Sandbox:Aditya

Epidemiology

Cortisol

Aldosterone

Incidence

United States The prevalence of Addison disease is 40-60 cases per 1 million population.

Mortality/Morbidity

Morbidity and mortality associated with Addison disease usually are due to failure or delay in making the diagnosis or a failure to institute adequate glucocorticoid and mineralocorticoid replacement. [6] If not treated promptly, acute addisonian crisis may result in death. This may be provoked either de novo, such as by adrenal hemorrhage, or in the setting of an acute event superimposed on chronic or inadequately treated adrenocortical insufficiency. With slow-onset chronic Addison disease, significant low-level, nonspecific, but debilitating, symptomatology may occur. Even after diagnosis and treatment, the risk of death is more than 2-fold higher in patients with Addison disease. Cardiovascular, malignant, and infectious diseases are responsible for the higher mortality rate. [7] White and Arlt examined the prevalence of and risk factors for adrenal crisis in patients with Addison disease, utilizing a survey of Addison patients in the United Kingdom, Canada, Australia, and New Zealand. The authors' results indicated that approximately 8% of patients diagnosed with Addison disease require annual hospital treatment for adrenal crisis. In addition, the investigators concluded that exposure to gastric infection is the most important risk factor for adrenal crisis in the presence of Addison disease; diabetes and/or asthma [8] concomitant with Addison disease also increase the risk, according to White and Arlt. [9] A study by Chantzichristos et al indicated that in patients with type 1 or 2 diabetes, those who also have Addison disease have a higher mortality rate than do those with diabetes alone. Over a median follow-up period of 5.9 years, the mortality rate for diabetes patients with Addison disease was 28%, compared with 10% for those without Addison disease. The increase in the estimated relative overall mortality risk was 3.89 for the Addison disease patients compared with the other group. Although cardiovascular deaths accounted for the highest mortality rate in both groups, the death rate from diabetes complications, infectious diseases, and unknown causes was greater in the patients with Addison disease than in those with diabetes alone. [10]

Race

Addison disease is not associated with a racial predilection.

Sex

Idiopathic autoimmune Addison disease tends to be more common in females and children.

Age

The most common age at presentation in adults is 30-50 years, but the disease could present earlier in patients with any of the polyglandular autoimmune syndromes, congenital adrenal hyperplasia (CAH), or if onset is due to a disorder of long-chain fatty acid metabolism.

Classification

Adrenal insufficiency disorders may be classified into acute and chronic forms, depending on the timing of presentation and duration and into primary and secondary, depending on the etiology of adrenal insufficiency.

Based on the duration of symptoms

Acute adrenal insufficiency

• Adrenal crisis

Chronic adrenal insufficiency

• Chronic primary adrenal insufficiency
• Chronic secondary adrenal insufficiency

Based on etiology

Primary adrenal insufficiency(Addisons disease)

• Anatomic destruction of the adrenal gland
• Infection (TB)
• Congenital adrenal hyperplasia

Secondary adrenal insufficiency

• Hypothalamic-pituitary axis suppression

Pathology

Cortisol is normally produced by the adrenal glands, which are located just above the kidneys. It belongs to a class of hormones called glucocorticoids, which affect almost every organ and tissue in the body. Scientists think that cortisol possibly has hundreds of effects in the body. Cortisol's most important job is to help the body respond to stress. Among its other vital tasks, cortisol;

Helps maintain blood pressure and cardiovascular function Helps slow the immune system's inflammatory response Helps balance the effects of insulin in breaking down sugar for energy Helps regulate the metabolism of proteins, carbohydrates, and fats Helps maintain proper arousal and sense of well-being Because cortisol is so vital to health, the amount of cortisol produced by the adrenals is precisely balanced. Like many other hormones, cortisol is regulated by the brain's hypothalamus and the pituitary gland, a bean-sized organ at the base of the brain. First, the hypothalamus sends "releasing hormones" to the pituitary gland. The pituitary responds by secreting hormones that regulate growth, thyroid function, adrenal function, and sex hormones such as estrogen and testosterone. One of the pituitary's main functions is to secrete ACTH (adrenocorticotropin), a hormone that stimulates the adrenal glands. When the adrenals receive the pituitary's signal in the form of ACTH, they respond by producing cortisol. Completing the cycle, cortisol then signals the pituitary to lower secretion of ACTH.

Aldosterone Aldosterone belongs to a class of hormones called mineralocorticoids, also produced by the adrenal glands. It helps maintain blood pressure and water and salt balance in the body by helping the kidney retain sodium and excrete potassium. When aldosterone production falls too low, the kidneys are not able to regulate salt and water balance, causing blood volume and blood pressure to drop.

Symptoms

Characteristics of the disease are:

Type of presentation	Harmone deficiency	Common symptoms	Less common symptoms
Acute adrenal insufficiency	Mainly cortisol	Sudden penetrating pain in the lower back, abdomen, or legs Severe vomiting and diarrhea Dehydration Low blood pressure - dizziness and fainting Loss of consciousness	In acute adrenal hemorrhage, Deteriorates with sudden collapse, Abdominal or flank pain, Nausea with or without hyperpyrexia.
Chronic adrenal insufficiency	Primary: Both glucocorticoid, mineralocorticoid	Hyperpigmentation (prominent on the sun-exposed areas of the skin, extensor surfaces, knuckles, elbows, knees) Progressive weakness, fatigue, poor appetite, and weight loss. Nausea, vomiting, and occasional diarrhea. Muscle pains Joint pains
	Secondary: Glucorticoid

Symptoms	Pathophysiology
Hyperpigmentation	Stimulant effect of excess ACTH on the melanocytes to produce melanin
Dizziness with orthostasis	Volume depletion, loss of the mineralocorticoid effect of aldosterone, Loss of the permissive effect of cortisol in enhancing the vasopressor effect of the catecholamines.
Myalgias and flaccid muscle paralysis	Hyperkalemia
Amenorrhea	Combined effect of weight loss and chronic ill health or secondary to premature autoimmune ovarian failure

History

A detailed and thorough history from the patient is necessary. Specific areas of focus when obtaining a history from the patient of addison's disease include:

• Recent changes in diet: Patients with Addison disease often crave salty foods and are often anorexic.
• Periods regularity: Oligomenorrhea or amenorrhea are features of Addison disease
• Any signs of postural hypotension
• Any recent changes in weight
• History of tuberculosis ? or any exposure to anyone who has been diagnosed with tuberculosis.
• History of any cancer?
• History of other autoimmune disease, such as Graves disease, Hashimoto thyroiditis, hypoparathyroidism, vitiligo , pernicious anemia, or diabetes mellitus
• Family history of Addison's disease or any other adrenal disorder?

Laboratory

Evaluating a patient with suspected adrenal insufficiency is a three-step process: establishing the diagnosis, differentiating between primary and secondary adrenal insufficiencies, and looking for the cause of adrenal insufficiency.

8 am cortisol

>15Ug/dL

3-15Ug/dL

<3Ug/dL

Adrenal insufficiency is ruled out

Measure ACTH

30 min cortisol during cosyntropin stimulation test

>18Ug/dL

<18Ug/dL

Adrenal insufficiency is ruled out

Adrenal insufficiency confirmed

Measure ACTH

Low/normal

Elevated

Secondary Adrenal insufficiency

Primary Adrenal insufficiency

Adrenal crisis=

Supportive Therapy

• IV access should be established immediately with an infusion of isotonic sodium chloride solution should be begun to restore volume deficit and correct hypotension.

Mecial Management

• Preferred regimen (1): Dexamethasone sodium phosphate 4 mg iv q24h
• Preferred regimen (2): Hydrocortisone sodium succinate 50-100 mg iv q8h
• Note: Infusion may be initiated with 100 mg of hydrocortisone as an IV bolus with saline and infuse over 24 h to avoid needing to renew the infusion every 8-10 hours.

