FEVER of Unknown Origin (FUO)

PYREXIA of Unknown Origin (PUO)

Essentials of Diagnosis

• Illness of at least 3 weeks duration.
• Fever over 38.3 °C on several occasions.
• Diagnosis has not been made after three outpatient visits or 3 days of hospitalization.

General Considerations

The intervals specified in the criteria for the diagnosis of FUO are arbitrary ones intended to exclude patients with protracted but self-limited viral illnesses and to allow time for the usual radiographic, serologic, and cultural studies to be performed. Because of costs of hospitalization and the availability of most screening tests on an outpatient basis, the original criterion requiring 1 week of hospitalization has been modified to accept patients in whom a diagnosis has not been made after three outpatient visits or 3 days of hospitalization.

Several additional categories of FUO have been added: (1) Hospital-associated FUO refers to the hospitalized patient with fever of 38.3 °C or higher on several occasions, due to a process not present or incubating at the time of admission, in whom initial cultures are negative and the diagnosis remains unknown after 3 days of investigation (see Hospital-Associated Infections, below). (2) Neutropenic FUO includes patients with fever of 38.3 °C or higher on several occasions with < 500 neutrophils per microliter in whom initial cultures are negative and the diagnosis remains uncertain after 3 days (see Chapter 2: Common Symptoms and Infections in the Immunocompromised Patient, below). (3) HIV-associated FUO pertains to HIV-positive patients with fever of 38.3 °C or higher who have been febrile for 4 weeks or more as an outpatient or 3 days as an inpatient, in whom the diagnosis remains uncertain after 3 days of investigation with at least 2 days for cultures to incubate (see Chapter 31: HIV Infection & AIDS). Although not usually considered separately, FUO in solid organ transplant recipients is a common scenario with a unique differential diagnosis and is discussed below.

For a general discussion of fever, see the section on fever and hyperthermia in Chapter 2: Common Symptoms.

Common Causes

Most cases represent unusual manifestations of common diseases and not rare or exotic diseases—eg, tuberculosis, endocarditis, gallbladder disease, and HIV (primary infection or opportunistic infection) are more common causes of FUO than Whipple disease or familial Mediterranean fever.

Age of Patient

In adults, infections (25–40% of cases) and cancer (25–40% of cases) account for the majority of FUOs. In children, infections are the most common cause of FUO (30–50% of cases) and cancer a rare cause (5–10% of cases). Autoimmune disorders occur with equal frequency in adults and children (10–20% of cases), but the diseases differ. Juvenile rheumatoid arthritis is particularly common in children, whereas systemic lupus erythematosus, Wegener granulomatosis, and polyarteritis nodosa are more common in adults. Still disease, giant cell arteritis, and polymyalgia rheumatica occur exclusively in adults. In the elderly (over 65 years of age), multisystem immune-mediated diseases such as temporal arteritis, polymyalgia rheumatica, sarcoidosis, rheumatoid arthritis, and Wegener granulomatosis account for 25–30% of all FUOs.

Duration of Fever

The cause of FUO changes dramatically in patients who have been febrile for 6 months or longer. Infection, cancer, and autoimmune disorders combined account for only 20% of FUOs in these patients. Instead, other entities such as granulomatous diseases (granulomatous hepatitis, Crohn disease, ulcerative colitis) and factitious fever become important causes. One-fourth of patients who say they have been febrile for 6 months or longer actually have no true fever or underlying disease. Instead, the usual normal circadian variation in temperature (temperature 0.5–1 °C higher in the afternoon than in the morning) is interpreted as abnormal. Patients with episodic or recurrent fever (ie, those who meet the criteria for FUO but have fever-free periods of 2 weeks or longer) are similar to those with prolonged fever. Infection, malignancy, and autoimmune disorders account for only 20–25% of such fevers, whereas various miscellaneous diseases (Crohn disease, familial Mediterranean fever, allergic alveolitis) account for another 25%. Approximately 50% remain undiagnosed but have a benign course with eventual resolution of symptoms.

Immunologic Status

In the neutropenic patient, fungal infections and occult bacterial infection are important causes of FUO. In the patient taking immunosuppressive medications (particularly organ transplant patients), cytomegalovirus (CMV) infections are a frequent cause of fever, as are fungal infections, nocardiosis, Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia, and mycobacterial infections.

Classification of Causes of FUO

Most patients with FUO will fit into one of five categories.

Infection

Both systemic and localized infections can cause FUO. Tuberculosis and endocarditis are the most common systemic infections, but mycoses, viral diseases (particularly infection with Epstein-Barr virus and CMV), toxoplasmosis, brucellosis, Q fever, cat-scratch disease, salmonellosis, malaria, and many other less common infections have been implicated. Primary infection with HIV or opportunistic infections associated with AIDS—particularly mycobacterial infections—can also present as FUO. The most common form of localized infection causing FUO is an occult abscess. Liver, spleen, kidney, brain, and bone abscesses may be difficult to detect. A collection of pus may form in the peritoneal cavity or in the subdiaphragmatic, subhepatic, paracolic, or other areas. Cholangitis, osteomyelitis, urinary tract infection, dental abscess, or paranasal sinusitis may cause prolonged fever.

Neoplasms

Many cancers can present as FUO. The most common are lymphoma (both Hodgkin and non-Hodgkin) and leukemia. Posttransplant lymphoproliferative disorders may also present with fever. Other diseases of lymph nodes, such as angioimmunoblastic lymphoma and Castleman disease, can also cause FUO. Primary and metastatic tumors of the liver are frequently associated with fever, as are renal cell carcinomas. Atrial myxoma is an often forgotten neoplasm that can result in fever. Chronic lymphocytic leukemia and multiple myeloma are rarely associated with fever, and the presence of fever in patients with these diseases should prompt a search for infection.

Autoimmune disorders

Still disease, systemic lupus erythematosus, cryoglobulinemia, and polyarteritis nodosa are the most common causes of autoimmune-associated FUO. Giant cell arteritis and polymyalgia rheumatica are seen almost exclusively in patients over 50 years of age and are nearly always associated with an elevated erythrocyte sedimentation rate (> 40 mm/h).

Miscellaneous causes

Many other conditions have been associated with FUO but less commonly than the foregoing types of illness. Examples include thyroiditis, sarcoidosis, Whipple disease, familial Mediterranean fever, recurrent pulmonary emboli, alcoholic hepatitis, drug fever, and factitious fever.

Undiagnosed FUO

Despite extensive evaluation, the diagnosis remains elusive in 15% or more of patients. Of these patients, the fever abates spontaneously in about 75% with no diagnosis; in the remainder, more classic manifestations of the underlying disease appear over time.

Clinical Findings

Because the evaluation of a patient with FUO is costly and time-consuming, it is imperative to first document the presence of fever. This is done by observing the patient while the temperature is being taken to ascertain that fever is not factitious (self-induced). Associated findings that accompany fever include tachycardia, chills, and piloerection. A thorough history—including family, occupational, social (sexual practices, use of injection drugs), dietary (unpasteurized products, raw meat), exposures (animals, chemicals), and travel—may give clues to the diagnosis. Repeated physical examination may reveal subtle, evanescent clinical findings essential to diagnosis.

Laboratory Tests

In addition to routine laboratory studies, blood cultures should always be obtained, preferably when the patient has not taken antibiotics for several days, and should be held by the laboratory for 2 weeks to detect slow-growing organisms. Cultures on special media are requested if Legionella, Bartonella, or nutritionally deficient streptococci are possible pathogens. "Screening tests" with immunologic or microbiologic serologies ("febrile agglutinins") are of low yield and should not be done. If the history or physical examination suggests a specific diagnosis, specific serologic tests with an associated fourfold rise or fall in titer may be useful. Because infection is the most common cause of FUO, other body fluids are usually cultured, ie, urine, sputum, stool, cerebrospinal fluid, and morning gastric aspirates (if one suspects tuberculosis). Direct examination of blood smears may establish a diagnosis of malaria or relapsing fever (Borrelia).

Imaging

All patients with FUO should have a chest radiograph. Studies such as sinus films, upper gastrointestinal series with small bowel follow-through, barium enema, proctosigmoidoscopy, and evaluation of gallbladder function are reserved for patients who have symptoms, signs, or a history that suggest disease in these body regions. CT scan of the abdomen and pelvis is also frequently performed and is particularly useful for looking at the liver, spleen, and retroperitoneum. When the CT scan is abnormal, the findings often lead to a specific diagnosis. A normal CT scan is not quite as useful; more invasive procedures such as biopsy or exploratory laparotomy may be needed. The role of MRI in the investigation of FUO has not been evaluated. In general, however, MRI is better than CT for detecting lesions of the nervous system and is useful in diagnosing various vasculitides. Ultrasound is sensitive for detecting lesions of the kidney, pancreas, and biliary tree. Echocardiography should be used if one is considering endocarditis or atrial myxoma. Transesophageal echocardiography is more sensitive than surface echocardiography for detecting valvular lesions, but even a negative transesophageal study does not exclude endocarditis (10% false-negative rate). The usefulness of radionuclide studies in diagnosing FUO is variable. Theoretically, a gallium or positron-emission (PET) scan would be more helpful than an indium-labeled white blood cell scan, because gallium and fluorodeoxy-glucose may be useful for detecting infection, inflammation, and neoplasm whereas the indium scan is useful only for detecting infection. Indium-labeled immunoglobulin may prove to be useful in detecting infection and neoplasm and can be used in the neutropenic patient. It is not sensitive for lesions of the liver, kidney, and heart because of high background activity. In general, radionuclide scans are plagued by high rates of false-positive and false-negative results that are not useful when used as screening tests and, if done at all, are limited to those patients whose history or examination suggests local inflammation or infection.

