiliar objects or faces.[rx] Their speech is fluent but not making any sense. Memory is affected late in the disease.
Non-fluent variant Primary Progressive Aphasia (nfvPPA) – Patients with this type of FTD presents clinically with effortful halted speech and paraphasia (jumbled words), difficulty in understanding complex sentences and naming objects.[rx] Their memory, abstract thinking, and calculating abilities are spared earlier in the disease course.
Various bedside tests can be performed if clinical suspicion for FTD is high.
Go-no-go test – In this test, the patient is asked to perform an action in response to a particular stimulus and inhibit that action in response to different stimuli.
Letter fluency test – In this test, the patient is asked to say as many words (except proper nouns), starting with a single letter in one minute.
Attention test – It is used to evaluate the attention span. It is done either by serial seven subtractions from 100 or spells the word “world” backward.
Similarities and differences – It is done to evaluate abstract thinking. The patient is instructed to compare items (table and chair, apple, and orange).
Patients with frontotemporal dementia should be evaluated as follows:
Laboratory – Neural and axonal cytoskeletons are mainly composed of neurofilaments, which are further made up of small subunits called neurofilament light chains. Neurofilament light chain, among other biomarkers, can be increasingly seen in blood and cerebrospinal fluid of FTD patients.
Radiographic tests – Magnetic resonance imaging,computed tomographyscan, or single-photon emission tomographycan be used to demonstrate atrophy and hypoperfusion in the frontal and temporal lobes. However, the findings are not specific. Imaging may aid in the diagnosis or to rule out other etiologies.[rx][rx]
Electroencephalography (EEG) – It is not very helpful for FTD as it is for Alzheimer’s disease; however, in comparison to the healthy group, a typical EEG pattern was observed in several FTD patients and was marked by the reduction of fast activities (alpha, beta1- beta3), but no difference in slow activities (delta & theta waves).[rx]
Neurocognitive exams – Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment, and Functional Cognitive Assessment. For primary care, the Cochrane dementia and cognitive improvement group supports the utilization of two tests; MMSE (the most commonly used test in primary care) and the Informant Questionnaire for Cognitive Disorders in the Elderly. MMSE assesses different domains of dementia, including but not limited to memory, cognition, language, attention/orientation, and executive functions.[rx][rx]
A magnetic resonance imaging (MRI) – scan shows changes in the size and shape of the brain, including the frontal and temporal lobes. It may reveal other potentially treatable causes of the person’s symptoms, such as a stroke or tumor. In the early stage of the disease, the MRI may appear normal. In this case, other types of imaging, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), may be useful. PET and SPECT scan to measure activity in the brain by monitoring blood flow, glucose usage, and oxygen usage. Other PET scans can help rule out a diagnosis of Alzheimer’s.
Cerebrospinal fluid – and serum protein biomarkers are presently utilized to exclude Alzheimer’s disease in the assessment of frontotemporal dementia and are under appraisal for prospective diagnostic indications and monitoring pathologic progression and response to potential therapies. Elevated CSF tau proteins and decreased beta-amyloid 42 protein concentrations can accurately confirm Alzheimer’s dementia and are validated for eliminating frontotemporal dementia from the differential.[rx]
Neurofilament light chain (NFL) – proteins are increased in serum and CSF samples of patients with frontotemporal dementia and other neurodegenerative disorders and have promising applications in future frontotemporal dementia assays.[rx] Gene-specific biomarkers such as progranulin and poly (GP) have the potential for investigating the expression of GRN and C9orf72 frontotemporal dementia mutations, respectively.[rx] As with potential imaging techniques, more data is needed to implement fluid biomarkers into a comprehensive frontotemporal dementia evaluation strategy.
Neuropsychological Testing – Performance patterns on cognitive testing may vary according to the subtype. Many patients with CBS will demonstrate deficits on tasks of executive function, writing, visuospatial, and construction tasks. Patients presenting with dominant frontal lobe involvement may show word-finding deficits, agrammatism, and spelling errors similar to patients with nonfluent agrammatic PPA.[rx]
Neuroimaging – Structural brain imaging in patients with CBS may show asymmetric frontal and parietal lobe atrophy,[rx] although imaging findings may overlap with those seen in other FTDs and AD. Thus, diagnosis at present is based on clinical criteria, with neuroimaging performed to rule out other structural causes of symptoms.
Treatment of Frontotemporal Neurocognitive Disorder
So far, there is no cure for frontotemporal disorders and no way to slow down or prevent them. However, there are ways to manage symptoms. A team of specialists—doctors, nurses, and speech, physical, and occupational therapists—familiar with these disorders can help guide treatment.
Non-Pharmacologic Treatment
It includes a multidisciplinary approach, such as social support services, physical therapy & occupational therapy, speech therapy, cognitive behavior therapy, rehabilitation services, and caregivers’ education. Regular monitoring of the behavior of both the patient and caregiver for assessing activities of daily living, such as financial account managing, driving, environmental modification, and eating, is mandatory.[rx]
Pharmacological Treatment
Acetylcholinesterase inhibitors and N-methyl-D-Aspartate inhibitors have no proven benefit. Similarly, selective serotonin reuptake inhibitors (SSRI) have a limited role. It can improve certain behaviors, but not cognition. Antipsychotics have mixed results but comes with a price of severe extrapyramidal side effects to which the FTD patients are susceptible; therefore, they are not approved by the US food and drug administration as a treatment for FTD. Selective dopaminergic antagonists can improve motivation and apathy. Several disease-modifying drugs like Salsalate (tau acetylation inhibitor) and Gosuraneb (anti-tau monoclonal antibodies) targeting different biomarkers are being studied, but no recommendations yet have been made. Several other promising disease-modifying drugs are currently under clinical trials.[rx][rx]
Managing Behavior
The behaviors of a person with bvFTD can upset and frustrate family members and other caregivers. It is natural to grieve for the “lost person,” but it is also important to learn how to best live with the person he or she has become. Understanding changes in personality and behavior and knowing how to respond can reduce caregivers’ frustration and help them cope with the challenges of caring for a person with a frontotemporal disorder.
Managing behavioral symptoms can involve several approaches. To ensure the safety of a person and his or her family, caregivers may have to take on new responsibilities or arrange care that was not needed before. For example, they may have to drive the person to appointments and errands, care for young children, or arrange for help at home.
It is helpful, though often difficult, to accept rather than challenge people with behavioral symptoms. Arguing or reasoning with them will not help because they cannot control their behaviors or even see that they are unusual or upsetting to others. Instead, be as sensitive as possible and understand that it’s the illness “talking.”
Frustrated caregivers can take a “timeout”—take deep breaths, count to 10, or leave the room for a few minutes.
To deal with apathy, limit choices and offer specific choices. Open-ended questions (“What would you like to do today?”) are more difficult to answer than specific ones (“Do you want to go to the movies or the shopping center today?”).
Maintaining the person’s schedule and modifying the environment can also help. A regular schedule is less confusing and can help people sleep better. If compulsive eating is an issue, caregivers may have to supervise eating, limit food choices, lock food cabinets and the refrigerator, and distract the person with other activities. To deal with other compulsive behaviors, caregivers may have to change schedules or offer new activities.
Medications are available to treat certain behavioral symptoms. Antidepressants called selective serotonin reuptake inhibitors are commonly prescribed to treat social disinhibition and impulsive behavior. Patients with aggression or delusions sometimes take low doses of antipsychotic medications. The use of Alzheimer’s disease medications to improve behavioral and cognitive symptoms in people with bvFTD and related disorders is being studied, though results so far have been mixed, with some medications making symptoms worse. If a particular medication is not working, a doctor may try another. Always consult a doctor before changing, adding, or stopping a drug.
Treating Language Problems
Treatment of primary progressive aphasia (PPA) has two goals—maintaining language skills and using new tools and other ways to communicate. Treatment tailored to a person’s specific language problem and stage of PPA generally works best. Since language ability declines over time, different strategies may be needed as the illness progresses.
To communicate without talking, a person with PPA may use a communication notebook (an album of photos labeled with names of people and objects), gestures, and drawings. Some people find it helpful to use or point to lists of words or phrases stored in a computer or personal digital assistant.
Caregivers can also learn new ways of talking to someone with PPA. For example, they can speak slowly and clearly, use simple sentences, wait for responses, and ask for clarification if they don’t understand something.
A speech-language pathologist who knows about PPA can test a person’s language skills and determine the best tools and strategies to use. Note that many speech-language pathologists are trained to treat aphasia caused by stroke, which requires different strategies from those used with PPA. (See the Resources section starting on page 27 to find speech-language pathologists and other experts who know about frontotemporal disorders.)
Managing Movement Problems
No treatment can slow down or stop frontotemporal-related movement disorders, though medications and physical and occupational therapy may provide modest relief.
For people with corticobasal syndrome (CBS), movement difficulties are sometimes treated with medications for Parkinson’s disease. But these medicines offer only minimal or temporary improvement. Physical and occupational therapy may help people with CBS move more easily. Speech therapy may help them manage language symptoms.
For people with progressive supranuclear palsy (PSP), sometimes Parkinson’s disease drugs provide temporary relief for slowness, stiffness, and balance problems. Exercises can keep the joints limber, and weighted walking aids— such as a walker with sandbags over the lower front rung—can help maintain balance. Speech, vision, and swallowing difficulties usually do not respond to any drug treatment. Antidepressants have shown modest success. For people with abnormal eye movements.
People with FTD-ALS typically decline quickly over the course of 2 to 3 years. During this time, physical therapy can help treat muscle symptoms, and a walker or wheelchair may be useful. Speech therapy may help a person speak more clearly at first. Later on, other ways of communicating, such as a speech synthesizer, can be used. The ALS symptoms of the disorder ultimately make it impossible to stand, walk, eat, and breathe on one’s own.
For any movement disorder caused by FTLD, a team of experts can help patients and their families address difficult medical and caregiving issues. Physicians, nurses, social workers, and physical, occupational, and speech therapists who are familiar with frontotemporal disorders can ensure that people with movement disorders get appropriate medical treatment and that their caregivers can help them live as well as possible.
The Future of Treatment
Researchers are continuing to explore the genetic and biological actions in the body that lead to frontotemporal disorders. In particular, they seek more information about genetic mutations that cause FTLD, as well as the disorders’ natural history and disease pathways. They also want to develop better ways, such as specialized brain imaging, to track its progression, so that treatments, when they become available, can be directed to the right people. The ultimate goal is to identify possible new drugs and other treatments to test.
Researchers are also looking for better treatments for frontotemporal disorders. Possible therapies that target the abnormal proteins found in the brain are being tested in the laboratory and in animals. Clinical trials and studies are testing a number of possible treatments in humans.
Clinical trials for individuals with frontotemporal disorders will require many participants. People with frontotemporal disorders and healthy people may be able to take part. To find out more about clinical trials, talk to your health care provider or visit www.clinicaltrials.gov.
Caring for a Person with a Frontotemporal Disorder
In addition to managing the medical and day-to-day care of people with frontotemporal disorders, caregivers can face a host of other challenges. These challenges may include changing family relationships, loss of work, poor health, decisions about long-term care, and end-of-life concerns.
Family Issues
People with frontotemporal disorders and their families often must cope with changing relationships, especially as symptoms get worse. For example, the wife of a man with bvFTD not only becomes her husband’s caregiver, but takes on household responsibilities he can no longer perform. Children may suffer the gradual “loss” of a parent at a critical time in their lives. The symptoms of bvFTD often embarrass family members and alienate friends. Life at home can become very stressful.
Work Issues
Frontotemporal disorders disrupt basic work skills, such as organizing, planning, and following through on tasks. Activities that were easy before the illness began might take much longer or become impossible. People lose their jobs because they can no longer perform them. As a result, the caregiver might need to take a second job to make ends meet—or reduce hours or even quit work to provide care and run the household. An employment attorney can offer information and advice about employee benefits, family leave, and disability if needed.
Workers diagnosed with any frontotemporal disorder can qualify quickly for Social Security disability benefits through the “compassionate allowances” program. For more information, see www.socialsecurity.gov/ compassionate allowances or call 1-800-772-1213.
Caregiver Health and Support
Caring for someone with a frontotemporal disorder can be very hard, both physically and emotionally. To stay healthy, caregivers can do the following:
Get regular health care.
Ask family and friends for help with child care, errands, and other tasks.
Spend time doing enjoyable activities, away from the demands of caregiving. Arrange for respite care—short-term caregiving services
that give the regular caregiver a break—or take the person to an adult daycare center, a safe, supervised environment for adults with
dementia or other disabilities.
Join a support group for caregivers of people with frontotemporal disorders. Such groups allow caregivers to learn coping strategies and share feelings with others in the same position.
The organizations listed in the Resources section can help with information about caregiver services and support.
For many caregivers, there comes a point when they can no longer take care of the person with a frontotemporal disorder without help. The caregiving demands are simply too great, perhaps requiring around-the-clock care. As the disease progresses, caregivers may want to get home health care services or look for a residential care facility, such as a group home, assisted living facility, or nursing home. The decision to move the person with a frontotemporal disorder to a care facility can be difficult, but it can also give caregivers peace of mind to know that the person is safe and getting good care. The decreased level of stress may also improve the caregivers’ relationship with his or her loved one.
End-of-Life Concerns
People with frontotemporal disorders typically live 6 to 8 years with their conditions, sometimes longer, sometimes less. Most people die of problems related to advanced disease. For example, as movement skills decline, a person can have trouble swallowing, leading to aspiration pneumonia, in which food or fluid gets into the lungs and causes infection. People with balance problems may fall and seriously injure themselves.
It is difficult, but important, to plan for the end of life. Legal documents, such as a will, living will, and durable powers of attorney for health care and finances should be created or updated as soon as possible after a diagnosis of bvFTD, PPA, or a related disorder. Early on, many people can understand and participate in legal decisions. But as their illness progresses, it becomes harder to make such decisions.
A physician who knows about frontotemporal disorders can help determine the person’s mental capacity. An attorney who specializes in elder law, disabilities, or estate planning can provide legal advice, prepare documents, and make financial arrangements for the caregiving spouse or partner and dependent children. If necessary, the person’s access to finances can be reduced or eliminated.
Next steps
Tips to help you get the most from a visit to your healthcare provider:
Know the reason for your visit and what you want to happen.
Before your visit, write down questions you want answered.
Bring someone with you to help you ask questions and remember what your provider tells you.
At the visit, write down the name of a new diagnosis, and any new medicines, treatments, or tests. Also write down any new instructions your provider gives you.
Know why a new medicine or treatment is prescribed, and how it will help you. Also know what the side effects are.
Ask if your condition can be treated in other ways.
Know why a test or procedure is recommended and what the results could mean.
Know what to expect if you do not take the medicine or have the test or procedure.
If you have a follow-up appointment, write down the date, time, and purpose for that visit.
Know how you can contact your provider if you have questions.
Altitude sickness occurs when you cannot get enough oxygen from the air at high altitudes. This causes symptoms such as a headache, loss of appetite, and trouble sleeping. It happens most often when people who are not used to high altitudes go quickly from lower altitudes to 8000 ft (2500 m) or higher. For example, you may get a headache when you drive over a high mountain pass, hike to a high altitude, or arrive at a mountain resort.
Acute mountain sickness (AMS) is a syndrome that arises in non-acclimatized individuals who ascend to high altitudes. It is a form of acute altitude illness that occurs due to a decrease in the atmospheric partial pressure of oxygen as the altitude increases, inducing hypoxia. This includes acute mountain sickness (AMS), high-altitude cerebral oedema (HACE), and high-altitude pulmonary edema (HAPE). This condition typically occurs at an altitude of >2500 meters; however, it can occur at lower elevations in high-risk individuals.[rx][rx]
Types of High Altitude Sickness
High altitude oxygenation is improving oxygenation or enriching the body with additional oxygen at high altitudes.[rx]
According to the Society of Mountain Medicine (Effects of high altitude on humans), there are three altitude regions:
High Altitude – 1500 to 3500 meters above sea level (4900-11500 ft.)
Very high altitude – 3500 to 5500 meters above sea level (11500 to 18000 ft.)
The onset of physiologic effects of diminished inspiratory oxygen pressure (PIO2) includes decreased exercise performance and increased ventilation (lowering of arterial PaCO2).
Minor impairment exists in arterial oxygen transport (arterial oxygen saturation [SaO2] at least 90%, but arterial PO2 is significantly diminished).
Because of the large number of people who ascend rapidly to 2500 to 3500 m, high-altitude illness is common in this range.
Very high altitude (3500 to 5500 m)
Maximum SaO2 falls below 90% as the arterial PO2 falls below 60 mm Hg.
Extreme hypoxemia may occur during exercise, during sleep and in the presence of high-altitude pulmonary edema or other acute lung conditions.
Severe altitude illness commonly occurs in this range.
Extreme altitude (above 5500 m)
Marked hypoxemia, hypocapnia and alkalosis are characteristic of extreme altitudes.
Progressive impairment of physiologic function eventually outstrips acclimatization. As a result, no human habitation occurs above 5500 m.[rx]
Most people who get altitude sickness get AMS, acute mountain sickness. Higher than 10,000 feet, 75% of people will get mild symptoms. There are three categories of AMS:
Mild AMS – Symptoms, such as mild headache and fatigue, don’t interfere with your normal activity. Symptoms improve after a few days as your body acclimates. You can likely stay at your current elevation as your body adjusts.
Moderate AMS – Symptoms start to interfere with your activities. You may experience severe headaches, nausea, and difficulty with coordination. You’ll need to descend to start to feel better.
Severe AMS – You may feel short of breath, even at rest. It can be difficult to walk. You need to descend immediately to a lower altitude and seek medical care.
HAPE (High-altitude pulmonary edema) – HAPE produces excess fluid on the lungs, causing breathlessness, even when resting. You feel very fatigued and weak and may feel like you’re suffocating.
HACE (High-altitude cerebral edema) – HACE involves excess fluid on the brain, causing brain swelling. You may experience confusion, lack of coordination, and possibly violent behavior.
Causes of Altitude Sickness
Acute Mountain Sickness is caused by the body’s reaction to the reduced oxygen level in respired air and resultant tissue hypoxia. At baseline metabolic levels, the brain is the most sensitive organ regarding hypoxia and oxygen stress. Thus, the symptoms of Acute Mountain Sickness (discussed below) are mediated by the central nervous system (CNS). In many travelers at altitude, respirations during sleep develop a periodic pattern that may contribute to the development of symptoms.[rx][rx]
Along with other illnesses related to altitude, HAPE occurs above 2500 meters but can occur at altitudes as low as 2000 meters. Risk factors include individual susceptibility due to low hypoxic ventilatory response (HVR), the altitude attained, a rapid rate of ascent, male sex, use of sleep medication, excessive salt ingestion, ambient cold temperature, and heavy physical exertion. Preexisting conditions such as those leading to increased pulmonary blood flow, pulmonary hypertension, increased pulmonary vascular reactivity, or patent foramen ovale may have a higher predisposition towards the development of HAPE. [rx][rx][rx]
Asthma
Bronchitis
Mucous plugging
Myocardial infarction
Pneumonia
Pneumothorax
Pulmonary embolism
Upper respiratory tract infection
Acute psychosis
Brain tumour
Carbon monoxide poisoning
Central nervous system infection
Cerebrovascular bleed or infarct
Cerebrovascular spasm
Diabetic ketoacidosis
Hypoglycemia
Hyponatremia
Ingestion of drugs
Seizure disorder
Coronary artery bypass
Eisenmenger syndrome
Severe symptomatic valvular heart disease
Severe decompensated congestive heart disease
Uncontrolled ventricular and supraventricular tachycardia
Uncontrolled hypertension
Unstable angina
History of altitude illness
The rate of ascent
The ultimate altitude reached
Other medical conditions such as pulmonary hypertension, chronic obstructive pulmonary disease, restrictive lung disease, pulmonary fibrosis, and congenital heart disease
The degree of cold
The amount of physical exertion
Use of alcohol and sleeping pills
Symptoms of Altitude Sickness
Some symptoms of low oxygen saturation levels include:
Shortness of breath
Cyanosis
Extreme fatigue and weakness
Mental confusion
Headaches
Symptoms of mild, short-term altitude sickness usually begin 12 to 24 hours after arriving at high altitude. They lessen in a day or two as your body adjusts. These symptoms include:
Dizziness.
Fatigue and loss of energy.
Shortness of breath.
Loss of appetite.
Sleep problems.
Symptoms of moderate altitude sickness are more intense and worsen instead of improving over time:
Worsening fatigue, weakness, and shortness of breath.
Coordination problems and difficulty walking.
Severe headache, nausea, and vomiting.
Chest tightness or congestion.
Difficulty doing regular activities, though you may still be able to walk independently.
Severe altitude sickness is an emergency. The symptoms are similar to moderate AMS but more severe and intense. If you start experiencing these symptoms, you must be taken to a lower altitude immediately for medical care:
Shortness of breath, even when resting.
Inability to walk.
Confusion.
Fluid buildup in the lungs or brain.
HAPE, when fluid builds up in the lungs, prevents oxygen from moving around your body. You need medical treatment for HAPE. Symptoms include:
Cyanosis, when your skin, nails or whites of your eyes start to turn blue.
Confusion and irrational behavior.
Shortness of breath even when resting.
Tightness in the chest.
Extreme fatigue and weakness.
Feeling like you’re suffocating at night.
Persistent cough, bringing up white, watery fluid.
HACE happens when the brain tissue starts to swell from the leaking fluid. You need medical treatment for HACE. Symptoms include:
The hallmark of Acute Mountain Sickness is a headache, with other symptoms including nausea, vomiting, loss of appetite, fatigue/malaise (particularly at rest), sleep disturbance, and dizziness/lightheadedness. Acute Mountain Sickness symptoms can begin after only a few hours and typically present the first day at a given altitude, resolving after one to three days, even without treatment, as the body adjusts physiologically (acclimates) to the lower oxygen levels.
The presence of facial or extremity edema can be present with or without Acute Mountain Sickness symptoms and is felt to be a marker for not yet being acclimated to the altitude. Rarely, retinal hemorrhages can occur and affect visual fields.
The onset of neurological findings such as a progressive decline in cognitive/mental function, the declining level of consciousness, impaired coordination, slurred speech, and/or lassitude signify the transition from AMS to HACE. A typical evaluation consists of an abnormal neurological exam, with ataxia often being the earliest finding.
Early symptoms may be misinterpreted as exhaustion and it is important to exclude these, as well as other disorders such as dehydration, hypoglycemia, hypothermia, or hyponatremia which all may have signs and symptoms that overlap with that of HACE. Though rarely available, laboratory testing may show an elevated white blood cell count in the setting of HACE, whereas any number of metabolic abnormalities may be present with the aforementioned others within the differential diagnosis.
Lumbar puncture may have an increased opening pressure with otherwise normal laboratory findings. CT may show cerebral edema, but MRI is a better study to evaluate for more subtle signs of edema and can remain abnormal for days up to weeks. To date, there has been no direct correlation between the severity of edema with clinical outcome.[rx][rx]
The Lake Louise Score for the diagnosis of acute mountain sickness.[rx]
Symptoms
Severity
Score
1. Headache
None
0
Mild
1
Moderate
2
Severe/incapacitating
3
2. Gastrointestinal
None
0
Poor appetite or nausea
1
Moderate nausea or vomiting
2
Severe nausea or vomiting/incapacitating
3
3. Fatigue/weakness
None
0
Mild
1
Moderate
2
Severe/incapacitating
3
4. Dizziness/lightheaded
None
0
Mild
1
Moderate
2
Severe/incapacitating
3
5. Difficulty sleeping
None
0
Not as well as usual
1
Poor night’s sleep
2
Unable to sleep
3
A diagnosis of acute mountain sickness (AMS) requires (a) score > 3, (b) presence of headache and (c) recent ascent.
High-altitude cerebral edema
With AMS
Altered mental status or/and ataxia
Without AMS
Altered mental status and ataxia
Acute mountain sickness (AMS)
- In the setting of a recent gain in altitude, there is the presence of headache and at least one of the following:
- Gastrointestinal (anorexia, nausea, or vomiting)
- Fatigue or weakness
- Dizziness or lightheadedness
- Difficulty sleeping
High-altitude cerebral edema (HACE)
- Can be considered “end-stage” or severe AMS. In the setting of a recent gain in altitude, there is either —
- the presence of a change in mental status and/ or ataxia in a person with AMS
- or the presence of both mental status changes and ataxia in a person without AMS.
High-altitude pulmonary edema (HAPE)
In the presence of a recent gain in altitude, the presence of the following:
At least two of the following symptoms —
- Dyspnea at rest
- Cough
- Weakness or decreased exercise performance
- Chest tightness or congestion
At least two of the following signs:
- Crackles or wheezing in at least one lung field
- Central cyanosis
- Tachypnea
- Tachycardia
Treatments of Altitude Sickness
Non-pharmacological
Pure oxygen – Giving pure oxygen can help a person with severe breathing problems caused by altitude sickness. Physicians at mountain resorts commonly provide this treatment.
A Gamow bag – This portable plastic hyperbaric chamber can be inflated with a foot pump and is used when a rapid descent is not possible. It can reduce the effective altitude by up to 5,000 ft (1,500 m). It is usually used as an aid to evacuate people with severe symptoms, not to treat them at high altitudes.
Gradual Ascent – The recommended method for the prevention of high-altitude illness is to allow the body time to acclimatize via gradual ascent. The WMS recommends one day of travel for every 1,500 ft ascent above 10,000 ft above sea level and a day of rest every 3 to 4 days of travel.
Descent – Non-severe AMS: Descent is not necessary for non-severe AMS. It responds well to rest and/or pharmacological treatment. If symptoms resolve, ascent may resume. Severe AMS is AMS with incapacitating symptoms. The appropriate and definitive treatment for severe AMS is immediate descent to a lower altitude.
Supplemental Oxygen – If available, supplemental oxygen should be administered with oxygen saturation of above 90% as a goal for both severe AMS and HACE. Supplemental oxygen should only be used in conjunction with evacuation or while waiting for it.
Portable Hyperbaric Chamber – These portable chambers are indicated for severe AMS and HACE when evacuation is delayed. Symptoms will recur when the patient exits the chamber. However, it may temporarily improve symptoms long enough for patients to be able to assist with their evacuation. The equipment and constant supervision make this a resource-intensive treatment, but it has the potential to save lives in remote areas where evacuation may be delayed.
Medication
Established drug treatments include acetazolamide, dexamethasone, and nifedipine. Acetazolamide is thought to be effective in treating AMS, creating an acidemia, increasing ventilation, and therefore, increasing the arterial oxygen content.[rx] Dexamethasone is effective at reducing edema and symptoms in HACE, just as it is in any other form of cerebral edema. Nifedipine is used in HAPE for its dilatory effect on the pulmonary vasculature; however, a recent study did not demonstrate any benefit over descent and supplemental oxygen in patients with HAPE.[rx] In addition to these established treatments, potential novel therapies have been suggested such as ibuprofen, nitrates, and intravenous (IV) iron supplementation.
Acetazolamide
Acetazolamide prevents AMS when taken before ascent; it can also help speed recovery if taken after symptoms have developed. The drug works by acidifying the blood and reducing the respiratory alkalosis associated with high elevations, thus increasing respiration and arterial oxygenation and speeding acclimatization. An effective dose that minimizes the common side effects of increased urination and paresthesias of the fingers and toes is 125 mg every 12 hours, beginning the day before ascent and continuing the first 2 days at elevation, or longer if ascent continues.
Acetazolamide (125mg PO every 12 hours)
Acetazolamide is the only medication proven to speed acclimatization. It induces metabolic acidosis by bicarbonate diuresis. This acidosis triggers compensatory hyperventilation helping acclimatization. There are two adverse effects of this medication worth considering. First, acetazolamide increases urination frequency and therefore increases the risk of dehydration, which is a concern during high altitude travel[rx]. Secondly, acetazolamide has a similar molecular structure to sulfa medications and should be used cautiously in patients with sulfa allergy. Although the risk of cross-reactivity is low, travelers with sulfa allergies are recommended to undergo a trial of acetazolamide before travel.[rx][rx]
Allergic reactions to acetazolamide are uncommon. As a nonantimicrobial sulfonamide, it does not cross-react with antimicrobial sulfonamides. However, it is best avoided by people with a history of anaphylaxis to any sulfa. People with a history of severe penicillin allergy have occasionally had allergic reactions to acetazolamide. The pediatric dose is 5 mg/kg/day in divided doses, up to 125 mg twice a day.
Dexamethasone
Dexamethasone (initial 8mg PO, IM, or IV followed in 6 hours by 4mg PO, IM, or IV every 6 hours). Dexamethasone is effective for preventing and treating AMS and HACE and prevents HAPE as well. Unlike acetazolamide, if the drug is discontinued at elevation before acclimatization, a mild rebound can occur. Acetazolamide is preferable to prevent AMS while ascending, with dexamethasone reserved as an adjunct treatment for the descent. The adult dose is 4 mg every 6 hours. An increasing trend is to use dexamethasone for “summit day” on high peaks such as Kilimanjaro and Aconcagua, in order to prevent abrupt altitude illness.
Dexamethasone (4mg PO, IM, or IV every 12 hours)
For those unable to take acetazolamide, dexamethasone may be used as a preventive agent. It also may be considered for individuals involved in an unusually high-risk situation (i.e., search and rescue personnel airlifted to above 11,000 ft). Dosages for dexamethasone is the same for PO, IM, and IV routes of administration. If used for longer than ten days, it must be tapered slowly to prevent withdrawal symptoms.
Nifedipine
Nifedipine both prevents and ameliorates HAPE. For prevention, it is generally reserved for people who are particularly susceptible to the condition. The adult dose for prevention or treatment is 30 mg of extended-release every 12 hours or 20 mg every 8 hours.
Painkillers or Ibuprofen
Acetaminophens, such as Tylenol, can be taken for headaches. Ibuprofen, an anti-inflammatory medicine, can also help. Other than the tight-fit hypothesis previously discussed, other possible mechanisms causing high-altitude headaches include activation of the trigeminovascular system by vasodilatation or inflammatory mediators[rx,rx] or alteration in the blood–brain barrier by inflammatory mediators causing vasogenic edema.]rx] The central role of inflammation in these mechanisms has led to an interest in nonsteroidal anti-inflammatory medications such as ibuprofen.
Nitrates
Nitric oxide (NO) regulates physiological processes in the human body, including vasodilation, immune function, platelet aggregation, glucose homeostasis, muscle contraction, and mitochondrial function.