The infusion method maintains plasma cortisol levels more adequately at steady stress levels, especially in the small percentage of patients who are rapid metabolizers and who may have low plasma cortisol levels between the IV boluses. Clinical improvement, especially blood pressure response, should be evident within 4-6 hours of hydrocortisone infusion. Otherwise, the diagnosis of adrenal insufficiency would be questionable. After 2-3 days, the stress hydrocortisone dose should be reduced to 100-150 mg, infused over a 24-hour period, irrespective of the patient's clinical status. This is to avoid stress gastrointestinal bleeding. As the patient improves and as the clinical situation allows, the hydrocortisone infusion can be gradually tapered over the next 4-5 days to daily replacement doses of approximately 3 mg/h (72-75 mg over 24 h) and eventually to daily oral replacement doses, when oral intake is possible. As long as the patient is receiving 100 mg or more of hydrocortisone in 24 hours, no mineralocorticoid replacement is necessary. The mineralocorticoid activity of hydrocortisone in this dosage is sufficient. Thereafter, as the hydrocortisone dose is weaned further, mineralocorticoid replacement should be instituted in doses equivalent to the daily adrenal gland aldosterone output of 0.05-0.20 mg every 24 hours. The usual mineralocorticoid used for this purpose is 9-alpha-fludrocortisone, usually in doses of 0.05-0.10 mg per day or every other day. Patients may need to be advised to increase salt intake in hot weather.

hese drugs are used for replacement therapy in Addison disease and secondary adrenocortical insufficiency. [3, 4] Prednisone (Deltasone, Sterapred, Orasone)

View full drug information Used for glucocorticoid hormone replacement. Longer acting than hydrocortisone, with a biologic half-life of 18-36 h. Fludrocortisone (Florinef)

View full drug information Synthetic adrenocortical steroid with very potent mineralocorticoid activity. For use in Addison disease and states of aldosterone deficiency. Hydrocortisone sodium succinate or phosphate (Cortef, Hydrocortone)

View full drug information Drug of choice for steroid replacement in acute adrenal crisis and for daily maintenance in patients with Addison disease or secondary adrenocortical insufficiency. Has both glucocorticoid and mineralocorticoid properties. Biologic half-life is 8-12 h. Easiest way to set up infusion is to have pharmacy mix 100 mg of hydrocortisone in 100 mL of 0.9 saline.

Surgery

Parenteral steroid coverage should be used in times of major stress, trauma, or surgery and during any major procedure. During surgical procedures, 100 mg of hydrocortisone should be given, preferably by the IM route, prior to the start of a continuous IV infusion. The IM dose of hydrocortisone assures steroid coverage in case of problems with the IV access. When continuous IV infusion is not practical, an intermittent IV bolus injection every 6-8 hours may be used. After the procedure, the hydrocortisone may be rapidly tapered within 24-36 hours to the usual replacement doses, or as gradually as the clinical situation dictates. Mineralocorticoid replacement usually can be withheld until the patient resumes daily replacement steroids. Addison’s disease (also known as primary adrenal insufficiency or hypoadrenalism) is a rare disorder of the adrenal glands. It affects the production of two essential hormones called cortisol and aldosterone.

PCOS

Historical Perspective

PCOS was first described in 1935 by American gynecologists Irving F. Stein, Sr. and Michael L. Leventhal, from whom its original name of Stein–Leventhal syndrome is taken. The earliest published description of PCOS was in 1721 in Italy. Cyst-related changes to the ovaries were described in 1844.

• In 1721, a description symptoms resembling PCOS was published in Italy
• In 1844, Cyst-related changes to the ovaries were first described.
• In 1935, Irving F. Stein, Sr. and Michael L. Leventhal, American gynecologists, described PCOS for the first time.

Pathophysiology

• The pathophysiology of PCOS is not well understood. There are several organ systems involved in the pathogenesis of PCOS like ovary, adrenal, hypothalamus, pituitary, or insulin-sensitive tissues. It is possible that there are subsets of women with PCOS wherein each of these proposed mechanisms serves as the primary defect.
• Insulin resistance leads to compensatory insulin hypersecretion by the pancreas in order to maintain normoglycemia.
• The resulting hyperinsulinemia promotes ovarian androgen output and may also promote adrenal androgen output.
• High insulin levels also suppress hepatic production of sex hormone binding globulin (SHBG), which exacerbates hyperandrogenemia by increasing the proportion of free circulating androgens.
• Another factor that promotes ovarian androgen output is the fact that women with PCOS are exposed long term to high levels of LH.
• This LH excess seems to be a result of an increased frequency of gonadotropin releasing hormone pulses from the hypothalamus.
• The abnormal hormonal milieu also probably contributes to incomplete follicular development which results in polycystic ovarian morphology.

↑ 5α-reductase reductivity

↓ Hβ-HSD1 activity

↑ Cortisol metabolism

↑ ACTH

↑ Adrenal androgens

Normal serum cortisol

PCOS

Risk Factors

Common risk factors in the development of polycystic ovary syndrome are

• Hyperinsulinemia secondary to insulin resistance; associated with type 2 diabetes mellitus
• Obesity
• Family history of PCOS among first-degree relatives

Associated Conditions

Common conditions associated with PCOS are

• Type 2 diabetes
• Endometrial hyperplasia and cancer
• Infertility
• Hypertension
• Gestational diabetes
• Preeclampsia
• Hirsutism
• Acne

History

Obtaining the history is the most important aspect of making a diagnosis of PCOS. It provides insight into the cause, precipitating factors and associated comorbid conditions.

• Menstrual abnormalities
• Infertility
• Signs of virilization on physical examination
• Family history of PCOS among first-degree relatives

Symptoms

The most common symptoms of PCOS include

• Amenorrhea or oligomenorrhea
• Abnormal uterine bleeding
• Androgenization, including hirsutism (often slowly progressive), acne, oily skin (common)
• Polycystic ovaries, with or without ovarian enlargement
• Insulin resistance
• Endometrial hyperplasia

Laboratory Findings

Measurement of the plasma levels of several hormones is helpful in supporting the diagnosis of PCOS and especially in excluding other disorders. Determining the LH/FSH ratio of 3:1 is virtually diagnostic of PCOS; however, a normal ratio does not exclude the diagnosis, as LH levels fluctuate widely throughout the course of a day. Other androgens are measured to screen for other virilizing adrenal tumors. Fasting blood glucose is measured to look for diabetes; screening for lipid abnormalities is also employed. Testosterone is measured to exclude a virilizing tumor. Prolactin is measured to exclude a prolactinoma. Thyroid-stimulating hormone (TSH) is measured to rule out hypothyroidism

Harmone		Normal value	PCOS Laboratory Findings
LH/FSH ratio		<3;1	A ratio >3:1 is indicative of PCOS
Testosterone		Free: 100 to 200 pg/dL Total: 20 to 80 ng/dL	An elevated free testosterone level (200-400 pg/dL) is suggestive of PCOS,
Prolactin		3.8 to 23.2 μg/L	A level >300 μg/L is virtually diagnostic of prolactinoma.
TSH		0.4 to 4.2 mIU/L	Levels are normal in patients with PCOS
Androgens	Sex hormone–binding globulin	1.5 to 2.0 μg/mL	Decreased
	Androstenedione	75 to 205 ng/dL	Increased
	Estrone:	1.5 to 25.0 pg/mL	Increased
	Dehydroepiandrosterone sulfate	50 to 450 μg/dL	Increased but are <800 μg/dL
	17-Hydroxyprogesterone (follicular phase)	15 to 70 ng/dL	Normal
Fasting blood glucose		<110 mg/dL	>126mg/dL Indicates DM