Biopsy

Invasive procedures are often required for diagnosis. Any abnormal finding should be aggressively evaluated: Headache calls for lumbar puncture (see illustration) to rule out meningitis; skin rash should be biopsied for cutaneous manifestations of collagen vascular disease or infection; and enlarged lymph nodes should be aspirated or biopsied for neoplasm and sent for culture. Bone marrow aspiration with biopsy is a relatively low-yield procedure (15–25%; except in HIV-positive patients, in whom mycobacterial infection is a common cause of FUO), but the risk is low and the procedure should be done if other less invasive tests have not yielded a diagnosis, particularly in persons with hematologic abnormalities. Liver biopsy will yield a specific diagnosis in 10–15% of patients with FUO and should be considered in any patient with abnormal liver function tests even if the liver is normal in size. CT scanning and MRI have decreased the need for exploratory laparotomy; however, surgical visualization and biopsies should be considered when there is continued deterioration or lack of diagnosis.

Treatment

An empiric course of antimicrobials (eg, quinolones for possible cystitis) should be considered if an infectious diagnosis is strongly suspected. However, if there is no clinical response, it is imperative to stop therapy and reevaluate. Once definitive culture results return, streamlining therapy to the most narrow spectrum antimicrobial should take place. Antituberculosis medications (particularly in the elderly or foreign-born) and broad-spectrum antibiotics may be reasonable in this setting.

Empiric administration of corticosteroids should be discouraged because they can suppress fever and exacerbate many infections.

When to Refer

• Any patient with FUO and progressive weight loss and other constitutional signs.
• Any immunocompromised patient (eg, transplant recipients and HIV-infected patients).
• Infectious diseases specialists may also be able to coordinate and interpret specialized testing (eg, Q fever serologies) with outside agencies, such as the US Centers for Disease Control and Prevention.

When to Admit

• Any patient who is rapidly declining with weight loss where hospital admission may expedite work-up.
• If FUO is present in immunocompromised patients, such as those who are neutropenic from recent chemotherapy or those who have undergone transplantation (particularly in the previous 6 months

Guillain-Barré Syndrome

What is Guillain-Barré Syndrome?

Guillain-Barré syndrome is a disorder in which the body's immune system attacks part of the peripheral nervous system. The first symptoms of this disorder include varying degrees of weakness or tingling sensations in the legs. In many instances, the weakness and abnormal sensations spread to the arms and upper body. These symptoms can increase in intensity until the muscles cannot be used at all and the patient is almost totally paralyzed. In these cases, the disorder is life-threatening and is considered a medical emergency. The patient is often put on a respirator to assist with breathing. Most patients, however, recover from even the most severe cases of Guillain-Barré syndrome, although some continue to have some degree of weakness. Guillain-Barré syndrome is rare. Usually Guillain-Barré occurs a few days or weeks after the patient has had symptoms of a respiratory or gastrointestinal viral infection. Occasionally, surgery or vaccinations will trigger the syndrome. The disorder can develop over the course of hours or days, or it may take up to 3 to 4 weeks. No one yet knows why Guillain-Barré strikes some people and not others or what sets the disease in motion. What scientists do know is that the body's immune system begins to attack the body itself, causing what is known as an autoimmune disease. Guillain-Barré is called a syndrome rather than a disease because it is not clear that a specific disease-causing agent is involved. Reflexes such as knee jerks are usually lost. Because the signals traveling along the nerve are slower, a nerve conduction velocity (NCV) test can give a doctor clues to aid the diagnosis. The cerebrospinal fluid that bathes the spinal cord and brain contains more protein than usual, so a physician may decide to perform a spinal tap.

Symptoms

Guillain-Barre syndrome often begins with weakness, tingling or loss of sensation starting in your feet and legs and spreading to your upper body and arms. These symptoms may begin — often not causing much notice — in your fingers and toes. In some people, symptoms begin in the arms or even the face. As the disorder progresses, muscle weakness can evolve into paralysis.

Signs and symptoms of Guillain-Barre syndrome may include:

• Prickling, "pins and needles" sensations in your fingers, toes or both
• Weakness or tingling sensations in your legs that spread to your upper body
• Unsteady walking or inability to walk
• Difficulty with eye movement, facial movement, speaking, chewing or swallowing
• Severe pain in your lower back
• Difficulty with bladder control or intestinal functions
• Very slow heart rate or low blood pressure
• Difficulty breathing

Most people with Guillain-Barre syndrome experience their most significant weakness within three weeks after symptoms begin. In some cases, signs and symptoms may progress very rapidly with complete paralysis of legs, arms and breathing muscles over the course of a few hours.

When to see a doctor
Call your doctor if you have mild tingling in your toes or fingers that doesn't seem to be spreading or getting worse.

Seek emergency medical help if you have any of the following severe signs or symptoms:

• Tingling that started in your feet or toes and is now ascending upward through your body
• Tingling or weakness that's spreading rapidly
• Tingling that involves both your hands and feet
• Difficulty catching your breath
• Choking on saliva

Guillain-Barre syndrome is a serious disease that requires immediate hospitalization because of the rapid rate at which it worsens. The sooner appropriate treatment is started, the better the chance of a good outcome.

Causes

The exact cause of Guillain-Barre syndrome is unknown. In about 60 percent of cases, an infection affecting either the lungs or the digestive tract precedes the disorder. But scientists don't know why such an infection can lead to Guillain-Barre syndrome for some people and not for others. Many cases appear to occur without any triggers.

In Guillain-Barre syndrome, your immune system — which usually only attacks foreign material and invading organisms — begins attacking the nerves that carry signals between your body and your brain. Specifically, the nerves' protective covering (myelin sheath) is damaged and this interferes with the signaling process, causing weakness, numbness or paralysis.

Diagnostic criteria

• Progressive, relatively symmetrical weakness of two or more limbs due to neuropathy
• Areflexia
• Disorder course < 4 weeks
• Exclusion of other causes (see below)

Supportive

• relatively symmetric weakness accompanied by numbness and/or tingling
• mild sensory involvement
• facial nerve or other cranial nerve involvement
• absence of fever
• typical CSF findings obtained from lumbar puncture
• electrophysiologic evidence of demyelination from electromyogram

Differential diagnosis:

• acute myelopathies with chronic back pain and sphincter dysfunction
• botulism with early loss of pupillary reactivity and descending paralysis
• diphtheria with early oropharyngeal dysfunction
• Lyme disease polyradiculitis and other tick-borne paralyses
porphyria with abdominal pain, seizures, psychosisvasculitis neuro
• pathy
• poliomyelitis with fever and meningeal signs
• CMV polyradiculitis in immunocompromised patients
• critical illness neuropathy
• myasthenia gravis
• poisonings with organophosphate, poison hemlock, thallium, or arsenic
• intoxication with Karwinskia humboldtiana leaves or seeds
• paresis caused by West Nile virus
• spinal astrocytoma
• motor neurone disease
• West Nile virus can cause severe, potentially fatal neurological illnesses, which include encephalitis, meningitis, Guillain-Barré syndrome, and anterior myelitis.

Treatments

Although some people can take months and even years to recover, most cases of Guillain-Barre syndrome follow this general timeline:

• Following the first symptoms, the condition tends to progressively worsen for about two weeks.
• Symptoms reach a plateau and remain steady for two to four weeks.
• Recovery begins, usually lasting six to 12 months.

There's no cure for Guillain-Barre syndrome. But two types of treatments speed recovery and reduce the severity of Guillain-Barre syndrome:

• Plasmapheresis. This treatment — also known as plasma exchange — is a type of "blood cleansing" in which damaging antibodies are removed from your blood. Plasmapheresis consists of removing the liquid portion of your blood (plasma) and separating it from the actual blood cells. The blood cells are then put back into your body, which manufactures more plasma to make up for what was removed. It's not clear why this treatment works, but scientists believe that plasmapheresis rids plasma of certain antibodies that contribute to the immune system attack on the peripheral nerves.
• Intravenous immunoglobulin. Immunoglobulin contains healthy antibodies from blood donors. High doses of immunoglobulin can block the damaging antibodies that may contribute to Guillain-Barre syndrome.