One possible means of eliciting this effect is via dietary nitrate supplementation (ie, nitrate-rich beetroot juice). Nitrate ingestion has been shown to increase plasma concentrations of NO metabolites (nitrate and nitrite),[rx] reduce steady-state oxygen consumption,[rx] improve arterial and tissue oxygenation,[rx] enhance exercise tolerance,[rx–rx] and improve performance,[rx] during acute normobaric hypoxia. Interestingly, under hypoxic conditions, nitrate supplementation in the form of beetroot juice resulted in faster muscle recovery and restored maximal oxidative ATP resynthesis and exercise tolerance to normoxic values, when compared to placebo.[rx,rx]
Both sildenafil (a selective phosphodiesterase type 5 [PDE-5] inhibitor) and bosentan (a nonselective endothelin-receptor antagonist) have been mooted as potential treatments for AMS, due to their effect on prolonging the effect of NO. Sildenafil has been demonstrated to reduce PASP, increase oxygen delivery, and minimize the decrease in exercise capacity in both normobaric hypoxia and actual high altitude.[rx] By dilating the pulmonary vascular bed, these drugs reduce the degree of hypoxic pulmonary vasoconstriction and consequent pulmonary hypertension, and therefore, the risk of HAPE.
IV iron supplementation
In hypoxic conditions, oxygen-dependent hydroxylase enzymes are unable to degrade HIF, so iron supplementation encourages the breakdown of HIF, as in normoxic conditions. This is significant as HIF is believed to coordinate the cellular inflammatory response to hypoxia.[rx]
IV iron supplementation immediately prior to ascent to high altitude resulted in a significantly lower rise in AMS score from sea level to altitude, compared to IV saline. However, there was no significant difference in absolute AMS score at altitude between the two groups.[rx] Iron supplementation is an intriguing prospect in the prophylactic management of AMS; however, its feasibility on field expeditions is questionable. Oral iron supplemental is a possible alternative that needs more investigation.
Exercise and AMS
While the exact mechanism underlying high-altitude illness remains hotly debated, exercise has been suggested as an independent risk factor for the development of AMS.[rx] High-intensity intermittent exercise on a trekking expedition was associated with increased interstitial lung fluid at 4,090 m,rx] suggesting that exercise increases the risk of HAPE. Corroborating this, AMS scores were significantly higher in trekkers with a higher rating of perceived exertion.[rx]
Conversely, several recent chamber studies have failed to demonstrate a statistical difference in the development of AMS between rest and exercise at simulated altitude.[rx–rx] Of note, in comparing the change in interstitial fluid between exercise in hypoxia at 4,090 m and exercise in simulated hypoxia, there was no significant increase in simulated hypoxia, while there was an increase in actual hypoxia.[rx] This suggests that chamber studies are possibly underestimating the effect of exercise on the development of AMS and HAPE and that this may be due to the difference between the normobaric hypoxia experienced in chamber studies and hypobaric hypoxia experienced at altitude.[rx]
Nutrition
There are a few nutritional concerns for athletes at high altitudes. First, there is an association between chronic high altitude exposure and significant weight loss.[rx] This seems to be primarily due to loss of fat-free mass, which may have significant negative effects on physical performance.[rx] Factors possibly contributing to this weight loss are decreased physical activity, hypoxia, irregular sleep pattern, cold exposure, and nutritional imbalance related to protein metabolism.[rx,rx]
Inspiratory muscle training
In addition to IHE and IHT, there are other potential techniques such as dietary nitrate supplementation (which has been discussed earlier) and inspiratory muscle training (IMT), which may attenuate arterial oxygen desaturation and a reduction in exercise performance during high-altitude exposure.
Acute exposure to hypoxia and the associated reduction in the arterial partial pressure of oxygen increases minute ventilation, in an attempt to normalize arterial oxygen saturation. However, this hyperventilation increases the work of breathing and in turn the demand for respiratory blood flow,[rx] making the respiratory muscles more susceptible to fatigue.
Already abroad and need to see a doctor?
The following list of resources can help international travelers identify health care providers and facilities around the world. CDC does not endorse any particular provider or medical insurance company, and accreditation does not ensure a good outcome.
The nearest US embassy or consulate can help travelers locate medical services and notify friends, family, or employers of an emergency. They are available for emergencies 24 hours a day, 7 days a week, overseas.
The Department of State maintains a list of travel medical and evacuation insurance providers.
The International Society of Travel Medicine maintains a directory of health care professionals with expertise in travel medicine in more than 80 countries.
The International Association for Medical Assistance to Travelers maintains a network of physicians, hospitals, and clinics that have agreed to provide care to members.
Travel agencies, hotels, and credit card companies (especially those with special privileges) may also provide information.
A number of countries or national travel medicine societies have websites related to travel medicine that provide access to clinicians, including the following:
Australia: Travel Medicine Alliance
Canada: Health Canada (www.phac-aspc.gc.ca and https://travel.gc.ca)
China: International Travel Healthcare Association
Great Britain: National Travel Health Network and Centre and British Global and Travel Health Association
South Africa: South African Society of Travel Medicine
Tips for acclimatization
Be sure you are in good shape before you travel – If you have significant medical problems, check with your doctor before you go; even with his approval, be sure to go slowly and listen to your body for warning symptoms. Travel is usually safe for men with mild to moderate heart or lung disease and for most with well-controlled high blood pressure or diabetes, but high altitudes are very dangerous for people with sickle cell anemia.
Ascend gradually – You can fly to Denver or Mexico City in one hop, but if you’re going higher, a few days of acclimation are worth your time. Above 8,000 feet, don’t go up more than 1,000 feet a day.
Travel high, sleep low – For example, if you ski at 9,000 feet, you’ll do best if your lodge is 1,000–1,500 feet lower. If you’re hiking, ascend in stages, and sleep at altitudes below your daily peak.
Limit your exercise during your first days at altitude — and take it easy throughout your trip if you have medical problems or you feel sick in any way.
Drink plenty of fluids – Dehydration is sneaky at altitude because you will lose lots of water through your lungs even if you don’t perspire. Drink enough to keep your urine clear and copious. Avoid alcohol or minimize your consumption, particularly for the first 48 hours at altitude. Avoid sedatives.
Be alert for symptoms – You can manage mild mountain sickness yourself (see “Treatment” below), but you’ll need help for anything more serious. Don’t ignore symptoms; instead, return to a lower elevation and get help.
Ascend gradually, if possible. Avoid going directly from low elevation to more than 9,000 ft (2,750 m) sleeping elevation in 1 day. Once above 9,000 ft (2,750 m), move sleeping elevation no higher than 1,600 ft (500 m) per day, and plan an extra day for acclimatization every 3,300 ft (1,000 m).
Consider using acetazolamide to speed acclimatization if abrupt ascent is unavoidable.
Avoid alcohol for the first 48 hours; continue caffeine if a regular user.
Participate in only mild exercise for the first 48 hours.
Having a high-elevation exposure (greater than 9,000 ft [2,750 m]) for 2 nights or more, within 30 days before the trip, is useful, but closer to the trip departure is better.
Dress warmly.
Wear sunglasses.
These steps can help your body acclimate:
Walk-up – Start below 10,000 feet and walk to a high altitude instead of driving or flying. If you drive or fly to an elevation higher than 10,000 feet, stay at your first stop for at least 24 hours before going higher.
Go slow – Once above 10,000 feet, don’t increase your altitude more than 1,000 feet a day.
Rest – Build a rest day into your schedule for every 3,000 feet you climb.
“Climb high and sleep low” – If you climb more than 1,000 feet in a day, come down to sleep at a lower altitude.
Know your body – Recognize the signs and symptoms of altitude sickness. Move to a lower altitude (or avoid climbing higher) if you notice any symptoms.
Stay hydrated – Drink 3-4 quarts of water per day.
Avoid alcohol – Alcohol can dehydrate your body. It also has stronger effects at higher elevations, which can impair judgment.
Eat carbs – Eat a diet that’s more than 70% carbohydrates.
Know the “don’ts – Avoid tobacco and depressant drugs, such as sleeping pills and tranquilizers.
What should I ask my doctor?
If you’re planning to travel to high altitudes, ask your healthcare provider:
Should I take preventive medication to avoid altitude sickness?
Do I have any risk factors that would prevent me from visiting high elevations?
What other steps can I take to prevent altitude sickness?
What steps should I take if I start to feel symptoms during my climb?
High Altitude Pulmonary Edema (HAPE) is a fatal form of severe high-altitude illness. HAPE is a form of noncardiogenic pulmonary edema that occurs secondary to hypoxia. It is a clinical diagnosis characterized by fatigue, dyspnea, and dry cough with exertion. If left untreated, it can progress to dyspnea at rest, rales, cyanosis, and a mortality rate of up to 50%.[rx][rx][rx]
Acute mountain sickness (AMS) is a syndrome that arises in non-acclimatized individuals who ascend to high altitudes. It is a form of acute altitude illness that occurs due to a decrease in the atmospheric partial pressure of oxygen as the altitude increases, inducing hypoxia. This includes acute mountain sickness (AMS), high-altitude cerebral oedema (HACE), and high-altitude pulmonary edema (HAPE). This condition typically occurs at an altitude of >2500 meters; however, it can occur at lower elevations in high-risk individuals.[rx][rx]
Types of High Altitude Sickness
High altitude oxygenation is improving oxygenation or enriching the body with additional oxygen at high altitudes.[rx]
According to the Society of Mountain Medicine (Effects of high altitude on humans), there are three altitude regions:
High Altitude – 1500 to 3500 meters above sea level (4900-11500 ft.)
Very high altitude – 3500 to 5500 meters above sea level (11500 to 18000 ft.)
The onset of physiologic effects of diminished inspiratory oxygen pressure (PIO2) includes decreased exercise performance and increased ventilation (lowering of arterial PaCO2).
Minor impairment exists in arterial oxygen transport (arterial oxygen saturation [SaO2] at least 90%, but arterial PO2 is significantly diminished).
Because of the large number of people who ascend rapidly to 2500 to 3500 m, high-altitude illness is common in this range.
Very high altitude (3500 to 5500 m)
Maximum SaO2 falls below 90% as the arterial PO2 falls below 60 mm Hg.
Extreme hypoxemia may occur during exercise, during sleep and in the presence of high-altitude pulmonary edema or other acute lung conditions.
Severe altitude illness commonly occurs in this range.
Extreme altitude (above 5500 m)
Marked hypoxemia, hypocapnia and alkalosis are characteristic of extreme altitudes.
Progressive impairment of physiologic function eventually outstrips acclimatization. As a result, no human habitation occurs above 5500 m.[rx]
Most people who get altitude sickness get AMS, acute mountain sickness. Higher than 10,000 feet, 75% of people will get mild symptoms. There are three categories of AMS:
Mild AMS – Symptoms, such as mild headache and fatigue, don’t interfere with your normal activity. Symptoms improve after a few days as your body acclimates. You can likely stay at your current elevation as your body adjusts.
Moderate AMS – Symptoms start to interfere with your activities. You may experience severe headaches, nausea, and difficulty with coordination. You’ll need to descend to start to feel better.
Severe AMS – You may feel short of breath, even at rest. It can be difficult to walk. You need to descend immediately to a lower altitude and seek medical care.
HAPE (High-altitude pulmonary edema) – HAPE produces excess fluid on the lungs, causing breathlessness, even when resting. You feel very fatigued and weak and may feel like you’re suffocating.
HACE (High-altitude cerebral edema) – HACE involves excess fluid on the brain, causing brain swelling. You may experience confusion, lack of coordination, and possibly violent behavior.
Causes of High Altitude Pulmonary Edema
Acute Mountain Sickness is caused by the body’s reaction to the reduced oxygen level in respired air and resultant tissue hypoxia. At baseline metabolic levels, the brain is the most sensitive organ regarding hypoxia and oxygen stress. Thus, the symptoms of Acute Mountain Sickness (discussed below) are mediated by the central nervous system (CNS). In many travelers at altitude, respirations during sleep develop a periodic pattern that may contribute to the development of symptoms.[rx][rx]
Along with other illnesses related to altitude, HAPE occurs above 2500 meters but can occur at altitudes as low as 2000 meters. Risk factors include individual susceptibility due to low hypoxic ventilatory response (HVR), the altitude attained, a rapid rate of ascent, male sex, use of sleep medication, excessive salt ingestion, ambient cold temperature, and heavy physical exertion. Preexisting conditions such as those leading to increased pulmonary blood flow, pulmonary hypertension, increased pulmonary vascular reactivity, or patent foramen ovale may have a higher predisposition towards the development of HAPE. [rx][rx][rx]
Asthma
Bronchitis
Mucous plugging
Myocardial infarction
Pneumonia
Pneumothorax
Pulmonary embolism
Upper respiratory tract infection
Acute psychosis
Brain tumour
Carbon monoxide poisoning
Central nervous system infection
Cerebrovascular bleed or infarct
Cerebrovascular spasm
Diabetic ketoacidosis
Hypoglycemia
Hyponatremia
Ingestion of drugs
Seizure disorder
Coronary artery bypass
Eisenmenger syndrome
Severe symptomatic valvular heart disease
Severe decompensated congestive heart disease
Uncontrolled ventricular and supraventricular tachycardia
Uncontrolled hypertension
Unstable angina
History of altitude illness
The rate of ascent
The ultimate altitude reached
Other medical conditions such as pulmonary hypertension, chronic obstructive pulmonary disease, restrictive lung disease, pulmonary fibrosis, and congenital heart disease
The degree of cold
The amount of physical exertion
Use of alcohol and sleeping pills
Symptoms of High Altitude Pulmonary Edema
Some symptoms of low oxygen saturation levels include:
Shortness of breath
Cyanosis
Extreme fatigue and weakness
Mental confusion
Headaches
Symptoms of mild, short-term altitude sickness usually begin 12 to 24 hours after arriving at high altitude. They lessen in a day or two as your body adjusts. These symptoms include:
Dizziness.
Fatigue and loss of energy.
Shortness of breath.
Loss of appetite.
Sleep problems.
Symptoms of moderate altitude sickness are more intense and worsen instead of improving over time:
Worsening fatigue, weakness, and shortness of breath.
Coordination problems and difficulty walking.
Severe headache, nausea, and vomiting.
Chest tightness or congestion.
Difficulty doing regular activities, though you may still be able to walk independently.
Severe altitude sickness is an emergency. The symptoms are similar to moderate AMS but more severe and intense. If you start experiencing these symptoms, you must be taken to a lower altitude immediately for medical care:
Shortness of breath, even when resting.
Inability to walk.
Confusion.
Fluid buildup in the lungs or brain.
HAPE, when fluid builds up in the lungs, prevents oxygen from moving around your body. You need medical treatment for HAPE. Symptoms include:
Cyanosis, when your skin, nails or whites of your eyes start to turn blue.
Confusion and irrational behavior.
Shortness of breath even when resting.
Tightness in the chest.
Extreme fatigue and weakness.
Feeling like you’re suffocating at night.
Persistent cough, bringing up white, watery fluid.
HACE happens when the brain tissue starts to swell from the leaking fluid. You need medical treatment for HACE. Symptoms include:
The hallmark of Acute Mountain Sickness is a headache, with other symptoms including nausea, vomiting, loss of appetite, fatigue/malaise (particularly at rest), sleep disturbance, and dizziness/lightheadedness. Acute Mountain Sickness symptoms can begin after only a few hours and typically present the first day at a given altitude, resolving after one to three days, even without treatment, as the body adjusts physiologically (acclimates) to the lower oxygen levels.
The presence of facial or extremity edema can be present with or without Acute Mountain Sickness symptoms and is felt to be a marker for not yet being acclimated to the altitude. Rarely, retinal hemorrhages can occur and affect visual fields.
The onset of neurological findings such as a progressive decline in cognitive/mental function, the declining level of consciousness, impaired coordination, slurred speech, and/or lassitude signify the transition from AMS to HACE. A typical evaluation consists of an abnormal neurological exam, with ataxia often being the earliest finding.
Early symptoms may be misinterpreted as exhaustion and it is important to exclude these, as well as other disorders such as dehydration, hypoglycemia, hypothermia, or hyponatremia which all may have signs and symptoms that overlap with that of HACE. Though rarely available, laboratory testing may show an elevated white blood cell count in the setting of HACE, whereas any number of metabolic abnormalities may be present with the aforementioned others within the differential diagnosis.
Lumbar puncture may have an increased opening pressure with otherwise normal laboratory findings. CT may show cerebral edema, but MRI is a better study to evaluate for more subtle signs of edema and can remain abnormal for days up to weeks. To date, there has been no direct correlation between the severity of edema with clinical outcome.[rx][rx]
The Lake Louise Score for the diagnosis of acute mountain sickness.[rx]
Symptoms
Severity
Score
1. Headache
None
0
Mild
1
Moderate
2
Severe/incapacitating
3
2. Gastrointestinal
None
0
Poor appetite or nausea
1
Moderate nausea or vomiting
2
Severe nausea or vomiting/incapacitating
3
3. Fatigue/weakness
None
0
Mild
1
Moderate
2
Severe/incapacitating
3
4. Dizziness/lightheaded
None
0
Mild
1
Moderate
2
Severe/incapacitating
3
5. Difficulty sleeping
None
0
Not as well as usual
1
Poor night’s sleep
2
Unable to sleep
3
A diagnosis of acute mountain sickness (AMS) requires (a) score > 3, (b) presence of headache and (c) recent ascent.
High-altitude cerebral edema
With AMS
Altered mental status or/and ataxia
Without AMS
Altered mental status and ataxia
Acute mountain sickness (AMS)
- In the setting of a recent gain in altitude, there is the presence of headache and at least one of the following:
- Gastrointestinal (anorexia, nausea, or vomiting)
- Fatigue or weakness
- Dizziness or lightheadedness
- Difficulty sleeping
High-altitude cerebral edema (HACE)
- Can be considered “end-stage” or severe AMS. In the setting of a recent gain in altitude, there is either —
- the presence of a change in mental status and/ or ataxia in a person with AMS
- or the presence of both mental status changes and ataxia in a person without AMS.
High-altitude pulmonary edema (HAPE)
In the presence of a recent gain in altitude, the presence of the following:
At least two of the following symptoms —
- Dyspnea at rest
- Cough
- Weakness or decreased exercise performance
- Chest tightness or congestion
At least two of the following signs:
- Crackles or wheezing in at least one lung field
- Central cyanosis
- Tachypnea
- Tachycardia
Treatments of High Altitude Pulmonary Edema
Non-pharmacological
Pure oxygen – Giving pure oxygen can help a person with severe breathing problems caused by altitude sickness. Physicians at mountain resorts commonly provide this treatment.
A Gamow bag – This portable plastic hyperbaric chamber can be inflated with a foot pump and is used when a rapid descent is not possible. It can reduce the effective altitude by up to 5,000 ft (1,500 m). It is usually used as an aid to evacuate people with severe symptoms, not to treat them at high altitudes.
Gradual Ascent – The recommended method for the prevention of high-altitude illness is to allow the body time to acclimatize via gradual ascent. The WMS recommends one day of travel for every 1,500 ft ascent above 10,000 ft above sea level and a day of rest every 3 to 4 days of travel.
Descent – Non-severe AMS: Descent is not necessary for non-severe AMS. It responds well to rest and/or pharmacological treatment. If symptoms resolve, ascent may resume. Severe AMS is AMS with incapacitating symptoms. The appropriate and definitive treatment for severe AMS is immediate descent to a lower altitude.
Supplemental Oxygen – If available, supplemental oxygen should be administered with oxygen saturation of above 90% as a goal for both severe AMS and HACE. Supplemental oxygen should only be used in conjunction with evacuation or while waiting for it.
Portable Hyperbaric Chamber – These portable chambers are indicated for severe AMS and HACE when evacuation is delayed. Symptoms will recur when the patient exits the chamber. However, it may temporarily improve symptoms long enough for patients to be able to assist with their evacuation. The equipment and constant supervision make this a resource-intensive treatment, but it has the potential to save lives in remote areas where evacuation may be delayed.
Medication
Established drug treatments include acetazolamide, dexamethasone, and nifedipine. Acetazolamide is thought to be effective in treating AMS, creating an acidemia, increasing ventilation, and therefore, increasing the arterial oxygen content.[rx] Dexamethasone is effective at reducing edema and symptoms in HACE, just as it is in any other form of cerebral edema. Nifedipine is used in HAPE for its dilatory effect on the pulmonary vasculature; however, a recent study did not demonstrate any benefit over descent and supplemental oxygen in patients with HAPE.[rx] In addition to these established treatments, potential novel therapies have been suggested such as ibuprofen, nitrates, and intravenous (IV) iron supplementation.
Acetazolamide
Acetazolamide prevents AMS when taken before ascent; it can also help speed recovery if taken after symptoms have developed. The drug works by acidifying the blood and reducing the respiratory alkalosis associated with high elevations, thus increasing respiration and arterial oxygenation and speeding acclimatization. An effective dose that minimizes the common side effects of increased urination and paresthesias of the fingers and toes is 125 mg every 12 hours, beginning the day before ascent and continuing the first 2 days at elevation, or longer if ascent continues.
Acetazolamide (125mg PO every 12 hours)
Acetazolamide is the only medication proven to speed acclimatization. It induces metabolic acidosis by bicarbonate diuresis. This acidosis triggers compensatory hyperventilation helping acclimatization. There are two adverse effects of this medication worth considering. First, acetazolamide increases urination frequency and therefore increases the risk of dehydration, which is a concern during high altitude travel[rx]. Secondly, acetazolamide has a similar molecular structure to sulfa medications and should be used cautiously in patients with sulfa allergy. Although the risk of cross-reactivity is low, travelers with sulfa allergies are recommended to undergo a trial of acetazolamide before travel.[rx][rx]
Allergic reactions to acetazolamide are uncommon. As a nonantimicrobial sulfonamide, it does not cross-react with antimicrobial sulfonamides. However, it is best avoided by people with a history of anaphylaxis to any sulfa. People with a history of severe penicillin allergy have occasionally had allergic reactions to acetazolamide. The pediatric dose is 5 mg/kg/day in divided doses, up to 125 mg twice a day.
Dexamethasone
Dexamethasone (initial 8mg PO, IM, or IV followed in 6 hours by 4mg PO, IM, or IV every 6 hours). Dexamethasone is effective for preventing and treating AMS and HACE and prevents HAPE as well. Unlike acetazolamide, if the drug is discontinued at elevation before acclimatization, the mild rebound can occur. Acetazolamide is preferable to prevent AMS while ascending, with dexamethasone reserved as an adjunct treatment for the descent. The adult dose is 4 mg every 6 hours. An increasing trend is to use dexamethasone for “summit day” on high peaks such as Kilimanjaro and Aconcagua, in order to prevent abrupt altitude illness.
Dexamethasone (4mg PO, IM, or IV every 12 hours)
For those unable to take acetazolamide, dexamethasone may be used as a preventive agent. It also may be considered for individuals involved in an unusually high-risk situation (i.e., search and rescue personnel airlifted to above 11,000 ft). Dosages for dexamethasone is the same for PO, IM, and IV routes of administration. If used for longer than ten days, it must be tapered slowly to prevent withdrawal symptoms.
Nifedipine
Nifedipine both prevents and ameliorates HAPE. For prevention, it is generally reserved for people who are particularly susceptible to the condition. The adult dose for prevention or treatment is 30 mg of extended-release every 12 hours or 20 mg every 8 hours.
Painkillers or Ibuprofen
Acetaminophens, such as Tylenol, can be taken for headaches. Ibuprofen, an anti-inflammatory medicine, can also help. Other than the tight-fit hypothesis previously discussed, other possible mechanisms causing high-altitude headaches include activation of the trigeminovascular system by vasodilatation or inflammatory mediators[rx,rx] or alteration in the blood–brain barrier by inflammatory mediators causing vasogenic edema.]rx] The central role of inflammation in these mechanisms has led to an interest in nonsteroidal anti-inflammatory medications such as ibuprofen.
Nitrates
Nitric oxide (NO) regulates physiological processes in the human body, including vasodilation, immune function, platelet aggregation, glucose homeostasis, muscle contraction, and mitochondrial function.
One possible means of eliciting this effect is via dietary nitrate supplementation (ie, nitrate-rich beetroot juice). Nitrate ingestion has been shown to increase plasma concentrations of NO metabolites (nitrate and nitrite),[rx] reduce steady-state oxygen consumption,[rx] improve arterial and tissue oxygenation,[rx] enhance exercise tolerance,[rx–rx] and improve performance,[rx] during acute normobaric hypoxia. Interestingly, under hypoxic conditions, nitrate supplementation in the form of beetroot juice resulted in faster muscle recovery and restored maximal oxidative ATP resynthesis and exercise tolerance to normoxic values, when compared to placebo.[rx,rx]
Both sildenafil (a selective phosphodiesterase type 5 [PDE-5] inhibitor) and bosentan (a nonselective endothelin-receptor antagonist) have been mooted as potential treatments for AMS, due to their effect on prolonging the effect of NO. Sildenafil has been demonstrated to reduce PASP, increase oxygen delivery, and minimize the decrease in exercise capacity in both normobaric hypoxia and actual high altitude.[rx] By dilating the pulmonary vascular bed, these drugs reduce the degree of hypoxic pulmonary vasoconstriction and consequent pulmonary hypertension, and therefore, the risk of HAPE.
IV iron supplementation
In hypoxic conditions, oxygen-dependent hydroxylase enzymes are unable to degrade HIF, so iron supplementation encourages the breakdown of HIF, as in normoxic conditions. This is significant as HIF is believed to coordinate the cellular inflammatory response to hypoxia.[rx]
IV iron supplementation immediately prior to ascent to high altitude resulted in a significantly lower rise in AMS score from sea level to altitude, compared to IV saline. However, there was no significant difference in absolute AMS score at altitude between the two groups.[rx] Iron supplementation is an intriguing prospect in the prophylactic management of AMS; however, its feasibility on field expeditions is questionable. Oral iron supplemental is a possible alternative that needs more investigation.
Exercise and AMS
While the exact mechanism underlying high-altitude illness remains hotly debated, exercise has been suggested as an independent risk factor for the development of AMS.[rx] High-intensity intermittent exercise on a trekking expedition was associated with increased interstitial lung fluid at 4,090 m,rx] suggesting that exercise increases the risk of HAPE. Corroborating this, AMS scores were significantly higher in trekkers with a higher rating of perceived exertion.[rx]
Conversely, several recent chamber studies have failed to demonstrate a statistical difference in the development of AMS between rest and exercise at simulated altitude.[rx–rx] Of note, in comparing the change in interstitial fluid between exercise in hypoxia at 4,090 m and exercise in simulated hypoxia, there was no significant increase in simulated hypoxia, while there was an increase in actual hypoxia.[rx] This suggests that chamber studies are possibly underestimating the effect of exercise on the development of AMS and HAPE and that this may be due to the difference between the normobaric hypoxia experienced in chamber studies and hypobaric hypoxia experienced at altitude.[rx]
Nutrition
There are a few nutritional concerns for athletes at high altitudes. First, there is an association between chronic high altitude exposure and significant weight loss.[rx] This seems to be primarily due to loss of fat-free mass, which may have significant negative effects on physical performance.[rx] Factors possibly contributing to this weight loss are decreased physical activity, hypoxia, irregular sleep pattern, cold exposure, and nutritional imbalance related to protein metabolism.[rx,rx]
Inspiratory muscle training
In addition to IHE and IHT, there are other potential techniques such as dietary nitrate supplementation (which has been discussed earlier) and inspiratory muscle training (IMT), which may attenuate arterial oxygen desaturation and a reduction in exercise performance during high-altitude exposure.
Acute exposure to hypoxia and the associated reduction in the arterial partial pressure of oxygen increases minute ventilation, in an attempt to normalize arterial oxygen saturation. However, this hyperventilation increases the work of breathing and in turn the demand for respiratory blood flow,[rx] making the respiratory muscles more susceptible to fatigue.
Already abroad and need to see a doctor?
The following list of resources can help international travelers identify health care providers and facilities around the world. CDC does not endorse any particular provider or medical insurance company, and accreditation does not ensure a good outcome.
The nearest US embassy or consulate can help travelers locate medical services and notify friends, family, or employers of an emergency. They are available for emergencies 24 hours a day, 7 days a week, overseas.
The Department of State maintains a list of travel medical and evacuation insurance providers.
The International Society of Travel Medicine maintains a directory of health care professionals with expertise in travel medicine in more than 80 countries.
The International Association for Medical Assistance to Travelers maintains a network of physicians, hospitals, and clinics that have agreed to provide care to members.
Travel agencies, hotels, and credit card companies (especially those with special privileges) may also provide information.
A number of countries or national travel medicine societies have websites related to travel medicine that provide access to clinicians, including the following:
Australia: Travel Medicine Alliance
Canada: Health Canada (www.phac-aspc.gc.ca and https://travel.gc.ca)
China: International Travel Healthcare Association
Great Britain: National Travel Health Network and Centre and British Global and Travel Health Association
South Africa: South African Society of Travel Medicine
Tips for acclimatization
Be sure you are in good shape before you travel – If you have significant medical problems, check with your doctor before you go; even with his approval, be sure to go slowly and listen to your body for warning symptoms. Travel is usually safe for men with mild to moderate heart or lung disease and for most with well-controlled high blood pressure or diabetes, but high altitudes are very dangerous for people with sickle cell anemia.
Ascend gradually – You can fly to Denver or Mexico City in one hop, but if you’re going higher, a few days of acclimation are worth your time. Above 8,000 feet, don’t go up more than 1,000 feet a day.
Travel high, sleep low – For example, if you ski at 9,000 feet, you’ll do best if your lodge is 1,000–1,500 feet lower. If you’re hiking, ascend in stages, and sleep at altitudes below your daily peak.
Limit your exercise during your first days at altitude — and take it easy throughout your trip if you have medical problems or you feel sick in any way.
Drink plenty of fluids – Dehydration is sneaky at altitude because you will lose lots of water through your lungs even if you don’t perspire. Drink enough to keep your urine clear and copious. Avoid alcohol or minimize your consumption, particularly for the first 48 hours at altitude. Avoid sedatives.
Be alert for symptoms – You can manage mild mountain sickness yourself (see “Treatment” below), but you’ll need help for anything more serious. Don’t ignore symptoms; instead, return to a lower elevation and get help.
Ascend gradually, if possible. Avoid going directly from low elevation to more than 9,000 ft (2,750 m) sleeping elevation in 1 day. Once above 9,000 ft (2,750 m), move sleeping elevation no higher than 1,600 ft (500 m) per day, and plan an extra day for acclimatization every 3,300 ft (1,000 m).
Consider using acetazolamide to speed acclimatization if abrupt ascent is unavoidable.