Ultrasound findings

Typical ultrasound findings in patients with PCOS include

• Two- to 5-fold ovarian enlargement
• Thickened stroma (tunica albuginea)
• Thecal hyperplasia with an increase in stromal content
• Multiple (12+) subcapsular follicles ranging from 2 to 9 mm in diameter ('pearl necklace' appearance)
• Hyperplastic endometrium despite low estrogen production (due to high estrone production from the increased circulating androgens and lack of opposition by progesterone)

Epidemiology and demographics

Prevalence

• Approximately 5% to 10% of women of reproductive age are affected
• Prevalence among first-degree relatives of patients with PCOS is 25% to 50%, suggesting a strong inheritance of the syndrome; there is evidence for possible X-linked dominant transmission

Age

• PCOS can appear anytime from menarche until menopause but generally is seen around menarche and is diagnosed then or in early adulthood

Differentiating PCOS from other diseases

Disease	Differentiating Features
Pregnancy	Pregnancy always should be excluded in a patient with a history of amenorrhea Features include amenorrhea or oligomenorrhea, abnormal uterine bleeding, nausea/vomiting, cravings, weight gain (although not in the early stages and not if vomiting), polyuria, abdominal cramps and constipation, fatigue, dizziness/lightheadedness, and increased pigmentation (moles, nipples) Uterine enlargement is detectable on abdominal examination at approximately 14 weeks of gestation Ectopic pregnancy may cause oligomenorrhea, amenorrhea, or abnormal uterine bleeding with abdominal pain and sometimes subtle or absent physical symptoms and signs of pregnancy
Hypothalamic amenorrhea	Diagnosis of exclusion Seen in athletes, people on crash diets, patients with significant systemic illness, and those experiencing undue stress or anxiety Predisposing features are as follows weight loss, particularly if features of anorexia nervosa are present or the BMI is <19 kg/m2 Recent administration of depot medroxyprogesterone, which may suppress ovarian activity for 6 months to a year Use of dopamine agonists (eg, antidepressants) and major tranquilizers Hyperthyroidism In patients with weight loss related to anorexia nervosa, fine hair growth (lanugo) may occur all over the body, but it differs from hirsutism in its fineness and wide distribution
Primary amenorrhea	Causes include reproductive system abnormalities, chromosomal abnormalities, or delayed puberty If secondary sexual characteristics are present, an anatomic abnormality (eg, imperforate hymen, which is rare) should be considered If secondary sexual characteristics are absent, a chromosomal abnormality (eg, Turner syndrome ) or delayed puberty should be considered
Cushing syndrome	Cushing syndrome is due to excessive glucocorticoid secretion from the adrenal glands, either primarily or secondary to stimulation from pituitary or ectopic hormones; can also be caused by exogenous steroid use Features include hypertension, weight gain (central distribution), acne, and abdominal striae Patients have low plasma sodium levels and elevated plasma cortisol levels on dexamethasone suppression testing
Hyperprolactinemia	Mild hyperprolactinemia may occur as part of PCOS-related hormonal dysfunction Other causes include stress, lactation, and use of dopamine antagonists A prolactinoma of the pituitary gland is an uncommon cause and should be suspected if prolactin levels are very high (>200 ng/mL) Physical examination findings are usually normal As in patients with PCOS, hyperprolactinemia may be associated with mild galactorrhea and oligomenorrhea or amenorrhea; however, galactorrhea also can occur with nipple stimulation and/or stress when prolactin levels are within normal ranges A large prolactinoma may cause headaches and visual field disturbance due to pressure on the optic chiasm, classically a gradually increasing bitemporal hemianopsia
Ovarian or adrenal tumor	Benign ovarian tumors and ovarian cancer are rarely causes of excessive androgen secretion; adrenocortical tumors also can increase the production of sex hormones Abdominal swelling or mass, abdominal pain due to fluid leakage or torsion, dyspareunia, abdominal ascites, and features of metastatic disease may be present Features of androgenization include hirsutism, weight gain, oligomenorrhea or amenorrhea, acne, clitoral hypertrophy, deepening of the voice, and high serum androgen (eg, testosterone, other androgens) levels In patients with an androgen-secreting tumor, serum testosterone is not suppressed by dexamethasone
Congenital adrenal hyperplasia	Congenital adrenal hyperplasia is a rare genetic condition resulting from 21-hydroxylase deficiency The late-onset form presents at or around menarche Patients have features of androgenization and subfertility Affects approximately 1% of hirsute patients More common in Ashkenazi Jews (19%), inhabitants of the former Yugoslavia (12%), and Italians (6%) Associated with high levels of 17-hydroxyprogesterone A short adrenocorticotropic hormone stimulation test with measurement of serum17-hydroxyprogesterone confirms the diagnosis Assays of a variety of androgenic hormones help define other rare adrenal enzyme deficiencies, which present similarly to 21-hydroxylase deficiency
Anabolic steroid abuse	Anabolic steroids are synthetic hormones that imitate the actions of testosterone by increasing muscle bulk and strength Should be considered if the patient is a serious sportswoman or bodybuilder Features include virilization (including acne and hirsutism), often increased muscle bulk in male pattern, oligomenorrhea or amenorrhea, clitoromegaly, gastritis, hepatic enlargement, alopecia, and aggression Altered liver function test results are seen
Hirsutism	Hirsutism is excessive facial and body hair, usually coarse and in a male pattern of distribution Approximately 10% of women report unwanted facial hair There is often a family history and typically some Mediterranean or Middle Eastern ancestry May also result from use of certain medications, both androgens, and others including danazol, glucocorticoids, cyclosporine, and phenytoin Menstrual history is normal When the cause is genetic, the excessive hair, especially on the face (upper lip), is present throughout adulthood, and there is no virilization When secondary to medications, the excessive hair is of new onset, and other features of virilization, such as acne and deepened voice, may be present

Complications

• Endometrial hyperplasia
• Endometrial cancer
• Type 2 diabetes and its microvascular and macrovascular complications

Prognosis

• The prognosis for fertility is very good with treatment. With careful follow-up, ovarian hyperstimulation, multiple pregnancy, and endometrial hyperplasia can be avoided
• Patients should be counseled regarding the long-term risk of diabetes, hypertension, and endometrial hyperplasia, including the importance of maintaining a BMI <25 kg/m2and control of type 2 diabetes.

Diagnostic Criteria

Two definitions are commonly used:

• In 1990 a consensus workshop sponsored by the NIH/NICHD suggested that a patient has PCOS if she has
  • Signs of androgen excess (clinical or biochemical)
  • Oligoovulation
  • Other entities are excluded that would cause polycystic ovaries.
• In 2003 a consensus workshop sponsored by ESHRE/ASRM in Rotterdam indicated PCOS to be present if 2 out of 3 criteria are met:
  • Oligoovulation and/or anovulation
  • Excess androgen activity
  • Polycystic ovaries (by gynecologic ultrasound), and other causes of PCOS are excluded.

The Rotterdam definition is wider, including many more patients, notably patients without androgen excess, whereas in the NIH/NICHD definition androgen excess is a prerequisite. Critics maintain that findings obtained from the study of patients with androgen excess cannot necessarily be extrapolated to patients without androgen excess.