Each of these treatments is equally effective. Mixing the treatments or administering one after the other is no more effective than using either method alone.

Often before recovery begins, caregivers may need to manually move your arms and legs to help keep your muscles flexible and strong. After recovery has begun, you'll likely need physical therapy to help regain strength and proper movement so that you'll be able to function on your own. You may need training with adaptive devices, such as a wheelchair or braces, to give you mobility and self-care skills.

Prognosis

Most of the time recovery starts after the fourth week from the onset of the disorder. Approximately 80% of patients have a complete recovery within a few months to a year, although minor findings may persist, such as areflexia. About 5–10% recover with severe disability, with most of such cases involving severe proximal motor and sensory axonal damage with inability of axonal regeneration. However, this is a grave disorder and despite all improvements in treatment and supportive care, the death rate among patients with this disorder is still about 2–3% even in the best intensive care units. Worldwide, the death rate runs slightly higher (4%), mostly from a lack of availability of life support equipment during the lengthy plateau lasting four to six weeks, and in some cases up to one year, when a ventilator is needed in the worst cases. About 5–10% of patients have one or more late relapses, in which case they are then classified as having chronic inflammatory demyelinating polyneuropathy (CIDP).

Poor prognostic factors include: 1) age, over 40 years, 2) history of preceding diarrheal illness, 3) requiring ventilator support, 4) high anti-GM1 titre and 5) poor upper limb muscle strength

Migraine

Migraine

Essentials of Diagnosis

• Headache, usually pulsatile.
• Pain is typically, but not always, unilateral.
• Nausea, vomiting, photophobia, and phonophobia are common accompaniments.
• May be transient neurologic symptoms (commonly visual) preceding headache of classic migraine.
• No preceding aura is common.

General Considerations

The pathophysiology of migraine probably relates to neurovascular dysfunction. Headache results from the dilatation of blood vessels innervated by the trigeminal nerve caused by release of neuropeptides from parasympathetic nerve fibers approximating these vessels. The probable underlying mechanism is activation of the trigeminal nucleus caudalis, nucleus tractus solitarius, and dorsal raphe nucleus. Imaging studies have revealed changes in brainstem regions involved in sensory modulation, suggesting that migraine relates to a failure of normal sensory processing. Before or simultaneous with symptom onset, regional cerebral blood flow is decreased in the cortex corresponding to the clinically affected area; after one to several hours, hyperemia occurs in this same region. Cortical spreading depression of Leão has been implicated.

Clinical Findings

Classic migrainous headache is a lateralized throbbing headache that occurs episodically following its onset in adolescence or early adult life. In many cases, however, the headaches do not conform to this pattern, although their associated features and response to antimigrainous preparations nevertheless suggest that they have a similar basis. In this broader sense, migrainous headaches may be lateralized or generalized, may be dull or throbbing, and are sometimes associated with anorexia, nausea, vomiting, photophobia, phonophobia, osmophobia, cognitive impairment, and blurring of vision. They usually build up gradually and may last for several hours or longer. Focal disturbances of neurologic function may precede or accompany the headaches and have been attributed to constriction of branches of the internal carotid artery. Visual disturbances occur commonly and may consist of field defects; of luminous visual hallucinations such as stars, sparks, unformed light flashes (photopsia), geometric patterns, or zigzags of light; or of some combination of field defects and luminous hallucinations (scintillating scotomas). Other focal disturbances such as aphasia or numbness, paresthesias, clumsiness, dysarthria, dysequilibrium, or weakness in a circumscribed distribution may also occur.

In rare instances, the neurologic or somatic disturbance accompanying typical migrainous headaches becomes the sole manifestation of an attack ("migraine equivalent"). Very rarely, the patient may be left with a permanent neurologic deficit following a migrainous attack.

Patients often give a family history of migraine. Attacks may be triggered by emotional or physical stress, lack or excess of sleep, missed meals, specific foods (eg, chocolate), alcoholic beverages, bright lights, loud noise, menstruation, or use of oral contraceptives.

An uncommon variant is basilar artery migraine, in which blindness or visual disturbances throughout both visual fields are initially accompanied or followed by dysarthria, dysequilibrium, tinnitus, and perioral and distal paresthesias and are sometimes followed by transient loss or impairment of consciousness or by a confusional state. This, in turn, is followed by a throbbing (usually occipital) headache, often with nausea and vomiting.

In ophthalmoplegic migraine, lateralized pain—often about the eye—is accompanied by nausea, vomiting, and diplopia due to transient external ophthalmoplegia. The ophthalmoplegia is due to third nerve palsy, sometimes with accompanying sixth nerve involvement, and may outlast the orbital pain by several days or even weeks. The ophthalmic division of the fifth nerve has also been affected in some patients. Ophthalmoplegic migraine is rare; more common causes of a painful ophthalmoplegia are internal carotid artery aneurysms and diabetes.

Familial hemiplegic migraine (FHM) designates the occurrence of migraine with aura including weakness when at least one first- or second-degree relative has a similar disorder. Specific genetic subtypes are recognized: in FHM1, mutations occur in the CACN1A gene on chromosome 19, and in FHM2, mutations occur in the ATP1A2 gene on chromosome 1. In sporadic hemiplegic migraine, no other family members are affected.

Treatment

Management of migraine consists of avoidance of any precipitating factors, together with prophylactic or symptomatic pharmacologic treatment if necessary.

Symptomatic Therapy

During acute attacks, many patients find it helpful to rest in a quiet, darkened room until symptoms subside. A simple analgesic (eg, aspirin, acetaminophen, ibuprofen, or naproxen) taken right away often provides relief, but treatment with prescription therapy is sometimes necessary. To prevent medication overuse, use of simple analgesics should be limited to 15 days or less per month, and combination analgesics should be limited to < 10 days per month.

Cafergot, a combination of ergotamine tartrate (1 mg) and caffeine (100 mg), is often particularly helpful; one or two tablets are taken at the onset of headache or warning symptoms, followed by one tablet every 30 minutes, if necessary, up to six tablets per attack and no more than 10 days per month. Because of impaired absorption or vomiting during acute attacks, oral medication sometimes fails to help. Cafergot given rectally as suppositories (one-half to one suppository containing 2 mg of ergotamine) or dihydroergotamine mesylate (0.5–1 mg intravenously or 1–2 mg subcutaneously or intramuscularly) may be useful in such cases. Alternatively, prochlorperazine administered rectally (25 mg suppository) or intravenously (10 mg) may be prescribed. Ergotamine-containing preparations may affect the gravid uterus and thus should be avoided during pregnancy.

Sumatriptan, which has a high affinity for serotonin₁ receptors, is a rapidly effective agent for aborting attacks when given subcutaneously by an autoinjection device (4–6 mg once subcutaneously, may repeat once after 2 hours if needed; maximum dose 12 mg/24 h). It can also be taken in a nasal form, but absorption is limited, and an oral preparation is available. Zolmitriptan, another selective serotonin₁ receptor agonist, has high bioavailability after oral administration and is also effective for the immediate treatment of migraine. The optimal initial oral dose is 5 mg, and relief usually occurs within 1 hour; may repeat once after 2 hours. It is also available in a nasal formulation, which has a rapid onset of action; the dose is 5 mg in one nostril once and it may be repeated once after 2 hours. The maximum dose for both formulations is 10 mg/24 h. A number of other triptans are available, including rizatriptan (5–10 mg orally at onset; may repeat every 2 hours twice [maximum dose 30 mg/24 h]), naratriptan (1–2.5 mg orally at onset; may repeat once after 4 hours [maximum dose 5 mg/24 h]), almotriptan (6.25–12.5 mg orally at onset; may repeat dose once after 2 hours [maximum dose 25 mg/24 h]), frovatriptan (2.5 mg orally at onset; may repeat after 2 hours once [maximum dose 7.5 mg/24]), and eletriptan (20–40 mg orally at onset; may repeat after 2 hours once [maximum dose 80 mg/24 h]).

Eletriptan is useful for immediate therapy and frovatriptan, which has a longer half-life, may be worthwhile for patients with prolonged attacks. Triptans may cause nausea and vomiting. They should probably be avoided in women who are pregnant, in patients with hemiplegic or basilar migraine, and in patients with risk factors for stroke (such as hypertension, prior stroke or transient ischemic attack, diabetes mellitus, hypercholesterolemia, obesity). Triptans are contraindicated in patients with coronary or peripheral vascular disease. Patients often experience greater benefit when the triptan is combined with naproxen (500 mg).

The neuroleptic droperidol is also helpful in aborting acute attacks. Metoclopramide given intravenously may be helpful and is being studied. Opioid analgesics are needed in rare instances, as when patients are unable to use vasoactive agents or nonsteroidal medications; options include meperidine (100 mg intramuscularly) or butorphanol tartrate by nasal spray (1 mg/spray in one nostril, repeated after 3 or 4 hours if necessary). Intravenous propofol in subanesthetic doses may help in intractable cases.