Avoid alcohol for the first 48 hours; continue caffeine if a regular user.
Participate in only mild exercise for the first 48 hours.
Having a high-elevation exposure (greater than 9,000 ft [2,750 m]) for 2 nights or more, within 30 days before the trip, is useful, but closer to the trip departure is better.
Dress warmly.
Wear sunglasses.
These steps can help your body acclimate:
Walk-up – Start below 10,000 feet and walk to a high altitude instead of driving or flying. If you drive or fly to an elevation higher than 10,000 feet, stay at your first stop for at least 24 hours before going higher.
Go slow – Once above 10,000 feet, don’t increase your altitude more than 1,000 feet a day.
Rest – Build a rest day into your schedule for every 3,000 feet you climb.
“Climb high and sleep low” – If you climb more than 1,000 feet in a day, come down to sleep at a lower altitude.
Know your body – Recognize the signs and symptoms of altitude sickness. Move to a lower altitude (or avoid climbing higher) if you notice any symptoms.
Stay hydrated – Drink 3-4 quarts of water per day.
Avoid alcohol – Alcohol can dehydrate your body. It also has stronger effects at higher elevations, which can impair judgment.
Eat carbs – Eat a diet that’s more than 70% carbohydrates.
Know the “don’ts – Avoid tobacco and depressant drugs, such as sleeping pills and tranquilizers.
What should I ask my doctor?
If you’re planning to travel to high altitudes, ask your healthcare provider:
Should I take preventive medication to avoid altitude sickness?
Do I have any risk factors that would prevent me from visiting high elevations?
What other steps can I take to prevent altitude sickness?
What steps should I take if I start to feel symptoms during my climb?
Cervical Fibroids are located in the wall of the cervix (neck of the uterus). Rarely, fibroids are found in the supporting structures (round ligament, broad ligament, or uterosacral ligament) of the uterus that also contain smooth muscle tissue.
Uterine Fibroids are the most common benign tumor affecting women. Fibroids originate from uterine smooth muscle cells (myometrium) whose growth is primarily dependent on the levels of circulating estrogen. Fibroids can either present as an asymptomatic incidental finding on imaging, or symptomatically. Common symptoms include abnormal uterine bleeding, pelvic pain, disruption of surrounding pelvic structures(bowel and bladder), and back pain. Uterine fibroids typically are seen in three significant locations: subserosal (outside the uterus), intramural (inside the myometrium), and submucosal (Inside the uterine cavity). They can further be broken down to pedunculated or not. Fibroids are classically diagnosed by physical exam and ultrasound imaging, which carries a high sensitivity for this pathology. Fibroids continue to be the leading indication for hysterectomy. [rx]
Uterine fibroids, also known as uterine leiomyomas or fibroids, are benign smooth muscle tumors of the uterus. Most women have no symptoms while others may have painful or heavy periods. If large enough, they may push on the bladder causing a frequent need to urinate. They may also cause pain during sex or lower back pain.[rx][rx] A woman can have one uterine fibroid or many. Occasionally, fibroids may make it difficult to become pregnant, although this is uncommon.[rx]
Types of Uterine Fibroids
Schematic drawing of various types of uterine fibroids: a=subserosal fibroids, b=intramural fibroids, c=submucosal fibroid, d=pedunculated submucosal fibroid, e=cervical fibroid, f=fibroid of the broad ligament
Growth and location are the main factors that determine if a fibroid leads to symptoms and problems.[6] A small lesion can be symptomatic if located within the uterine cavity while a large lesion on the outside of the uterus may go unnoticed. Different locations are classified as follows:
Intramural fibroids are located within the muscular wall of the uterus. Unless they are large, they may be asymptomatic. Intramural fibroids begin as small nodules in the muscular wall of the uterus. With time, intramural fibroids may expand inwards, causing distortion and elongation of the uterine cavity.
Subserosal fibroids – are located on the surface of the uterus. They can also grow outward from the surface and remain attached by a small piece of tissue and then are called pedunculated fibroids.[rx]
Submucosal fibroids – are most common type, located in the muscle beneath the endometrium of the uterus and distort the uterine cavity; even small lesions in this location may lead to bleeding and infertility. A pedunculated lesion within the cavity is termed an intracavitary fibroid and can be passed through the cervix.
Cervical fibroids – are located in the wall of the cervix (neck of the uterus). Rarely, fibroids are found in the supporting structures (round ligament, broad ligament, or uterosacral ligament) of the uterus that also contain smooth muscle tissue.
Fibroids may be single or multiple. Most fibroids start in the muscular wall of the uterus. With further growth, some lesions may develop towards the outside of the uterus or towards the internal cavity. Secondary changes that may develop within fibroids are hemorrhage, necrosis, calcification, and cystic changes. They tend to calcify after menopause.[rx]
If the uterus contains too many to count, it is referred to as diffuse uterine leiomyomatosis.
Extrauterine fibroids of uterine origin, metastatic fibroids
Fibroids of uterine origin located in other parts of the body, sometimes also called parasitic myomas have been historically extremely rare, but are now diagnosed with increasing frequency. They may be related or identical to metastasizing leiomyoma.
They are in most cases still hormone dependent but may cause life-threatening complications when they appear in distant organs. Some sources suggest that a substantial share of the cases may be late complications of surgeries such as myomectomy or hysterectomy. Particularly laparoscopic myomectomy using a morcellator has been associated with an increased risk of this complication.[rx][rx][rx]
There are a number of rare conditions in which fibroids metastasize. They still grow in a benign fashion, but can be dangerous depending on their location.[rx]
In leiomyoma with vascular invasion – an ordinary-appearing fibroid invades into a vessel but there is no risk of recurrence.
In intravenous leiomyomatosis – leiomyomata grow in veins with uterine fibroids as their source. Involvement of the heart can be fatal.
In benign metastasizing leiomyoma – leiomyomata grow in more distant sites such as the lungs and lymph nodes. The source is not entirely clear. Pulmonary involvement can be fatal.
In disseminated intraperitoneal leiomyomatosis – leiomyomata grow diffusely on the peritoneal and omental surfaces, with uterine fibroids as their source. This can simulate a malignant tumor but behaves benignly.
Causes of Uterine Fibroids
The exact pathophysiology behind the development of uterine fibroids is unclear.[rx] Research suggests that the starting event for fibroid development begins with a single uterine smooth muscle cell(myometrium), which is then followed by deviations from the normal signaling pathways of cellular division.[rx] Fibroids are considered to be estrogen-dependent tumors, and there is evidence showing that leiomyomas overexpress certain estrogen and progesterone receptors when compared to normal surrounding myometrium.[rx]
Fibroids are a result of the inappropriate growth of uterine smooth muscle tissue or myometrium. Their growth is dependent on estrogen and progesterone levels. The underlying pathophysiology is uncertain.
Genetic changes – Many fibroids contain changes in genes that differ from those in normal uterine muscle cells. Hormones – Estrogen and progesterone, two hormones that stimulate development of the uterine lining during each menstrual cycle in preparation for pregnancy, appear to promote the growth of fibroids. Fibroids contain more estrogen and progesterone receptors than normal uterine muscle cells do. Fibroids tend to shrink after menopause due to a decrease in hormone production.
Other growth factors – Substances that help the body maintain tissues, such as insulin-like growth factor, may affect fibroid growth.
Extracellular matrix (ECM) – ECM is the material that makes cells stick together, like mortar between bricks. ECM is increased in fibroids and makes them fibrous. ECM also stores growth factors and causes biologic changes in the cells themselves.
Fibroids can grow
In the muscle wall of the uterus (myometrial)
Just under the surface of the uterine lining (submucosal)
Just under the outside lining of the uterus (subserosal)
On a long stalk on the outside the uterus or inside the uterus (pedunculated)
Fibroids are more common in the following groups of women
Black women: Fibroids are two to three times more common in black women – but the exact reason is not known.
Women who have never been pregnant.
Women whose mother or sister has had fibroids.
Women who are very overweight. But it’s not clear whether the extra weight itself is the cause.
Fibroids are less common in these women
Women who have had several children.
Women who have used birth control pills for several years.
It’s not clear whether there’s a link between your diet and the development of fibroids.
Symptoms of Uterine Fibroids
Many women who have fibroids don’t have any symptoms. In those that do, symptoms can be influenced by the location, size and number of fibroids.
In women who have symptoms, the most common signs and symptoms of uterine fibroids include
Heavy menstrual bleeding
Menstrual periods lasting more than a week
Pelvic pressure or pain
Heavy bleeding (which can be heavy enough to cause anemia) or painful periods
Feeling of fullness in the pelvic area (lower stomach area)
Enlargement of the lower abdomen
Frequent urination
Pain during sex
Bleeding between periods
Heavy bleeding during your period, sometimes with blood clots
Periods that may last longer than normal
Needing to urinate more often
Pelvic cramping or pain with periods
Feeling fullness or pressure in your lower belly
Pain during intercourse
Complications during pregnancy and labor, including a six-time greater risk of cesarean section
Reproductive problems, such as infertility, which is very rare
Frequent urination
Difficulty emptying the bladder
Constipation
Backache or leg pains
Rarely, a fibroid can cause acute pain when it outgrows its blood supply, and begins to die.
Fibroids are generally classified by their location. Intramural fibroids grow within the muscular uterine wall. Submucosal fibroids bulge into the uterine cavity. Subserosal fibroids project to the outside of the uterus.
Diagnosis of Uterine Fibroids
History and Physical
History and physical exam include a thorough menstrual history to determine the timing, quantity, and any potential aggravating factors for the abnormal bleeding. Common presenting symptoms include metrorrhagia, menorrhagia, or a combination of the two. Less common presenting symptoms include dyspareunia, pelvic pain, bowel problems, urinary symptoms, or signs and symptoms related to anemia. Most of the less frequent symptoms are a reflection of the mass effect produced by leiomyomas on surrounding structures. Patients may also be completely asymptomatic with an incidental finding of fibroids on imaging.
A speculum exam with a bimanual exam should be performed to rule out any vaginal or cervical pathology, as well as assess the size, and shape of the female reproductive organs. A large asymmetric uterus felt upon the exam is indicative of fibroids. Finally, consider evaluating for conjunctival pallor and thyroid pathology to identify potential secondary symptoms or causes of abnormal bleeding.
Laboratory studies
The initial evaluation should include a beta-human chorionic gonadotropin test to rule out pregnancy, CBC, TSH, and a prolactin level to evaluate for the non-structural causes in the differential. Include an endometrial biopsy for women over 35.
The International Federation of Gynecology and Obstetrics (FIGO) has developed a classification system that allows for the determination of the extent of invasion into the endometrial cavity. The FIGO scale ranges from 0 to 8, with the lower number indicating closer proximity to the endometrium[rx][rx].
If bleeding is the predominant symptom and there is a concern for anemia or other sequelae of recurrent blood loss, a complete blood count (CBC) is indicated. Further evaluation of blood work should include a thyroid-stimulating hormone level to rule out thyroid disease as the cause of abnormal bleeding if the index of suspicion is low for leiomyomata as the etiology [rx].
Radiologic studies
Transvaginal ultrasound – is the gold standard for imaging uterine fibroids. It has a sensitivity of around 90 to 99% for the detection of uterine fibroids. Ultrasound can improve with the use of saline-infused sonography, which helps increase the sensitivity for the detection of subserosal and intramural fibromas.[rx][rx] Fibroid appearance is as a firm, well-circumscribed, hypoechoic mass. On ultrasound, tend to have a variable amount of shadowing, and calcifications or necrosis may distort the echogenicity.[rx]
Ultrasound – Ultrasounds use sound waves to take a picture of your uterus. A technician will place a device either in your vagina or on your abdomen to get the images. Then your doctor can see if you have fibroids and where and how large they are.
Lab tests – Your doctor may want you to have blood tests to help figure out why you have fibroids. Your complete blood count (CBC) can help them decide whether you have anemia (low levels of red blood cells) or other bleeding disorders.
Magnetic resonance imaging (MRI) – If your doctor needs more information after you have an ultrasound, you may also have an MRI. MRIs show more detailed images of fibroids and can help doctors decide the best treatment. Your doctor may also suggest an MRI if you have a large uterus or are close to menopause.
Hysterosonography – In this test, a technician pushes saline into your uterine cavity to make it larger. This helps them see fibroids that are growing into your uterus (submucosal fibroids) and the lining of your uterus. This is useful if you’re trying to get pregnant or have heavy periods.
Hysterosalpingography – If your doctor needs to see if your fallopian tubes are blocked, you might have a hysterosalpingography. Your doctor uses dye to highlight your uterus and fallopian tubes on an X-ray to help see these areas better.
Hysteroscopy – is where the physician uses a hysteroscope to visualize the inside of the uterus. This imaging modality allows for better visualization of fibroids inside the uterine cavity. This method allows for the direct removal of intrauterine growths during the procedure.
Electric Magnetic Resonance Imaging MRI – has the benefit of providing a better picture of the number, size, vascular supply, and boundaries of the fibroids as they relate to the pelvis. Nevertheless, it is unnecessary for a routine diagnosis when fibroids are suspected. It has not been shown to differentiate leiomyosarcoma from leiomyoma.[rx]
Hysterosalpingography – is a special X-ray test. It may detect abnormal changes in the size and shape of the uterus and fallopian tubes.
Sonohysterography – is a test in which fluid is put into the uterus through the cervix. Ultrasonography is then used to show the inside of the uterus. The fluid provides a clear picture of the uterine lining.
Laparoscopy – uses a slender device (the laparoscope) to help your health care professional see the inside of the abdomen. It is inserted through a small cut just below or through the navel. Fibroids on the outside of the uterus can be seen with the laparoscope.
Treatment of Uterine Fibroids
While deciding on treatment options for uterine fibroids, the patient’s age, presenting symptoms, and desire for fertility preservation all merit consideration. The locations and size of the fibroids will both determine the available treatment options.[rx] Management options can be broken down into three categories starting at surveillance with progression to medical management or surgical therapy with increasing severity of symptoms.
Surveillance – This is the preferred method in women with asymptomatic fibroids. The current recommendations do not require serial imaging when following these patients.[rx] Most fibroids do not require treatment unless they are causing symptoms. After menopause, fibroids shrink, and it is unusual for them to cause problems.
Symptomatic uterine fibroids can be treated by
medication to control symptoms (i.e., symptomatic management)
medication aimed at shrinking tumors
ultrasound fibroid destruction
myomectomy or radiofrequency ablation
hysterectomy
uterine artery embolization
In those who have symptoms, uterine artery embolization and surgical options have similar outcomes with respect to satisfaction.[rx]
Medical Management
Primarily revolves around decreasing the severity of bleeding and pain symptoms.
Gonadotropin-releasing hormone (GnRH) agonists. Medications called GnRH agonists treat fibroids by blocking the production of estrogen and progesterone, putting you into a temporary menopause-like state. As a result, menstruation stops, fibroids shrink and anemia often improves. GnRH agonists include leuprolide (Lupron, Eligard, others), goserelin (Zoladex) and triptorelin (Trelstar, Triptodur Kit). Many women have significant hot flashes while using GnRH agonists. GnRH agonists typically are used for no more than three to six months because symptoms return when the medication is stopped and long-term use can cause loss of bone. Your doctor may prescribe a GnRH agonist to shrink the size of your fibroids before a planned surgery or to help transition you to menopause.
Progestin-releasing intrauterine device (IUD). A progestin-releasing IUD can relieve heavy bleeding caused by fibroids. A progestin-releasing IUD provides symptom relief only and doesn’t shrink fibroids or make them disappear. It also prevents pregnancy.
Tranexamic acid (Lysteda, Cyklokapron). This nonhormonal medication is taken to ease heavy menstrual periods. It’s taken only on heavy bleeding days. Tranexamic acid improves blood clotting and is used to reduce heavy menstrual bleeding and to minimize postoperative blood loss. Tranexamic acid is a derivative of the amino acid, lysine. This medication is a reversible inhibitor of lysine receptor sites on plasminogen that, when bound, prevent fibrin degradation and functionally stabilize clot formation [rx].
Selective estrogen receptor modulators – bind to estrogen receptors to mimic or block estrogen activity, and have differential effects across tissue types (e.g., bone, brain, liver). Tamoxifen was introduced to block estrogen action in the treatment of breast cancer, but has estrogen–like effects on the uterus. Raloxifene has estrogen-like effects on bone, but anti-estrogen effects in the breast and uterus. It is used to treat osteoporosis and prevent breast cancer, and reduce fibroid size.
Hormonal contraceptives – This treatment group includes oral contraceptive pills (OCP) and the levonorgestrel intrauterine device(IUD). OCPs are common options in the management of abnormal uterine bleeding related to symptomatic fibroids. However, there is only limited data showing their effectiveness in uterine fibroids, and larger randomized controlled trials are necessary.[rx][rx][rx] The levonorgestrel IUD is currently the recommended hormonal therapy for symptomatic fibroids due to the lack of systemic effects and low side effect profile.[rx] Caution should is necessary when treating fibroids that distort the intrauterine cavity as they can lead to a higher rate of expulsion.
GnRH Agonist (leuprolide) – This method works by acting on the pituitary gland to decrease gonadal hormone production, thus decreasing the hormone-stimulated growth of the fibroid. A study by Friedman et al. showed a decrease in uterine size by 45% at 24 weeks of treatment on a GnRH agonist with a return to pretreatment size 24 weeks after cessation.[rx] Long-term therapy with a GnRH agonist has also been shown to result in statistically significant bone loss. Because of this and its relatively short-term effect, the American College of Obstetricians and Gynecologists (ACOG) has recommended that it’s use be limited to 6 months or less.[rx][rx][rx] Leuprolide is most effective when used as a pre-surgical therapy for symptomatic fibroids.[rx]
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) – Anti-inflammatories have been shown to decrease prostaglandin levels, which are elevated in women with heavy menstrual bleeding and are responsible for the painful cramping experienced in menstruation. They have not been shown to decrease the size of the fibroids.[rx]
Levonorgestrel intrauterine devices – are effective in limiting menstrual blood flow and improving other symptoms. Side effects are typically few as the levonorgestrel (a progestin) is released in low concentration locally.[rx] While most levongestrel-IUD studies concentrated on treatment of women without fibroids a few reported good results specifically for women with fibroids including a substantial regression of fibroids.[rx][rx]
Cabergoline – in a moderate and well-tolerated dose has been shown in two studies to shrink fibroids effectively. The mechanism of action responsible for how cabergoline shrinks fibroids is unclear.[rx]
Ulipristal acetate – is a synthetic selective progesterone receptor modulator (SPRM) that has tentative evidence to support its use for presurgical treatment of fibroids with low side-effects.[rx] Long-term UPA-treated fibroids have shown volume reduction of about 70%.[rx] In some cases UPA alone is used to relieve symptoms without surgery.[rx]
Danazol – is an effective treatment to shrink fibroids and control symptoms. Its use is limited by unpleasant side effects. Mechanism of action is thought to be antiestrogenic effects. Recent experience indicates that safety and side effect profile can be improved by more cautious dosing.[rx]
Progesterone antagonists – such as mifepristone have been tested, there is evidence that it relieves some symptoms and improves quality of life but because of adverse histological changes that have been observed in several trials it can not be currently recommended outside of research setting.[rx][rx] Fibroid growth has recurred after antiprogestin treatment was stopped.[rx]
Aromatase inhibitors – have been used experimentally to reduce fibroids. The effect is believed to be due partially by lowering systemic estrogen levels and partially by inhibiting locally overexpressed aromatase in fibroids.[rx] However, fibroid growth has recurred after treatment was stopped.[rx] Experience from experimental aromatase inhibitor treatment of endometriosis indicates that aromatase inhibitors might be particularly useful in combination with a progestogenic ovulation inhibitor.
Other potential medical therapies include aromatase inhibitors, and selective estrogen receptor modulators (SERM), such as raloxifene or tamoxifen. There is little evidence supporting the use of these medications in the treatment for symptomatic uterine fibroids.[rx] Tranexamic acid has been approved for the treatment of abnormal and heavy uterine bleeding but has not been approved or shown to decrease the disease burden in uterine fibroids.[rx][rx]
Surgical Therapy
Endometrial Ablation – It offers an alternative to surgery in patients whose primary complaint is heavy or abnormal bleeding. There is a larger risk of a failed procedure with submucosal fibroids because they cause disruption of the uterine cavity and can prevent proper cauterization of the entire endometrium.
Uterine Artery Embolization – A minimally invasive approach for those who wish to preserve fertility. This technique works by decreasing the total blood supply to the uterus, thereby decreasing the flow to the fibroids and minimizing bleeding symptoms. The procedure has been shown effective in controlling menorrhagia. However, according to De La Cruz et al., only limited studies show the effects on fertility preservation with this technique. [rx]
Myomectomy – An invasive surgical option for those who desire fertility preservation. There is no large randomized controlled trial showing that myomectomy can improve fertility for patients.[rx][rx] Furthermore, the outcome is highly dependent on the location and size of the fibroid.[rx][rx] Nevertheless, it can be an effective treatment option in those wishing to avoid hysterectomy.
Hysterectomy – Hysterectomy was the classical method of treating fibroids. Although it is now recommended only as last option, fibroids are still the leading cause of hysterectomies in the US.
Endometrial ablation – Endometrial ablation can be used if the fibroids are only within the uterus and not intramural and relatively small. High failure and recurrence rates are expected in the presence of larger or intramural fibroids.
There are three types of myomectomy
In a hysteroscopic myomectomy (also called transcervical resection) – the fibroid can be removed by either the use of a resectoscope, an endoscopic instrument inserted through the vagina and cervix that can use high-frequency electrical energy to cut tissue, or a similar device.
A laparoscopic – myomectomy is done through a small incision near the navel. The physician uses a laparoscope and surgical instruments to remove the fibroids. Studies have suggested that laparoscopic myomectomy leads to lower morbidity rates and faster recovery than does laparotomic myomectomy.[53]
A laparotomic – myomectomy (also known as an open or abdominal myomectomy) is the most invasive surgical procedure to remove fibroids. The physician makes an incision in the abdominal wall and removes the fibroids from the uterus. Laparoscopic myomectomy has less pain and shorter time in hospital than open surgery.[rx]
Other procedures
Radiofrequency ablation is a minimally invasive treatments for fibroids.[rx] In this technique the fibroid is shrunk by inserting a needle-like device into the fibroid through the abdomen and heating it with radio-frequency (RF) electrical energy to cause necrosis of cells. The treatment is a potential option for women who have fibroids, have completed child-bearing and want to avoid a hysterectomy.
MRI guided focused ultrasound surgery – This treatment option utilizes MRI and ultrasound waves to focus on the fibroid, resulting in cauterization. As a relatively new treatment, there is not enough clinical evidence to support its long term effectiveness at this time.
Hysterectomy – Remains the definitive treatment for fibroids.
Myolysis – A needle is inserted into the fibroids, usually guided by laparoscopy, and electric current or freezing is used to destroy the fibroids.
Uterine Fibroid Embolization (UFE), or Uterine Artery Embolization (UAE) – A thin tube is thread into the blood vessels that supply blood to the fibroid. Then, tiny plastic or gel particles are injected into the blood vessels. This blocks the blood supply to the fibroid, causing it to shrink. UFE can be an outpatient or inpatient procedure. Complications, including early menopause, are uncommon but can occur. Studies suggest fibroids are not likely to grow back after UFE, but more long-term research is needed. Not all fibroids can be treated with UFE. The best candidates for UFE are women who:
Have fibroids that are causing heavy bleeding
Have fibroids that are causing pain or pressing on the bladder or rectum
Don’t want to have a hysterectomy
Don’t want to have children in the future
Noninvasive procedure
MRI-guided focused ultrasound surgery (FUS) is:
A noninvasive treatment option – for uterine fibroids that preserves your uterus, requires no incision and is done on an outpatient basis.
Performed while you’re inside an MRI scanner – equipped with a high-energy ultrasound transducer for treatment. The images give your doctor the precise location of the uterine fibroids. When the location of the fibroid is targeted, the ultrasound transducer focuses sound waves (sonications) into the fibroid to heat and destroy small areas of fibroid tissue.
Newer technology – so researchers are learning more about the long-term safety and effectiveness. But so far data collected show that FUS for uterine fibroids is safe and effective.
Minimally invasive procedures
Certain procedures can destroy uterine fibroids without actually removing them through surgery. They include:
Uterine artery embolization – Small particles (embolic agents) are injected into the arteries supplying the uterus, cutting off blood flow to fibroids, causing them to shrink and die. This technique can be effective in shrinking fibroids and relieving the symptoms they cause. Complications may occur if the blood supply to your ovaries or other organs is compromised. However, research shows that complications are similar to surgical fibroid treatments and the risk of transfusion is substantially reduced.
Radiofrequency ablation – In this procedure, radiofrequency energy destroys uterine fibroids and shrinks the blood vessels that feed them. This can be done during a laparoscopic or transcervical procedure. A similar procedure called cryomyolysis freezes the fibroids. With laparoscopic radiofrequency ablation, also called Lap-RFA, your doctor makes two small incisions in the abdomen to insert a slim viewing instrument (laparoscope) with a camera at the tip. Using the laparoscopic camera and a laparoscopic ultrasound tool, your doctor locates fibroids to be treated. After locating a fibroid, your doctor uses a specialized device to deploy several small needles into the fibroid. The needles heat up the fibroid tissue, destroying it. The destroyed fibroid immediately changes consistency, for instance from being hard like a golf ball to being soft like a marshmallow. During the next three to 12 months, the fibroid continues to shrink, improving symptoms. Because there’s no cutting of uterine tissue, doctors consider Lap-RFA a less invasive alternative to hysterectomy and myomectomy. Most women who have the procedure get back to regular activities after 5 to 7 days of recovery. The transcervical — or through the cervix — approach to radiofrequency ablation also uses ultrasound guidance to locate fibroids.
Laparoscopic or robotic myomectomy – In a myomectomy, your surgeon removes the fibroids, leaving the uterus in place. If the fibroids are few in number, you and your doctor may opt for a laparoscopic or robotic procedure, which uses slender instruments inserted through small incisions in your abdomen to remove the fibroids from your uterus. Larger fibroids can be removed through smaller incisions by breaking them into pieces (morcellation), which can be done inside a surgical bag, or by extending one incision to remove the fibroids.
Hysteroscopic myomectomy – This procedure may be an option if the fibroids are contained inside the uterus (submucosal). Your surgeon accesses and removes fibroids using instruments inserted through your vagina and cervix into your uterus.
Endometrial ablation – This treatment, performed with a specialized instrument inserted into your uterus, uses heat, microwave energy, hot water or electric current to destroy the lining of your uterus, either ending menstruation or reducing your menstrual flow. Typically, endometrial ablation is effective in stopping abnormal bleeding. Submucosal fibroids can be removed at the time of hysteroscopy for endometrial ablation, but this doesn’t affect fibroids outside the interior lining of the uterus. Women aren’t likely to get pregnant following endometrial ablation, but birth control is needed to prevent a pregnancy from developing in a fallopian tube (ectopic pregnancy).
Abdominal myomectomy – If you have multiple fibroids, very large fibroids or very deep fibroids, your doctor may use an open abdominal surgical procedure to remove the fibroids. Many women who are told that hysterectomy is their only option can have an abdominal myomectomy instead. However, scarring after surgery can affect future fertility.
Hysterectomy – This surgery — the removal of the uterus — remains the only proven permanent solution for uterine fibroids. But hysterectomy is major surgery. Hysterectomy ends your ability to bear children. If you also elect to have your ovaries removed, the surgery brings on menopause and the question of whether you’ll take hormone replacement therapy. Most women with uterine fibroids may be able to choose to keep their ovaries.
Morcellation during fibroid removal
Morcellation — a process of breaking fibroids into smaller pieces — may increase the risk of spreading cancer if a previously undiagnosed cancerous mass undergoes morcellation during myomectomy. There are several ways to reduce that risk, such as evaluating risk factors before surgery, morcellating the fibroid in a bag or expanding an incision to avoid morcellation.
All myomectomies – carry the risk of cutting into an undiagnosed cancer, but younger, premenopausal women generally have a lower risk of undiagnosed cancer than do older women.
Also, complications during open surgery are more common than the chance of spreading an undiagnosed cancer in a fibroid during a minimally invasive procedure. If your doctor is planning to use morcellation, discuss your individual risks before treatment.
The Food and Drug Administration (FDA) advises against the use of a device to morcellate the tissue (power morcellator) for most women having fibroids removed through myomectomy or hysterectomy. In particular, the FDA recommends that women who are approaching menopause or who have reached menopause avoid power morcellation. Older women in or entering menopause may have a higher cancer risk, and women who are no longer concerned about preserving their fertility have additional treatment options for fibroids.
What if I become pregnant and have fibroids?
Women who have fibroids are more likely to have problems during pregnancy and delivery. This doesn’t mean there will be problems. Most women with fibroids have normal pregnancies. The most common problems seen in women with fibroids are:
Cesarean section – The risk of needing a c-section is six times greater for women with fibroids.
Baby is breech – The baby is not positioned well for vaginal delivery.
Labor fails to progress
Placental abruption – The placenta breaks away from the wall of the uterus before delivery. When this happens, the fetus does not get enough oxygen.
Preterm delivery
Talk to your obstetrician if you have fibroids and become pregnant. All obstetricians have experience dealing with fibroids and pregnancy. Most women who have fibroids and become pregnant do not need to see an OB who deals with high-risk pregnancies.
Possible Complications
Complications of fibroids include
Severe pain or very heavy bleeding that needs emergency surgery.
Twisting of the fibroid – This can cause blocked blood vessels that feed the tumor. You may need surgery if this happens.
Anemia (not having enough red blood cells) from heavy bleeding.
Urinary tract infections – If the fibroid presses on the bladder, it can be hard to empty your bladder completely.
Infertility, in rare cases.
If you are pregnant, there’s a small risk that fibroids may cause complications
You may deliver your baby early because there is not enough room in your womb.
If the fibroid blocks the birth canal or puts the baby in a dangerous position, you may need to have a cesarean section (C-section).
You may have heavy bleeding right after giving birth.
Treatment of Tuberculous Spondylitis – Causes, Symptoms, /Tuberculous Spondylitis also is known as Pott disease, refers to vertebral body osteomyelitis and intervertebral diskitis from tuberculosis (TB). The spine is the most frequent location of musculoskeletal tuberculosis, and commonly related symptoms are back pain and lower limb weakness/paraplegia.