Surgery

Surgery is not considered first-line therapy for PCOS and it does not affect insulin resistance or obesity

Indication

Surgery is indicated in the treatment of PCOS only in patients desiring fertility in whom at least 1 year of conservative therapy has failed

Surgial options

Ovarian drilling

• Laparoscopic surgery that uses a laser or electrosurgical needle to puncture a number of small follicles visible on the surface of the ovary, which are presumably the source of hormone production

Complications

• Bleeding and/or infection
• Postoperative adhesions

Medical Therapy

The first step in the management of PCOS is weight loss if the patient is obese, and treatment of type 2 diabetes, if present, with metformin. In significantly overweight patients, weight loss alone usually effects a cure and should always be vigorously attempted. Diet and exercise are recommended in all women with PCOS. The next step is initiation of treatment to break the self-perpetuating anovulatory cycling, either by stimulating ovulation or suppressing androgenic and ovarian activity. The selection of treatment depends on whether pregnancy is desired. All antiandrogen treatments will take at least 3 months to affect hirsutism. The goals of treatment are:

• Exclude androgen-secreting tumors, endometrial tumors, and endometrial hyperplasia
• Reduce ovarian androgen secretion and/or antagonist activity at target tissues
• Interrupt the self-sustaining abnormal hormonal cycle
• Normalize the endometrium
• Restore fertility by correcting anovulation, if desired
• Reduce insulin resistance

Medical Management

If fertility is not desired

• Preferred regimen (1): Combined oral contraceptive pills one tablet of formulations containing 30 to 35 μg estrogen orally daily for 21 days, then nothing for 7 days
• Preferred regimen (2): Progesterone-only contraceptive pills (eg, norethindrone , norgestrel ) are the treatment of choice if combined oral contraceptive pills are contraindicated
• Alternative regimen(1): Medroxyprogesterone may be used, although it is not approved by the U.S. Food and Drug Administration (FDA) for this indication
• Alternative regimen(2): Glucocorticoids (eg, hydrocortisone , cortisone , dexamethasone ) may be used to suppress adrenal androgen production, although they are not approved by the FDA for this indication
• Alternative regimen(3): Spironolactone and flutamide are androgen receptor antagonists that may be added to the oral contraceptive pill, but they are not approved by the FDA for this indication; flutamide is not usually recommended because of its unproven efficacy and associated risk of hepatic impairment

If fertility is desired

• Preferred regimen (1): Clomiphene, alone or in combination with glucocorticoids, is the first-choice treatment
• Preferred regimen (2): Follicle-stimulating hormone may be administered in conjunction with timed human chorionic gonadotropin for ovulation induction
• Preferred regimen (3): Metformin

Primary Prevention

There is no established method for prevention of PCOS

Secondary Prevention

Secondary preventive measures for PCOS include

• Weight loss and metformin may prevent diabetes and atherosclerosis.
• Lifestyle modification, including increased physical activity and healthy diet resulting in weight loss, is also likely to prevent diabetes in PCOS.

Disease	Headache	Symptoms	Diagnosis
			CT/MRI	Other Investigation Findings
Subarachnoid hemorrhage		Severe headache (as a worst headache of the life) Double vision Nausea and vomiting Symptoms of meningeal irritation Sudden decreased level of consciousness Rapid progression of symptoms	CT shows hyperattenuating material filling the subarachnoid space.	LP will show: Elevated opening pressure Elevated red blood cell (RBC) Xanthochromia
Meningitis		Headache   Neck stiffness Fever Photophobia  Phonophobia  Irritability, altered mental status (in small children)	CT scan of the head may be performed before LP to determine the risk of herniation.	Diagnosis is based on clinical presentation in combination with CSF analysis. For more information on CSF analysis in meningitis please click here.
Intracranial mass		Headache Nausea Vomiting Change in mental status Seizures Focal symptoms of brain damage Associated co-morbid conditions like tuberculosis, etc	Imaging tests determine the location of intracranial mass lesion(s) and help in guiding therapy.	Biopsy of the lesion is needed to identify the nature of the lesion such as: Tumor Abscess
Cerebral hemorrhage		Headache Vomiting Depressed level of consciousness from increased intracranial pressure (ICP)   Progression of focal neurological deficits over periods of hours	CT is very sensitive for identifying acute hemorrhage which appears as hyperattenuating clot. Gradient echo and T2 susceptibility-weighted MRI are as sensitive as CT for detection of acute hemorrhage and are more sensitive for identification of prior hemorrhage.	PT/ INR and aPTT should be checked to rule out coagulopathy.
Cerebral Infarction		The symptoms of an ischemic stroke vary widely depending on the site and blood supply of the area involved. For more information on symptoms of ischemic stroke based on area involved please click here.	CT may show hypo-attenuation and swelling of involved area.	Carotid doppler may be done to check for patency of carotid arteries and blood supply to the brain. Cerebral angiogram is an invasive test and detect abnormalities of the blood vessels, including narrowing, blockage, or malformations (such as aneurysms or arterio-venous malformations).
Intracranial venous thrombosis		Headache: It is a common presentation (present in 90% of cases) (thunderclap headache).[1]  Inability to move one or more limbs. Weakness on one side of the face. Seizures Depressed level of consciousness and otherwise unexplained changes in mental status [4]	The classic finding of sinus thrombosis on unenhanced CT images is a hyperattenuating thrombus in the occluded sinus. CT and MRI may identify Cerebral edema and venous infarction may be apparent.	CT venography detects the thrombus, computed tomography with radiocontrast in the venous phase (CT venography or CTV) has a detection rate that in some regards exceeds that of MRI. Cerebral angiography may demonstrate smaller clots, and obstructed veins may give the "corkscrew appearance".
Migraine		Headache which is often one-sided and pulsating) lasts between several hours to three days. Other symptoms include gastrointestinal upsets, such as nausea and vomiting, and a heightened sensitivity to bright lights (photophobia) and noise (phonophobia). Approximately one third of people who experience migraine get a preceding aura.[4]	CT and MRI may be needed to rule out other suspected possible causes of headache.	Migraine is a clinical diagnosis. Laboratory tests can be ordered to rule out any suspected coexistent metabolic problems or to determine the baseline status of the patient before initiation of migraine therapy.
Head injury		Headache Confusion Drowsiness Personality change Seizures Nausea and vomiting Loss of consciousness lucid interval	CT scan demonstrates hemorrhage as hyperattenuating clot following head injury. MRI is more sensitive, is done in patients with symptoms unexplained and a neagtive CT scan.	The Glasgow Coma Scale is a tool for measuring degree of unconsciousness and is thus a useful tool for determining severity of injury.
Lymphocytic hypophysitis		Seen in late pregnancy or the postpartum period with the following symptoms: Hypopituitarism Mass lesion effect such as headache , visual field defects	CT & MRI typically reveal features of a pituitary mass.
Radiation injury		Headache Impairment of mental function personality change Impairment of memory Confusion Learning difficulties. Focal neurological abnormalities [[Raised ICP].	CT & MRI will show: Focal radiation necrosis Diffuse white matter injury Contrast-enhancing mass surrounded by edema and mass effect	PET scan Radiation necrosis is hypo metabolic and will have decreased uptake of fluorodeoxyglucose.

Medical Therapy

Pharmacotherapy

Medical treatment of PCOS is tailored to the patient's goals. Broadly, these may be considered under three categories:

• Restoration of fertility
• Treatment of hirsutism or acne
• Restoration of regular menstruation, and prevention of endometrial hyperplasia and endometrial cancer

In each of these areas, there is considerable debate as to the optimal treatment. One of the major reasons for this is the lack of large scale clinical trials comparing different treatments. Smaller trials tend to be less reliable, and hence may produce conflicting results.

General interventions that help to reduce weight or insulin resistance can be beneficial for all these aims, because they address what is believed to be the underlying cause of the syndrome. Where PCOS is associated with overweight or obesity, successful weight loss is probably the most effective method of restoring normal ovulation/menstruation, but many women find it very difficult to achieve and sustain significant weight loss. Low-carbohydrate diets and sustained regular exercise may help, and some experts recommend a low-GI diet in which a significant part of the total carbohydrates are obtained from fruit, vegetables and wholegrain sources.