Preventive Therapy

Preventive treatment may be necessary if migrainous headaches occur more frequently than two or three times a month or significant disability is associated with attacks. Some of the more common drugs used for this purpose are listed in Table 24–1. Their mode of action is unclear but may involve alteration of central neurotransmission. Several drugs may have to be tried in turn before the headaches are brought under control. Once a drug has been found to help, it should be continued for several months. If the patient remains headache-free, the dose can then be tapered and the drug eventually withdrawn. Botulinum toxin type A may be effective for migraine prevention in some patients; it has few systemic side effects and need only be given at intervals of several months. However, no statistically significant between-group differences were found in frequency of migraine episodes per 30-day period in a randomized, double-blind, placebo-controlled exploratory study. Although acupuncture has been widely used in the prophylaxis of migraine, a randomized controlled trial failed to show any difference between it and sham acupuncture.

Therapeutic Effects of Lowering Cholesterol

Therapeutic Effects of Lowering Cholesterol

Reducing cholesterol levels in healthy middle-aged men without CHD (primary prevention) reduces their risk in proportion to the reduction in LDL cholesterol and the increase in HDL cholesterol. Treated patients have statistically significant and clinically important reductions in the rates of myocardial infarctions, new cases of angina, and need for coronary artery bypass procedures. The West of Scotland Study showed a 31% decrease in myocardial infarctions in middle-aged men treated with pravastatin compared with placebo. The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) study showed similar results with lovastatin. As with any primary prevention interventions, large numbers of healthy patients need to be treated to prevent a single event. The numbers of patients needed to treat (NNT) to prevent a nonfatal myocardial infarction or a coronary artery disease death in these two studies were 46 and 50, respectively. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) study of atorvastatin in subjects with hypertension and other risk factors but without CHD also demonstrated a convincing 36% reduction in CHD events. The Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) showed a 44% reduction in a combined end point of myocardial infarction, stroke, revascularization, hospitalization for unstable angina, or death from cardiovascular causes. The NNT for 1 year to prevent one event was 169.

Primary prevention studies have found a less consistent effect on total mortality. The West of Scotland study found a 20% decrease in total mortality, tending toward statistical significance. The AFCAPS/TexCAPS study with lovastatin showed no difference in total mortality. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT) also showed no reduction either in all-cause mortality or in CHD events when pravastatin was compared with usual care. Subjects treated with atorvastatin in the ASCOT study had a 13% reduction in mortality, but the result was not statistically significant. This study, however, was stopped early due to the marked reduction in CHD events. The JUPITER trial demonstrated a statistically significant 20% reduction in death from any cause. The NNT for 1 year was 400.

In patients with CHD, the benefits of cholesterol lowering are clearer. Major studies with statins have shown significant reductions in cardiovascular events, cardiovascular deaths, and all-cause mortality in men and women with coronary artery disease. The NNT to prevent a nonfatal myocardial infarction or a coronary artery disease death in these three studies were between 12 and 34. Aggressive cholesterol lowering with these agents causes regression of atherosclerotic plaques in some patients, reduces the progression of atherosclerosis in saphenous vein grafts, and can slow or reverse carotid artery atherosclerosis. Meta-analysis suggests that this latter effect results in a significant decrease in strokes. Results with other classes of medications have been less consistent. For example, gemfibrozil treatment subjects had fewer cardiovascular events, but there was no benefit in all-cause mortality when compared with placebo.

The disparities in results between primary and secondary prevention studies highlight several important points. The benefits and adverse effects of cholesterol lowering may be specific to each type of drug; the clinician cannot assume that the effects will generalize to other classes of medication. Second, the net benefits from cholesterol lowering depend on the underlying risk of CHD and of other disease. In patients with atherosclerosis, morbidity and mortality rates associated with CHD are high, and measures that reduce it are more likely to be beneficial even if they have no effect—or even slightly harmful effects—on other diseases.

Facial Pain Due to Other Causes

Facial Pain Due to Other Causes

Facial pain may be caused by temporomandibular joint dysfunction in patients with malocclusion, abnormal bite, or faulty dentures. There may be tenderness of the masticatory muscles, and an association between pain onset and jaw movement is sometimes noted. This pattern differs from that of jaw (masticatory) claudication, a symptom of giant cell arteritis, in which pain develops progressively with mastication. Treatment of the underlying joint dysfunction relieves symptoms.

A relationship of facial pain to chewing or temperature changes may suggest a dental disturbance. The cause is sometimes not obvious, and diagnosis requires careful dental examination and radiographs. Sinusitis and ear infections causing facial pain are usually recognized by the history of respiratory tract infection, fever, and, in some instances, aural discharge. There may be localized tenderness. Radiologic evidence of sinus infection or mastoiditis is confirmatory.

Glaucoma is an important ocular cause of facial pain, usually localized to the periorbital region.

On occasion, pain in the jaw may be the principal manifestation of angina pectoris. Precipitation by exertion and radiation to more typical areas establish the cardiac origin.

When to Refer

• Worsening pain unresponsive to simple measures.
• Continuing pain of uncertain cause.
• For consideration of surgical treatment (trigeminal or glossopharyngeal neuralgia).

Postherpetic Neuralgia

Postherpetic Neuralgia

Herpes zoster (shingles) is due to infection of the nervous system by varicella-zoster virus. About 15% of patients who develop shingles suffer from postherpetic neuralgia. This complication seems especially likely to occur in the elderly, when the rash is severe, and when the first division of the trigeminal nerve is affected. It also relates to the duration of the rash before medical consultation. A history of shingles and the presence of cutaneous scarring resulting from shingles aid in the diagnosis. Severe pain with shingles correlates with the intensity of postherpetic symptoms.

The incidence of postherpetic neuralgia may be reduced by the treatment of shingles with oral acyclovir or famciclovir, but this is disputed; systemic corticosteroids do not help. Zoster vaccine markedly reduces morbidity from herpes zoster and postherpetic neuralgia among older adults. Management of the established complication is essentially medical. If simple analgesics fail to help, a trial of a tricyclic antidepressant (eg, amitriptyline, up to 100–150 mg/d) in conjunction with a phenothiazine (eg, perphenazine, 2–8 mg/d) is often effective. Other patients respond to carbamazepine (up to 1200 mg/d), phenytoin (300 mg/d), or gabapentin (up to 3600 mg/d), or pregabalin (up to 300 mg/d). A combination of gabapentin and morphine taken orally may provide better analgesia at lower doses of each agent than either taken alone. Topical application of capsaicin cream (eg, Zostrix, 0.025%) is sometimes helpful, perhaps because of depletion of pain-mediating peptides from peripheral sensory neurons, and topical lidocaine (5%) is also worthy of trial. The administration of live-attenuated zoster vaccine to patients over the age of 60 years is important in preventing the occurrence of herpes zoster and thus of postherpetic neuralgia.

Glossopharyngeal Neuralgia

Glossopharyngeal Neuralgia

Glossopharyngeal neuralgia is an uncommon disorder in which pain similar in quality to that in trigeminal neuralgia occurs in the throat, about the tonsillar fossa, and sometimes deep in the ear and at the back of the tongue. The pain may be precipitated by swallowing, chewing, talking, or yawning and is sometimes accompanied by syncope. In most instances, no underlying structural abnormality is present; multiple sclerosis is sometimes responsible. Oxcarbazepine and carbamazepine (see Table 24–3) are the treatments of choice and should be tried before any surgical procedures are considered. Microvascular decompression is generally preferred over destructive surgical procedures such as partial rhizotomy in medically refractory cases and is often effective without causing severe complications.

Atypical Facial Pain

Atypical Facial Pain

Facial pain without the typical features of trigeminal neuralgia is generally a constant, often burning pain that may have a restricted distribution at its onset but soon spreads to the rest of the face on the affected side and sometimes involves the other side, the neck, or the back of the head as well. The disorder is especially common in middle-aged women, many of them depressed, but it is not clear whether depression is the cause of or a reaction to the pain. Simple analgesics should be given a trial, as should tricyclic antidepressants, carbamazepine, oxcarbazepine, and phenytoin; the response is often disappointing. Opioid analgesics pose a danger of addiction in patients with this disorder. Attempts at surgical treatment are not indicated.

Trigeminal Neuralgia

Essentials of Diagnosis

• Brief episodes of stabbing facial pain.
• Pain is in the territory of the second and third division of the trigeminal nerve.
• Pain exacerbated by touch.

General Considerations

Trigeminal neuralgia ("tic douloureux") is most common in middle and later life. It affects women more frequently than men.