Spinal tuberculosis is a destructive form of tuberculosis. It accounts for approximately half of all cases of musculoskeletal tuberculosis. Spinal tuberculosis is more common in children and young adults. The incidence of spinal tuberculosis is increasing in developed nations. Genetic susceptibility to spinal tuberculosis has recently been demonstrated. Characteristically, there is the destruction of the intervertebral disk space and the adjacent vertebral bodies, the collapse of the spinal elements, and anterior wedging leading to kyphosis and gibbus formation. The thoracic region of the vertebral column is most frequently affected. The formation of a ‘cold’ abscess around the lesion is another characteristic feature.
Scrotal tuberculosis (testes, epididymis, seminal vesicles, vas deferens)
Tuberculous pelvic inflammatory disease (female)
tuberculosis of the Fallopian tube
Skeletal Tuberculosis
Tuberculosis of spine (Pott’s disease)
Tuberculous osteomyelitis
Tuberculous dactylitis (spina ventosa)
Tuberculous arthropathy
Phemister triad
Shoulder tuberculous arthropathy
Tuberculosis of tendon sheath and bursae
Latent TB – In this condition, you have a TB infection, but the bacteria remain in your body in an inactive state and cause no symptoms. Latent TB, also called inactive TB or TB infection, isn’t contagious. It can turn into active TB, so treatment is important for the person with latent TB and to help control the spread of TB. An estimated 2 billion people have latent TB.
Active TB – This condition makes you sick and can spread to others. It can occur in the first few weeks after infection with the TB bacteria, or it might occur years later.
Causes Of Tuberculous Spondylitis
Early infection
begins in the metaphysics of the vertebral body
spreads under the anterior longitudinal ligament and leads to
contiguous multilevel involvement
skip lesion or non-contiguous segments (15%)
paraspinal abscess formation (50%) usually anterior and can be quite large (much more common in TB than pyogenic infections)
initially does not involve the disc space (distinguishes from pyogenic osteomyelitis, but can be misdiagnosed as a neoplastic lesion)
Chronic infection
Severe kyphosis
mean deformity in nonoperative cases is 15° in 5% of patients, the deformity is >60°
infection is often diagnosed late, there is often much more severe kyphosis in granulomatous spinal infections compared to pyogenic infections
in adults kyphosis stays static after healing of disease
in children, kyphosis progresses in 40% of cases because of a growth spurt
Various types of vertebral involvement in spinal tuberculosis
Type of involvement
Mechanisms of involvement
Radiological appearances
Paradiskal
Spread of disease via the arteries
Involves adjacent margins of two consecutive vertebrae. The intervening disk space is reduced
Central
Spread of infection along Batson’s plexus of veins
Involves central portion of a single vertebra; proximal and distal disk spaces intact
Anterior marginal
Abscess extension beneath the anterior longitudinal ligament and the periosteum
Begins as a destructive lesion in one of the anterior margins of the body of a vertebra, minimally involving the disk space but sparing the vertebrae on either side
Skipped lesions
Spread of infection along Batson’s plexus of veins
circumferentially involvement of two noncontiguous vertebral levels without destruction of the adjacent vertebral bodies and intervertebral disks
Posterior
Spread via the posterior external venous plexus of vertebral veins or direct spread
Involves posterior arch without the involvement of the vertebral body
Synovial
Hematogenous spread through subsynovial vessels
Involves synovial membrane of atlantoaxial and atlanto-occipital joints
Symptoms Tuberculous Spondylitis
Symptoms and signs of tuberculosis
Cough—usually productive
Sputum—usually mucopurulent or purulent
Haemoptysis—not always a feature, volume variable
Breathlessness—gradual increase rather than sudden
Weight loss—gradual
Anorexia—variable
Fever—may be associated with night sweats
Malaise— the patient may realize only retrospectively when feeling better after treatment
Signs may include kyphosis (common) and/or a paravertebral swelling.
Affected patients tend to assume a protective, upright, stiff position.
If there is neural involvement there will be neurological signs.
A psoas abscess may present as a lump in the groin and resemble a hernia
A psoas abscess most often originates from a tuberculous abscess of the lumbar vertebra that tracks from the spine inside the sheath of the psoas muscle.
Other causes include an extension of renal sepsis and posterior perforation of the bowel.
There is a tender swelling below the inguinal ligament and they are usually apyrexial.
The condition may be confused with a femoral hernia or enlarged inguinal lymph nodes.
Diagnosis of Tuberculous Spondylitis
The clinical presentation of spinal tuberculosis is variable. The manifestations depend upon the duration of illness, the severity of the disease, site of the lesion, and the presence of associated complications including deformity and neurological deficit.[rx] Rest pain is pathognomonic, and rarely, radicular pain can be the main presenting symptom. Constitutional symptoms including weight or appetite loss, fever, and malaise/ fatigue are less commonly associated with extrapulmonary tuberculosis than pulmonary disease.[rx][rx]
Cold Abscess
These abscesses typically lack all the inflammatory signs obvious in abscesses; and hence the name. In the cervical spine, they can present in the retropharyngeal space, anterior or posterior triangles of the neck or axilla. In the thoracic spine, they may present as pre- or paravertebral abscesses; or over the chest wall. In the lumbar spine, they may track down along the psoas muscle, Petit’s triangle, Scarpa’s triangle, or the gluteal region.[rx]
Deformity
The clinical appearance of kyphotic deformity has been classified as knuckle (one vertebral involvement), gibbous (two vertebrae), and rounded kyphosis (more than three vertebrae). Owing to the greater involvement of the anterior spinal column in TB, the spinal column progressively develops a kyphotic orientation; especially in the thoracic and thoracolumbar spine.[rx] Jain et al. observed that kyphotic deformity greater than 60 degrees leads to significant disability and can potentially inflict neurological deficits.[rx]
Neurological Deficit
A neurological deficit can occur either at the active stage of the disease (secondary to compression from an abscess, inflammatory tissue, sequestrum, or spinal instability) or during the healed stage (usually secondary to mechanical traction over the internal gibbus or spinal instability).[rx][rx]
The initial compression in TB is secondary to vertebral body collapse, leading to anterior spinal tract involvement (exaggerated deep tendon reflexes and Babinski sign, further progression on to UMN-type motor deficit).
There were five stages of Pott paraplegia
Stage 1– Deficit only evident, based on the clinical examination by the clinician (ankle clonus, exaggerated deep tendon reflexes and Babinski or plantar extensor)
Stage 2– The patient has UMN-type of a motor deficit with spasticity, however, is still ambulatory. The anticipated motor score in tetraparesis is 60 to 100 and in paraparesis is between 80 and 100; sensory deficit involves the lateral column
Stage 3 – The patient is bedridden and spastic. The anticipated motor score in tetraparesis is 0 to 30, and in paraparesis is between 50 and 80; sensory deficit involves the lateral column
Stage 4 – The patient is bedridden with severe sensory loss/ pressure sores. The Anticipated motor score in tetraplegia is 0, and in paraplegia is between 50; sensory deficit involves posterior and lateral columns
Stage 5 – Similar to stage 4 +/- bladder/bowel involvement +/- flexor spasms/ flaccid tetraplegia/ paraplegia
Pediatric Spinal TB
Owing to the immaturity and increased flexibility of the spine in children, they are particularly prone to developing severe deformity progression. Such worsening of deformity in children can also occur after the disease has completely healed, and therefore the need to follow-up this patient population until skeletal maturity cannot be understated. Rajasekaran et al. described 4 signs of “spine at risk” in children, which include:
Retropulsion of the posterior aspect of the involved vertebra
Faceted subluxation (separation of facets on lateral radiographs)
Lateral translation of vertebrae (as observed on anteroposterior radiographs)
The toppling of one vertebra over the other (defined by a line along the anterior surface of caudal normal vertebra crossing the mid-point of the anterior surface of the cranial normal vertebral bone)
He proposed that children with two or more of these signs had posterior facet disruption and required surgical intervention. He also proposed a classification system for the progression of the deformity in children:
Type 1 – curves where curvature increases until growth cessation or skeletal maturity and surgical intervention was required
Type 2 – curves where the deformity decreased with growth progression
Type 3 – curves where there was minimal change in the deformity either during the active or healed phases of the disease[rx][rx]
Atypical Presentations
Some of the atypical clinical presentations may include intervertebral disc prolapse, isolated abscess without skeletal involvement, and pure intraspinal granulomas. Similarly, atypical radiological presentations may include skipping lesions, concentric vertebral collapse, circumferential vertebral involvement, isolated posterior arch involvement, ivory vertebra, isolated meningeal, neural or perineural involvement without any vertebral destruction and multifocal osseous lesions.[rx]
Imaging Modalities
Plain radiographs (15% sensitivity) – Early stages (less than 30% vertebral destruction) – not much role; later stages (beyond 30% vertebral destruction) – can present with disc space reduction, endplate rarefaction, vertebral body destruction, instability, and spinal deformity. The chest x-ray is also an important investigation, as up to thirds of these patients with spinal TB can also have a concomitant pulmonary disease.
The following are radiographic changes characteristic of spinal tuberculosis on plain radiography
Increased anterior wedging
Lytic destruction of the anterior portion of the vertebral body
Collapse of vertebral body
Reactive sclerosis on a progressive lytic process
Enlarged psoas shadow with or without calcification
Additional radiographic findings may include the following
Vertebral endplates are osteoporotic.
Intervertebral disks may be shrunk or destroyed.
Vertebral bodies show variable degrees of destruction.
Bone lesions may occur at more than one level.[rx]
Computed tomography (CT) (100% sensitivity) – Can help in the diagnosis at a much earlier stage than plain x-rays. The types of vertebral destructive lesions by CT in spinal TB include fragmentary, osteolytic, subperiosteal, and localized sclerosis. CT scans can also aid in image-guided biopsy for establishing the diagnosis.[rx][rx][rx]
Magnetic resonance imaging (MRI) (100% sensitivity and 80% specificity) – MRI is the most useful modality in the diagnosis of spinal TB. MRI best detects the extent of soft tissue enhancement, the location of the abscess, and spinal canal compromise. Gadolinium-enhanced MRI may provide additional information regarding the diagnosis. Screening sequences involving the whole spine can also help us in identifying non-contiguous vertebral involvement. MRI can also assess response to treatment.[rx][rx]
Nuclear imaging – 18 F-fluorodeoxyglucose (18F-FDG) labeled positron emission tomography (PET) scan provides evidence of functional activity in the involved tissues, based on the rationale that 18F-FDG is known to accumulate in macrophages at the inflammation site.[rx] These modalities cannot help in distinguishing tubercular infections from malignancy or other pyogenic infections.
Erythrocyte sedimentation rate (ESR) (60% to 90% sensitivity) – is usually more than 20 mm/hour in TB and decreases with treatment response. Nevertheless, it is not a very sensitive test. C-reactive protein (CRP) (71% sensitivity) is more specific than ESR.[rx]
Serological examination of IgG and IgM antibody levels against TB antigen – cannot effectively distinguish between active or healed disease; natural TB infection or vaccinated persons; and is raised in both active and chronic stages of infection.[rx][rx]
Acid-fast bacilli (AFB) staining (25% to 75% sensitivity and 99% specificity) – Using the Ziehl-Neelsen technique, tubercle bacillus presents with a bright red stain. At least, a concentration of 1 to 10 bacteria/ ml is necessary for detection.
TB culture – BACTEC radiometric culture assay (56% sensitivity and 100% specificity) takes 2 weeks of incubation time; while traditional culture on Lowenstein-Jenson (LJ) medium takes up to 6 weeks (47% sensitivity and 100% specificity).[rx] Growth on the LJ medium requires a concentration of at least 10 to 100 bacteria/ml.
Molecular testing and polymerase chain reaction (PCR) (75% sensitivity and 97% specificity)[rx] – This technique requires only a concentration of 1 to 10 bacilli/ ml. This is a very useful technique in paucibacillary, extrapulmonary TB infections.
Gene Xpert MTB/RIF– This is a fully automated test, which yields results within 90 minutes (82.9% sensitivity and 98% specificity). This test also helps in diagnosing resistance to rifampicin. WHO, in March 2017 recommended Xpert MTB/RIF Ultra (87.8% sensitivity and 94.8% specificity) as an investigation with good yield in pediatric and extrapulmonary patients.[rx][rx]
Histopathological evaluation – Characteristic findings including caseating necrosis, epithelioid cell granuloma, and Langhans giant cells can be found in 72% to 97% of patients.[rx][rx]
Tests to Detect Latent Tuberculosis
Mantoux test (40% to 55% sensitivity and 75% specificity)– Skin hypersensitivity test (purified protein derivative [PPD]) has been recommended as a low-cost test in developing nations; nevertheless, it is not an accurate test in endemic countries or immunodeficient patients.
Interferon-gamma release assay (50% to 65% sensitivity and 85% specificity) – Measuring interferons produced in response to tubercular antigens; not useful in endemic regions.[rx]
Clinico-Radiological Staging of Pott Spine (Prognostic Staging)[rx]
I – Predestructive stage; straightening of curvature, perivertebral muscle spasm, hyperemia on scintiscan (Duration fewer than 3 months)
II – Early destructive stage; disc space reduction and paradisiacal erosion, knuckle less than 10 degrees, MRI demonstrates marrow edema, and CT shows erosions or cavitations (Duration 2 to 4 months)
III – Mild angular kyphosis; 2 to 3 vertebrae involved and kyphosis 10 – 30 degrees (Duration 3 to 9 months)
IV – Moderate angular kyphosis; 2 to 3 vertebrae involved and kyphosis 30 to 60 degrees (Duration 6 to 24 months)
V – Severe angular kyphosis; more than 3 vertebrae involved and kyphosis greater than 60 degrees (Duration more than 24 months)
Treatment of Tuberculous Spondylitis
It is essential to classify spinal TB disease into a complicated and uncomplicated disease, based on their presentation. While uncomplicated spinal TB is essentially a medical disease; complicated TB spine patients need surgical intervention in addition to chemotherapy.[rx][rx]
Dosages of first-line antituberculosis drugs and major adverse effects
Drug
Dosage
Adverse effects
Daily
Twice or thrice weekly
Isoniazid
5 mg/kg oral (maximum 300 mg)
900 mg twice weekly
600 mg thrice weekly
Hepatitis, peripheral neuritis, drug-induced lupus, seizures, and hypersensitivity with rash and fever. Drug interactions with Dilantin and disulfiram
Rifampicin
10 mg/kg oral (maximum 600 mg)
10 mg/kg
600 mg twice weekly
600 mg thrice weekly
Orange body secretions, flu-like syndrome, hepatitis, thrombocytopenia, nausea, anorexia, diarrhea, renal failure, and multiple drug interactions
Pyrazinamide
25-30 mg/kg oral
30-35 mg/kg
Hyperuricemia, hepatitis, rash, nausea, and anorexia
Ethambutol
25 mg/kg initial 2 months, then 15 mg/kg oral
50 mg/kg twice weekly
30 mg/kg thrice weekly
Optic neuritis and gastrointestinal discomfort
Streptomycin
15 mg/kg intravenously or intramuscularly (maximum 1.0 g) 5 days a week
15 mg/kg (maximum 1.5 g) twice weekly or thrice weekly
Ototoxicity, vestibular dysfunction, nephrotoxicity, rash, and hypersensitivity reactions
First Line
All first-line anti-tuberculous drug names have a standard three-letter and a single-letter abbreviation:
ethambutol is EMB or E,
isoniazid is INH or H,
pyrazinamide is PZA or Z,
rifampicin is RMP or R,
streptomycin is SM or S.
First-line anti-tuberculous drug names are often remembered with the mnemonic “RIPE,” referring to the use of a rifamycin (like rifampin), isoniazid, pyrazinamide, and ethambutol. The US uses abbreviations and names that are not internationally recognized, rifampicin is called rifampin and abbreviated RIF; streptomycin is abbreviated STM. In the US only, streptomycin is no longer considered a first-line drug by ATS/IDSA/CDC because of high rates of resistance. The WHO have made no such recommendation.
Second Line
The second-line drugs (WHO groups 2, 3, and 4) are only used to treat the disease that is resistant to first-line therapy (i.e., for extensively drug-resistant tuberculosis (XDR-TB) or multidrug-resistant tuberculosis (MDR-TB)). A drug may be classed as second-line instead of first-line for one of three possible reasons: it may be less effective than the first-line drugs (e.g., p-aminosalicylic acid); or, it may have toxic side-effects (e.g., cycloserine); or it may be effective, but unavailable in many developing countries (e.g., fluoroquinolones):
aminoglycosides (WHO group 2): e.g., amikacin (AMK), kanamycin (KM);
polypeptides (WHO group 2): e.g., capreomycin, viomycin, enviomycin;
fluoroquinolones (WHO group 3): e.g., ciprofloxacin (CIP), levofloxacin, moxifloxacin (MXF);
thioamides (WHO group 4): e.g. ethionamide, prothionamide
cycloserine (WHO group 4)
terizidone (WHO group 5)
Third Line
Third-line drugs (WHO group 5) include drugs that may be useful, but have doubtful or unproven efficacy:
rifabutin
macrolides: e.g., clarithromycin (CLR);
linezolid (LZD);
thioacetazone (T);
thioridazine;
arginine;
vitamin D;
bedaquiline.
These drugs are listed here either because they are not very effective (e.g., clarithromycin) or because their efficacy has not been proven (e.g., linezolid, R207910). Rifabutin is effective but is not included on the WHO list because for most developing countries, it is impractically expensive.
Chemotherapy
The mainstay of treatment in spinal TB – is chemotherapy (antitubercular treatment [ATT]). Tubercle bacilli may exist as intracellular or extracellular forms or as dormant or rapidly multiplying forms.[rx] Therefore, multi-drug treatment is essential to attack the bacilli in various stages or forms and reduce the instance of drug resistance. The duration (6, 9, 12, or 18 months) and frequency (daily versus alternate-day regimen) of administration of ATT have been controversial.[rx]
WHO recommends 6 months of multidrug anti-tubercular therapy – including 2 months of four- or five-drug treatment (isoniazid, rifampicin, pyrazinamide, ethambutol, and/ or streptomycin) constituting the initiation” phase, followed by 4 months of “continuation” phase therapy with a two-drug regimen including isoniazid and rifampicin.
The American Thoracic Spine Society – recommends a regimen involving 9 months of treatment with the same drugs (“continuation” phase extending for a period of 7 months). The Canadian Thoracic Society recommends treatment for 9 to 12 months duration.[rx]
Other second-line anti-tubercular drugs including – kanamycin, capreomycin, pyrazinamide, amikacin, among others are typically indicated when there is resistance or poor tolerance to first-line medications. A recent meta-analysis has not demonstrated any difference between self-administered and directly observed treatment (directly observed therapy, short course); nevertheless WHO has continued to recommend DOTS therapy for optimum results.[rx][rx][rx]
Multidrug Resistance
MDR-TB is defined as TB infection resistant to INH and rifampicin. Extensively drug-resistant TB (XDR-TB) is defined as infection resistant to INH and rifampicin, along with resistance to a fluoroquinolone and at least one injectable second-line medication. Velayati et al. described the term “totally drug-resistant” TB, where the tubercular strain is resistant to all first- and second-line drugs.[rx][rx][rx]
Surgical Management
Traditionally, TB was treated by radical debridement through an anterior approach.[rx][rx] However, following successful outcomes with multidrug chemotherapy and Medical Research Council observations,[rx]. Introduced the concept of “middle path regimen” in the treatment of tuberculosis.[rx] This regimen recommended medical management in all patients, along with surgical management necessitated in the following situations:
Lack of response to chemotherapy
Recurrent disease
Severe neurological weakness
Static or progressive neuro deficit despite a course of ATT
Deformity
Debilitating pain
Instability
Anterior Approach
As TB spine involves the anterior vertebral structures predominantly, debridement through anterior approach and fusion has been traditionally used to manage the diseased tissues directly. Nevertheless, the anterior approach has been reported to be associated with serious complications including graft-related complications (subsidence, slippage, fracture, absorption among others), approach-related complications (respiratory compromise) and even mortality. An ideal indication for anterior surgery includes patients without any posterior vertebral structure involvement, in other words, no prevertebral disease.[rx][rx][rx]
Posterior Approach
In modern spine surgery, posterior approaches are more preferred in TB spondylitis in view of the following reasons[rx][rx][rx][rx][rx]
Ease and familiarity of the approach
Availability of more robust pedicle screw system
Less approach-related morbidity
Ability to perform circumferential decompression through a transpedicular approach
Ability to perform global reconstruction through transpedicular, transplacental, costotrans versectomy or intracavitary-extrapleural approaches
Combined (Anterior and Posterior) Approach
Typically, this approach should be reserved for severe destructive lesions with severe deformities or inherently unstable spines only, as it is associated with significant morbidities and complications. The approaches can be performed in single or more than one stage.[rx][rx]
Minimally Invasive Surgery
Recently, minimally invasive approaches including thoracoscopic debridement, minimally invasive fusion procedures and posterolateral endoscopic debridement have been demonstrated to provide an excellent outcome in TB spondylitis.[rx][rx][rx]
Surgery in Healed Tuberculosis
Surgery may be indicated in healed disease with instability or kyphotic deformity more than 60 degrees.[rx][rx] The decision to perform surgery in such cases should be made after taking into consideration multiple factors including age, associated comorbidities, the severity of the deformity, the location of the spine involved, number of involved levels, and the surgeon’s preference.
Anterior approach can be particularly difficult in thoracic and thoracolumbar levels at the apex of kyphosis. Posterior approaches are the most popular and include transpedicular decancellation, Ponte’s osteotomy, pedicle subtraction osteotomy/ closing wedge osteotomy, posterior vertebral column resection, and closing opening wedge osteotomy.[rx][rx] Combined anterior and posterior approaches may be required in more severe deformities, the disease involving two or three vertebrae or complex revision surgeries.[rx]
Differential Diagnosis
Radiological Differentials
Pyogenic and fungal infections
Neoplastic – Lytic benign, benign aggressive and malignant (primary tumors and spinal metastases): In general, spinal metastasis and primary spinal malignancies present with primary vertebral body involvement and disc space preservation as compared to TB and other infections. Tuberculosis also presents with soft tissue and perivertebral abscess, in comparison with malignant tumors.
Differentials Based on Pathological Appearance
Other pathologies involving granulomatous infections and clinically mimic TB include
Other pathologies – presenting with non-caseating granulomas include Sarcoidosis, Wegener’s granulomatosis, Crohn disease, and leprosy.
Poor Prognostic Factors in Pott Paraplegia
Level of disease (junctional vertebral levels) pan-vertebral involvement, long duration of neuro deficit, rapidity of progression of neuro deficit, the severity of deficit, nature of compression (abscess versus granuloma) and presence of spinal cord changes
Poor Prognosis for Deformity Progression
Age less than 10 years Kyphosis angle greater than 30 degrees, three or more vertebrae involved, greater than or equal to 1.5 vertebral body loss, pan-vertebral disease, and evidence of instability
Complications
Failure of treatment: Depends on the presentation (complicated versus uncomplicated), clinical and radiological prognostic factors, patient compliance to chemotherapy, stage of the disease, drug resistance and other patient-related factors (socio-economic factors, general health, nourishment among others)
Indications of Terbinafine/Terbinafine is a synthetic allylamine derivative with antifungal activity. Terbinafine exerts its effect through inhibition of squalene epoxidase, thereby blocking the biosynthesis of ergosterol, an important component of fungal cell membranes. As a result, this agent disrupts fungal cell membrane synthesis and inhibits fungal growth. Terbinafine is an Allylamine Antifungal. The chemical classification of terbinafine is Allylamine.
Terbinafine is an orally and topically active allylamine fungicidal agent which is used to treat superficial fungal infections of the skin and nails. Terbinafine has been clearly linked to rare instances of acute liver injury that can be severe and sometimes fatal.
Mechanism of Action of Terbinafine
Terbinafine is hypothesized to act by inhibiting squalene monooxygenase, thus blocking the biosynthesis of ergosterol, an essential component of fungal cell membranes. This inhibition also results in an accumulation of squalene, which is a substrate catalyzed to 2,3-oxy do squalene by squalene monooxygenase. The resultant high concentration of squalene and decreased amount of ergosterol are both thought to contribute to terbinafine’s antifungal activity.
Terbinafine hydrochloride (Lamisil) is a synthetic allylamine antifungal. It is highly lipophilic in nature and tends to accumulate in the skin, nails, and fatty tissues. Like other allylamines, terbinafine inhibits ergosterol synthesis by inhibiting the fungal squalene monooxygenase (squalene 2, 3-epoxidase), an enzyme that is part of the fungal cell wall synthesis pathway.
Indications of Terbinafine
For the treatment of dermatophyte infections of the toenail or fingernail caused by susceptible fungi. Also for the treatment of tinea capitis (scalp ringworm) and tinea corporis (body ringworm) or tinea cruris (jock itch).
Treatment of onychomycosis
Terbinafine hydrochloride is indicated to treat fungal skin and nail infections caused by Trichophyton species, Microsporum canis, Epidermophyton floccosum,[rx] and Tinea species.[rx] Terbinafine hydrochloride also treats yeast infections of the skin caused by Candida species and Malassezia furfur.12
This medication should not be used during pregnancy unless the benefits outweigh the risks. If you become pregnant while taking this medication, contact your doctor immediately.
Breast-feeding
This medication passes into breast milk. If you are a breast-feeding mother and are taking terbinafine, it may affect your baby. Women taking terbinafine tablets should not breast-feed. If you are using the cream or spray, talk to your doctor about whether you should continue breast-feeding. The safety and effectiveness of using this medication have not been established for children.
Food Diet Exercises To Get Bigger Arm Chest /Biceps Brachii Exercises that someone showing off their muscles, envisioning the person revealing popping biceps muscles. The muscles termed short head and long head makes up the biceps brachii. The biceps rest on the upper arm, starting their connection to the body on the scapula and running downward and inserting into the forearm, more specifically, the radius bone. You can do certain exercises to train your biceps muscles.
Food Diet Exercises To Get Bigger Arm Chest
Barbell Curls
Barbell biceps curls are an effective exercise to do to build up your biceps. Start with a barbell in both hands, holding it with a supine grip, palms facing out. Keep your feet shoulder-width apart and your knees soft. Slowly curl the barbell up toward your shoulders, hold it there for one second and then slowly bring it back down to the starting position.
Incline Dumbbell Hammer Curl
The incline bench position increases the stretch on the long head of the biceps muscle and also locks your body against the bench so you can’t cheat more weight during reps by rocking backward. An added benefit to hammers is that your wrist and elbow are less vulnerable to strain than during reps of other curls. Dumbbells allow the wrists to move freely, so most people adopt for a slight rotation of the wrist and forearm as they curl, which thickens the muscle group.
Incline Inner-Biceps Curl
The incline dumbbell curl is a regular dumbbell curl, only you are now sitting back on an incline. This allows your arm to hang, which stretches out your bicep, making it work harder. To begin the exercise, sit on an incline bench with your feet flat on the floor. Allow each arm to hang by your side and, one at a time, curl the dumbbell up. This exercise also stretches the long head of the biceps. The more horizontal the bench during your workout, the more the long head of the muscle will be stretched during reps.
These are awesome to add to your isolation workout because they truly isolate the biceps muscle!
Standing Concentration Dumbbell Curl
Concentration curls place the arm in front of the body with a bent elbow and a rotation in the shoulder. While this decreases recruitment of the long head, it potentially increases biceps thickness and peak by better recruitment of surrounding muscles during your workout.
With your free hand on your off leg to support your body weight, when you hit failure you can switch over to a hammer grip and burn out a few extra reps.
EZ-Bar Curl
A lot of people think the EZ-bar curl is the best all-around addition to your biceps workout. It engages both the short and long heads of the biceps muscle and for some people, it’s a lot more comfortable on the joints and forearms than a straight barbell!
Wide-Grip Standing Barbell Curl
This is definitely one of the more common ways to hit this muscle group. Taking a wider-than-normal grip will cause you to externally rotate at the shoulder, so your upper arm changes its position, prompting more involvement from the short head of the biceps muscle.
You can overload during your workout by using bands, chains, or a partner for forced reps, which you can’t do very well using only a dumbbell.
Zottman Curl
In this movement, you hold a dumbbell in each hand and have a palms-up (supinated) grip on the way up and a palms-down (pronated) grip as you lower the weight, so all of your elbow flexors get hit! Some of your elbow flexors act as supinators as well, so rotating the wrist and forearm during the curl instead of at the bottom will load up that function.
Regular-Grip Barbell Curl
The classic. If you did only this movement in your biceps workout, you would still come out ahead.
Of course, you can play around with your grip width, which may reduce the discomfort that some people experience with a barbell, as well as emphasize a different part of the biceps. A narrower grip will emphasize the long head of the muscle, while a wider grip will emphasize the short head of the muscle.
Dumbbells allow the wrists to move freely, so most people adopt for a slight rotation of the wrist and forearm as they curl, which thickens the muscle group.
Hammer Curl
The hammer will typically be our strongest curl during a biceps workout. This is because all of our elbow flexors are actively involved, and the forearm and wrist are in a power position. Doing this movement like a concentration curl or preacher curl (on a preacher bench) will minimize cheating and maximize muscle recruitment during the workout.
Overhead Cable Curl
This is a great way to practice your front double biceps pose as you train. You can do both cables at once, or alternate between arms!
For an alternative arm workout, check out this article and video for some sleeve-splitting exercises.
Hammer Curls
Hammer curls are a variation of the traditional bicep curl. This exercise is done with a set of dumbbells rather than a barbell. Take a dumbbell in each hand, and standing with your feet shoulder-width apart and knees soft, keep your arms down at your sides and palms facing your sides. Slowly curl the weights up to your shoulders, keeping your palms facing one another, hold for one second and then lower them back down.
Cable Curls
Having access to a cable machine allows you to target your biceps muscles without the use of free weights. Stand in front of the machine, set your desired weight and take a handle or the bar in each hand. Using the same arm motion as a barbell curl, pull the bar from your thighs toward your shoulders, and then slowly return it to the starting position.
Guidelines
The reps and sets you use for these exercises depend on your goals. If you are trying to hypertrophy your biceps muscles, work toward a higher weight with lower repetitions. If you are trying to get toned muscles, work with a lighter weight and higher sets and reps — for example, one to three sets of 10 to 15 repetition
Food that helps in biceps muscle building and
Food Diet Exercises To Get Bigger Arm Chest
Load Up on Carbohydrates
Carbs are an athlete’s main fuel. Your body changes them to glucose, a form of sugar, and stores it in your muscles as glycogen. When you exercise, your body changes glycogen into energy. If you exercise for under 90 minutes, you have enough glycogen in your muscles, even for high-intensity activities.
Get Enough Protein, But Not Too Much
Protein doesn’t provide a lot of fuel for energy. But you need it to maintain your muscles.