Many women find insulin-lowering medications such as metformin hydrochloride (Glucophage®), pioglitazone hydrochloride (Actos®), and rosiglitazone maleate (Avandia®) helpful, and ovulation may resume when they use these agents. Many women report that metformin use is associated with upset stomach, diarrhea, and weight-loss. Such side effects usually resolve within 2–3 weeks. Starting with a lower dosage and gradually increasing the dosage over 2–3 weeks and taking the medication toward the end of a meal may reduce side effects. It may take up to six months to see results, but when combined with exercise and a low glycemic index diet up to 85% will improve menstrual cycle regularity and ovulation.

Treatment of Infertility

• Clomiphene citrate and metformin are the principal treatments used to help infertility.
• In a random trial, 626 women were randomized to three groups: metformin alone, clomiphene alone, or both. The live birth rates after 6 months were 7.2% (metformin), 22.5% (clomiphene), and 26.8% (both).
• The major complication of clomiphene was multiple pregnancies, affecting 0%, 6% and 3.1% of women respectively.
• However, many specialists continue to recommend metformin which has, separately, been shown to increase ovulation rates and reduce miscarriage rates.. Metformin may be a rational choice in women in whom significant insulin resistance is diagnosed or suspected, as clomiphene works through a different mechanism and does not affect insulin resistance.

Diet adjustments and weight loss also increase rates of pregnancy. The most drastic increase in ovulation rate occurs with a combination of diet modification, weight loss, and treatment with metformin and clomiphene citrate. It is currently unknown if diet change and weight loss alone have an effect on live birth rates comparable to those reported with clomiphene and metformin.

Though the use of basal body temperature or BBT charts is sometimes advised to predict ovulation, clinical trials have not supported a useful role.

For patients who do not respond to clomiphene, metformin, other insulin-sensitizing agents, diet and lifestyle modification, there are options available including assisted reproductive technology procedures such as controlled ovarian hyperstimulation and in vitro fertilisation. Ovarian stimulation has an associated risk of ovarian hyperstimulation in women with PCOS — a dangerous condition with morbidity and rare mortality. Thus recent developments have allowed the oocytes present in the multiple follicles to extracted in natural, unstimulated cycles and then matured in vitro, prior to IVF. This technique is known as IVM (in-vitro-maturation)

Though surgery is usually the treatment option of last resort, the polycystic ovaries can be treated with surgical procedures such as

• laparoscopy electrocauterization or laser cauterization
• ovarian wedge resection (rarely done now because it is more invasive and has a 30% risk of adhesions, sometimes very severe, which can impair fertility) was an older therapy
• ovarian drilling

Treatment of Hirsutism and Acne

Cyproterone acetate is an anti-androgen, which blocks the action of male hormones that are believed to contribute to acne and the growth of unwanted facial and body hair. Cyproterone acetate is also contained in the contraceptive pill Dianette®. Spironolactone also has some benefits, again through anti-androgen activity, and metformin can also help. Eflornithine is a drug which is applied to the skin in cream form (Vaniqa®), and acts directly on the hair follicles to inhibit hair growth. It is usually applied to the face.

Although all of these agents have shown some efficacy in clinical trials, the average reduction in hair growth is generally in the region of 25%, which may not be enough to eliminate the social embarrassment of hirsutism, or the inconvenience of plucking/shaving. Individuals may vary in their response to different therapies, and it is usually worth trying other drug treatments if one does not work, but drug treatments do not work well for all individuals. Alternatives include electrolysis and various forms of laser therapy.

Treatment of Menstrual Irregularity and Prevention of Endometrial Hyperplasia/Cancer

• If fertility is not the primary aim, then menstruation can usually be regulated with a contraceptive pill.
• Most brands of contraceptive pill result in a withdrawal bleed every 28 days.
• Dianette® (a contraceptive pill containing cyproterone acetate) is also beneficial for hirsutism and is therefore often prescribed in PCOS.
• If a regular menstrual cycle is not desired, then a standard contraceptive pill is not appropriate.
• Women who are having irregular menses do not necessarily require any therapy; most experts consider that if a menstrual bleed occurs at least every three months, then the endometrium (womb lining) is being shed sufficiently often to prevent an increased risk of endometrial abnormalities or cancer.
• If menstruation occurs less often or not at all, some form of progestogen replacement is recommended. Some women prefer a uterine progestogen implant such as the Mirena® coil, which provides simultaneous contraception and endometrial protection for years, though often with unpredictable minor bleeding.
• An alternative is oral progestogen taken at intervals (e.g. every three months) to induce a predictable menstrual bleed.

Approach to hyperandrogenism

Signs of hyperandrogenism hirsutism, alopecia, masculine appearance, acne

History of Drug use

Presence of oligomenorrhea

Stop using the drug PCOS ruled out

Perform an ultrsound of pelvis

Normal morphology of ovaries

Cystic morphology of ovaries

PCOS is ruled out Look for adrenal tumors, ovarian tumors

Measure testosterone levels

*17-hydroxyprogesterone/DHEAs elevated = CAH,adrenal tumors *Cortisol elevated = Cushings syndrome, cortisol resistance Prolactin,TSH,IGF1 abnormal = hyperprolactinoma, thyroid dysfunction acromegaly

Normal

Elevated

Risk factors of hirutism present?

PCOS

No

Yes

PCOS ruled out

Hirutism present?

Mild hirutism

Severe Hirutism

PCOS

Trial of OCP

Positive response

Negative worsening of symptoms

Idiopathic hirutism

PCOS

Schistosomiasis

Historical Perspective

• In 1847, Japanese Doctor Y. Fujii described “Katayama fever” as a manifestation of acute schistosomiasis.
• 1851, Dr.Theodore Billharz, working in Egypt, identified the worms responsible for Schistosomiasis.
• 1904, S. japonicum was identified in a housecat.
• 1915, the snail was identified as an intermediate host for Schistosomiasis.

Classification

Organ involved	Species	Geographical distribution
Intestinal schistosomiasis	Schistosoma mansoni	Africa, the Middle East, the Caribbean, Brazil, Venezuela and Suriname
	Schistosoma japonicum	China, Indonesia, the Philippines
	Schistosoma mekongi	Several districts of Cambodia and the Lao People’s Democratic Republic
	Schistosoma guineensis S. intercalatum	Rain forest areas of central Africa
Urogenital schistosomiasis	Schistoma haematobium	Africa, the Middle East, Corsica (France)

Pathophysiology

• Schistosomes have a typical trematode vertebrate-invertebrate lifecycle, with humans being the definitive host.
• The life cycles of all five human schistosomes are broadly similar

Snail cycle

• Parasite eggs are released into the environment from infected individuals, hatching on contact with fresh water to release the free-swimming miracidium.
• Miracidia infect fresh-water snails by penetrating the snail's foot.
• After infection, the miracidium transforms into a primary (mother) sporocyst.
• Germ cells within the primary sporocyst will then begin dividing to produce secondary (daughter) sporocysts, which migrate to the snail's hepatopancreas.
• Once at the hepatopancreas, germ cells within the secondary sporocyst begin to divide producing thousands of new parasites, known as cercariae, which are the larvae capable of infecting mammals.
• Cercariae emerge daily from the snail host in a circadian rhythm, dependent on ambient temperature and light.
• Young cercariae are highly motile, alternating between vigorous upward movement and sinking to maintain their position in the water.
• Cercarial activity is particularly stimulated by water turbulence, by shadows and by chemicals found on human skin.