Clinical Findings

Momentary episodes of sudden lancinating facial pain occur and commonly arise near one side of the mouth and shoot toward the ear, eye, or nostril on that side. The pain may be triggered or precipitated by such factors as touch, movement, drafts, and eating. Indeed, in order to lessen the likelihood of triggering further attacks, many patients try to hold the face still while talking. Spontaneous remissions for several months or longer may occur. As the disorder progresses, however, the episodes of pain become more frequent, remissions become shorter and less common, and a dull ache may persist between the episodes of stabbing pain. Symptoms remain confined to the distribution of the trigeminal nerve (usually the second or third division) on one side only.

Differential Diagnosis

The characteristic features of the pain in trigeminal neuralgia usually distinguish it from other causes of facial pain. Neurologic examination shows no abnormality except in a few patients in whom trigeminal neuralgia is symptomatic of some underlying lesion, such as multiple sclerosis or a brainstem neoplasm, in which case the finding will depend on the nature and site of the lesion. Similarly, CT scans and radiologic contrast studies are often normal in patients with classic trigeminal neuralgia.

In a young patient presenting with trigeminal neuralgia, multiple sclerosis must be suspected even if there are no other neurologic signs. In such circumstances, findings on evoked potential testing and examination of cerebrospinal fluid may be corroborative. When the facial pain is due to a posterior fossa tumor, CT scanning and MRI generally reveal the lesion.

Treatment

The drugs most helpful for treatment are oxcarbazepine (although not approved by the US Food and Drug Administration [FDA] for this indication) or carbamazepine, with monitoring by serial blood counts and liver function tests. If these medications are ineffective or cannot be tolerated, phenytoin should be tried. (Doses and side effects of these drugs are shown in Table 24–3.) Baclofen (10–20 mg three or four times daily) or lamotrigine (400 mg orally daily) may also be helpful, either alone or in combination with one of these other agents. Gabapentin may also relieve pain, especially in patients who do not respond to conventional medical therapy and those with multiple sclerosis. Depending on response and tolerance, up to 2400 mg/d is given in divided doses.

Tension-Type Headache

Tension-Type Headache

Although this is the most common type of primary headache disorder, many patients do not seek medical attention. Patients frequently complain of pericranial tenderness, poor concentration, and other vague nonspecific symptoms, in addition to constant daily headaches that are often vise-like or tight in quality but are not pulsatile. Headaches may be exacerbated by emotional stress, fatigue, noise, or glare. The headaches are usually generalized, may be most intense about the neck or back of the head, and are not associated with focal neurologic symptoms.

When treatment with simple analgesics is not effective, a trial of antimigrainous agents (see Migraine, below) is worthwhile. Techniques to induce relaxation are also useful and include massage, hot baths, and biofeedback. Acupuncture has helped some patients. Exploration of underlying causes of chronic anxiety is often rewarding. Local injection of botulinum toxin type A is sometimes helpful, has few systemic adverse effects, and requires only infrequent administration.

Cluster Headache

Cluster Headache

Cluster headache affects predominantly middle-aged men. The pathophysiology is unclear but may relate to activation of cells in the ipsilateral hypothalamus, triggering the trigeminal autonomic vascular system. There is often no family history of headache or migraine. Episodes of severe unilateral periorbital pain occur daily for several weeks and are often accompanied by one or more of the following: ipsilateral nasal congestion, rhinorrhea, lacrimation, redness of the eye, and Horner syndrome. During attacks, patients are often restless and agitated. Episodes often occur at night, awaken the patient, and last for between 15 minutes and 3 hours. Spontaneous remission then occurs, and the patient remains well for weeks or months before another bout of closely spaced attacks occurs. Bouts may last for 4 to 8 weeks and may occur up to several times per year. During a bout, many patients report that alcohol triggers an attack; others report that stress, glare, or ingestion of specific foods occasionally precipitates attacks. In occasional patients, typical attacks of pain and associated symptoms recur at intervals without remission. This variant has been referred to as chronic cluster headache.

Examination reveals no abnormality apart from Horner syndrome that either occurs transiently during an attack or, in longstanding cases, remains as a residual deficit between attacks.

Treatment of an individual attack with oral drugs is generally unsatisfactory, but subcutaneous (6 mg dose) or intranasal (20-mg/spray) sumatriptan or inhalation of 100% oxygen (12–15 L/min for 15 minutes via a non-rebreather mask) may be effective. Zolmitriptan (5- and 10-mg nasal spray) is also effective. Dihydroergotamine (0.5–1 mg intramuscularly or intravenously) is sometimes used. Viscous lidocaine (1 mg of 4–6% solution) intranasally is sometimes effective.

Various prophylactic agents that have been found to be effective in individual patients are cyproheptadine, lithium carbonate (monitored by plasma lithium determination), verapamil (240–960 mg daily), topiramate (100–400 mg daily), valproate (750–1500 mg daily), and methysergide (2–12 mg daily). As there is often a delay before these medications are effective, transitional therapy is often used. Ergotamine tartrate is effective and can be given as rectal suppositories (0.5–1 mg at night or twice daily), by mouth (2 mg daily), or by subcutaneous injection (0.25 mg three times daily for 5 days per week). Other options include prednisone (60 mg daily for 5 days followed by gradual withdrawal), dihydroergotamine (9.25 mg intravenously over several days or 0.5 mg intramuscularly twice daily), or greater occipital nerve injection with lidocaine and corticosteroid.

Mesothelioma

Mesothelioma is a rare form of cancer that primarily affects the lining of the lungs. In less common cases, the heart and abdomen can also be affected by mesothelioma cancer. Approximately 2,000 to 3,000 cases of mesothelioma are diagnosed each year in the United States, comprising around 3 percent of all cancer diagnoses. This cancer occurs about four times more frequently in men than in women and all forms of mesothelioma, except for benign mesothelioma, are terminal since no cure has been discovered.
The life expectancy for mesothelioma patients is generally reported as less than one year following diagnosis. However, a patient’s prognosis is affected by several factors, including how early the cancer is diagnosed and how aggressively it is treated.
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Symptoms

Signs and symptoms of mesothelioma vary depending on where the cancer occurs.
Pleural mesothelioma, which affects the tissue that surrounds the lungs, causes signs and symptoms that may include:

• Chest pain under the rib cage
• Painful coughing
• Shortness of breath
• Unusual lumps of tissue under the skin on your chest
• Unexplained weight loss

Peritoneal mesothelioma, which occurs in tissue in the abdomen, causes signs and symptoms that may include:

• Abdominal pain
• Abdominal swelling
• Lumps of tissue in the abdomen
• Unexplained weight loss

Other forms of mesothelioma
Signs and symptoms of other types of mesothelioma are unclear. Other forms of mesothelioma are so rare that not much information is available. Pericardial mesothelioma, which affects tissue that surrounds the heart, can cause signs and symptoms such as breathing difficulty and chest pains. Mesothelioma of tunica vaginalis, which affects tissue surrounding the testicles, may be first detected as a mass on a testicle.

Who Gets Mesothelioma?

Statistics show that, because of their work history, the disease most often affects men between the ages of 50 and 70 who were employed in an asbestos-laden environment before asbesto regulations were imposed in the late 1970s. Though women still have a much lower frequency of the disease, cases of second-hand exposure to asbestos has prompted more diagnoses among women, especially those whose male family members worked with asbestos. The occupations most associated with mesothelioma are shipyard workers, electricians, plumbers, construction industry workers, pipefitters, boilermakers, and anyone subject to heavy exposure to dangerous airborne asbestos fibers.
An abundance of cases have also shown us that mesothelioma can develop among people who lived in communities where asbestos factories or mines were located. In some instances, entire towns have been adversely affected by the presence of asbestos in the air. For example, in Libby, Montana - site of a former vermiculite asbestos mine - hundreds have already died of mesothelioma.
Though still significantly rarer than other cancers, an estimated 2,000 to 3,000 new cases of mesothelioma are diagnosed each year in the United States. Other countries, notably the United Kingdom and Australia, report a much higher incidence of the disease. Nevertheless, the United States - like many other countries - has seen an increase in asbestos-caused cancer as men who worked in U.S. shipyards in the 1940s and 1950s, at the height of production, are now being diagnosed with mesothelioma.

Causes

In general, cancer begins when a series of genetic mutations occur within a cell, causing the cell to grow and multiply out of control. It isn't clear what causes the initial genetic mutations that lead to mesothelioma, though researchers have identified factors that may increase the risk. It's likely that cancers form because of an interaction between many factors, such as inherited conditions, your environment, your health conditions and your lifestyle choices.

Mesothelioma doesn't include a noncancerous tumor
A form of noncancerous (benign) tumor that can occur in the chest is sometimes called benign mesothelioma. However, this name is misleading. Benign mesothelioma doesn't begin in the same cells where the cancerous forms of mesothelioma begin. And, in a minority of cases, benign mesothelioma can be very aggressive, despite the term "benign." For this reason, some doctors now refer to this tumor as solitary fibrous tumor.
Solitary fibrous tumor usually doesn't cause signs and symptoms. Most cases are inadvertently discovered during tests and procedures for other conditions. It isn't clear what causes solitary fibrous tumors, but they aren't linked to asbestos exposure. Treatment for solitary fibrous tumor typically includes surgery.