Know what you need – The average person needs 1.2 to 1.4 grams of protein per kilogram of body weight a day. That’s about 88 grams of protein for a 150-pound person. A strength athlete may need up to 1.7 grams per kilogram of body weight. That’s about 150 grams of protein for a 200-pound athlete.
Favor foods – Getting too much protein can put a strain on your kidneys. Instead of protein supplements, eat high-quality protein, such as lean meats, fish, poultry, nuts, beans, eggs, or milk.
Drink up – Milk is one of the best foods for recovery after an event because it provides a good balance of protein and carbohydrates,” Dubost says. Milk also has both casein and whey protein. The combination may be particularly helpful for athletes. Research shows that whey protein is absorbed quickly, which can help speed recovery immediately after an event. Casein is digested more slowly, helping to ensure long-term recovery of muscle after a grueling event.
Replace Lost Electrolytes
Sweating removes both fluids and electrolytes. Electrolytes help transmit nerve signals in your body. To replenish them, reach for sports drinks. If you’re also losing a lot of fluid as you sweat, dilute sports drinks with equal amounts of water to get the best balance of fluid and electrolytes.
Salmon
This oily fish is packed with lean, muscle-building protein and omega-3 fatty acids, which reduces the inflammation that can happen with continual athletic activity. It is also a natural artery cleanser, helping to prevent heart disease, which can affect even the most active people. Get creative and enjoy salmon in burgers, salads or pasta to get the recommended eight-ounce serving per week.
Beans/Legumes
Vegetarians and meat-eaters alike can get their fill of plant-based protein by eating beans and legumes. Black beans, pinto beans, kidney beans, lima beans… the varieties are endless! You can add them to a salad or cook them into a stew or chili. Unlike meat, beans and legumes don’t have saturated fat and contain fiber, which will help you feel fuller longer.
Pasta
Not all carbs are bad! In fact, they’re an important part of the athlete’s diet. While the body burns fat and protein, it must first convert them into carbohydrates, making the bodywork harder. Straight carbs act as a fuel for the active person. Keep in mind that pasta contains fiber, which can cause gastrointestinal stress, so don’t overdo it before a big event where you’ll be competing or playing. Whole grain pasta typically contains less sugar than white pasta, which can also help athletic performance.
Bananas
Bananas are a low-calorie, excellent source of natural electrolytes, which need to be replaced after a workout or sporting event. They’re also high in potassium, which makes them the perfect post-event snack. Eating one banana will help you regulate your fluid intake (since you’re drinking more water before, after and during physical exertion). It will also protect you from muscle spasms or cramps.
Cruciferous Vegetables
Dark, leafy greens such as spinach and kale, as well as broccoli, cauliflower and Brussel sprouts are rich in antioxidants, vitamins, and minerals to boost your athletic abilities. They also contain high levels of vitamins A, K and B6, and calcium and iron, all of which protect the body against inflammation. Iron also means more oxygen being supplied to working muscles. Kale contains carotenoids and flavonoids, two powerful antioxidants, and fiber, which helps lower cholesterol.
Nuts are high in protein and healthy fats, making them a mainstay in athletes’ diets. Eaten with carbs, they help level out your blood sugar and sustain the carbs over a longer period of time, rather than burning them off right away. They’re also easier to digest and don’t upset your stomach. Another plant-based protein, nuts are rich in fiber and antioxidants like vitamin E. The anti-inflammatory nutrients found in nuts makes them great for bone health, which is needed by every athlete. They also lower bad cholesterol, which is good for heart health.
Milk (Even Chocolate Milk!)
Milk is loaded with carbs and protein, which makes it a great post-workout drink for muscle recovery. The caffeine found in chocolate dilates the blood vessels, helping them to relax after a workout. Interestingly enough, when carbs and protein are consumed together, muscle tissues repair themselves more quickly than they do when consumed separately!
Hydrating Foods
Radishes, watermelon, bell peppers, spinach, celery, dates and oranges are just a handful of the refreshing foods you can eat to replenish your lost fluids. If you’re tired of downing water bottles (not that you shouldn’t), opt for one of these snacks to feel refreshed after exercising.
Sweet Potatoes
Sweet potatoes are rich in vitamins A and C, both antioxidants that remove free radicals from your body. They lower blood pressure, which is important for athletes to their heart health when participating in sports. They’re high in vitamin and mineral content and contain the levels of potassium, iron, manganese and copper athletes need for healthy muscles.
Oatmeal
Oatmeal is an excellent source of energy carbs for athletes and is high in fiber, helping you feel fuller, longer. It’s 100 percent whole grain, helping to lower your risk of heart disease. If you’re looking to gain weight, oatmeal is a delicious way to help you achieve your goal weight. Be sure to choose steel-cut oats as opposed to instant oats. The instant oats have a higher glycemic index, which will cause your insulin levels to spike, causing you to end up storing the carbs as fat.
Whey Protein
Whey protein contains the essential amino acids. Quickly absorbed by the body, it lacks fat and cholesterol, which makes it an ideal formula for athletes to consume. Whey contains the levels of protein and amino acids necessary to rebuild muscles and protects against muscle breakdown.
Flaxseed, Olive and Coconut Oil
The monounsaturated fats found in olive oil have anti-inflammatory properties, which athletes need when putting so much stress on their bodies. Flaxseed oil contains omega-3s, which is also anti-inflammatory, to help recover quickly with bumps and bruises. It also contains fiber and protein. Coconut oil is filled with medium-chain triglycerides (MCTs), which can help with your endurance during a grueling workout. The MCTs in coconut oil can also help with metabolism and energy from fat.
Cherries
An antioxidant-filled fruit, cherries aid in preventing muscle pain after running. It reduces inflammation, which is what causes such striking pain. Many athletes consume cherry juice as another way to lower exercise-based muscle damage, which can help reduce soreness.
Poor eating habits will eventually lead to poor performance. As you can see from the foods mentioned, athletes benefit most from foods high in protein, vitamins, and fiber to enhance their performance. Whether you’re a recreational or competitive athlete, your body needs the right nutrients to fuel itself during high-intensity activity. These foods provide the restorative, energy-boosting properties necessary to stay healthy while putting your body through exercise or other endurance activities.
What are the early signs of hepatitis B?/Hepatitis B Virus (HBV) infection is a major global health problem leading to severe liver diseases such as cirrhosis and hepatocellular carcinoma (HCC). HBV is a circular, partly double-stranded DNA virus with various serological markers: hepatitis B surface antigen (HBsAg) and anti-HBs, anti-HBc IgM and IgG, and hepatitis B e antigen (HBeAg) and anti-HBe. It is transmitted by the sexual, parenteral and vertical routes. One significant method to diminish the burden of this disease is the timely diagnosis of acute, chronic and occult cases of HBV. The first step of HBV diagnosis is achieved by using serological markers for detecting antigens and antibodies.
Hepatitis B is a liver infection caused by the hepatitis B virus (HBV). Hepatitis B is transmitted when blood, semen, or another body fluid from a person infected with the hepatitis B virus enters the body of someone who is not infected. This can happen through sexual contact; sharing needles, syringes, or other drug-injection equipment; or from mother to baby at birth. For some people, hepatitis B is an acute, or short-term, illness but for others, it can become a long-term, chronic infection. The risk for chronic infection is related to age at infection approximately 90% of infected infants become chronically infected, compared with 2%–6% of adults. Chronic hepatitis B can lead to serious health issues, like cirrhosis or liver cancer. The best way to prevent hepatitis B is by getting vaccinated.
Mechanisms of Hepatitis B
Hepatitis B virus primarily interferes with the functions of the liver by replicating in hepatocytes. A functional receptor is NTCP.[rx] There is evidence that the receptor in the closely related duck hepatitis B virus is carboxypeptidase D.[rx][rx] The virions bind to the host cell via the preS domain of the viral surface antigen and are subsequently internalized by endocytosis. HBV-preS-specific receptors are expressed primarily on hepatocytes; however, viral DNA and proteins have also been detected in extrahepatic sites, suggesting that cellular receptors for HBV may also exist on extrahepatic cells.[rx] During HBV infection, the host immune response causes both hepatocellular damage and viral clearance. Although the innate immune response does not play a significant role in these processes, the adaptive immune response, in particular, virus-specific cytotoxic T lymphocytes(CTLs), contributes to most of the liver injury associated with HBV infection. CTLs eliminate HBV infection by killing infected cells and producing antiviral cytokines, which are then used to purge HBV from viable hepatocytes.[rx] Although liver damage is initiated and mediated by the CTLs, antigen-nonspecific inflammatory cells can worsen CTL-induced immunopathology, and platelets activated at the site of infection may facilitate the accumulation of CTLs in the liver.[rx]
Types of Hepatitis B
Hepatitis B vaccine can prevent hepatitis B. Hepatitis B is a liver disease that can cause mild illness lasting a few weeks, or it can lead to a serious, lifelong illness.
Acute hepatitis B infection is a short-term illness that can lead to fever, fatigue, loss of appetite, nausea, vomiting, jaundice (yellow skin or eyes, dark urine, clay-colored bowel movements), and pain in the muscles, joints, and stomach.
Chronic hepatitis B infection is a long-term illness that occurs when the hepatitis B virus remains in a person’s body. Most people who go on to develop chronic hepatitis B do not have symptoms, but it is still very serious and can lead to liver damage (cirrhosis), liver cancer, and death. Chronically-infected people can spread hepatitis B virus to others, even if they do not feel or look sick themselves.
Transmitted of Hepatitis B
Hepatitis B is spread when blood, semen, or other body fluid infected with the hepatitis B virus enters the body of a person who is not infected. People can become infected through:
Birth (if a mother has hepatitis B, her baby can become infected)
Sharing items such as razors or toothbrushes with an infected person
Contact with the blood or open sores of an infected person
Sex with an infected partner
Sharing needles, syringes, or other drug-injection equipment
Exposure to blood from needlesticks or other sharp instruments
Most people who are vaccinated with hepatitis B vaccine are immune for life
Who Is At Risk For HBV Infection?
The following populations are at increased risk of becoming infected with HBV
Infants born to infected mothers
Sex partners of infected persons
Men who have sex with men
Injection drug users
Household contacts or sexual partners of known persons with chronic HBV infection
Health care and public safety workers at risk for occupational exposure to blood or blood-contaminated body fluids, and
Hemodialysis patients
Who should be screened for HBV?
Screening should include testing to three HBV screening zero markers (HBsAg, antibody to HBsAg [anti-HBs], and antibody to hepatitis B core antigen [anti-HBc]) so that persons can be classified into the appropriate hepatitis B category and properly recommended to receive vaccination, counseling, and linkage to care and treatment[rx].
Persons born in countries with 2% or higher HBV prevalence
Men who have sex with men
Persons who inject drugs
HIV-positive persons
Household and sexual contacts of HBV-infected persons
Persons requiring immunosuppressive therapy
Persons with end-stage renal disease (including hemodialysis patients)
Blood and tissue donors
Persons with elevated alanine aminotransferase levels (>19 IU/L for women and >30 IU/L for men)
Pregnant women (HBsAg only is recommended)
Infants born to HBV-infected mothers (HBsAg and anti-HBs are only recommended)
Causes of Hepatitis B
Transmission – Transmission of hepatitis B virus results from exposure to infectious blood or body fluids containing blood. It is 50 to 100 times more infectious than the human immunodeficiency virus (HIV).[rx] Possible forms of transmission include sexual contact,[rx] blood transfusions and transfusion with other human blood products,[rx] re-use of contaminated needles and syringes,[rx] and vertical transmission from mother to child (MTCT) during childbirth. Without intervention, a mother who is positive for HBsAg has a 20% risk of passing the infection to her offspring at the time of birth.
Sexual contact – You may get hepatitis B if you have unprotected sex with someone who is infected. The virus can pass to you if the person’s blood, saliva, semen or vaginal secretions enter your body.
Sharing of needles – HBV easily spreads through needles and syringes contaminated with infected blood. Sharing IV drug paraphernalia puts you at high risk of hepatitis B.
Accidental needle sticks – Hepatitis B is a concern for health care workers and anyone else who comes in contact with human blood.
Mother to child – Pregnant women infected with HBV can pass the virus to their babies during childbirth. However, the newborn can be vaccinated to avoid getting infected in almost all cases. Talk to your doctor about being tested for hepatitis B if you are pregnant or want to become pregnant.
Symptoms of Hepatitis B
Newly acquired (acute) HBV infections only cause symptoms some of the time. The presence of signs and symptoms varies by age. Most children under age 5 years and newly infected immunosuppressed adults are generally asymptomatic, whereas 30%–50% of persons aged ≥5 years have signs and symptoms [rx].
Some acute HBV infections will resolve on their own, but some will develop into a chronic infection. Most persons with chronic HBV infection are asymptomatic and have no evidence of liver disease. However, some persons may develop chronic hepatitis (elevation of AST/ALT), cirrhosis, or hepatocellular carcinoma (a type of liver cancer).
Diagnosis of Hepatitis B
Laboratory diagnosis of hepatitis B infection focuses on the detection of the hepatitis B surface antigen HBsAg. WHO recommends that all blood donations be tested for hepatitis B to ensure blood safety and avoid accidental transmission to people who receive blood products.
Acute HBV infection – is characterized by the presence of HBsAg and immunoglobulin M (IgM) antibody to the core antigen, HBcAg. During the initial phase of infection, patients are also seropositive for hepatitis B e antigen (HBeAg). HBeAg is usually a marker of high levels of replication of the virus. The presence of HBeAg indicates that the blood and body fluids of the infected individual are highly infectious.
Chronic infection – is characterized by the persistence of HBsAg for at least 6 months (with or without concurrent HBeAg). Persistence of HBsAg is the principal marker of risk for developing chronic liver disease and liver cancer (hepatocellular carcinoma) later in life.
Blood tests – Blood tests can detect signs of the hepatitis B virus in your body and tell your doctor whether it’s acute or chronic. A simple blood test can also determine if you’re immune to the condition.
Liver ultrasound – A special ultrasound called transient elastography can show the amount of liver damage.
Liver biopsy – Your doctor might remove a small sample of your liver for testing (liver biopsy) to check for liver damage. During this test, your doctor inserts a thin needle through your skin and into your liver and removes a tissue sample for laboratory analysis.
Hepatitis B Serology
Hepatitis B surface antigen (HBsAg) – The presence of HBsAg, a protein on the surface of HBV, indicates that the person is infectious. It can be detected in high levels in serum during acute or chronic HBV infection. The body normally produces antibodies to HBsAg as part of the normal immune response to infection. HBsAg is the antigen used to make the hepatitis B vaccine.
Hepatitis B surface antibody (anti-HBs) – The presence of anti-HBs is generally interpreted as indicating recovery and immunity from HBV infection. Anti-HBs also develops in a person who has been successfully vaccinated against hepatitis B.
Total hepatitis B core antibody (anti-HBc) – Appears at the onset of symptoms in acute hepatitis B and persists for life. The presence of anti-HBc indicates previous or ongoing infection with HBV in an undefined time frame.
IgM antibody to hepatitis B core antigen (IgM anti-HBc) – Positivity indicates recent infection with HBV (≤6 months). Its presence indicates acute infection.
Hepatitis B e antigen (HBeAg) – The presence indicates that the virus is replicating and the infected person has high levels of HBV. HBeAg is a secreted product of the nucleocapsid gene of HBV that is found in serum during acute and chronic hepatitis B.
Hepatitis B e antibody (HBeAb or anti-HBe) – Spontaneous conversion from e antigen to e antibody (a change known as seroconversion) is a predictor of long-term clearance of HBV in patients undergoing antiviral therapy and indicates lower levels of HBV. HBeAg is produced by the immune system temporarily during acute HBV infection or consistently during or after a burst in viral replication.
HBV DNA – HBV DNA concentration correlates with levels of HBV virus particles. HBV DNA is measured as IU/mL or copies/ml by the polymerase chain reaction assay. HBV viral DNA can be detected and quantified in serum. There are several commercial assays that can detect and quantify HBV DNA, some to limits as low as 10 IU/ml.
The following table provides interpretations for different combinations and results of hepatitis B serologic markers.
[stextbox id=’custom’]
Antibody and Antigen Biomarkers for Hepatitis B Infection [rx]
Clinical state
HBsAg
Total Anti-HBs
Total anti-HBc
Action
Table. Antibody and Antigen Biomarkers for Hepatitis B Infection
Chronic infection
Positive
Negative
Positive
Link to hepatitis B-directed care
Acute
Positive
Negative
Positive
(IgM anti-HBc)
Link to hepatitis B-directed care
Resolved infection
Negative
Positive
Positive
Counseling, reassurance
Immune (immunization)
Negative
Positive
Negative
Reassurance
Susceptible
(never infected and no evidence of immunization)
Negative
Negative
Negative
Vaccinate
*Isolated core antibody
Negative
Negative
Positive
Depends on the situation
False-positive: Repeat testing required
[/stextbox]
Past infection – No action needed
Occult HBV infection – Needs to be known if the patient ever becomes immunosuppressed or given chemotherapy or treated with antiviral therapy for hepatitis C virus infection. Consider monitoring HBV DNA.
Passive transfer to an infant born to HBsAg-positive mother No specific action needed.
Hepatitis B surface antigen (HBsAg) – A protein on the surface of HBV; it can be detected in high levels in serum during acute or chronic HBV infection. The presence of HBsAg indicates that the person is infectious. The body normally produces antibodies to HBsAg as part of the normal immune response to infection. HBsAg is the antigen used to make the hepatitis B vaccine.
Hepatitis B surface antibody (anti-HBs) – The presence of anti-HBs is generally interpreted as indicating recovery and immunity from HBV infection. Anti-HBs also develops in a person who has been successfully vaccinated against hepatitis B.
Total hepatitis B core antibody (anti-HBc) – Appears at the onset of symptoms in acute hepatitis B and persists for life. The presence of anti-HBc indicates previous or ongoing infection with HBV in an undefined time frame.
IgM antibody to hepatitis B core antigen (IgM anti-HBc) – Positivity indicates recent infection with HBV (≤6 months). Its presence indicates acute infection.
[stextbox id=’info’]
Hepatitis B Virus Serological and Virological Markers
HBsAg
HBV infection, both acute and chronic
HBeAg
High-level HBV replication and infectivity; marker for treatment response
HBV DNA
Level of HBV replication; primary virologic marker for treatment response
Anti-HBc (IgM)
Acute HBV infection; could be seen in flare of chronic hepatitis B
Anti-HBc (IgG)
Recovered or chronic HBV infection
Anti-HBs
Recovered HBV infection or marker of HBV vaccination; immunity to HBV infection (titer can be measured to assess vaccine efficacy)
Anti-HBe
Low-level HBV replication and infectivity; marker for treatment response
HBV, hepatitis B virus; RFLP, restriction fragment length polymorphism; PCR, polymerase chain reaction.
[/stextbox]
Treatment of Hepatitis B
In this guideline we cover the following:
Information needs of people with chronic hepatitis B and their carers
Where children, young people, and adults with chronic hepatitis B should be assessed
Assessment of liver disease, including the use of non-invasive tests and genotype testing
Criteria for offering antiviral treatment
The efficacy, safety, and cost-effectiveness of currently available treatments
Selection of first-line therapy
Management of treatment failure or drug resistance
Whether there is a role for combination therapy
When it is possible to stop treatment
Managing the care of pregnant and breastfeeding women and prevention of vertical transmission
Prophylactic treatment during immunosuppressive therapy
Monitoring for treatment response, the severity of fibrosis and development of HCC.
If the infection is active for longer than 6 months, he’ll tell you that you have chronic active hepatitis B. He may prescribe some of these medications to treat it:
Get plenty of rest
Take over-the-counter painkillers, such as paracetamol or ibuprofen, for tummy pain
Maintain a cool, well-ventilated environment, wear loose clothing, and avoid hot baths or showers if itching is a problem
Take medication such as metoclopramide, to stop you feeling sick, and chlorphenamine to reduce itching – your doctor can give you a prescription for these if necessary
Antiviral medications – Several antiviral medications — including entecavir (Baraclude), tenofovir (Viread), lamivudine (Epivir), adefovir (Hepsera) and telbivudine (Tyzeka) — can help fight the virus and slow its ability to damage your liver. These drugs are taken by mouth. Talk to your doctor about which medication might be right for you.
Entecavir (Baraclude ) – This is the newest drug for hepatitis B. You can take it as a liquid or tablet.
Tenofovir (Viread) – This drug comes as a powder or tablet. If you take it, your doctor will check often to make sure it doesn’t hurt your kidneys.
Lamivudine (3tc, , Epivir A/F, Epivir HBV, Heptovir) – It comes as a liquid or tablet you take once a day. Most people don’t have a problem with it. But if you take it for a long time, the virus might stop responding to the drug.
Adefovir dipivoxil ( Hepsera ) – This drug, which you take as a tablet, works well for people who don’t respond to lamivudine. High doses can cause kidney problems.
Interferon alfa ( Intron A, Roferon A, Sylatron) – This medicine boosts your immune system. You take it as a shot for at least 6 months. It doesn’t cure the disease. It treats liver inflammation. Long-acting interferon, peginterferon alfa2a (Pegasys, Pegasys Proclick) can also help. This drug can make you feel bad all over or depressed, and it can and zap your appetite. It also lowers your white blood cell count, which makes it harder to fight off infection.
Interferon injections – Interferon alfa-2b (Intron A) is a man-made version of a substance produced by the body to fight infection. It’s used mainly for young people with hepatitis B who wish to avoid long-term treatment or women who might want to get pregnant within a few years, after completing a finite course of therapy. Interferon should not be used during pregnancy. Side effects may include nausea, vomiting, difficulty breathing and depression.
[stextbox id=’grey’]
Indications for treatment and recommended strategy for chronic hepatitis B
AASLD 2009
EASL 2012
APASL 2012
HBeAg positive hepatitis
Indications for treatment
HBV DNA > 20000 IU/mL and ALT > 2 × ULN
HBV DNA > 2000 IU/mL and ALT > ULN
HBV DNA > 20000 IU/mL and ALT > 2 × ULN
Biopsy recommended
HBV DNA >20000 IU/mL and ALT 1-2 × UNL especially if age > 40 yr or family history of HCC
HBV DNA > 2000 IU/mL and Age > 30 yr or family history of HCC
HBV DNA > 20000 IU/mL or high normal or minimally raised ALT and age > 40 yr
Preferred drugs for naïve patients
PEG-IFN, ETV, TDF
PEG-IFN, ETV, TDF
IFN-based therapy, ETV, TDF
HBeAg negative hepatitis
Indications for treatment
HBV DNA >20000 IU/mL2 and ALT > 2 × ULN
HBV DNA > 2000 IU/mL and ALT > ULN
HBV DNA > 2000 IU/mL and ALT > 2 × ULN
Biopsy recommended
HBV DNA >2000 IU/mL and ALT 1- > 2 × UNL
Unmentioned
HBV DNA > 2000 IU/mL or high normal or minimally raised ALT and age > 40 yr
Preferred drugs for naïve patients
PEG-IFN, ETV, TDF
PEG-IFN, ETV, TDF
IFN-based therapy, ETV, TDF
Liver cirrhosis
Indication for treatment
Compensated: HBV DNA >2000 IU/mL; consider treating HBV < 2000 IU/mL if ALT > UNL Decompensated: any detectable HBV DNA
Any detectable HBV DNA
Compensated: HBV DNA > 2000 IU/mL Decompensated: any detectable HBV DNA
ETV, TDF (consider also IFN-based therapy if compensated LC and ALT < 5 × UNL)
Consider treatment if moderate to severe inflammation or significant fibrosis is shown on liver biopsy; noninvasive methods may be useful in EASL and APASL guidelines; Treatment may be considered in patients with HBV DNA 2000-20000 IU/mL, particularly if they are older or have cirrhosis.AASLD: The American Association for the Study of the Liver Diseases; EASL: European Association for the Study of the Liver; APASL: The Asian Pacific Association for the Study of the Liver; ULN: The upper limit of normal; PEG-IFN: Pegylated interferon; ETV: Entecavir; TDF: Tenofovir; IFN: Interferon; LAM: Lamivudine; LDT: Telbivudine; ADV: Adefovir.
[/stextbox]
Pegylated interferon – The most important advantage of PEG-IFN use in clinical practice is finite duration of treatment. In addition, the antiviral response is more durable with higher HBeAg seroconversion and HBsAg seroconversion after treatment compared with NAs. However, frequent adverse events, low degree of compliance due to injection-related problems[rx]
LAM – Although LAM is the first approved oral antiviral agent against HBV, the emergence of drug-resistant tyrosine-methionine-aspartate-aspartate (YMDD) mutants has been a major hindrance to long-term LAM treatment. The frequency of genotypic resistance was reported to be as high as 60%-70% after 5 years of treatment[rx,rx]. Therefore, it is no longer recommended as the first-line treatment for CHB patients in the current international guidelines, but it may be recommended in combination therapies with ADV or TDF for liver cirrhosis[rx].
ADV – ADV is the acyclic analog of dAMP with therapeutic efficacy against both the wild-type and YMDD mutant HBV. Two previous major phases III clinical studies showed that ADV demonstrated significant virological and biochemical responses, and histological improvement in HBeAg-positive and -negative naïve CHB patients[rx,rx]. ADV has also demonstrated virological improvement in patients with LAM-resistant HBV, regardless if used alone or in combination with ongoing LAM therapy[rx,rx]. Although ADV has been widely accepted as advantageous over LAM in terms of the development of genotypic resistance, it is not recommended as the first-line drug for HBeAg-positive and -negative CHB patients in the current international guidelines as it is less effective than other NAs such as ETV and TDF in antiviral activity[rx], and possesses a significant risk of nephrotoxicity[rx].
Entecavir – ETV is a deoxyguanosine nucleoside analog that has highly potent antiviral activity and a high genetic barrier to resistance against HBV. In long-term follow-up studies of ETV for the treatment of chronic HBV infection for up to 5 years, it was very safe and well-tolerated and showed high rates of HBV-DNA suppression, ALT normalization and serological responses in both HBeAg-positive and -negative CHB patients[rx,rx].
LdT – LdT is the L-nucleoside analog of L-deoxythymidine and displays potent antiviral activity comparable to that of ETV. HBV-DNA was undetectable (< 300 copies/mL) in 60% of HBeAg-positive CHB patients and 88% of HBeAg-negative CHB patients treated with LdT[rx]. In addition, ALT normalization was found in 77% and 74%, respectively[rx]. HBeAg seroconversion in HBeAg-positive CHB patients was observed in 23% and 30% at year 2 in two studies[rx,rx].
Clevudine – Clevudine is a pyrimidine analogue with potent and sustained antiviral activity against HBV. Previous clinical studies conducted in Korea have demonstrated that clevudine showed potent antiviral activity during therapy and induced a sustained post-treatment antiviral effect for 6 mo after a 12- and 24-wk treatment period[rx,rx].
TDF – TDF is an acyclic nucleotide inhibitor and has been proved to be a highly powerful antiviral agent against HBV without resistance to TDF during the treatment period[rx,rx]. In a three-year follow-up study, levels of HBV-DNA below 400 copies/mL at week 144 was observed in 72% of HBeAg-positive and in 87% of HBeAg-negative patients treated with TDF monotherapy[rx].
[stextbox id=’custom’]
Recommended treatment for drug resistance
Resistance to
AASLD 2009
EASL 2012
APASL 2012
LAM
Add ADV or TDF Switch to Truvada1
Switch to TDF (add ADV if TDF is not available)
Add ADV Switch to TDF Switch to IFN-based therapy
LDT
Add ADV or TDF Switch to Truvada1
Switch to or add TDF (add ADV if TDF is not available)
Add ADV Switch to TDF
ADV
Add LAM Switch to Truvada1Switch to or add ETV
Switch to ETV or TDF Switch to TDF and add a nucleoside analogue if the patient has been treated with LAM
Add LAM, LDT or ETV Switch to TDF Switch to ETV plus TDF, if the patient has been treated with LAM or LDT
ETV
Switch to TDF or Truvada1
Switch to or add TDF (add ADV if TDF is not available)
Add TDF or ADV
TDF
Unmentioned
Add ETV, LDT, LAM or emtricitabine Switch to ETV if the patient has not been treated with LAM in the past
Unmentioned
MDR
Unmentioned
Combination of a nucleoside and a nucleotide
Unmentioned
Truvada is a combination pill containing emtricitabine 200 mg and tenofovir 300 mg. LAM: Lamivudine; LDT: Telbivudine; ADV: Adefovir; ETV: Entecavir; TDF:Tenofovir; MDR: Multidrug resistance; IFN: Interferon.
[/stextbox]
Lamivudine resistance – Although LAM is safe and tolerated in compensated and decompensated liver diseases due to HBV, it has limited clinical use in CHB patients due to a high rate of drug resistance. Previously, ADV alone or in combination with ongoing LAM therapy was used for the treatment of rtM204V/I mutant by LAM[rx]. However, the rate of ADV resistance after direct switching from LAM to ADV in LAM-resistant patients was as high as 18% at year 1 and 65.6% at year 5, respectively[rx,rx].
Adefovir resistance – ADV resistance is caused by rtN236T mutation in the D domain and rtA181T/V in the B domain of the HBV polymerase gene. A long-term follow-up study of ADV monotherapy for 48 wk in HBeAg-negative CHB showed ADV resistance in 0% at year 1 and 29% of patients at year 5[rx]
Liver transplant – If your liver has been severely damaged, a liver transplant may be an option. During a liver transplant, the surgeon removes your damaged liver and replaces it with a healthy liver. Most transplanted livers come from deceased donors, though a small number come from living donors who donate a portion of their livers.
FDA Approved Treatment of Hepatitis B
[stextbox id=’info’]
Approved Treatments for Hepatitis B
Brand Name
Generic
Names
Manufacturer Name
Indication
Baraclude
entecavir
Bristol-Myers Squibb
chronic hepatitis B virus infection with evidence of active viral replication
Epivir HBV
lamivudine
GlaxoSmithKline
chronic hepatitis B associated with hepatitis B viral replication and active liver inflammation
Hepsera
adefovir dipivoxil
Gilead Sciences
chronic hepatitis B in patients 12 years of age
Intron A
interferon-alpha-2b
Schering
chronic hepatitis B in patients 1 year of age or older with compensated liver disease
Pegasys
pegylated interferon
Roche
treatment of adult patients with HBeAg positive and HBeAg negative chronic hepatitis B who have compensated liver disease and evidence of viral replication and liver inflammation
Tyzeka
telbivudine
Novartis
chronic hepatitis B in adult patients with evidence of viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease
Vemlidy
tenofovir alafenamide
Gilead Sciences
indicated for the treatment of chronic hepatitis B virus infection in adults with compensated liver disease
Viread
tenofovir
Gilead Sciences
chronic hepatitis B in adults.