Human cycle

• Penetration of the human skin occurs after the cercaria have attached to and explored the skin.
• The parasite secretes enzymes that break down the skin's protein to enable penetration of the cercarial head through the skin.
• As the cercaria penetrates the skin it transforms into a migrating schistosomulum stage.
• The newly transformed schistosomulum may remain in the skin for 2 days before locating a post-capillary venule. The schistosomulum travels from the skin to the lungs where it undergoes further developmental changes necessary for subsequent migration to the liver.
• Eight to ten days after penetration of the skin, the parasite migrates to the liver sinusoids.
• S. japonicum migrates more quickly than S. mansoni, and usually reaches the liver within 8 days of penetration.
• Juvenile S. mansoni and S. japonicum worms develop an oral sucker after arriving at the liver. During this period that the parasite begins to feed on red blood cells.
• The nearly-mature worms pair, with the longer female worm residing in the gynaecophoric channel of the male.

• Adult worms are about 10 mm long. Worm pairs of S. mansoni and S. japonicum relocate to the mesenteric or rectal veins.
• S. haematobium schistosomula ultimately migrate from the liver to the perivesical venous plexus of the bladder, ureters, and kidneys through the hemorrhoidal plexus.
• Parasites reach maturity in six to eight weeks, at which time they begin to produce eggs.
• Adult S. mansoni pairs residing in the mesenteric vessels may produce up to 300 eggs per day during their reproductive lives.
• S. japonicum may produce up to 3000 eggs per day. Many of the eggs pass through the walls of the blood vessels, and through the intestinal wall, to be passed out of the body in faeces.
• S. haematobium eggs pass through the ureteral or bladder wall and into the urine. Only mature eggs are capable of crossing into the digestive tract, possibly through the release of proteolytic enzymes, but also as a function of host immune response, which fosters local tissue ulceration.
• Up to half the eggs released by the worm pairs become trapped in the mesenteric veins, or will be washed back into the liver, where they will become lodged.
• Worm pairs can live in the body for an average of four and a half years but may persist up to 20 years.
• Trapped eggs mature normally, secreting antigens that elicit a vigorous immune response.
• The eggs themselves do not damage the body rather it is the cellular infiltration resultant from the immune response that causes the pathology classically associated with schistosomiasis.

Pathogenesis

Transmission

Infection can occur by penetration of the human skin by cercaria or following the handling of contaminated soil or through the consumption of contaminated water or food sources (eg, unwashed garden vegetables).

Dissemination

Cercaria gets transformed into migrating schistosomulum stage in the skin. Then migrating schistosomulum are transported via the blood stream to respective organ system.

Incubation period

The incubation period for acute schistosomiasis is usually 14-84 days. However, many people are asymptomatic and have subclinical disease during both acute and chronic stages of schistosomiasis.

Infective stages

• Cercaria are the infective stage of schistosomiasis to humans

Diagnostic stages

• Miracidium are diagnostic for schistosomiasis.

Pathogenesis

• The pathogenesis of acute human schistosomiasis is mainly related to egg deposition and liberation of antigens of adult worms and eggs.
• A strong inflammatory response characterized by high levels of pro-inflammatory cytokines, such as interleukins 1 and 6 and tumor necrosis factor-α, and by circulating immune complexes participates in the pathogenesis of the acute phase of the disease.

Immune response

• Both the early and late manifestations of schistosomiasis are immunologically mediated.
• The major pathology of infection occurs with chronic schistosomiasis in which retention of eggs in the host tissues is associated with chronic granulomatous injury.
• Eggs may be trapped at sites of deposition (urinary bladder, ureters, intestine) or be carried by the bloodstream to other organs, most commonly the liver and less often the lungs and central nervous system.
• The host response to these eggs involves local as well as systemic manifestations.
• The cell-mediated immune response leads to granulomas composed of lymphocytes, macrophages, and eosinophils that surround the trapped eggs and add significantly to the degree of tissue destruction.
• Granuloma formation in the bladder wall and at the ureterovesical junction results in the major disease manifestations of schistosomiasis haematobia (hematuria, dysuria, and obstructive uropathy).
• Intestinal as well as hepatic granulomas underlie the pathologic sequelae of the other schistosome infections( ulcerations and fibrosis of intestinal wall, hepatosplenomegaly, and portal hypertension) due to pre-sinusoidal obstruction of blood flow.
• In terms of systemic disease, antischistosome inflammation increases circulating levels of proinflammatory cytokines such as tumor necrosis factor-α and interleukin-6, associated with elevated levels of C-reactive protein.
• These responses are associated with hepcidin-mediated inhibition of iron uptake and use, leading to anemia of chronic inflammation.
• Schistosomiasis-related undernutrition may be the result of similar pathways of chronic inflammation.
• Acquired partial protective immunity against schistosomiasis has been demonstrated in some animal species and may occur in humans.

Associated conditions

• Recurrent Salmonella infections can occur in patients with schistosomiasis. Salmonella bacteria live in symbiosis within the parasite's integument, allowing them to evade eradication by many antibiotics.
• Chloramphenicol-sensitive Salmonella entericaserotype Typhi has been shown to be refractory to chloramphenicol therapy in patients coinfected with Schistosoma.
• Patients coinfected with hepatitis C virus and Schistosoma have increased progression of liver fibrosis compared to patients with hepatitis C alone.
• Urogenital schistosomiasis is a co-factor in the spread and progression of human immunodeficiency virus (HIV) infection and other sexually transmitted infections, especially in women, and also is associated with female infertility.

Microscopic Findings

• Adult worms are about 10 mm long

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Associated conditions

• Recurrent Salmonella infections can occur in patients with schistosomiasis. Salmonella bacteria live in symbiosis within the parasite's integument, allowing them to evade eradication by many antibiotics.
• Chloramphenicol-sensitive Salmonella entericaserotype Typhi has been shown to be refractory to chloramphenicol therapy in patients coinfected with Schistosoma.
• Patients coinfected with hepatitis C virus and Schistosoma have increased progression of liver fibrosis compared to patients with hepatitis C alone.
• Urogenital schistosomiasis is a co-factor in the spread and progression of human immunodeficiency virus (HIV) infection and other sexually transmitted infections, especially in women, and also is associated with female infertility.

Differentiating schistosomiasis from other diseases

Schistosomiasis must be differentiated from other tapeworms that cause abdominal pain, fever,chills, cough, and muscle aches such as diphyllobothriasis, taeniasis, hymenolepiasis. The table below summarizes the findings that differentiate schistosomiasis from other conditions that may cause abdominal pain, fever,chills, cough, and muscle aches.

Infections	Common causative threadworms	Suggestive findings	Diagnostic approach	Treatment
Schistosomiasis	Schistosoma japonicum Schistosoma mansoni Schistosoma haematobium	Abdominal pain Cough Diarrhea Fever Fatigue	Stool examination for the eggs Ultrasound of liver	Praziquantel
Diphyllobothriasis	Diphyllobothrium latum	Epigastric pain Diarrhea Fatigue Nausea Vomiting Numbness Tingling	Stool examination for the eggs and adults PCR	Praziquantel
Taeniasis	Taenia solium Taenia saginata	Nausea Vomiting Epigastric pain	Stool examination for the eggs and proglottids Brain CT scan or Biopsy (for cysticercosis)	Praziquantel
Hymenolepiasis	Hymenolepis nana	Nausea Vomiting Abdominal pain Dizziness	Stool examination for the eggs and proglottids	Praziquantel

Symptoms

Clinical manifestations of schistosomiasis are divided into schistosome dermatitis, acute schistosomiasis (Katayama fever), and chronic schistosomiasis.

Acute schistosomiasis(Katayama fever)

• Acute schistosomiasis occurs 20 to 50 days after primary exposure.
• Malaise, diarrhea, weight loss, cough, dyspnea, chest pain, restrictive respiratory insufficiency, and pericarditis are important symptoms of acute schistosomiasis.
• Mild disease resolves on its own, as the infection progress into an asymptomatic phase, which is often misinterpreted for an effective antibiotic therapy.
• The clinical syndrome (i.e., fever, chills, liver and spleen enlargement, and marked eosinophilia) originally described for S. japonicum infection is increasingly being diagnosed in Brazil in individuals with S. mansoni infection with similar presentation.
• Acute disease is not observed in individuals living in endemic areas of schistosomiasis because of the down-modulation of the immune response by antigens or idiotypes transferred from mother to child.