Mesothelioma Symptoms

Symptoms of mesothelioma typically do not appear until 20 to 50 years after someone's initial exposure to asbestos occurred. Mesothelioma symptoms often resemble less-serious conditions, which can make a diagnosis difficult. Below is a list of several common symptoms mesothelioma patients may experience.
Pleural Symptoms: Shortness of breath, chest pain, persistent cough, fatigue, lumps under the skin on the chest
Peritoneal Symptoms: Weight loss, abdominal pain and swelling, bowel obstruction, nausea
Pericardial Symptoms: Heart palpitations, irregular heartbeat, chest pain, difficulty breathing, night sweats
Testicular Symptoms: Painful or painless testicular lumps

Diagnosis

CXR demonstrating a mesothelioma

CT scan of a patient with mesothelioma, coronal section (the section follows the plane that divides the body in a front and a back half). The mesothelioma is indicated by yellow arrows, the central pleural effusion (fluid collection) is marked with a yellow star. Red numbers: (1) right lung, (2) spine, (3) left lung, (4) ribs, (5) descending part of the aorta, (6) spleen, (7) left kidney, (8) right kidney, (9) liver.

Micrograph of a pleural fluid cytopathology specimen showing mesothelioma.

Micrographs showing mesothelioma in a core biopsy.

Diagnosing mesothelioma is often difficult, because the symptoms are similar to those of a number of other conditions. Diagnosis begins with a review of the patient's medical history. A history of exposure to asbestos may increase clinical suspicion for mesothelioma. A physical examination is performed, followed by chest X-ray and often lung function tests. The X-ray may reveal pleural thickening commonly seen after asbestos exposure and increases suspicion of mesothelioma. A CT (or CAT) scan or an MRI is usually performed. If a large amount of fluid is present, abnormal cells may be detected by cytopathology if this fluid is aspirated with a syringe. For pleural fluid, this is done by thoracentesis or tube thoracostomy (chest tube); for ascites, with paracentesis or ascitic drain; and for pericardialeffusion with pericardiocentesis. While absence of malignant cells on cytology does not completely exclude mesothelioma, it makes it much more unlikely, especially if an alternative diagnosis can be made (e.g. tuberculosis, heart failure). Unfortunately, the diagnosis of malignant mesothelioma by cytology alone is difficult, even with expert pathologists.
Generally, a biopsy is needed to confirm a diagnosis of malignant mesothelioma. A doctor removes a sample of tissue for examination under a microscope by a pathologist. A biopsy may be done in different ways, depending on where the abnormal area is located. If the cancer is in the chest, the doctor may perform a thoracoscopy. In this procedure, the doctor makes a small cut through the chest wall and puts a thin, lighted tube called a thoracoscope into the chest between two ribs. Thoracoscopy allows the doctor to look inside the chest and obtain tissue samples. Alternatively, the chest surgeon might directly open the chest (thoracotomy). If the cancer is in the abdomen, the doctor may perform a laparoscopy. To obtain tissue for examination, the doctor makes a small incision in the abdomen and inserts a special instrument into the abdominal cavity. If these procedures do not yield enough tissue, more extensive diagnostic surgery may be necessary.
Immunohistochemical studies play an important role for the pathologist in differentiating malignant mesothelioma from neoplastic mimics. There are numerous tests and panels available. No single test is perfect for distinguishing mesothelioma from carcinoma or even benign versus malignant.

Typical immunohistochemistry results

Positive	Negative
EMA (epithelial membrane antigen) in a membranous distribution	CEA (carcinoembryonic antigen)
WT1 (Wilms' tumour 1)	B72.3
Calretinin	MOC-3 1
Mesothelin-1	CD15
Cytokeratin 5/6	Ber-EP4
HBME-1 (human mesothelial cell 1)	TTF-1 (thyroid transcription factor-1)

There are three histological types of malignant mesothelioma: (1) Epithelioid; (2) Sarcomatoid; and (3) Biphasic (Mixed). Epithelioid comprises about 50-60% of malignant mesothelioma cases and generally holds a better prognosis than the Sarcomatoid or Biphasic subtypes.

Staging

Staging of mesothelioma is based on the recommendation by the International Mesothelioma Interest Group.TNM classification of the primary tumor, lymph node involvement, and distant metastasis is performed. Mesothelioma is staged Ia–IV (one-A to four) based on the TNM status.

Treatment

The prognosis for malignant mesothelioma remains disappointing, although there have been some modest improvements in prognosis from newer chemotherapies and multimodality treatments.Treatment of malignant mesothelioma at earlier stages has a better prognosis, but cures are exceedingly rare. Clinical behavior of the malignancy is affected by several factors including the continuous mesothelial surface of the pleural cavity which favors local metastasis via exfoliated cells, invasion to underlying tissue and other organs within the pleural cavity, and the extremely long latency period between asbestos exposure and development of the disease. The histological subtype and the patient's age and health status also help predict prognosis.

Surgery

Surgery, by itself, has proved disappointing. In one large series, the median survival with surgery (including extrapleural pneumonectomy) was only 11.7 monthsHowever, research indicates varied success when used in combination with radiation and chemotherapy (Duke, 2008). (For more information on multimodality therapy with surgery, see below). A pleurectomy/decortication is the most common surgery, in which the lining of the chest is removed. Less common is an extrapleural pneumonectomy (EPP), in which the lung, lining of the inside of the chest, the hemi-diaphragm and the pericardium are removed.

Radiation

For patients with localized disease, and who can tolerate a radical surgery, radiation is often given post-operatively as a consolidative treatment. The entire hemi-thorax is treated with radiation therapy, often given simultaneously with chemotherapy. This approach of using surgery followed by radiation with chemotherapy has been pioneered by the thoracic oncology team at Brigham & Women's Hospital in Boston. Delivering radiation and chemotherapy after a radical surgery has led to extended life expectancy in selected patient populations with some patients surviving more than 5 years. As part of a curative approach to mesothelioma, radiotherapy is also commonly applied to the sites of chest drain insertion, in order to prevent growth of the tumor along the track in the chest wall.
Although mesothelioma is generally resistant to curative treatment with radiotherapy alone, palliative treatment regimens are sometimes used to relieve symptoms arising from tumor growth, such as obstruction of a major blood vessel. Radiation therapy when given alone with curative intent has never been shown to improve survival from mesothelioma. The necessary radiation dose to treat mesothelioma that has not been surgically removed would be very toxic.

 Chemotherapy

Chemotherapy is the only treatment for mesothelioma that has been proven to improve survival in randomised and controlled trials. The landmark study published in 2003 by Vogelzang and colleagues compared cisplatin chemotherapy alone with a combination of cisplatin and pemetrexed (brand name Alimta) chemotherapy in patients who had not received chemotherapy for malignant pleural mesothelioma previously and were not candidates for more aggressive "curative" surgery.This trial was the first to report a survival advantage from chemotherapy in malignant pleural mesothelioma, showing a statistically significant improvement in median survival from 10 months in the patients treated with cisplatin alone to 13.3 months in the group of patients treated with cisplatin in the combination with pemetrexed and who also received supplementation with folate and vitamin B₁₂. Vitamin supplementation was given to most patients in the trial and pemetrexed related side effects were significantly less in patients receiving pemetrexed when they also received daily oral folate 500mcg and intramuscular vitamin B₁₂ 1000mcg every 9 weeks compared with patients receiving pemetrexed without vitamin supplementation. The objective response rate increased from 20% in the cisplatin group to 46% in the combination pemetrexed group. Some side effects such as nausea and vomiting, stomatitis, and diarrhoea were more common in the combination pemetrexed group but only affected a minority of patients and overall the combination of pemetrexed and cisplatin was well tolerated when patients received vitamin supplementation; both quality of life and lung function tests improved in the combination pemetrexed group. In February 2004, the United States Food and Drug Administration approved pemetrexed for treatment of malignant pleural mesothelioma. However, there are still unanswered questions about the optimal use of chemotherapy, including when to start treatment, and the optimal number of cycles to give.
Cisplatin in combination with raltitrexed has shown an improvement in survival similar to that reported for pemetrexed in combination with cisplatin, but raltitrexed is no longer commercially available for this indication. For patients unable to tolerate pemetrexed, cisplatin in combination with gemcitabine or vinorelbine is an alternative, or vinorelbine on its own, although a survival benefit has not been shown for these drugs. For patients in whom cisplatin cannot be used, carboplatin can be substituted but non-randomised data have shown lower response rates and high rates of haematological toxicity for carboplatin-based combinations, albeit with similar survival figures to patients receiving cisplatin.
In January 2009, the United States FDA approved using conventional therapies such as surgery in combination with radiation and or chemotherapy on stage I or II Mesothelioma after research conducted by a nationwide study by Duke University concluded an almost 50 point increase in remission rates.