For additional information on approved treatments for Hepatitis, you can search drugs@fda[rx] orDailyMed[rx].
Approved Treatments for Hepatitis C
Brand Name
Generic Names
Manufacturer Name
Indication
CoPegus
ribavirin
Roche
use in combination with Pegasys or with Roferon for the treatment of adults with chronic hepatitis C virus infection who have compensated liver disease and have not been previously treated with interferon-alpha
Daklinza
daclatasvir
Bristol-Myers Squibb Company
an NS5A replication complex inhibitor is indicated for use with sofosbuvir for the treatment of patients with chronic HCV genotype 3 infection. Sustained virologic response (SVR) rates are reduced in HCV genotype 3-infected patients with cirrhosis receiving this regimen. The recommended dosage of DAKLINZA is 60 mg, taken orally, once daily in combination with sofosbuvir for 12 weeks. DAKLINZA may be taken with or without food. The optimal duration of DAKLINZA and sofosbuvir for patients with cirrhosis has not been established.
Epclusa
sofosbuvir, velpatasvir
Gilead
a fixed-dose combination of sofosbuvir, a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor, and velpatasvir, an HCV NS5A inhibitor, and is indicated for the treatment of adult patients with chronic HCV genotype 1, 2, 3, 4, 5, or 6 infection -without cirrhosis or with compensated cirrhosis or with decompensated cirrhosis for use in combination with ribavirin
Harvoni
ledipasvir/sofosbuvir
Gilead
a fixed-dose combination of ledipasvir, a hepatitis C virus (HCV) NS5A inhibitor, and sofosbuvir, an HCV nucleotide analog NS5B polymerase inhibitor, and is indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection in adults.
Incivek
telaprevir
Vertex Pharmaceuticals
in combination with peginterferon alfa and ribavirin, for the treatment of genotype 1 chronic hepatitis C (CHC) in adult patients with compensated liver disease, including cirrhosis, who are treatment-naïve or who have been previously treated with interferon-based treatment, including prior null responders, partial responders, and relapsers
Infergen
interferon aphacon-1
Three Rivers Pharma
treatment of chronic hepatitis C in patients 18 years of age or older with compensated liver disease who have anti-HCV serum antibodies and/or HCV RNA
Intron A
interferon alpha-2b
Schering
treatment of chronic hepatitis C in patients 18 years of age or older with compensated liver disease who have a history of blood or blood-product exposure and/or are HCV antibody positive
Mavyret
glecaprevir and pibrentasvir
AbbieVie
is indicated for the treatment of adult patients with chronic HCV genotype 1, 2, 3, 4, 5 6 infections without cirrhosis
with compensated cirrhosis (Child-Pugh A).
indicated for the treatment of adult patients with HCV genotype 1 infection, who previously have been treated with a regimen containing an HCV NS5A inhibitor or an NS3/4A protease inhibitor (PI), but not both
Olysio
simeprevir
Janssen Pharmaceuticals
for the treatment of chronic hepatitis C (CHC) genotype 1 infection as a component of a combination antiviral treatment regimen
Pegasys
pegylated interferon
Roche
treatment of adults with chronic hepatitis C virus infection who have compensated liver disease and have not been previously treated with interferon-alpha
Pegintron
pegylated interferon-alpha-2b
Schering
in combination with rebetol, is indicated for the treatment of chronic hepatitis C in patients 3 years of age and older with compensated liver disease use alone for the treatment of chronic hepatitis C in patients with compensated liver disease previously untreated with interferon-alpha and who are at least 18 years of age and intolerant to ribavirin
Rebetol
ribavirin
Schering
use in combination with Pegintron for treatment of chronic hepatitis C in patients with compensated liver disease who have not been previously treated with interferon-alpha and are at least 18 years of age
Roferon
interferon-alpha-2a
Roche
treatment of chronic hepatitis C in patients 18 years of age or older
Sovaldi
sofosbuvir
Gilead Sciences
for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen
Technivie
ombitasvir, paritaprevir and ritonavir
AbbVie Inc.
a fixed-dose combination containing ombitasvir, a hepatitis C virus NS5A inhibitor; paritaprevir, a hepatitis C virus NS3/4A protease inhibitor; and ritonavir, a CYP3A inhibitor. The product is indicated in combination with ribavirin for the treatment of patients with genotype 4 chronic hepatitis C virus (HCV) infection without cirrhosis.
Victrelis
boceprevir
Merck & Co.
treatment of chronic hepatitis C (CHC) genotype 1 infection, in combination with peginterferon alfa and ribavirin, in adult patients (18 years of age and older) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy.
Viekira Pak
ombitasvir, paritaprevir and ritonavir tablets co-packaged with dasabuvir tablets
AbbVie Inc.
use with or without ribavirin for the treatment of patients with genotype 1 chronic hepatitis C virus (HCV) infection including those with compensated cirrhosis
Vosevi
treatment approved for patients who have been previously treated with the direct-acting antiviral drug sofosbuvir, or other drugs for HCV that inhibit a protein called NS5A
Zepatier
elbasvir, grazoprevir
Merck Sharp Dohme
a fixed-dose combination product containing elbasvir, a hepatitis C virus (HCV) NS5A inhibitor, and grazoprevir, an HCV NS3/4A protease inhibitor, and is indicated with or without ribavirin for treatment of chronic HCV genotypes 1 or 4 infections in adults
[/stextbox]
Hepatitis B Vaccination
Who should be vaccinated against hepatitis B?
The Advisory Committee on Immunization Practices (ACIP) recommends that the following people receive hepatitis B vaccination:
All infants
Unvaccinated children aged <19 years
People at risk for infection by sexual exposure
Sex partners of hepatitis B surface antigen (HBsAg)–positive persons
Sexually active people who are not in a long-term, mutually monogamous relationship (e.g., persons with more than one sex partner during the previous 6 months)
People seeking evaluation or treatment for a sexually transmitted infection
Men who have sex with men
People at risk for infection by percutaneous or mucosal exposure to blood
Current or recent injection-drug users
Household contacts of people who are HBsAg-positive
Residents and staff of facilities for developmentally disabled people
Health care and public safety personnel with reasonably anticipated risk for exposure to blood or blood-contaminated body fluids
Hemodialysis patients and predialysis, peritoneal dialysis, and home dialysis patients
People with diabetes aged 19–59 years; persons with diabetes aged ≥60 years at the discretion of the treating clinician
International travelers to countries with high or intermediate levels of endemic hepatitis B virus (HBV) infection (HBsAg prevalence of ≥2%)
People with hepatitis C virus infection
People with chronic liver disease (including, but not limited to, persons with cirrhosis, fatty liver disease, alcoholic liver disease, autoimmune hepatitis, and an alanine aminotransferase [ALT] or aspartate aminotransferase [AST] level greater than twice the upper limit of normal)
People with HIV infection
People who are incarcerated
All other people seeking protection from HBV infection
Is hepatitis B vaccination recommended in certain settings?
Yes. In certain health care, evaluation, or treatment settings, a high proportion of clients have known risk factors for HBV infection. The Advisory Committee on Immunization Practices recommends universal vaccination of adults who receive care in those settings, including:
Sexually transmitted disease treatment facilities
HIV testing and treatment facilities
Facilities providing drug-abuse treatment and prevention services
Health care settings targeting services to injection drug users
Correctional facilities
Health care settings targeting services to men who have sex with men
Chronic hemodialysis facilities and end-stage renal disease programs
Institutions and nonresidential day care facilities for developmentally disabled persons
What are the hepatitis B vaccines licensed for use in the United States?
Three single-antigen vaccines and three combination vaccines are currently licensed in the United States.
Single-antigen hepatitis B vaccines
ENGERIX-B
RECOMBIVAX HB
HEPLISAV-B™
Combination vaccines
PEDIARIX – Combined hepatitis B, diphtheria, tetanus, acellular pertussis (DTaP), and inactivated poliovirus (IPV) vaccine. It cannot be administered before age 6 weeks or after age 7 years.
TWINRIX – Combined Hepatitis A and hepatitis B vaccine. Recommended for persons aged ≥18 years who are at increased risk for both Hepatitis A virus and HBV infections.
Who Get The Hepatitis B vaccine
Hepatitis B vaccine is usually given as 2, 3, or 4 shots.
Infants – should get their first dose of the hepatitis B vaccine at birth and will usually complete the series at 6 months of age (sometimes it will take longer than 6 months to complete the series).
Children and adolescents who are – younger than 19 years of age who have not yet gotten the vaccine should also be vaccinated.
Hepatitis B vaccine is also recommended for certain unvaccinated adults
People whose sex partners have hepatitis B
Sexually active persons who are not in a long-term monogamous relationship
Persons seeking evaluation or treatment for a sexually transmitted disease
Men who have sexual contact with other men
People who share needles, syringes, or other drug-injection equipment
People who have household contact with someone infected with the hepatitis B virus
Health care and public safety workers at risk for exposure to blood or body fluids
Residents and staff of facilities for developmentally disabled persons
Persons in correctional facilities
Victims of sexual assault or abuse
Travelers to regions with increased rates of hepatitis B
People with chronic liver disease, kidney disease, HIV infection, infection with hepatitis C, or diabetes
Anyone who wants to be protected from hepatitis B
Hepatitis B vaccine may be given at the same time as other vaccines.
Tell your vaccine provider if the person getting the vaccine
Has had an allergic reaction after a previous dose of hepatitis B vaccine, or has any severe, life-threatening allergies.
In some cases, your health care provider may decide to postpone hepatitis B vaccination to a future visit. People with minor illnesses, such as a cold, maybe vaccinated. People who are moderately or severely ill should usually wait until they recover before getting the hepatitis B vaccine. Risks of a vaccine reaction Soreness where the shot is given or fever can happen after the hepatitis B vaccine.
People sometimes faint after medical procedures, including vaccination. Tell your provider if you feel dizzy or have vision changes or ringing in the ears. As with any medicine, there is a very remote chance of a vaccine causing a severe allergic reaction, another serious injury, or death.
Prevention of Hepatitis B
Babies born to hepatitis B-infected mothers
Close family and sexual partners of someone with hepatitis B
People traveling to a part of the world where hepatitis B is widespread, such as sub-Saharan Africa, east and southeast Asia, and the Pacific Islands
Families adopting or fostering children from high-risk countries
People who inject drugs or have a sexual partner who injects drugs
People who change their sexual partner frequently
Men who have sex with men
Male and female sex workers
People who work somewhere that places them at risk of contact with blood or body fluids, such as nurses, prison staff, doctors, dentists and laboratory staff
People with chronic liver disease
people with chronic kidney disease
Prisoners
People who receive regular blood or blood products, and their carers
The hepatitis B vaccine is the mainstay of hepatitis B prevention. WHO recommends that all infants receive the hepatitis B vaccine as soon as possible after birth, preferably within 24 hours. Routine infant immunization against hepatitis B has increased globally with an estimated coverage (third dose) of 84% in 2017. The low prevalence of chronic HBV infection in children under 5 years of age, estimated at 1.3% in 2015, can be attributed to the widespread use of hepatitis B vaccine. In most cases, 1 of the following 2 options is considered appropriate:
a 3-dose schedule of hepatitis B vaccine, with the first dose (monovalent) given at birth and the second and third doses (monovalent or combined vaccine) given at the same time as the first and third doses of diphtheria, pertussis (whooping cough), and tetanus – (DTP vaccine); or
a 4-dose schedule, where a monovalent birth dose is followed by 3 monovalent or combined vaccine doses, usually given with other routine infant vaccines.
The complete vaccine series induces protective antibody levels in more than 95% of infants, children and young adults. Protection lasts at least 20 years and is probably lifelong. Thus, the WHO does not recommend booster vaccinations for persons who have completed the 3 dose vaccination schedule.
All children and adolescents younger than 18 years and not previously vaccinated should receive the vaccine if they live in countries where there is low or intermediate endemicity. In those settings, it is possible that more people in high-risk groups may acquire the infection and they should also be vaccinated. This includes:
people who frequently require blood or blood products, dialysis patients and recipients of solid organ transplantations;
people in prisons;
people who inject drugs;
household and sexual contacts of people with chronic HBV infection;
people with multiple sexual partners;
healthcare workers and others who may be exposed to blood and blood products through their work; and
travelers who have not completed their HBV series, who should be offered the vaccine before leaving for endemic areas.
The vaccine has an excellent record of safety and effectiveness. Since 1982, over 1 billion doses of hepatitis B vaccine have been used worldwide. In many countries where 8–15% of children used to become chronically infected with the hepatitis B virus, vaccination has reduced the rate of chronic infection to less than 1% among immunized children.
In addition to infant vaccination, the implementation of blood safety strategies, including quality-assured screening of all donated blood and blood components used for transfusion, can prevent transmission of HBV. Worldwide, in 2013, 97% of blood donations were screened and quality assured, but gaps persist. Safe injection practices, eliminating unnecessary and unsafe injections, can be effective strategies to protect against HBV transmission. Unsafe injections decreased from 39% in 2000 to 5% in 2010 worldwide. Furthermore, safer sex practices, including minimizing the number of partners and using barrier protective measures (condoms), also protect against transmission.
WHO Response For Hepatitis B
In March 2015, WHO launched its first “Guidelines for the prevention, care and treatment of persons living with chronic hepatitis B infection”. The recommendations include:
promote the use of simple, non-invasive diagnostic tests to assess the stage of liver disease and eligibility for treatment;
prioritize treatment for those with the most advanced liver disease and at greatest risk of mortality; and
recommend the preferred use of the nucleos(t)ide analogs with a high barrier to drug resistance (tenofovir and entecavir, and entecavir in children aged 2–11 years) for first- and second-line treatment.
These guidelines also recommend lifelong treatment for those with cirrhosis and those with high HBV DNA and evidence of liver inflammation, and regular monitoring for those on treatment, as well as those not yet on treatment for disease progression, indications for treatment and early detection of liver cancer.
In May 2016, the World Health Assembly adopted the first “Global health sector strategy on viral hepatitis, 2016-2020”. The strategy highlights the critical role of universal health coverage and sets targets that align with those of the Sustainable Development Goals.
The strategy has the vision to eliminate viral hepatitis as a public health problem. This is encapsulated in the global targets to reduce new viral hepatitis infections by 90% and reduce deaths due to viral hepatitis by 65% by 2030. Actions to be taken by countries and the WHO Secretariat to reach these targets are outlined in the strategy.
To support countries in achieving the global hepatitis elimination targets under the Sustainable Development Agenda 2030, WHO is working to:
raise awareness, promote partnerships and mobilize resources;
formulate evidence-based policy and data for action;
prevent transmission; and
scale-up screening, care and treatment services.
WHO recently published the “Progress report on HIV, viral hepatitis and sexually transmitted infections, 2019”, outlining its progress towards elimination. The report sets out global statistics on viral hepatitis B and C, the rates of new infections, the prevalence of chronic infections and mortality caused by these 2 high-burden viruses, and coverage of key interventions, all current at the end of 2016 and 2017.
Since 2011, together with national governments, partners and civil society, WHO has organized annual World Hepatitis Day campaigns (as 1 of its 9 flagship annual health campaigns) to increase awareness and understanding of viral hepatitis. The date of 28 July was chosen because it is the birthday of Nobel-prize winning scientist Dr Baruch Bloomberg, who discovered the hepatitis B virus and developed a diagnostic test and vaccine for it.
For World Hepatitis Day 2019, WHO is focusing on the theme “Invest in eliminating hepatitis” to highlight the need for increased domestic and international funding to scale up hepatitis prevention, testing and treatment services, in order to achieve the 2030 elimination targets.
Gangrene Infection/Gangrene localized death of animal soft tissue, caused by prolonged interruption of the blood supply that may result from injury or infection. Diseases in which gangrene is prone to occur include arteriosclerosis, diabetes, Raynaud’s disease, thromboangiitis obliterans (Buerger’s disease), and typhus. It also may occur after severe burns, freezing, or prolonged bed rest (bed sores).
Gangrene is an acute, rapidly progressive, and potentially fatal, infective necrotizing fasciitis affecting the external genitalia, perineal or perianal regions, which commonly affects men, but can also occur in women and children.
Gangrene is a rapidly progressive life-threatening infection of skeletal muscle caused by clostridia (principally Clostridium perfringens). It is due to wound contamination in the setting of severe tissue trauma, inadequate surgical débridement, immunosuppression, and impaired blood supply. Rarely, nontraumatic gas gangrene caused by Clostridium septicum may occur in patients with occult gastrointestinal malignancies and lead to transient bacteremia.
Gangrene is a type of tissue death caused by a lack of blood supply.[rx] Symptoms may include a change in skin color to red or black, numbness, swelling, pain, skin breakdown, and coolness.[rx] The feet and hands are most commonly affected.[rx] Certain types may present with a fever or sepsis.[rx]
Types of Gangrene
Dry gangrene
Dry gangrene is a form of coagulative necrosis that develops in ischemic tissue, where the blood supply is inadequate to keep tissue viable. It is not a disease itself, but a symptom of other diseases.[rx] Dry gangrene is often due to peripheral artery disease but can be due to acute limb ischemia. As a result, people with arteriosclerosis, high cholesterol, diabetes, and smoking commonly have dry gangrene.[rx]
The affected area becomes cold and numb.
Initially, the affected area becomes red.
Then, it develops a brown discoloration.
Finally, it becomes black and shriveled.
Wet gangrene
Wet or infected, gangrene is characterized by thriving bacteria and has a poor prognosis (compared to dry gangrene) due to sepsis resulting from the free communication between infected fluid and circulatory fluid. In wet gangrene, the tissue is infected by saprogenic microorganisms (Clostridium perfringens or Bacillus fusiformis, for example), which cause the tissue to swell and emit a bad smell. Wet gangrene usually develops rapidly due to blockage of venous (mainly) or arterial blood flow.[rx] The affected part is saturated with stagnant blood, which promotes the rapid growth of bacteria.
The affected area becomes swollen and decays.
It is extremely painful.
Local oozing occurs.
It produces a foul-smelling odor.
It becomes black.
The affected person develops a fever.
Gas gangrene
Gas gangrene is a bacterial infection that produces gas within tissues. It can be caused by Clostridium, most commonly alpha toxin-producing C. perfringens, or various nonclostridial species.[rx][rx] The infection spreads rapidly as the gases produced by the bacteria expand and infiltrate healthy tissue in the vicinity. Because of its ability to quickly spread to surrounding tissues, gas gangrene should be treated as a medical emergency.
A brown-red or bloody discharge may ooze from the affected tissues.
Gas produced by Clostridia may produce a crackling sensation when the affected area is pressed.
It becomes swollen, and blisters may develop.
Pain in the affected area is severe.
The affected person develops fever, increased heart rate, and rapid breathing if the toxins spread into the bloodstream.
Clinical consideration when gas gangrene is present.
(I) Clostridial myonecrosis (true gas gangrene)
(A) Localized – crepitant or noncrepitant
(B) Diffuse – crepitant or noncrepitant together with toxemia
(II) Clostridial cellulitis – anaerobic or crepitant
(B) Nonbacterial – mechanical trauma; infiltration from air-hose
injury.
Internal gangrene
Gangrene that affects one or more of your organs, such as your intestines, gallbladder or appendix, is called internal gangrene. This type of gangrene occurs when blood flow to an internal organ is blocked — for example, when your intestines bulge through a weakened area of muscle in your abdomen (hernia) and become twisted. Internal gangrene may cause fever and severe pain. Left untreated, internal gangrene can be fatal.
Fournier’s gangrene
Fournier’s gangrene involves genital organs. Men are more often affected, but women can develop this type of gangrene as well. Fournier’s gangrene usually arises due to an infection in the genital area or urinary tract and causes genital pain, tenderness, redness, and swelling.
This rare type of gangrene typically occurs after an operation, with painful skin lesions developing one to two weeks after surgery.
Other Types
Necrotizing fasciitis, also known as hemolytic streptococcal gangrene, is an infection that spreads deep into the body along tissue planes. It is characterized by infection with S.pyogenes, a gram-positive cocci bacteria.[rx]
Noma is a gangrene of the face.
Fournier gangrene is a type of necrotizing fasciitis that usually affects the genitals and groin.[rx]
Venous limb gangrene may be caused by heparin-induced thrombocytopenia and thrombosis.[rx]
Severe mesenteric ischemia may result in gangrene of the small intestine.
Severe ischemic colitis may result in gangrene of the large intestine.
Causes of Gangrene
All forms of gangrene happen because of a loss of blood supply to a certain area. This deprives tissue of oxygen and nutrients, causing the tissue to die.
Dry forms can also result from:
Vascular problems – Most commonly due to the poor health of arteries and veins in the legs and toes. This usually develops over time due to conditions such as diabetes, peripheral arterial disease, and high blood pressure.
Severe burns, scalds, and cold – Heat, chemical agents, and extreme cold, including frostbite, can all lead to dry gangrene. Wet gangrene may develop later.
Raynaud’s disease – There is impaired circulation to the ends of fingers and toes, especially in cold weather. Raynaud’s is implicated in some cases of gangrene.
Diabetes – Imbalanced blood sugar levels can damage blood vessels and nerves, reducing the oxygen supply to extremities.
Injury – Deep, crushing, or penetrating wounds that are sustained in conditions that allow bacterial infection can lead to gangrene. Examples are war zones and railway, machinery, and street accidents if lacerated and bruised tissues are contaminated.
Dry gangrene – If the area is infected with bacteria.
Embolism – The sudden blockage of an artery can lead to dry gangrene, but it also increases the risk of infection, and therefore wet gangrene.
Immune deficiency – If an immune system is weakened, for example by HIV, diabetes, long-time alcohol or drug abuse, or recent chemotherapy or radiotherapy, minor infections escalate more quickly and can become gangrenous.
Anorectal Causes
Trauma
Ischiorectal, perirectal, or perianal abscesses, appendicitis,
Electrolytes, BUN, creatinine, blood glucose levels: acidosis with hyperglycemia or hypoglycemia may be present. Dehydration occurs as the disease progresses.
ABG sampling to provide a more accurate assessment of acid/base disturbance.
Blood and urine cultures.
Disseminated intravascular coagulation (DIC) panel (coagulation studies, fibrinogen/fibrin degradation product levels) to find evidence of severe sepsis.
Cultures of any open wound or abscess.
Fluid or tissue culture – where a small tissue or fluid sample from the affected area is tested to find out which bacteria are responsible for the condition and determine the most effective antibiotic to treat it with
Blood cultures – where a sample of blood is taken and put into special culture bottles and placed in a warm environment (incubated) to encourage the growth of bacteria so they can be examined further
Imaging tests – a range of imaging tests, such as X-rays, magnetic resonance imaging (MRI) scans or computerized tomography (CT) scans can be used to confirm the presence and spread of gangrene; these tests can also be used to study blood vessels so any blockages can be identified
Ankle-brachial index test – This test helps in determining arterial blood circulation and blood pressure in the lower extremities.[rx]
Carotid duplex test – This test is done to know the rate of blood flow through carotid arteries. It helps in exploring the presence of any plaques that may cause carotid artery disease.[rx]
Computed angiography and magnetic resonance angiography – These are the computerized imaging tests that are useful in studying in the blood vessels. These techniques help the vascular surgeons to know the severity of the disease.[rx]
Duplex ultrasound – Duplex ultrasound is used to assess the blood flow status in blood vessels. With this technique, vascular surgeons easily explore the existence of an occlusion or clot and plan the treatment.[rx]
Skin perfusion pressure (SPP) and skin vascular resistance – SPP and skin vascular resistance measurements also help in distinguishing the patients who require vascular reconstruction or major amputation and the patients who only require foot care or require minor amputation [rx]. A prospective, double-blinded study by Castronuovo et al concluded that in ~80% cases, SPP helps in diagnosing the critical limb ischemia accurately.[rx],[rx]
Ultrasonography – A US finding in Fournier gangrene is a thickened wall containing hyperechoic foci that demonstrate reverberation artifacts, causing “dirty” shadowing that represents gas within the scrotal wall. Evidence of gas within the scrotal wall may be seen prior to clinical crepitus. Reactive unilateral or bilateral hydroceles may also be present. If testicular involvement occurs, there is likely an intraabdominal or retroperitoneal source of infection. US is also useful in differentiating Fournier gangrene from an inguinoscrotal incarcerated hernia; in the latter condition, gas is observed in the obstructed bowel lumen, away from the scrotal wall [rx].
Computed Tomography – The CT features of Fournier gangrene include soft-tissue thickening and inflammation. CT can demonstrate asymmetric fascial thickening, any coexisting fluid collection or abscess, fat stranding around the involved structures, and subcutaneous emphysema secondary to gas-forming bacteria. The underlying cause of the Fournier gangrene, such as a perianal abscess, a fistulous tract, or an intraabdominal or retroperitoneal infectious process, may also be demonstrated at CT. In early Fournier gangrene, CT can depict progressive soft-tissue infiltration, possibly with no evidence of subcutaneous emphysema. Because the infection progresses rapidly, the early stage with lack of subcutaneous emphysema is brief and is rarely seen at CT [rx].
Treatment of Gangrene
Broad-Spectrum Antibiotics Coverage
Empiric broad-spectrum antibiotic therapy should be instituted as soon as possible until the culture results could make adjusted the therapy. The antibiotic regimen chosen must have a high degree of effectiveness against staphylococcal and streptococcal bacteria, gram-negative, coliforms, pseudomonas, Bacteroides, and clostridium.
Classically Triple therapy is usually recommended. Third generation cefalosporins or aminoglycosides, plus penicillin and metronidazole.
Clindamycin may be used as it is shown to suppress toxin production and modulate cytokine production; also use of linezolid, daptomycin, and tigecycline is warranted in cases of previous hospitalizations with prolonged antibiotic therapy which may lead to resistant Bacteroides [rx].
[stextbox id=’custom’]
Pharmacologic approaches for gangrene management
Pharmacologic approach
Drugs class examples
Mechanism of action
Pain management
Opioids and opioid-like analgesics Morphine, oxycodone, dextromethorphan, tapentadol, tramadol
Mimic the actions of endogenous opioid peptides by interacting with mu, delta, or kappa opioid receptors
Cause activation of anticlotting factors, direct inhibition of thrombin, inhibition of synthesis of blood coagulation factor precursors (zymogens), and activation of protein C
Cause lysis of thrombi/clot to recanalize the occluded vessels
Antibiotics
Penicillins: flucloxacillin
Inhibit bacterial cell wall synthesis by binding to specific penicillin-binding proteins located inside the bacterial cell wall
Fluoroquinolones: ciprofloxacin
Inhibit topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair, strand supercoiling repair, and recombination
Antiprotozoals: metronidazole
In reduced form, they covalently bind to DNA, disrupt its helix structure, inhibiting bacterial nucleic acid synthesis, and cause bacterial cell death
Carbapenems: ertapenem, meropenem
Show bactericidal activity by inhibiting the bacterial cell wall synthesis
Glycopeptides: teicoplanin, vancomycin
Inhibit the bacterial cell wall synthesis and cause cell death
Tetracyclines: doxycycline
Reversibly bind to 30S ribosomal subunits and possibly to 50S subunits, block the binding of aminoacyl tRNA to mRNA, and inhibit bacterial protein synthesis
Lincosamides: clindamycin
Inhibit bacterial protein synthesis by binding to 50S ribosomal subunits of the bacteria
Oxazolidinones: linezolid
Selectively inhibit bacterial protein synthesis by binding to bacterial ribosomes and prevent the formation of a functional 70S initiation complex
Early IV antibiotics with early surgical debridement followed by hyperbaric oxygen therapy can salvage patients with an otherwise nearly always fatal disease. Intravenous antibiotics and early surgical debridement of the necrotic tissue reduce fatality rate to about 30%. With the addition of hyperbaric oxygen therapy, this can be reduced down to 5 to 10%.
Hyperbaric oxygen therapy helps by halting exotoxin production by the bacteria, helps to improve the bactericidal effect of the antibiotic, treats the tissue ischemia, improves reperfusion injury of the tissue, and promotes the activation and migration of stem cells and polymorphonuclear cells.
Pain management
Gangrene is usually associated with intermittent claudication in the limbs of patients. Thus, it is important to effectively manage the pain to let the patient continue exercises to improve circulation.
Opioid analgesics are recommended for pain associated with chronic limb ischemia. Apart from vascular factors, neuropathic pain should also be managed as a priority.[rx]
Circulation management
As the senile/dry gangrene is a consequence of ischemia, improving the blood circulation in limbs helps overcome peripheral artery disease.[rx] As per the American Diabetes Association, antiplatelet therapy or platelet aggregation inhibitors are highly recommended for preventing the vascular complications in diabetes patients.[rx] In some cases, surgery may be carried out to restore the blood flow to the affected area. The main techniques used to achieve this are:
Bypass surgery – where the surgeon redirects the flow of blood and bypasses the blockage by connecting (grafting) one of your veins to a healthy part of an artery
Angioplasty – where a tiny balloon is placed into a narrow or blocked artery and is inflated to open up the vessel; a small metal tube, known as a stent, may also be inserted into the artery to help keep it open
Research suggests that both techniques are equally effective in restoring blood flow and preventing the need for amputation in the short-term. An angioplasty has the advantage of having a faster recovery time than bypass surgery, although it may not be as effective in the long-term as bypass surgery.
Lipid-lowering agents
Dyslipidemia plays a major role in the progression of diabetic toe gangrene. Thus, diabetes patients should undergo a regular lipid profile check-up. In a descriptive case series study performed by Memon et al, 55.11% cases were reported to have abnormal lipid profile and 44.89% cases had lipid profile within the normal range.
As per Wagner’s scale, the percentage of patients with superficial ulcers (Grade I), ulcer extension (Grade II), deep ulcer with abscess (Grade III), gangrene of ore foot (Grade IV), and extensive gangrene foot (Grade V) was found to be 30.61%, 19.39%, 21.42%, 16.33%, and 12.25% respectively. A significant difference (p=0.001) was found in the gangrenous diabetic foot, grade IV and grade V.[rx]
Larval debridement therapy (biosurgery)
In some cases, it may be possible to use larval debridement therapy, also known as biosurgery, instead of conventional surgery to remove the dead tissue. Certain types of fly larvae are ideal for this because they feed on dead and infected tissue but leave healthy tissue alone. They also help fight infection by releasing substances that kill bacteria and stimulate the healing process.