Chronic schistosomiasis

• In chronic schistosomiasis, abdominal pain, irregular bowel movements, and blood in the stool are the main symptoms of intestinal involvement.
• Colonic polyposis may occur.
  • Hepatosplenic involvement is the most important cause of morbidity with S. mansoni and S. japonicum infection.
  • Patients may remain asymptomatic until the manifestation of hepatic fibrosis and portal hypertension develops.
  • Hepatic fibrosis is caused by a granulomatous reaction to Schistosoma eggs that have been carried to the liver.
• Hematemesis from bleeding esophageal or gastric varices may occur.
  • In such cases, anemia and decreasing levels of serum albumin are observed. Some patients have severe hepatosplenic disease with decompensated liver disease. Jaundice, ascites, and liver failure are then observed.
• Concomitant infection by Salmonella species, and less extensively by other gram-negative bacteria, with S. mansoni or S. haematobium leads to a picture of prolonged fever, hepatosplenomegaly, and mild leukocytosis with eosinophilia.
• Glomerulonephritis, infantilism, and hypersplenism are other complications associated with hepatosplenic schistosomiasis.
• The detection of pulmonary hypertension is increasing with the use of more advanced diagnostic technology.
  • Pulmonary hypertension, which used to be exclusively linked to the hepatosplenic form of the disease, has been documented in patients without liver fibrosis.
• In hospitalized adult patients with S. japonicum infection, cerebral schistosomiasis occurs in 1.7 to 4.3%.
  • It may occur as early as 6 weeks after infection, and the most common sign is focal jacksonian epilepsy.
  • Signs and symptoms of generalized encephalitis may occasionally be found. In S. mansoni infection, neurologic involvement is rare and mainly characterized by transverse myelitis, which occurs mainly in patients without liver fibrosis and hepatosplenomegaly.

Less common symptoms

Schistosome dermatitis

• Schistosome dermatitis, or swimmer's itch, is an uncommon manifestation seen mainly when avian cercariae penetrate the skin and are destroyed.
• Schistosome dermatitis is a sensitization phenomenon occurring in previously exposed persons.
• The cercariae evoke an acute inflammatory response with edema, early infiltration of neutrophils and lymphocytes, and later invasion of eosinophils.
• A pruritic papular rash occurs within 24 hours after the penetration of cercariae and reaches maximal intensity in 2 to 3 days.

	Symtoms
Acute schistosomiasis (Katayama fever)	Fever Malaise Arthralgia/myalgia Dry cough, wheezing Abdominal discomfort Diarrhea
Chronic schistosomiasis	Schistosomal nephropathy present with varying degrees of fatigue and asthenia
	Intestinal schistosomiasis may develop episodic intestinal bleeding and tenesmus. Patients infected with S japonicumcan develop upper abdominal pain unrelated to meals, gastric bleeding, and pyloric obstruction due to eosinophilic inflammation and fibrosis. Patients infected with S mansonican develop inflammation with symptoms that resemble those of Crohn disease or ulcerative colitis. Hepatosplenic schistosomiasis may present with cataclysmic esophageal variceal hemorrhage.
	Urinary schistosomiasis presents with hematuria and dysuria Urogenital schistosomiasis present with genital pain, pelvic pain, coital bleeding, and dyspareunia.
	Neuro-schistosomiasis may present with seizures, transverse myelitis or symptoms similar to those of cauda equina syndrome (eg, low back pain, lower extremity weakness, bowel and bladder symptoms) due to inflammation at the nerve roots Granulomatous inflammation in the CNS can result in conus medullaris syndrome or schistosomal cerebritis (most commonly caused by S. japonicum)
	Pulmonary schistosomiasis experience dyspnea on exertion, fatigue, and hemoptysis.
Schistosome dermatitis ( swimmer's itch)	Uncommon manifestation. A pruritic papular rash occurs within 24 hours after the penetration of cercariae and reaches maximal intensity in 2 to 3 days.

Risk factors

The most potent risk factor in the development of schistosomiasis is skin exposure to contaminated fresh water (wading, swimming, washing, or working in fresh water that is infested with cercariae). Other risk factors include travel to endemic areas.

Screening

Screening is recommended only to guide mass public health treatment programs to targeted villages in endemic areas. Routine screening of travelers is not recommended.

Epidemiology

Incidence and prevalence

• More than 600 million persons are exposed to Schistosoma parasites, 200 million persons are infected, and 20 million symptomatic cases of schistosomiasis are reported worldwide

Demographics

Race

• There is no racial predilection to schistosomiasis.

Gender

• Schistosomiasis affects men and women equally.

Geographic Distrubution

• Schistosoma species are endemic in many areas of Africa, South America, the Caribbean, Southeast Asia, and the Middle East.

Natural History

If left untreated, most of the patients with schistosomiasis may progress to develop ulceration or cancer of the bladder, liver or kidney failure.

Complications

Common complications of schistosomiasis include:

• Hematuria
• Malnutrition and growth retardation
• Anemia of chronic disease
• Cervicitis
• Iron-deficiency anemia
• Splenomegaly
• Intestinal polyps
• Hydronephrosis
• Glomerulonephritis
• Recurrent Salmonella bacteremia
• Bladder polyps
• Bladder cancer
• Infertility (male, female)
• Ectopic pregnancy
• Portal hypertension
• Esophageal varices
• Ascites
• Intestinal obstruction
• Obstructive uropathy
• Renal failure
• Generalized seizures
• Spinal cord compression
• Cor pulmonale

Prognosis

• Depending on the extent of the disease progression at the time of diagnosis, the prognosis of schistosomiasis may vary. However, the prognosis is generally regarded as good with treatment.
• The 1-year mortality rate of patients with schistosomiasis ranges approximately 0.1-11% depending upon underlying complications.
• If symptoms of schistosomiasis persisting after 2 rounds of praziquantel treatment, more urine or stool samples should be taken and tested for viable parasite eggs, and re-treatment must be given if persistent infection is detected.

Physical Examination

Common physical examination findings of schistosomiasis include generalized lymphadenopathy, hepatosplenomegaly, rash, fever, right upper quadrant tenderness, urticaria, bloody stool.

Appearance of the Patient

Patients withg schistosomiasis usually appear tired.

Vital Signs

• High-grade / low-grade fever.
• Tachycardia with a regular pulse.
• Tachypnea
• High blood pressure

Skin

• Pallor
• Urticaria
• Purpuric rash

Neck

• Cervical lymphadenopathy
• Jugular venous distension in cases of cor pulmanale.

Lungs

• Normal vesicular breathe sounds.
• Ocassional Wheezeing

Heart

• Normal S1, S2
• Signs of right hear failure in cases cor-pulmonale

Abdomen

• Right upper quadrant tenderness
• Abdominal distention
• Hepatosplenomegaly
• Distended abdominal veins
• Ascites

Genitourinary

• Genital ulcers
• Hypertrophic lesions or nodular lesions of the cervix, vulva, or vagina
• Vesicovaginal fistula.
• Uterine enlargement
• Pelvic pain
• Dysuria

Neuromuscular

• Joint tenderness

Extremities

• Clubbing

Laboratory Findings

Visualization of schistosoma eggs in stool, urine, and crushed biopsy tissues is diagnostic of schistosomiasis. Laboratory findings consistent with the diagnosis of schistosomiasis include detection of circulating antibodies to schistosomes and schistosomal antigen in serum. Diagnostic tests for schistosomiasis include the following:

• Microscopic examination of stool
• Urine testing for schistosome eggs
• Serologic testing
• Schistosomal antigen testing (urine or serum)
• Microscopic examination of tissue
• PCR to detect schistosomal DNA

Microscopic examination of stool

• The classic and most commonly used method for identification of schistosome eggs in stool is a modified Kato-Katz thick smear.
• Testing should be done on formed stool, as schistosomiasis typically does not cause diarrhea.
• Several areas of a stool specimen should be evaluated independently, as eggs are not deposited uniformly throughout. In addition, eggs are not deposited uniformly throughout the day, and, thus, three different stool specimens should be evaluated.
• One to 99 eggs/g is suggestive of mild infection, 100 to 299 eggs/g indicate moderate infection, and more than 300 eggs/g are indicative of high-intensity infection.
• Kato Katz smears are not sufficiently sensitive for detection of low-intensity infections. Other techniques may be superior but often are unavailable or more difficult to use.