 Immunotherapy

Treatment regimens involving immunotherapy have yielded variable results. For example, intrapleural inoculation of Bacillus Calmette-Guérin (BCG) in an attempt to boost the immune response, was found to be of no benefit to the patient (while it may benefit patients with bladder cancer). Mesothelioma cells proved susceptible to in vitro lysis by LAK cells following activation by interleukin-2 (IL-2), but patients undergoing this particular therapy experienced major side effects. Indeed, this trial was suspended in view of the unacceptably high levels of IL-2 toxicity and the severity of side effects such as fever and cachexia. Nonetheless, other trials involving interferon alpha have proved more encouraging with 20% of patients experiencing a greater than 50% reduction in tumor mass combined with minimal side effects.

 Heated Intraoperative Intraperitoneal Chemotherapy

A procedure known as heated intraoperative intraperitoneal chemotherapy was developed by Paul Sugarbaker at the Washington Cancer Institute. The surgeon removes as much of the tumor as possible followed by the direct administration of a chemotherapy agent, heated to between 40 and 48°C, in the abdomen. The fluid is perfused for 60 to 120 minutes and then drained.
This technique permits the administration of high concentrations of selected drugs into the abdominal and pelvic surfaces. Heating the chemotherapy treatment increases the penetration of the drugs into tissues. Also, heating itself damages the malignant cells more than the normal cells.
This technique is also used in patients with malignant pleural mesothelioma.

 Multimodality Therapy

All of the standard approaches to treating solid tumors—radiation, chemotherapy, and surgery—have been investigated in patients with malignant pleural mesothelioma. Although surgery, by itself, is not very effective, surgery combined with adjuvant chemotherapy and radiation (trimodality therapy) has produced significant survival extension (3–14 years) among patients with favorable prognostic factors. However, other large series of examining multimodality treatment have only demonstrated modest improvement in survival (median survival 14.5 months and only 29.6% surviving 2 years). Reducing the bulk of the tumor with cytoreductive surgery is key to extending survival. Two surgeries have been developed: extrapleural pneumonectomy and pleurectomy/decortication. The indications for performing these operations are unique. The choice of operation depends on the size of the patient's tumor. This is an important consideration because tumor volume has been identified as a prognostic factor in mesothelioma. Pleurectomy/decortication spares the underlying lung and is performed in patients with early stage disease when the intention is to remove all gross visible tumor (macroscopic complete resection), not simply palliation. Extrapleural pneumonectomy is a more extensive operation that involves resection of the parietal and visceral pleurae, underlying lung, ipsilateral diaphragm, and ipsilateral pericardium. This operation is indicated for a subset of patients with more advanced tumors, who can tolerate a pneumonectomy.

Tricuspid valve disease

For more information on valve disease and its treatment,
The tricuspid valve is located between the right atrium (top chamber) and right ventricle (bottom chamber). Its role is to make sure blood flows in a forward direction from the right atrium to the ventricle.
Tricuspid valve disease refers to abnormal function of the tricuspid valve. Two types of tricuspid disease include:

• Tricuspid regurgitation - the valve is leaky or doesn't close tight enough, causing blood to leak backwards across the valve
• Tricuspid stenosis - the valve leaflets are stiff and do not open widely enough, causing a restriction in the forward flow of blood. Your physician may refer to this as an increased pressure gradient across the valve, found by echocardiogram or cardiac catheterization.

Tricuspid valve disease can be caused by

Tricuspid Regurgitation

• Infection, such as rheumatic fever or infective endocarditis
• A dilated right ventricle, causing the annulus (a ring of tough fibrous tissue which is attached to and supports the leaflets of the valve) of the tricuspid valve to enlarge
• Increased pressure through the tricuspid valve (seen with pulmonary hypertension)
• Less common causes include congenital defects, trauma, carcinoid heart disease, tumor, tricuspid valve prolapse, Ebstein's anomaly, systemic lupus, and trauma.

Tricuspid valve disease, if caused by rheumatic fever, is often combined with mitral and/or aortic valve disease.

What are the symptoms?

Tricuspid valve disease may be tolerated for a long time without any symptoms. Symptoms may include:

Edwards MC ³ Annuloplasty System

• Irregular heart rhythm (atrial fibrillation)
• Easily tired (fatigue)
• A fluttering discomfort in the neck
• With severe disease, heart failure symptoms (right abdominal pain, shortness of breath, swelling in the legs or abdomen, cold skin)

How is Tricuspid Valve Disease diagnosed?

Tricuspid valve disease may first be diagnosed during a physical exam. The doctor will often hear a murmur (abnormal blood flow through the valve). Other signs your doctor may find are an irregular pulse and a fluttering or abnormal pulsation in your neck (jugular vein).
Tests used to diagnose valve disease may include:

• Electrocardiography (ECG)
• Chest X-ray
• Echocardiography
• Transesophageal echocardiography
• Cardiac Catheterization (cardiac cath or angiogram)
• Radionuclide scans
• Magnetic resonance imaging (MRI)

Rx

Medical Management

• Your doctor will want to monitor the progress of your valve disease with regular appointments. They may be spaced once a year or more often, if your doctor feels you need to be followed more closely.
  

  Lanyard and template handle assists with placement of ring
• Your appointment will include a medical exam. Diagnostic studies may be repeated at regular intervals.
• Your physician may prescribe medications to treat your symptoms. These medications may include drugs to treat heart failure or medications to control irregular heart rhythms.

Surgical Management:

Tricuspid valve repair

When valve disease is severe, it may be necessary to repair or replace the diseased valve. Tricuspid valve repair using an annuloplasty ring is the preferred surgical approach for tricuspid regurgitation and may be performed for primary tricuspid disease or for combined cases with other valve surgery (mitral, aortic). See illustrations to the right. For more information and to view actual surgery,
When the valve can not be repaired, a valve replacement will be performed. Find more information about valve surgery.

Endocarditis prevention

Anatomically correct design conforms to the 3-D tricuspid valve opening.

If you have tricuspid valve disease, you are at risk for getting endocarditis, an infection that causes damage to the heart valves (even if your valve has been repaired or replaced with surgery). You will need to follow these guidelines:

• Tell your doctors and dentist you have valve disease. You may want to carry a card with this information.
• Call your doctor if you have symptoms of an infection (sore throat, general body achiness, and fever). Colds and flus do not cause endocarditis. But, infections, which may have the same symptoms, do. So, to be safe, call your doctor.
• Take good care of your teeth and gums to prevent infections. See your dentist for regular visits.
• Take antibiotics before you undergo any procedure that may cause bleeding:
  • any dental work (even a basic teeth cleaning)
  • invasive tests
  • most major or minor surgery

Tricuspid Regurgitation

Background:

Mild Tricuspid regurgitation may be detected in over 90% of the normal population by color Doppler echocardiogram. This is usually a benign finding and does not require any follow up or treatment. Virtually all of the normal population will have a mild degree of leakage in one, two, or three of the heart valves by echocardiogram. We call this physiologic regurgitation and many cardiologists prefer not to mention it to parents, as they may become concerned about a common and benign echocardiogram finding.

Pathologic tricuspid regurgitation is a disorder involving backward flow of blood across the tricuspid valve from the right ventricle (lower heart chamber) to the right atrium (upper heart chamber). Leakage occurs during contraction of the right ventricle and may be caused by damage or malformation of the tricuspid valve or and/or by significant enlargement of the right heart. The tricuspid valve may have been damaged by infection (endocarditis). In other cases, it may be a congenital malformation in the valve itself such as a dysplastic pulmonary valve or Ebstein’s anomaly of the tricuspid valve.

 

Tricuspid regurgitation may also be present in cases of distal anatomic obstructions such as pulmonary valve atresia or in cases of pulmonary hypertension (high pressures in the lungs). Rarely it may be caused by an unusual tumor called a carcinoid, rheumatoid arthritis, radiation therapy, Marfan’s syndrome, or chest trauma. Finally, tricuspid regurgitation is found in many patients with a single ventricle, corrected transposition of the great arteries or those who underwent the Fontan procedure in which the right ventricle is acting as the main pump of the heart. Those patients require lifetime follow up with serial echocardiograms. The tricuspid regurgitation may become severe enough to require heart surgery.

 

Other potential causes of significant tricuspid regurgitation include restrictive cardiomyopathy and constrictive pericarditis.