Maggots used for larval therapy are specially bred in a laboratory using eggs that have been treated to remove bacteria. The maggots are placed on the wound and covered with gauze, under a firm dressing, which keeps them on the wound (and out of sight). After a few days, the dressing is cut away and the maggots are removed. Medical studies have shown larval debridement therapy can achieve more effective results than surgical debridement. However, because of the nature of this type of treatment, many people are reluctant to try it.
Exercise
Apart from drugs, in dry gangrene patients with peripheral arterial disease, guideline-directed management and therapy should be followed to decrease arterial occlusion or impaired perfusion, prevent the progression of chronic critical limb ischemia, and improve the functional status of affected limbs.
This involves exercises which are done under structured or unstructured programs. Structured exercise programs include intermittent walking followed by alternate rest time. These are organized in the health care facilities and are supervised by a trained health care professional. Unstructured home-based exercise programs also include walking as a major exercise without any supervisor’s guidance.[rx,rx]
Massage therapy
Massage Therapy is also recommended to improve the circulation in limbs. Only light pressure massage is given to the affected limb to avoid any clot formation. Massage should be cautiously done in patients with a stent, with special instructions given by the health care professional.[rx]
Fasciotomy
It may be necessary to relieve compartment pressures. As the infection progresses into deep tissue along and under the fascia tissue compartment pressures increase, which perpetuates further tissue ischemia and necrosis. Surgical debridement should focus on removing all the necrotic tissue, and foreign bodies such as soil, debris, and shrapnel. It is also important to irrigate the wounds with copious amounts of sterile normal saline.
Hyperbaric oxygen therapy
It should be added to standard therapy of antibiotics and surgical debridement to help improve survival.[rx][rx] It is important to have coordinated care of these critically ill patients with an intensivist, general surgeon, orthopedic surgeon, urologist (in the setting of Fournier’s gangrene of the testicles and perineal structures), gynecologist (in the setting of uterine gas gangrene), infectious disease specialist, hematologist/oncologist, gastroenterologist (in the setting of spontaneous gas gangrene), and hyperbaric oxygen therapy specialist. The flow of consultation starts with usually an emergency department provider and early recognition of the disease.
Conventional Radiography
At radiography, hyperlucencies representing soft tissue gas may be seen in the region overlying the scrotum or perineum. Subcutaneous emphysema may be seen extending from the scrotum and perineum to the inguinal regions, anterior abdominal wall, and thighs.
However, the absence of subcutaneous air in the scrotum or perineum does not exclude the diagnosis of Fournier gangrene. Up to 90% of patients with Fournier gangrene have been reported to have subcutaneous emphysema so that at least 10% do not demonstrate this finding [rx].
Radiography may also demonstrate significant swelling of scrotal soft tissue. Deep fascial gas is rarely seen at radiography, which represents a significant weakness of this modality in the diagnosis and evaluation of Fournier gangrene [rx].
Radical Surgical Debridement
A debridement of the necrotic tissue as soon as possible it is widely recommended Laor et al. found no significant difference between the onset time of symptoms, early surgical treatment, and mortality, but other studies from Kabay et al. [rx] and Korkut et al. [rx] show that this time interval should be as short as possible.
Debridement of deep fascia and muscle is not usually required as these areas are rarely involved similar to testes. Debridement should be stopped when the separation of the skin and the subcutaneous is not performed easily because the cutaneous necrosis is not a good marker. Multiple surgical debridements is the rule rather than the exception, with an average of 3.5 procedures required per patient [rx]
Fecal and Urinary Diversion
Colostomy has been used for fecal diversion in cases of severe perineal involvement. The rationale for rectal diversion includes a decrease in the number of germs in the perineal region and improved wound healing. Justifications for its construction are anal sphincter involving, fecal incontinence, or continues fecal contamination of the wound’s margins. In several papers, the percentage of patients with a colostomy is around 15% depending on the series [rx].
Topical Therapy
There have been reports of the use of honey to aid wound healing. Honey has a low pH of 3.6 and contains enzymes which digest necrotic tissues it also has antibacterial property due to phenolic acid. These changes occur within a week of applying honey to the wound. Unfortunately, there is no randomized study on the efficacy of honey in these special situations. [rx]
Hyperbaric Oxygen Therapy
Hyperbaric oxygen therapy implies placing the patient in an environment of increased ambient pressure while breathing 100% oxygen, resulting in enhanced oxygenation of the arterial blood and tissues and demonstrated benefits of hyperbaric oxygen include adequate oxygenation for optimal neutrophil phagocytic function, inhibition of anaerobic growth, increased fibroblast proliferation and angiogenesis, reduction of edema by vasoconstriction, and increased intracellular antibiotics transportation [rx].
Vacuum-Assisted Closure
With the recent advent of the vacuum-assisted closure (VAC) system dressing, there seems to be a dramatic improvement with minimizing skin defects and speeding tissue healing. It simply works by exposing a wound to subatmospheric pressure for an extended period to promote debridement and healing.
Weinfeld et al. treated four consecutive cases using negative pressure dressings (VAC) to bolster skin grafts in male genital reconstruction.
Plastic Reconstruction
Various workers have used different techniques to provide skin cover including transplantation of testes, free skin grafts, axial groin flaps, and myocutaneous flaps. Split thickness skin graft seems to be the treatment of choice in treating perineal and scrotal skin defects.
Home Exercise
A healthy, well-balanced diet and regular exercise will keep your blood pressure and cholesterol levels at a healthy level, helping prevent your blood vessels become damaged.
Unless advised otherwise by your doctor, you should be aiming for at least 150 minutes (2.5 hours) of moderately intense physical exercise a week.
Moderate-intensity physical activity is any activity that increases your heart and breathing rate. It may make you sweat but you’ll still be able to hold a normal conversation. Examples include:
fast walking
cycling on level ground or with few hills
swimming
tennis
You should choose physical activities you enjoy because you’re more likely to continue doing them. It’s probably unrealistic to meet these exercise targets immediately if you haven’t exercised much in the past. Aim to start gradually and build up the amount of exercise you do overtime.
Diet
Eating an unhealthy diet high in fat will make any existing atherosclerosis worse and increase your risk of developing gangrene.
Continuing to eat high-fat foods will cause more fatty plaques to build-up in your arteries. This is because fatty foods contain cholesterol.
There are 2 types of fat-saturated and unsaturated. Avoid foods that contain saturated fats because they increase levels of “bad cholesterol” in your blood.
Foods high in saturated fat include:
meat pies
sausages and fatty cuts of meat
butter
ghee (a type of butter often used in Indian cooking)
lard
cream
hard cheese
cakes and biscuits
food containing coconut or palm oil
Prevention of Gangrene
Our emergency clinicians should be aware of this severe and potentially fatal infectious disease and should not delay treatment or prompt orthopedic surgery consultation. Gas gangrene, while rare in now peace days, can be a devastating complication of almost any small wound or surgical procedure even one as common as closed reduction of fractures. It is our experience that we should give sufficient extension of the wound to provide adequate visualization of the surgical field so as to be certain that all the necrotic or foreign material has been removed.
Strict aseptic techniques should be observed for even the most minor procedure. Clostridial spores are ubiquitous and can reside in hospital environments, possibly on surgeons’ hands, patients’ skin, topical application, and so on.
The best way to prevent gas gangrene is meticulous wound debridement and delayed closure for all potentially contaminated wounds regardless of closed or open fractures.
Once gas gangrene is diagnosed, careful and adequate debridement should be instituted immediately to avoid further deterioration excision of necrotic tissue still the cornerstone of treatment, which should be involved with antibiotics and all other supportive treatments.
Systematic resuscitative efforts should be instituted immediately in whom the diagnosis of incipient gas gangrene is even considered. This cannot be overemphasized.
Recognized that gas gangrene may occur spontaneously and often in an immunocompromised patient, postoperative wounds may also develop gas gangrene due to the local soft tissue damage and decreasing blood supply.
Keep wounds clean and sterile by cleaning all wounds thoroughly with an antiseptic solution.
Watch for signs of infection, such as pus, redness, swelling, or unusual pain.
Consult a health-care provider if any wound becomes infected.
People with diabetes should control their blood sugar levels with proper medication.
Education about proper foot care is vital for people with diabetes. They should routinely examine their feet for any signs of injury or change in skin color. Any small injury should be immediately cared for. They should keep their nails trimmed and wear comfortable well-fitting shoes.
Antibiotic For Gas Gangrene/Gas Gangrene is a bacterial infection that produces gas within tissues. It can be caused by Clostridium, most commonly alpha toxin-producing C. perfringens, or various nonclostridial species.[rx][rx] The infection spreads rapidly as the gases produced by the bacteria expand and infiltrate healthy tissue in the vicinity. Because of its ability to quickly spread to surrounding tissues, gas gangrene should be treated as a medical emergency.
Gangrene localized death of animal soft tissue, caused by prolonged interruption of the blood supply that may result from injury or infection. Diseases in which gangrene is prone to occur include arteriosclerosis, diabetes, Raynaud’s disease, thromboangiitis obliterans (Buerger’s disease), and typhus. It also may occur after severe burns, freezing, or prolonged bed rest (bed sores).
Gangrene is a rapidly progressive life-threatening infection of skeletal muscle caused by clostridia (principally Clostridium perfringens). It is due to wound contamination in the setting of severe tissue trauma, inadequate surgical débridement, immunosuppression, and impaired blood supply. Rarely, nontraumatic gas gangrene caused by Clostridium septicum may occur in patients with occult gastrointestinal malignancies and lead to transient bacteremia.
Gangrene is a type of tissue death caused by a lack of blood supply.[rx] Symptoms may include a change in skin color to red or black, numbness, swelling, pain, skin breakdown, and coolness.[rx] The feet and hands are most commonly affected.[rx] Certain types may present with a fever or sepsis.[rx]
Types of Gangrene
Dry gangrene
Dry gangrene is a form of coagulative necrosis that develops in ischemic tissue, where the blood supply is inadequate to keep tissue viable. It is not a disease itself, but a symptom of other diseases.[rx] Dry gangrene is often due to peripheral artery disease but can be due to acute limb ischemia. As a result, people with arteriosclerosis, high cholesterol, diabetes, and smoking commonly have dry gangrene.[rx]
The affected area becomes cold and numb.
Initially, the affected area becomes red.
Then, it develops a brown discoloration.
Finally, it becomes black and shriveled.
Wet gangrene
Wet or infected, gangrene is characterized by thriving bacteria and has a poor prognosis (compared to dry gangrene) due to sepsis resulting from the free communication between infected fluid and circulatory fluid. In wet gangrene, the tissue is infected by saprogenic microorganisms (Clostridium perfringens or Bacillus fusiformis, for example), which cause the tissue to swell and emit a bad smell. Wet gangrene usually develops rapidly due to blockage of venous (mainly) or arterial blood flow.[rx] The affected part is saturated with stagnant blood, which promotes the rapid growth of bacteria.
The affected area becomes swollen and decays.
It is extremely painful.
Local oozing occurs.
It produces a foul-smelling odor.
It becomes black.
The affected person develops a fever.
Gas gangrene
Gas gangrene is a bacterial infection that produces gas within tissues. It can be caused by Clostridium, most commonly alpha toxin-producing C. perfringens, or various nonclostridial species.[rx][rx] The infection spreads rapidly as the gases produced by the bacteria expand and infiltrate healthy tissue in the vicinity. Because of its ability to quickly spread to surrounding tissues, gas gangrene should be treated as a medical emergency.
A brown-red or bloody discharge may ooze from the affected tissues.
The gas produced by Clostridia may produce a crackling sensation when the affected area is pressed.
It becomes swollen, and blisters may develop.
Pain in the affected area is severe.
The affected person develops fever, increased heart rate, and rapid breathing if the toxins spread into the bloodstream.
Clinical consideration when gas gangrene is present.
(I) Clostridial myonecrosis (true gas gangrene)
(A) Localized – crepitant or noncrepitant
(B) Diffuse – crepitant or noncrepitant together with toxemia
(II) Clostridial cellulitis – anaerobic or crepitant
(B) Nonbacterial – mechanical trauma; infiltration from air-hose
injury.
Internal gangrene
Gangrene that affects one or more of your organs, such as your intestines, gallbladder or appendix, is called internal gangrene. This type of gangrene occurs when blood flow to an internal organ is blocked — for example, when your intestines bulge through a weakened area of muscle in your abdomen (hernia) and become twisted. Internal gangrene may cause fever and severe pain. Left untreated, internal gangrene can be fatal.
Fournier’s gangrene
Fournier’s gangrene involves genital organs. Men are more often affected, but women can develop this type of gangrene as well. Fournier’s gangrene usually arises due to an infection in the genital area or urinary tract and causes genital pain, tenderness, redness, and swelling.
This rare type of gangrene typically occurs after an operation, with painful skin lesions developing one to two weeks after surgery.
Other Types
Necrotizing fasciitis, also known as hemolytic streptococcal gangrene, is an infection that spreads deep into the body along tissue planes. It is characterized by infection with S.pyogenes, a gram-positive cocci bacteria.[rx]
Noma is a gangrene of the face.
Fournier gangrene is a type of necrotizing fasciitis that usually affects the genitals and groin.[rx]
Venous limb gangrene may be caused by heparin-induced thrombocytopenia and thrombosis.[rx]
Severe mesenteric ischemia may result in gangrene of the small intestine.
Severe ischemic colitis may result in gangrene of the large intestine.
Causes of Gangrene
All forms of gangrene happen because of a loss of blood supply to a certain area. This deprives tissue of oxygen and nutrients, causing the tissue to die.
Dry forms can also result from:
Vascular problems – Most commonly due to the poor health of arteries and veins in the legs and toes. This usually develops over time due to conditions such as diabetes, peripheral arterial disease, and high blood pressure.
Severe burns, scalds, and cold – Heat, chemical agents, and extreme cold, including frostbite, can all lead to dry gangrene. Wet gangrene may develop later.
Raynaud’s disease – There is impaired circulation to the ends of fingers and toes, especially in cold weather. Raynaud’s is implicated in some cases of gangrene.
Diabetes – Imbalanced blood sugar levels can damage blood vessels and nerves, reducing the oxygen supply to extremities.
Injury – Deep, crushing, or penetrating wounds that are sustained in conditions that allow bacterial infection can lead to gangrene. Examples are war zones and railway, machinery, and street accidents if lacerated and bruised tissues are contaminated.
Dry gangrene – If the area is infected with bacteria.
Embolism – The sudden blockage of an artery can lead to dry gangrene, but it also increases the risk of infection, and therefore wet gangrene.
Immune deficiency – If an immune system is weakened, for example by HIV, diabetes, long-time alcohol or drug abuse, or recent chemotherapy or radiotherapy, minor infections escalate more quickly and can become gangrenous.
Anorectal Causes
Trauma
Ischiorectal, perirectal, or perianal abscesses, appendicitis,
Electrolytes, BUN, creatinine, blood glucose levels: acidosis with hyperglycemia or hypoglycemia may be present. Dehydration occurs as the disease progresses.
ABG sampling to provide a more accurate assessment of acid/base disturbance.
Blood and urine cultures.
Disseminated intravascular coagulation (DIC) panel (coagulation studies, fibrinogen/fibrin degradation product levels) to find evidence of severe sepsis.
Cultures of any open wound or abscess.
Fluid or tissue culture – where a small tissue or fluid sample from the affected area is tested to find out which bacteria are responsible for the condition and determine the most effective antibiotic to treat it with
Blood cultures – where a sample of blood is taken and put into special culture bottles and placed in a warm environment (incubated) to encourage the growth of bacteria so they can be examined further
Imaging tests – a range of imaging tests, such as X-rays, magnetic resonance imaging (MRI) scans or computerized tomography (CT) scans can be used to confirm the presence and spread of gangrene; these tests can also be used to study blood vessels so any blockages can be identified
Ankle-brachial index test – This test helps in determining arterial blood circulation and blood pressure in the lower extremities.[rx]
Carotid duplex test – This test is done to know the rate of blood flow through carotid arteries. It helps in exploring the presence of any plaques that may cause carotid artery disease.[rx]
Computed angiography and magnetic resonance angiography – These are the computerized imaging tests that are useful in studying in the blood vessels. These techniques help the vascular surgeons to know the severity of the disease.[rx]
Duplex ultrasound – Duplex ultrasound is used to assess the blood flow status in blood vessels. With this technique, vascular surgeons easily explore the existence of an occlusion or clot and plan the treatment.[rx]
Skin perfusion pressure (SPP) and skin vascular resistance – SPP and skin vascular resistance measurements also help in distinguishing the patients who require vascular reconstruction or major amputation and the patients who only require foot care or require minor amputation [rx]. A prospective, double-blinded study by Castronuovo et al concluded that in ~80% cases, SPP helps in diagnosing the critical limb ischemia accurately.[rx],[rx]
Ultrasonography – A US finding in Fournier gangrene is a thickened wall containing hyperechoic foci that demonstrate reverberation artifacts, causing “dirty” shadowing that represents gas within the scrotal wall. Evidence of gas within the scrotal wall may be seen prior to clinical crepitus. Reactive unilateral or bilateral hydroceles may also be present. If testicular involvement occurs, there is likely an intraabdominal or retroperitoneal source of infection. US is also useful in differentiating Fournier gangrene from an inguinoscrotal incarcerated hernia; in the latter condition, gas is observed in the obstructed bowel lumen, away from the scrotal wall [rx].
Computed Tomography – The CT features of Fournier gangrene include soft-tissue thickening and inflammation. CT can demonstrate asymmetric fascial thickening, any coexisting fluid collection or abscess, fat stranding around the involved structures, and subcutaneous emphysema secondary to gas-forming bacteria. The underlying cause of the Fournier gangrene, such as a perianal abscess, a fistulous tract, or an intraabdominal or retroperitoneal infectious process, may also be demonstrated at CT. In early Fournier gangrene, CT can depict progressive soft-tissue infiltration, possibly with no evidence of subcutaneous emphysema. Because the infection progresses rapidly, the early stage with lack of subcutaneous emphysema is brief and is rarely seen at CT [rx].
Treatment of Gangrene
Broad-Spectrum Antibiotics Coverage
Empiric broad-spectrum antibiotic therapy should be instituted as soon as possible until the culture results could make adjusted the therapy. The antibiotic regimen chosen must have a high degree of effectiveness against staphylococcal and streptococcal bacteria, gram-negative, coliforms, pseudomonas, Bacteroides, and clostridium.
Classically Triple therapy is usually recommended. Third generation cefalosporins or aminoglycosides, plus penicillin and metronidazole.
Clindamycin may be used as it is shown to suppress toxin production and modulate cytokine production; also use of linezolid, daptomycin, and tigecycline is warranted in cases of previous hospitalizations with prolonged antibiotic therapy which may lead to resistant Bacteroides [rx].
[stextbox id=’custom’]
Pharmacologic approaches for gangrene management
Pharmacologic approach
Drugs class examples
Mechanism of action
Pain management
Opioids and opioid-like analgesics Morphine, oxycodone, dextromethorphan, tapentadol, tramadol
Mimic the actions of endogenous opioid peptides by interacting with mu, delta, or kappa opioid receptors
Cause activation of anticlotting factors, direct inhibition of thrombin, inhibition of synthesis of blood coagulation factor precursors (zymogens), and activation of protein C
Cause lysis of thrombi/clot to recanalize the occluded vessels
Antibiotics
Penicillins: flucloxacillin
Inhibit bacterial cell wall synthesis by binding to specific penicillin-binding proteins located inside the bacterial cell wall
Fluoroquinolones: ciprofloxacin
Inhibit topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair, strand supercoiling repair, and recombination
Antiprotozoals: metronidazole
In reduced form, they covalently bind to DNA, disrupt its helix structure, inhibiting bacterial nucleic acid synthesis, and cause bacterial cell death
Carbapenems: ertapenem, meropenem
Show bactericidal activity by inhibiting the bacterial cell wall synthesis
Glycopeptides: teicoplanin, vancomycin
Inhibit the bacterial cell wall synthesis and cause cell death
Tetracyclines: doxycycline
Reversibly bind to 30S ribosomal subunits and possibly to 50S subunits, block the binding of aminoacyl tRNA to mRNA, and inhibit bacterial protein synthesis
Lincosamides: clindamycin
Inhibit bacterial protein synthesis by binding to 50S ribosomal subunits of the bacteria
Oxazolidinones: linezolid
Selectively inhibit bacterial protein synthesis by binding to bacterial ribosomes and prevent the formation of a functional 70S initiation complex
Early IV antibiotics with early surgical debridement followed by hyperbaric oxygen therapy can salvage patients with an otherwise nearly always fatal disease. Intravenous antibiotics and early surgical debridement of the necrotic tissue reduce fatality rate to about 30%. With the addition of hyperbaric oxygen therapy, this can be reduced down to 5 to 10%.
Hyperbaric oxygen therapy helps by halting exotoxin production by the bacteria, helps to improve the bactericidal effect of the antibiotic, treats the tissue ischemia, improves reperfusion injury of the tissue, and promotes the activation and migration of stem cells and polymorphonuclear cells.
Pain management
Gangrene is usually associated with intermittent claudication in the limbs of patients. Thus, it is important to effectively manage the pain to let the patient continue exercises to improve circulation.
Opioid analgesics are recommended for pain associated with chronic limb ischemia. Apart from vascular factors, neuropathic pain should also be managed as a priority.[rx]
Circulation management
As the senile/dry gangrene is a consequence of ischemia, improving the blood circulation in limbs helps overcome peripheral artery disease.[rx] As per the American Diabetes Association, antiplatelet therapy or platelet aggregation inhibitors are highly recommended for preventing the vascular complications in diabetes patients.[rx] In some cases, surgery may be carried out to restore the blood flow to the affected area. The main techniques used to achieve this are:
Bypass surgery – where the surgeon redirects the flow of blood and bypasses the blockage by connecting (grafting) one of your veins to a healthy part of an artery
Angioplasty – where a tiny balloon is placed into a narrow or blocked artery and is inflated to open up the vessel; a small metal tube, known as a stent, may also be inserted into the artery to help keep it open
Research suggests that both techniques are equally effective in restoring blood flow and preventing the need for amputation in the short-term. An angioplasty has the advantage of having a faster recovery time than bypass surgery, although it may not be as effective in the long-term as bypass surgery.
Lipid-lowering agents
Dyslipidemia plays a major role in the progression of diabetic toe gangrene. Thus, diabetes patients should undergo a regular lipid profile check-up. In a descriptive case series study performed by Memon et al, 55.11% cases were reported to have abnormal lipid profile and 44.89% cases had lipid profile within the normal range.
As per Wagner’s scale, the percentage of patients with superficial ulcers (Grade I), ulcer extension (Grade II), deep ulcer with abscess (Grade III), gangrene of ore foot (Grade IV), and extensive gangrene foot (Grade V) was found to be 30.61%, 19.39%, 21.42%, 16.33%, and 12.25% respectively. A significant difference (p=0.001) was found in the gangrenous diabetic foot, grade IV and grade V.[rx]
Larval debridement therapy (biosurgery)
In some cases, it may be possible to use larval debridement therapy, also known as biosurgery, instead of conventional surgery to remove the dead tissue. Certain types of fly larvae are ideal for this because they feed on dead and infected tissue but leave healthy tissue alone. They also help fight infection by releasing substances that kill bacteria and stimulate the healing process.
Maggots used for larval therapy are specially bred in a laboratory using eggs that have been treated to remove bacteria. The maggots are placed on the wound and covered with gauze, under a firm dressing, which keeps them on the wound (and out of sight). After a few days, the dressing is cut away and the maggots are removed. Medical studies have shown larval debridement therapy can achieve more effective results than surgical debridement. However, because of the nature of this type of treatment, many people are reluctant to try it.
Exercise
Apart from drugs, in dry gangrene patients with peripheral arterial disease, guideline-directed management and therapy should be followed to decrease arterial occlusion or impaired perfusion, prevent the progression of chronic critical limb ischemia, and improve the functional status of affected limbs.
This involves exercises which are done under structured or unstructured programs. Structured exercise programs include intermittent walking followed by alternate rest time. These are organized in the health care facilities and are supervised by a trained health care professional. Unstructured home-based exercise programs also include walking as a major exercise without any supervisor’s guidance.[rx,rx]
Massage therapy
Massage Therapy is also recommended to improve the circulation in limbs. Only light pressure massage is given to the affected limb to avoid any clot formation. Massage should be cautiously done in patients with a stent, with special instructions given by the health care professional.[rx]
Fasciotomy
It may be necessary to relieve compartment pressures. As the infection progresses into deep tissue along and under the fascia tissue compartment pressures increase, which perpetuates further tissue ischemia and necrosis. Surgical debridement should focus on removing all the necrotic tissue, and foreign bodies such as soil, debris, and shrapnel. It is also important to irrigate the wounds with copious amounts of sterile normal saline.
Hyperbaric oxygen therapy
It should be added to standard therapy of antibiotics and surgical debridement to help improve survival.[rx][rx] It is important to have coordinated care of these critically ill patients with an intensivist, general surgeon, orthopedic surgeon, urologist (in the setting of Fournier’s gangrene of the testicles and perineal structures), gynecologist (in the setting of uterine gas gangrene), infectious disease specialist, hematologist/oncologist, gastroenterologist (in the setting of spontaneous gas gangrene), and hyperbaric oxygen therapy specialist. The flow of consultation starts with usually an emergency department provider and early recognition of the disease.
Conventional Radiography
At radiography, hyperlucencies representing soft tissue gas may be seen in the region overlying the scrotum or perineum. Subcutaneous emphysema may be seen extending from the scrotum and perineum to the inguinal regions, anterior abdominal wall, and thighs.
However, the absence of subcutaneous air in the scrotum or perineum does not exclude the diagnosis of Fournier gangrene. Up to 90% of patients with Fournier gangrene have been reported to have subcutaneous emphysema so that at least 10% do not demonstrate this finding [rx].
Radiography may also demonstrate significant swelling of scrotal soft tissue. Deep fascial gas is rarely seen at radiography, which represents a significant weakness of this modality in the diagnosis and evaluation of Fournier gangrene [rx].
Radical Surgical Debridement
A debridement of the necrotic tissue as soon as possible it is widely recommended Laor et al. found no significant difference between the onset time of symptoms, early surgical treatment, and mortality, but other studies from Kabay et al. [rx] and Korkut et al. [rx] show that this time interval should be as short as possible.
Debridement of deep fascia and muscle is not usually required as these areas are rarely involved similar to testes. Debridement should be stopped when the separation of the skin and the subcutaneous is not performed easily because the cutaneous necrosis is not a good marker. Multiple surgical debridements is the rule rather than the exception, with an average of 3.5 procedures required per patient [rx]
Fecal and Urinary Diversion
Colostomy has been used for fecal diversion in cases of severe perineal involvement. The rationale for rectal diversion includes a decrease in the number of germs in the perineal region and improved wound healing. Justifications for its construction are anal sphincter involving, fecal incontinence, or continues fecal contamination of the wound’s margins. In several papers, the percentage of patients with a colostomy is around 15% depending on the series [rx].
Topical Therapy
There have been reports of the use of honey to aid wound healing. Honey has a low pH of 3.6 and contains enzymes which digest necrotic tissues it also has antibacterial property due to phenolic acid. These changes occur within a week of applying honey to the wound. Unfortunately, there is no randomized study on the efficacy of honey in these special situations. [rx]
Hyperbaric Oxygen Therapy
Hyperbaric oxygen therapy implies placing the patient in an environment of increased ambient pressure while breathing 100% oxygen, resulting in enhanced oxygenation of the arterial blood and tissues and demonstrated benefits of hyperbaric oxygen include adequate oxygenation for optimal neutrophil phagocytic function, inhibition of anaerobic growth, increased fibroblast proliferation and angiogenesis, reduction of edema by vasoconstriction, and increased intracellular antibiotics transportation [rx].
Vacuum-Assisted Closure
With the recent advent of the vacuum-assisted closure (VAC) system dressing, there seems to be a dramatic improvement with minimizing skin defects and speeding tissue healing. It simply works by exposing a wound to subatmospheric pressure for an extended period to promote debridement and healing.
Weinfeld et al. treated four consecutive cases using negative pressure dressings (VAC) to bolster skin grafts in male genital reconstruction.
Plastic Reconstruction
Various workers have used different techniques to provide skin cover including transplantation of testes, free skin grafts, axial groin flaps, and myocutaneous flaps. Split thickness skin graft seems to be the treatment of choice in treating perineal and scrotal skin defects.
Home Exercise
A healthy, well-balanced diet and regular exercise will keep your blood pressure and cholesterol levels at a healthy level, helping prevent your blood vessels become damaged.
Unless advised otherwise by your doctor, you should be aiming for at least 150 minutes (2.5 hours) of moderately intense physical exercise a week.
Moderate-intensity physical activity is any activity that increases your heart and breathing rate. It may make you sweat but you’ll still be able to hold a normal conversation. Examples include:
fast walking
cycling on level ground or with few hills
swimming
tennis
You should choose physical activities you enjoy because you’re more likely to continue doing them. It’s probably unrealistic to meet these exercise targets immediately if you haven’t exercised much in the past. Aim to start gradually and build up the amount of exercise you do overtime.
Diet
Eating an unhealthy diet high in fat will make any existing atherosclerosis worse and increase your risk of developing gangrene.
Continuing to eat high-fat foods will cause more fatty plaques to build-up in your arteries. This is because fatty foods contain cholesterol.
There are 2 types of fat-saturated and unsaturated. Avoid foods that contain saturated fats because they increase levels of “bad cholesterol” in your blood.
Foods high in saturated fat include:
meat pies
sausages and fatty cuts of meat
butter
ghee (a type of butter often used in Indian cooking)
lard
cream
hard cheese
cakes and biscuits
food containing coconut or palm oil
Prevention of Gangrene
Our emergency clinicians should be aware of this severe and potentially fatal infectious disease and should not delay treatment or prompt orthopedic surgery consultation. Gas gangrene, while rare in now peace days, can be a devastating complication of almost any small wound or surgical procedure even one as common as closed reduction of fractures. It is our experience that we should give sufficient extension of the wound to provide adequate visualization of the surgical field so as to be certain that all the necrotic or foreign material has been removed.
Strict aseptic techniques should be observed for even the most minor procedure. Clostridial spores are ubiquitous and can reside in hospital environments, possibly on surgeons’ hands, patients’ skin, topical application, and so on.
The best way to prevent gas gangrene is meticulous wound debridement and delayed closure for all potentially contaminated wounds regardless of closed or open fractures.
Once gas gangrene is diagnosed, careful and adequate debridement should be instituted immediately to avoid further deterioration excision of necrotic tissue still the cornerstone of treatment, which should be involved with antibiotics and all other supportive treatments.