 

Symptoms:

Mild to moderate tricuspid regurgitation may not produce any symptoms at all in patients with normal pulmonary pressures. Patients with pulmonary hypertension and/or severe tricuspid regurgitation may experience these symptoms:

 Fatigue, tiredness

 Weakness

 Difficulty breathing

 Shortness of breath, especially on exertion

 General swelling

 Swelling of the abdomen

 Swelling of the feet and ankles

 Active pulsing in the neck veins

 Palpitations or “racing heart”

 Weight loss

 Loss of appetite

 Heart failure

Diagnosis and Cardiovascular Tests:

In cases of mild tricuspid regurgitation, the physical examination may be completely normal without an audible heart murmur. In cases of moderate severe tricuspid regurgitation, a heart murmur may be present and the liver may be enlarged. The abdomen may be distended and edema (swollen extremities) may be present. The electrocardiogram and chest x-ray may be abnormal. The echocardiogram is very helpful in determining the degree of tricuspid regurgitation, the size of the right heart, and its function. In addition, it may show the veins draining into the heart as being dilated. An echo may show any malformation or damage to the tricuspid valve or if an associated heart defect is present. Doppler echocardiography is used to estimate the pressures inside the heart and lungs. In more severe cases, the patient may require an MRI or cardiac catheterization.

Treatment:

Most patients with mild tricuspid regurgitation will not require any medical treatment. Patients with a normal heart and very mild forms of tricuspid regurgitation do not require any follow up. In more severe cases, the patients may require diuretics (water pills), while other patients may benefit from other medications that help improve the contractility of the heart. Medical treatment may depend on the underlying condition. For example, patients with pulmonary hypertension may require specific medications to lower lung pressures.

In general, patients with a single ventricle and the Fontan procedure may be on a few medications that may help release some of the volume overload or workload of the right ventricle and others may help improve the contractility of the heart pump.

Patients with an anatomical or structural problem of the tricuspid valve may require heart surgery. Some patients with progressive tricuspid regurgitation may also require surgery to prevent further deterioration of heart function.

Outcome:

Patients with an otherwise normal heart and mild to moderate tricuspid regurgitation lead a normal life and have no restrictions. Most of the restrictions to sports are associated with an underlying associated heart defect or underlying condition such as pulmonary hypertension. Therefore, prognosis in general may depend on the underlying condition and potential risk factors and not as much on the severity of the tricuspid regurgitation. Long-term complications may include heart failure, endocarditis, weight loss, and liver damage (cirrhosis).

Aortic Regurgitation

Aortic Regurgitation

The aortic valve is between the heart's left ventricle (lower chamber that pumps blood to the body) and the aorta (the large artery that receives blood from the heart's left ventricle and distributes it to the body). Regurgitation means the valve doesn't close properly, and blood can leak backward through it. This means the left ventricle must pump more blood than normal, and will gradually get bigger because of the extra workload. Aortic regurgitation can range from mild to severe. Some people may have no symptoms for years. But as the condition worsens, symptoms will appear. These can include

• fatigue (especially during times of increased activity)
• shortness of breath
• edema (retention of fluid) in certain parts of the body such as the ankles
• heart arrhythmias (abnormal heartbeats)
• angina pectoris (chest pain or discomfort caused by reduced blood supply to the heart muscle)

What causes aortic regurgitation?

Aortic regurgitation can be caused by several things. It may be due to a bicuspid aortic valve. This is a congenital (existing at birth) deformity of the valve. In it, the valve has two cusps (flaps) rather than the normal three cusps. It can also be found in other kinds of congenital heart disease. Aortic regurgitation can also be caused by infections of the heart, such as rheumatic fever or infective endocarditis. Diseases that can cause the aortic root (the part of the aorta attached to the ventricle) to widen, such as the Marfan syndrome or high blood pressure, are other causes.

What should be done?

Patients with mild aortic regurgitation who have few or no symptoms need to see their physician regularly. As conditions worsen, medications may be used. These drugs can help regulate the heart rhythm, rid the body of fluids to control edema, and/or help the left ventricle pump better.
Serious cases may require surgical treatment. This involves replacing the diseased valve with an artificial one.
People with aortic regurgitation are at increased risk for developing an infection of the heart valve or lining of the heart (endocarditis). In the past, the American Heart Association has recommended that patients with aortic regurgitation take a dose of antibiotics before certain dental or surgical procedures. However, our association no longer recommends antibiotics before dental procedures except for patients at the highest level of risk for bad outcomes from endocarditis, such as

• patients with a prosthetic cardiac valve,
• patients who have had endocarditis before,
• patients with certain kinds of congenital heart disease, or
• heart transplant patients who develop a problem with a heart valve. 

Also, the American Heart Association no longer recommends routine antibiotics to prevent endocarditis in patients undergoing gastrointestinal (GI) or genitourinary (GU) tract procedures
.

Frequency

United States

Rheumatic fever and syphilis used to be major causes of aortic regurgitation, but these diseases have diminished in recent years because of the introduction of new antibiotics.

Mortality/Morbidity

• Three fourths of patients with significant aortic regurgitation survive 5 years after diagnosis; half survive for 10 years. Patients with mild-to-moderate regurgitation survive 10 years in 80-95% of the cases.
• Average survival after onset of congestive heart failure (CHF) is less than 2 years.
• Acute aortic regurgitation is associated with significant morbidity, which can progress from pulmonary edema to refractory heart failure and cardiogenic shock.

Age

Chronic aortic regurgitation often begins in the late 50s and is documented most frequently in patients older than 80 years.

History

• General

  • The clinical signs of aortic regurgitation are caused by forward and backward flow of blood across the aortic valve, leading to increased stroke volume.
  • The degree of regurgitation is determined by the degree of valvular incompetence; left ventricular compliance; and end-ventricular, end-diastolic volume.
• Acute aortic regurgitation: Symptoms are manifestations of cardiovascular collapse.

  • Weakness
  • Severe dyspnea
  • Hypotension
  • Angina
• Chronic aortic regurgitation

  • Exertional dyspnea
  • Nocturnal dyspnea
  • Orthopnea
  • Diaphoresis
  • Abdominal discomfort
  • Uncomfortable awareness of heartbeat
  • Palpitations

Differentials

• Abdominal Trauma, Blunt
• Acute Coronary Syndrome
• Congestive Heart Failure and Pulmonary Edema
• Endocarditis
• Mitral Regurgitation
• Mitral Stenosis
• Myocardial Infarction

Laboratory Studies

• CBC
• Prothrombin time (PT)/activated partial thromboplastin time (aPPT)
• Type and screen
• Electrolytes
• Myocardial muscle creatine kinase isoenzyme (CK-MB)
• Lactate dehydrogenase panel
• Isoenzymes
   

  Emergency Department Care

  • General

    • Provide adequate airway management.
    • Intubate when necessary.
    • Consider prompt surgical intervention in acute aortic regurgitation.
  • Acute aortic regurgitation

    • Administer a positive inotrope (eg, dopamine, dobutamine) and a vasodilator (eg, nitroprusside). Rarely, administration of cardiac glycosides (eg, digoxin) for rate control may be necessary.
    • Avoid beta-blockers in the acute setting.
    • Administration of vasodilators may be appropriate to improve systolic function and to decrease afterload.
  • Chronic aortic regurgitation

    • Consider antibiotic prophylaxis for patients with endocarditis when performing procedures likely to result in bacteremia.
    • Administration of pressors and/or vasodilators may be appropriate.
  • Hemodynamically significant aortic regurgitation may require surgical intervention according to the following criteria:

    • Cardiac-thoracic ratio >0.64
    • Fractional shortening < 25-29%
    • End-systolic diameter >55 mm
    • End-diastolic radius to myocardial wall thickness ratio >4.0
    • Ejection fraction < 0.45
    • Cardiac index < 2.2-2.5 L/min/m²

   

  What are the treatments for aortic regurgitation?

  If the backflow of blood is mild and you have no symptoms then you may not need any treatment. If you develop symptoms or complications, various medicines may be advised to ease the symptoms. Surgery may be advised if symptoms become worse.

  Medication

  Medication may be advised to help ease symptoms of heart failure if heart failure develops. For example:
  

  • Diuretics (water tablets) usually help if you are breathless. They make the kidneys produce more urine. This gets rid of excess blood and fluid which may build up in the lungs or other parts of the body with heart failure.
  • Angiotensin-converting enzyme (ACE) inhibitors are medicines which help to reduce the amount of work the heart does and to ease symptoms of heart failure.

  Valve replacement surgery

  This may be with a mechanical or a tissue valve. Mechanical valves are made of materials which are not likely to react with your body, such as titanium. Tissue valves are made from treated animal tissue, such as valves from a pig. If you need surgery, a surgeon will advise on which is the best option for your situation.
  
  Surgical treatment has greatly improved the outlook in most people with more severe regurgitation. Surgery to replace the valve has a very good success rate. The outlook is good if the valve is treated before the heart becomes badly damaged.

  Antibiotics to prevent endocarditis

  Antibiotics used to be offered to all people with heart valve disease before dental treatment and some surgical procedures to prevent the development of endocarditis. However, the National Institute for Health and Clinical Excellence (NICE) issued guidance in 2008 which advised that people at risk of endocarditis only need to take antibiotics if they actually have an infection at the time that dental or surgical procedures are undertaken.