Systematic resuscitative efforts should be instituted immediately in whom the diagnosis of incipient gas gangrene is even considered. This cannot be overemphasized.
Recognized that gas gangrene may occur spontaneously and often in an immunocompromised patient, postoperative wounds may also develop gas gangrene due to the local soft tissue damage and decreasing blood supply.
Keep wounds clean and sterile by cleaning all wounds thoroughly with an antiseptic solution.
Watch for signs of infection, such as pus, redness, swelling, or unusual pain.
Consult a health-care provider if any wound becomes infected.
People with diabetes should control their blood sugar levels with proper medication.
Education about proper foot care is vital for people with diabetes. They should routinely examine their feet for any signs of injury or change in skin color. Any small injury should be immediately cared for. They should keep their nails trimmed and wear comfortable well-fitting shoes.
What Is The Best Treatment of Wet Gangrene/Wet Gangrene is characterized by thriving bacteria and has a poor prognosis (compared to dry gangrene) due to sepsis resulting from the free communication between infected fluid and circulatory fluid. In wet gangrene, the tissue is infected by saprogenic microorganisms (Clostridium perfringens or Bacillus fusiformis, for example), which cause the tissue to swell and emit a bad smell. Wet gangrene usually develops rapidly due to blockage of venous (mainly) or arterial blood flow.[rx] The affected part is saturated with stagnant blood, which promotes the rapid growth of bacteria.
Gangrene localized death of animal soft tissue, caused by prolonged interruption of the blood supply that may result from injury or infection. Diseases in which gangrene is prone to occur include arteriosclerosis, diabetes, Raynaud’s disease, thromboangiitis obliterans (Buerger’s disease), and typhus. It also may occur after severe burns, freezing, or prolonged bed rest (bed sores).
Gangrene is a rapidly progressive life-threatening infection of skeletal muscle caused by clostridia (principally Clostridium perfringens). It is due to wound contamination in the setting of severe tissue trauma, inadequate surgical débridement, immunosuppression, and impaired blood supply. Rarely, nontraumatic gas gangrene caused by Clostridium septicum may occur in patients with occult gastrointestinal malignancies and lead to transient bacteremia.
Gangrene is a type of tissue death caused by a lack of blood supply.[rx] Symptoms may include a change in skin color to red or black, numbness, swelling, pain, skin breakdown, and coolness.[rx] The feet and hands are most commonly affected.[rx] Certain types may present with a fever or sepsis.[rx]
Types of Gangrene
Dry gangrene
Dry gangrene is a form of coagulative necrosis that develops in ischemic tissue, where the blood supply is inadequate to keep tissue viable. It is not a disease itself, but a symptom of other diseases.[rx] Dry gangrene is often due to peripheral artery disease but can be due to acute limb ischemia. As a result, people with arteriosclerosis, high cholesterol, diabetes, and smoking commonly have dry gangrene.[rx]
The affected area becomes cold and numb.
Initially, the affected area becomes red.
Then, it develops a brown discoloration.
Finally, it becomes black and shriveled.
Wet gangrene
Wet or infected, gangrene is characterized by thriving bacteria and has a poor prognosis (compared to dry gangrene) due to sepsis resulting from the free communication between infected fluid and circulatory fluid. In wet gangrene, the tissue is infected by saprogenic microorganisms (Clostridium perfringens or Bacillus fusiformis, for example), which cause the tissue to swell and emit a bad smell. Wet gangrene usually develops rapidly due to blockage of venous (mainly) or arterial blood flow.[rx] The affected part is saturated with stagnant blood, which promotes the rapid growth of bacteria.
The affected area becomes swollen and decays.
It is extremely painful.
Local oozing occurs.
It produces a foul-smelling odor.
It becomes black.
The affected person develops a fever.
Gas gangrene
Gas gangrene is a bacterial infection that produces gas within tissues. It can be caused by Clostridium, most commonly alpha toxin-producing C. perfringens, or various nonclostridial species.[rx][rx] The infection spreads rapidly as the gases produced by the bacteria expand and infiltrate healthy tissue in the vicinity. Because of its ability to quickly spread to surrounding tissues, gas gangrene should be treated as a medical emergency.
A brown-red or bloody discharge may ooze from the affected tissues.
The gas produced by Clostridia may produce a crackling sensation when the affected area is pressed.
It becomes swollen, and blisters may develop.
Pain in the affected area is severe.
The affected person develops fever, increased heart rate, and rapid breathing if the toxins spread into the bloodstream.
Clinical consideration when gas gangrene is present.
(I) Clostridial myonecrosis (true gas gangrene)
(A) Localized – crepitant or noncrepitant
(B) Diffuse – crepitant or noncrepitant together with toxemia
(II) Clostridial cellulitis – anaerobic or crepitant
(B) Nonbacterial – mechanical trauma; infiltration from air-hose
injury.
Internal gangrene
Gangrene that affects one or more of your organs, such as your intestines, gallbladder or appendix, is called internal gangrene. This type of gangrene occurs when blood flow to an internal organ is blocked — for example, when your intestines bulge through a weakened area of muscle in your abdomen (hernia) and become twisted. Internal gangrene may cause fever and severe pain. Left untreated, internal gangrene can be fatal.
Fournier’s gangrene
Fournier’s gangrene involves genital organs. Men are more often affected, but women can develop this type of gangrene as well. Fournier’s gangrene usually arises due to an infection in the genital area or urinary tract and causes genital pain, tenderness, redness, and swelling.
This rare type of gangrene typically occurs after an operation, with painful skin lesions developing one to two weeks after surgery.
Other Types
Necrotizing fasciitis, also known as hemolytic streptococcal gangrene, is an infection that spreads deep into the body along tissue planes. It is characterized by infection with S.pyogenes, a gram-positive cocci bacteria.[rx]
Noma is a gangrene of the face.
Fournier gangrene is a type of necrotizing fasciitis that usually affects the genitals and groin.[rx]
Venous limb gangrene may be caused by heparin-induced thrombocytopenia and thrombosis.[rx]
Severe mesenteric ischemia may result in gangrene of the small intestine.
Severe ischemic colitis may result in gangrene of the large intestine.
Causes of Gangrene
All forms of gangrene happen because of a loss of blood supply to a certain area. This deprives tissue of oxygen and nutrients, causing the tissue to die.
Dry forms can also result from:
Vascular problems – Most commonly due to the poor health of arteries and veins in the legs and toes. This usually develops over time due to conditions such as diabetes, peripheral arterial disease, and high blood pressure.
Severe burns, scalds, and cold – Heat, chemical agents, and extreme cold, including frostbite, can all lead to dry gangrene. Wet gangrene may develop later.
Raynaud’s disease – There is impaired circulation to the ends of fingers and toes, especially in cold weather. Raynaud’s is implicated in some cases of gangrene.
Diabetes – Imbalanced blood sugar levels can damage blood vessels and nerves, reducing the oxygen supply to extremities.
Injury – Deep, crushing, or penetrating wounds that are sustained in conditions that allow bacterial infection can lead to gangrene. Examples are war zones and railway, machinery, and street accidents if lacerated and bruised tissues are contaminated.
Dry gangrene – If the area is infected with bacteria.
Embolism – The sudden blockage of an artery can lead to dry gangrene, but it also increases the risk of infection, and therefore wet gangrene.
Immune deficiency – If an immune system is weakened, for example by HIV, diabetes, long-time alcohol or drug abuse, or recent chemotherapy or radiotherapy, minor infections escalate more quickly and can become gangrenous.
Anorectal Causes
Trauma
Ischiorectal, perirectal, or perianal abscesses, appendicitis,
Electrolytes, BUN, creatinine, blood glucose levels: acidosis with hyperglycemia or hypoglycemia may be present. Dehydration occurs as the disease progresses.
ABG sampling to provide a more accurate assessment of acid/base disturbance.
Blood and urine cultures.
Disseminated intravascular coagulation (DIC) panel (coagulation studies, fibrinogen/fibrin degradation product levels) to find evidence of severe sepsis.
Cultures of any open wound or abscess.
Fluid or tissue culture – where a small tissue or fluid sample from the affected area is tested to find out which bacteria are responsible for the condition and determine the most effective antibiotic to treat it with
Blood cultures – where a sample of blood is taken and put into special culture bottles and placed in a warm environment (incubated) to encourage the growth of bacteria so they can be examined further
Imaging tests – a range of imaging tests, such as X-rays, magnetic resonance imaging (MRI) scans or computerized tomography (CT) scans can be used to confirm the presence and spread of gangrene; these tests can also be used to study blood vessels so any blockages can be identified
Ankle-brachial index test – This test helps in determining arterial blood circulation and blood pressure in the lower extremities.[rx]
Carotid duplex test – This test is done to know the rate of blood flow through carotid arteries. It helps in exploring the presence of any plaques that may cause carotid artery disease.[rx]
Computed angiography and magnetic resonance angiography – These are the computerized imaging tests that are useful in studying in the blood vessels. These techniques help the vascular surgeons to know the severity of the disease.[rx]
Duplex ultrasound – Duplex ultrasound is used to assess the blood flow status in blood vessels. With this technique, vascular surgeons easily explore the existence of an occlusion or clot and plan the treatment.[rx]
Skin perfusion pressure (SPP) and skin vascular resistance – SPP and skin vascular resistance measurements also help in distinguishing the patients who require vascular reconstruction or major amputation and the patients who only require foot care or require minor amputation [rx]. A prospective, double-blinded study by Castronuovo et al concluded that in ~80% cases, SPP helps in diagnosing the critical limb ischemia accurately.[rx],[rx]
Ultrasonography – A US finding in Fournier gangrene is a thickened wall containing hyperechoic foci that demonstrate reverberation artifacts, causing “dirty” shadowing that represents gas within the scrotal wall. Evidence of gas within the scrotal wall may be seen prior to clinical crepitus. Reactive unilateral or bilateral hydroceles may also be present. If testicular involvement occurs, there is likely an intraabdominal or retroperitoneal source of infection. US is also useful in differentiating Fournier gangrene from an inguinoscrotal incarcerated hernia; in the latter condition, gas is observed in the obstructed bowel lumen, away from the scrotal wall [rx].
Computed Tomography – The CT features of Fournier gangrene include soft-tissue thickening and inflammation. CT can demonstrate asymmetric fascial thickening, any coexisting fluid collection or abscess, fat stranding around the involved structures, and subcutaneous emphysema secondary to gas-forming bacteria. The underlying cause of the Fournier gangrene, such as a perianal abscess, a fistulous tract, or an intraabdominal or retroperitoneal infectious process, may also be demonstrated at CT. In early Fournier gangrene, CT can depict progressive soft-tissue infiltration, possibly with no evidence of subcutaneous emphysema. Because the infection progresses rapidly, the early stage with lack of subcutaneous emphysema is brief and is rarely seen at CT [rx].
Treatment of Gangrene
Broad-Spectrum Antibiotics Coverage
Empiric broad-spectrum antibiotic therapy should be instituted as soon as possible until the culture results could make adjusted the therapy. The antibiotic regimen chosen must have a high degree of effectiveness against staphylococcal and streptococcal bacteria, gram-negative, coliforms, pseudomonas, Bacteroides, and clostridium.
Classically Triple therapy is usually recommended. Third generation cefalosporins or aminoglycosides, plus penicillin and metronidazole.
Clindamycin may be used as it is shown to suppress toxin production and modulate cytokine production; also use of linezolid, daptomycin, and tigecycline is warranted in cases of previous hospitalizations with prolonged antibiotic therapy which may lead to resistant Bacteroides [rx].
[stextbox id=’custom’]
Pharmacologic approaches for gangrene management
Pharmacologic approach
Drugs class examples
Mechanism of action
Pain management
Opioids and opioid-like analgesics Morphine, oxycodone, dextromethorphan, tapentadol, tramadol
Mimic the actions of endogenous opioid peptides by interacting with mu, delta, or kappa opioid receptors
Cause activation of anticlotting factors, direct inhibition of thrombin, inhibition of synthesis of blood coagulation factor precursors (zymogens), and activation of protein C
Cause lysis of thrombi/clot to recanalize the occluded vessels
Antibiotics
Penicillins: flucloxacillin
Inhibit bacterial cell wall synthesis by binding to specific penicillin-binding proteins located inside the bacterial cell wall
Fluoroquinolones: ciprofloxacin
Inhibit topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair, strand supercoiling repair, and recombination
Antiprotozoals: metronidazole
In reduced form, they covalently bind to DNA, disrupt its helix structure, inhibiting bacterial nucleic acid synthesis, and cause bacterial cell death
Carbapenems: ertapenem, meropenem
Show bactericidal activity by inhibiting the bacterial cell wall synthesis
Glycopeptides: teicoplanin, vancomycin
Inhibit the bacterial cell wall synthesis and cause cell death
Tetracyclines: doxycycline
Reversibly bind to 30S ribosomal subunits and possibly to 50S subunits, block the binding of aminoacyl tRNA to mRNA, and inhibit bacterial protein synthesis
Lincosamides: clindamycin
Inhibit bacterial protein synthesis by binding to 50S ribosomal subunits of the bacteria
Oxazolidinones: linezolid
Selectively inhibit bacterial protein synthesis by binding to bacterial ribosomes and prevent the formation of a functional 70S initiation complex
Early IV antibiotics with early surgical debridement followed by hyperbaric oxygen therapy can salvage patients with an otherwise nearly always fatal disease. Intravenous antibiotics and early surgical debridement of the necrotic tissue reduce fatality rate to about 30%. With the addition of hyperbaric oxygen therapy, this can be reduced down to 5 to 10%.
Hyperbaric oxygen therapy helps by halting exotoxin production by the bacteria, helps to improve the bactericidal effect of the antibiotic, treats the tissue ischemia, improves reperfusion injury of the tissue, and promotes the activation and migration of stem cells and polymorphonuclear cells.
Pain management
Gangrene is usually associated with intermittent claudication in the limbs of patients. Thus, it is important to effectively manage the pain to let the patient continue exercises to improve circulation.
Opioid analgesics are recommended for pain associated with chronic limb ischemia. Apart from vascular factors, neuropathic pain should also be managed as a priority.[rx]
Circulation management
As the senile/dry gangrene is a consequence of ischemia, improving the blood circulation in limbs helps overcome peripheral artery disease.[rx] As per the American Diabetes Association, antiplatelet therapy or platelet aggregation inhibitors are highly recommended for preventing the vascular complications in diabetes patients.[rx] In some cases, surgery may be carried out to restore the blood flow to the affected area. The main techniques used to achieve this are:
Bypass surgery – where the surgeon redirects the flow of blood and bypasses the blockage by connecting (grafting) one of your veins to a healthy part of an artery
Angioplasty – where a tiny balloon is placed into a narrow or blocked artery and is inflated to open up the vessel; a small metal tube, known as a stent, may also be inserted into the artery to help keep it open
Research suggests that both techniques are equally effective in restoring blood flow and preventing the need for amputation in the short-term. An angioplasty has the advantage of having a faster recovery time than bypass surgery, although it may not be as effective in the long-term as bypass surgery.
Lipid-lowering agents
Dyslipidemia plays a major role in the progression of diabetic toe gangrene. Thus, diabetes patients should undergo a regular lipid profile check-up. In a descriptive case series study performed by Memon et al, 55.11% cases were reported to have abnormal lipid profile and 44.89% cases had lipid profile within the normal range.
As per Wagner’s scale, the percentage of patients with superficial ulcers (Grade I), ulcer extension (Grade II), deep ulcer with abscess (Grade III), gangrene of ore foot (Grade IV), and extensive gangrene foot (Grade V) was found to be 30.61%, 19.39%, 21.42%, 16.33%, and 12.25% respectively. A significant difference (p=0.001) was found in the gangrenous diabetic foot, grade IV and grade V.[rx]
Larval debridement therapy (biosurgery)
In some cases, it may be possible to use larval debridement therapy, also known as biosurgery, instead of conventional surgery to remove the dead tissue. Certain types of fly larvae are ideal for this because they feed on dead and infected tissue but leave healthy tissue alone. They also help fight infection by releasing substances that kill bacteria and stimulate the healing process.
Maggots used for larval therapy are specially bred in a laboratory using eggs that have been treated to remove bacteria. The maggots are placed on the wound and covered with gauze, under a firm dressing, which keeps them on the wound (and out of sight). After a few days, the dressing is cut away and the maggots are removed. Medical studies have shown larval debridement therapy can achieve more effective results than surgical debridement. However, because of the nature of this type of treatment, many people are reluctant to try it.
Exercise
Apart from drugs, in dry gangrene patients with peripheral arterial disease, guideline-directed management and therapy should be followed to decrease arterial occlusion or impaired perfusion, prevent the progression of chronic critical limb ischemia, and improve the functional status of affected limbs.
This involves exercises which are done under structured or unstructured programs. Structured exercise programs include intermittent walking followed by alternate rest time. These are organized in the health care facilities and are supervised by a trained health care professional. Unstructured home-based exercise programs also include walking as a major exercise without any supervisor’s guidance.[rx,rx]
Massage therapy
Massage Therapy is also recommended to improve the circulation in limbs. Only light pressure massage is given to the affected limb to avoid any clot formation. Massage should be cautiously done in patients with a stent, with special instructions given by the health care professional.[rx]
Fasciotomy
It may be necessary to relieve compartment pressures. As the infection progresses into deep tissue along and under the fascia tissue compartment pressures increase, which perpetuates further tissue ischemia and necrosis. Surgical debridement should focus on removing all the necrotic tissue, and foreign bodies such as soil, debris, and shrapnel. It is also important to irrigate the wounds with copious amounts of sterile normal saline.
Hyperbaric oxygen therapy
It should be added to standard therapy of antibiotics and surgical debridement to help improve survival.[rx][rx] It is important to have coordinated care of these critically ill patients with an intensivist, general surgeon, orthopedic surgeon, urologist (in the setting of Fournier’s gangrene of the testicles and perineal structures), gynecologist (in the setting of uterine gas gangrene), infectious disease specialist, hematologist/oncologist, gastroenterologist (in the setting of spontaneous gas gangrene), and hyperbaric oxygen therapy specialist. The flow of consultation starts with usually an emergency department provider and early recognition of the disease.
Conventional Radiography
At radiography, hyperlucencies representing soft tissue gas may be seen in the region overlying the scrotum or perineum. Subcutaneous emphysema may be seen extending from the scrotum and perineum to the inguinal regions, anterior abdominal wall, and thighs.
However, the absence of subcutaneous air in the scrotum or perineum does not exclude the diagnosis of Fournier gangrene. Up to 90% of patients with Fournier gangrene have been reported to have subcutaneous emphysema so that at least 10% do not demonstrate this finding [rx].
Radiography may also demonstrate significant swelling of scrotal soft tissue. Deep fascial gas is rarely seen at radiography, which represents a significant weakness of this modality in the diagnosis and evaluation of Fournier gangrene [rx].
Radical Surgical Debridement
A debridement of the necrotic tissue as soon as possible it is widely recommended Laor et al. found no significant difference between the onset time of symptoms, early surgical treatment, and mortality, but other studies from Kabay et al. [rx] and Korkut et al. [rx] show that this time interval should be as short as possible.
Debridement of deep fascia and muscle is not usually required as these areas are rarely involved similar to testes. Debridement should be stopped when the separation of the skin and the subcutaneous is not performed easily because the cutaneous necrosis is not a good marker. Multiple surgical debridements is the rule rather than the exception, with an average of 3.5 procedures required per patient [rx]
Fecal and Urinary Diversion
Colostomy has been used for fecal diversion in cases of severe perineal involvement. The rationale for rectal diversion includes a decrease in the number of germs in the perineal region and improved wound healing. Justifications for its construction are anal sphincter involving, fecal incontinence, or continues fecal contamination of the wound’s margins. In several papers, the percentage of patients with a colostomy is around 15% depending on the series [rx].
Topical Therapy
There have been reports of the use of honey to aid wound healing. Honey has a low pH of 3.6 and contains enzymes which digest necrotic tissues it also has antibacterial property due to phenolic acid. These changes occur within a week of applying honey to the wound. Unfortunately, there is no randomized study on the efficacy of honey in these special situations. [rx]
Hyperbaric Oxygen Therapy
Hyperbaric oxygen therapy implies placing the patient in an environment of increased ambient pressure while breathing 100% oxygen, resulting in enhanced oxygenation of the arterial blood and tissues and demonstrated benefits of hyperbaric oxygen include adequate oxygenation for optimal neutrophil phagocytic function, inhibition of anaerobic growth, increased fibroblast proliferation and angiogenesis, reduction of edema by vasoconstriction, and increased intracellular antibiotics transportation [rx].
Vacuum-Assisted Closure
With the recent advent of the vacuum-assisted closure (VAC) system dressing, there seems to be a dramatic improvement with minimizing skin defects and speeding tissue healing. It simply works by exposing a wound to subatmospheric pressure for an extended period to promote debridement and healing.
Weinfeld et al. treated four consecutive cases using negative pressure dressings (VAC) to bolster skin grafts in male genital reconstruction.
Plastic Reconstruction
Various workers have used different techniques to provide skin cover including transplantation of testes, free skin grafts, axial groin flaps, and myocutaneous flaps. Split thickness skin graft seems to be the treatment of choice in treating perineal and scrotal skin defects.
Home Exercise
A healthy, well-balanced diet and regular exercise will keep your blood pressure and cholesterol levels at a healthy level, helping prevent your blood vessels become damaged.
Unless advised otherwise by your doctor, you should be aiming for at least 150 minutes (2.5 hours) of moderately intense physical exercise a week.
Moderate-intensity physical activity is any activity that increases your heart and breathing rate. It may make you sweat but you’ll still be able to hold a normal conversation. Examples include:
fast walking
cycling on level ground or with few hills
swimming
tennis
You should choose physical activities you enjoy because you’re more likely to continue doing them. It’s probably unrealistic to meet these exercise targets immediately if you haven’t exercised much in the past. Aim to start gradually and build up the amount of exercise you do overtime.
Diet
Eating an unhealthy diet high in fat will make any existing atherosclerosis worse and increase your risk of developing gangrene.
Continuing to eat high-fat foods will cause more fatty plaques to build-up in your arteries. This is because fatty foods contain cholesterol.
There are 2 types of fat-saturated and unsaturated. Avoid foods that contain saturated fats because they increase levels of “bad cholesterol” in your blood.
Foods high in saturated fat include:
meat pies
sausages and fatty cuts of meat
butter
ghee (a type of butter often used in Indian cooking)
lard
cream
hard cheese
cakes and biscuits
food containing coconut or palm oil
Prevention of Gangrene
Our emergency clinicians should be aware of this severe and potentially fatal infectious disease and should not delay treatment or prompt orthopedic surgery consultation. Gas gangrene, while rare in now peace days, can be a devastating complication of almost any small wound or surgical procedure even one as common as closed reduction of fractures. It is our experience that we should give sufficient extension of the wound to provide adequate visualization of the surgical field so as to be certain that all the necrotic or foreign material has been removed.
Strict aseptic techniques should be observed for even the most minor procedure. Clostridial spores are ubiquitous and can reside in hospital environments, possibly on surgeons’ hands, patients’ skin, topical application, and so on.
The best way to prevent gas gangrene is meticulous wound debridement and delayed closure for all potentially contaminated wounds regardless of closed or open fractures.
Once gas gangrene is diagnosed, careful and adequate debridement should be instituted immediately to avoid further deterioration excision of necrotic tissue still the cornerstone of treatment, which should be involved with antibiotics and all other supportive treatments.
Systematic resuscitative efforts should be instituted immediately in whom the diagnosis of incipient gas gangrene is even considered. This cannot be overemphasized.
Recognized that gas gangrene may occur spontaneously and often in an immunocompromised patient, postoperative wounds may also develop gas gangrene due to the local soft tissue damage and decreasing blood supply.
Keep wounds clean and sterile by cleaning all wounds thoroughly with an antiseptic solution.
Watch for signs of infection, such as pus, redness, swelling, or unusual pain.
Consult a health-care provider if any wound becomes infected.
People with diabetes should control their blood sugar levels with proper medication.
Education about proper foot care is vital for people with diabetes. They should routinely examine their feet for any signs of injury or change in skin color. Any small injury should be immediately cared for. They should keep their nails trimmed and wear comfortable well-fitting shoes.
Current Treatment Options For Penile Fractures/Penile fracture is defined as the traumatic rupture of the tunica albuginea of the corpora cavernosum. Traumatic rupture of the penis is relatively uncommon and is considered a urologic emergency [rx]. The tunica albuginea is a bilaminar structure (inner circular, outer longitudinal) composed of collagen and elastin. Penile fracture has typical clinical signs reported as trauma to the penis, audible clicking sound, post erection detumescence with hematoma, and swelling. Structural anomalies could alter the mechanical properties of the tunica albuginea, representing a weakening factor of the corpora cavernosa and thus a predisposing factor for traumatic rupture of the penis.[rx] The need for immediate surgery is emphasized, in order to avoid erectile failure and curvature, which are typical complications of conservative treatment.[rx] Many conditions can simulate fracture penis as dorsal vein tears in the penis may mimic penile fracture.[rx]
Penile fracture is a rupture of one or both of the tunica albuginea, the fibrous coverings that envelop the penis’s corpora cavernosa. It is caused by rapid blunt force to an erect penis, usually during Sexual intercourse, or aggressive masturbation.[rx] It sometimes also involves partial or complete rupture of the urethra or injury to the dorsal nerves, veins, and arteries.[rx]
Anatomy of Penile Fracture
Fracture of the penis is a relatively uncommon form of urologic trauma. It is a disruption of the tunica albuginea of one or both corpus cavernosum due to blunt trauma to the erect penis [rx]. It can be accompanied by partial or complete urethral rupture or by injury of the dorsal nerve and vessels [rx].
Tunica albuginea is one of the strongest fasciae in the human body. One reason for the increased risk of penile fracture is that the tunica albuginea stretches and thins significantly during erection: in the flaccid state it is up to 2.4 mm thick; during erection, it becomes as thin as 0.25 to 0.5 mm. Bitsch et al. and De Rose et al. proposed that an intracorporal pressure of 1500 mmHg or more during erection can tear the tunica albuginea [rx,rx].
Causes of Penile Fracture
Vigorous sexual intercourse is the main cause of penile fracture in the Western world.
Trauma during sexual intercourse was the most common cause of the penile fracture.
Because of high energy trauma, urethral rupture is associated in up to 38% of penile fractures [rx].
Fracture of the penis is a urological emergency resulting from a tear in the tunica albuginea of the penis often due to forceful manipulation, vigorous vaginal or anal intercourse or masturbation, gunshot wounds, or any other mechanical trauma that causes forcible bending of an erect penis.
Less common etiologies include turning over in bed, a direct blow, forced bending, or hastily removing or applying to clothe when the penis is erect [rx].
Most commonly, it involves one of the corpora cavernosa. It may also affect both corpora cavernous, corpus spongiosum or urethra [rx].
During an erection, the thickness of the tunica albuginea decreases from 2 mm in the flaccid state to 0.25–0.5 mm. Therefore the penis is more vulnerable to traumatic injury [rx].
The most common mechanism of injury is when the penis slips out of the vagina and strikes against the symphysis pubis or perineum.
Symptoms of Penile Fracture
A popping or cracking sound, significant pain, swelling, immediate loss of erection leading to flaccidity, and skin hematoma of various sizes are commonly associated with the sexual event.[rx][rx]
Acute onset of pain, swelling, and ecchymosis of the penis during sexual intercourse indicate a penile fracture until proven otherwise.[rx]
Detumescence voiding difficulties and penile swelling and deviation may accompany.
Swelling and ecchymosis spreads to perineum, scrotum, and lower abdominal wall within the Colles fascia if the buck’s fascia gives way and produces typical butterfly-pattern ecchymosis.
Rolling sign can be demonstrated in fracture penis which is the movement of penile skin over the organized hematoma at the site of rupture of tunica albuginea.
Audible snapping or popping sound
Sudden loss of your erection
Severe pain following the injury
Dark bruising above the injured area
Bent penis
Blood leaking from penis
Difficult urination
Diagnosis of Penile Fracture
A doctor can typically diagnose a penile fracture by asking questions about how the fracture occurred and inspecting the penis.
Imaging studies for penile injuries include
X-ray – can be used to map out an injury to the penis that is thought to be a penile fracture. These techniques can be used to detect whether the urethra has been torn or damaged. They can also be used to identify other concerns such as injury to the arteries and veins of the penis.
Ultrasound – Tunica albuginea is usually seen as a hyperechoic linear band in the penis covering two corpora cavernosa and the corpora spongiosa. A hypoechoic breach in this band may be seen especially along the longitudinal axis of the penis. The associated collection is also seen along with the breach.
MRI – Tunica albuginea is a hypointense band on all sequences. A tear can be seen as a T2 hyperintense breach in this band. MRI can accurately determine if the fracture is transversely or longitudinally oriented. Also, it can accurately depict the depth and extent of tear. Magnetic resonance imaging (MRI) with a scanner that uses a magnetic field and radio-energy pulses to create detailed images of the inside of the penis.
Cavernosography – It is an interventional procedure and usually avoided, however, may depict the tear in corpora cavernosa.
Retrograde urethrography – Urethral rupture or post-traumatic stricture can be depicted by this imaging.
Early conservative treatment with cold applications – pressure dressings, catheterization, anti-inflammatory drugs, antibiotics and erection suppressing drugs is now replaced with immediate surgical repair.
A broad-spectrum antibiotic – low molecular heparin (dalteparin) were given during the hospital stay. Nocturnal erections recovered on the third postoperative day and they were mitigated with diazepam. On day 12 the catheter was removed and on day 13 the patient was released home. The antibiotic was continued at home for the next 10 days.
Surgery
Penile fracture is a medical emergency – and emergency surgical repair is the usual treatment. Delay in seeking treatment increases the complication rate. Non-surgical approaches result in 10–50% complication rates including erectile dysfunction, permanent penile curvature, damage to the urethra and pain during sexual intercourse, while operatively treated patients experience an 11% complication rate.[rx][rx] In some cases, retrograde urethrogram may be performed to rule out concurrent urethral injury.
Recovery time varies significantly – depending on the type of fracture and the specific surgical procedure. Men may be in the hospital for anywhere between one day and three weeks.
Fortunately – only a small fraction of men with penile fractures experience significant complications after surgery. Found that fewer than 2 percent of men who had surgery for penile fracture experienced long-term erectile dysfunction.
In addition – less than 3 percent experienced permanent curvature of the penis. Those numbers were significantly higher for men whose penile fractures were managed more conservatively.