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S. japonicum eggs in hepatic portal tract.

Other Methods

Formalin-ethyl acetate sedimentation

• In formalin-ethyl acetate sedimentation 2 to 5 g of stool is mixed, strained, diluted with normal saline solution.
• It is then centrifuged.
• The sediment is collected and treated with formalin-ethyl acetate and subsequently used for slide preparation
• A single formalin-ethyl acetate sedimentation test is not as sensitive for detection of low-intensity infection as multiple Kato-Katz smears

Urine testing for schistosome eggs

• The classic method used for identification of S.haematobium eggs is filter concentration of a urine sample collected over 4 hours (ending around noon) into a jug with formalin preservative
• 10 mL of urine is filtered through a 12-μm pore membrane that traps the eggs, and the membrane surface then is examined under a microscope.
• Standard microscopic urinalysis will not identify low-intensity Schistosoma infections.
• Each separate microscopic urinalysis has a sensitivity of 55% to 62% for detection of low-intensity infection; therefore, at least three different urine samples need to be evaluated to achieve diagnostic accuracy.

Schistosomal antigen testing (urine or serum)

• Urine sample is taken for measurement of circulating cathodic antigen released by schistosomes or serum sample for measurement of both circulating cathodic and anodic antigen.
• Identifies active infection rather than past infection
• May not be sufficiently sensitive for detection of low-intensity infection

Serologic testing

• Serologic testing help in detection of schistosoma-specific antibodies in serum. These tests include:
  • Enzyme-linked immunosorbent assay
  • Indirect hemagglutination assay
  • Indirect immunofluorescent antibody testing
• More useful for evaluating recent travelers than immigrants, as it is not possible to distinguish between active infection and past infection.
• Due to the long life of schistosomes, positive test results cannot be discounted simply because exposure was historically distant.
• Sensitivity is highest when the assay is targeted to the suspected species (S.mansoni, S.japonicum, or S.haematobium)

Microscopic examination of tissue

• A biopsy specimen is obtained from the rectum during anoscopy, genital tissues, or the urinary bladder wall during cystoscopy and then crushed and examined under a microscope
• S.mansoni and S.japonicum eggs can be identified in crushed random rectal biopsy specimens.
• S.haematobium eggs can be identified in crushed biopsy specimens from genital tissues or the urinary bladder wall
• Sensitivity of microscopic analysis of six crushed rectal biopsies is similar to that of two Kato-Katz thick smears.
• Liver biopsy is notoriously insensitive for diagnosis of schistosomiasis; a negative liver biopsy result does not exclude infection
• Standard sectioned intestinal biopsies are not sufficiently sensitive for diagnosis of intestinal schistosomiasis

PCR to detect schistosomal DNA

• Gene amplification technique used to detect schistosomal DNA.

Other laboratory tests

Other diagnostic tests that are helpful in diagnosis of schistosomiasis include

• Urinalysis, including dipstick testing and microscopic analysis for leukocytes, erythrocytes, and casts.
  • If obstruction is causing a urinary tract infection, leukocyte esterase or nitrites may be present
  • Erythrocytes are seen in the urine of patients with glomerulonephritis.
  • Urinary casts, which are aggregates of protein, blood cells, tubular epithelial cell constituents, or all three, develop secondary to urinary stasis in renal tubules and significant proteinuria.
• Measurement of blood urea nitrogen (BUN) and serum creatinine to test renal function.
• Liver function tests.
  • AST and ALT levels usually remain normal, even in patients with hepatosplenic disease
  • Albumin levels may be low due to malnutrition or nephrotic forms of schistosomiasis
• Complete blood count (CBC).
  • Anemia may be seen in patients with chronic blood loss due to intestinal or urinary schistosomiasis and in those with glomerular disease.
  • Eosinophilia may be prominent early in the disease course but may be minimal in patients with longstanding disease.

=MAIN

Eggs can be present in the stool in infections with all Schistosoma species. The examination can be performed on a simple smear (1 to 2 mg of fecal material). Since eggs may be passed intermittently or in small amounts, their detection will be enhanced by repeated examinations and/or concentration procedures (such as the formalin-ethyl acetate technique). In addition, for field surveys and investigational purposes, the egg output can be quantified by using the Kato-Katz technique (20 to 50 mg of fecal material) or the Ritchie technique.

Eggs can be found in the urine in infections with (recommended time for collection: between noon and 3 PM) S. japonicum' and with S. intercalatum. Detection will be enhanced by centrifugation and examination of the sediment. Quantification is possible by using filtration through a nucleopore membrane of a standard volume of urine followed by egg counts on the membrane. Investigation of S. haematobium should also include a pelvic x-ray as bladder wall calcificaition is highly characteristic of chronic infection.

Recently a field evaluation of a novel handheld microscope was undertaken in Uganda for the diagnosis of intestinal schistosomiasis by a team led by Dr. Russell Stothard who heads the Schistosomiasis Control Iniative at the Natural History Museum, London. His report abstract may be found here: [1]

Electrocardiogram

There are no ECG findings associated with schistosomiasis.

Chest X-ray

There are no x-ray findings associated with schistosomiasis. However, chest radiographs can demonstrate patchy infiltrates in acute schistosomiasis. Chest radiographs can also demonstrate signs of increased vascular and interstitial marking and mild lymphadenopathy in cases presence of pulmonary hypertension and cor-pulmonale.

• Abdominal X-ray in urinary schistosomiasis may demonstrate bladder and ureteral calcifications("fetal head" calcification)

CT scan

There are no CT scan findings associated with schistosomiasis. However, a CT scan may be helpful in the diagnosis of complications of schistosomiasis, which includes CNS disease or in the detection of periportal fibrosis.

• CT scan of the brain in CNS schistosomiasis may demonstrate nodular and ring-enhancing lesions with surrounding edema.
• CT scan of the liver in hepatosplenic schistosomiasis may demonstrate calcified capsules.
• CT scan of the lung in pulmonary schistosomiasis may demonstrate interstitial fibrosis.

Ultrasound

Abdominal ultrasound

• Multiple echogenic areas, each with central echolucency are characteristic of classic periportal fibrosis.

Urogenital ultrasonography

• Urogenital ultrasonography may demonstrate scarring patterns of bladder characteristic of urogenital schistosomiasis.
• Urogenital ultrasonography is more sensitive than intravenous pyelography and plain radiography for detection of urinary tract pathologies.

MRI

There are no MRI findings associated with schistosomiasis.

Primary Prevention

• The most important preventive measure is education regarding the risk associated with contact with fresh water in endemic areas reduces parasite acquisition.
• Avoid swimming or wading in freshwater.
• Although schistosomiasis is not transmitted by swallowing contaminated water, if mouth or lips come in contact with water containing the parasites, infection can occur.
• Water used for bathing should be brought to a rolling boil for 1 minute to kill any cercariae, and then cooled before bathing to avoid scalding.
• Water held in a storage tank for at least 1 - 2 days should be safe for bathing.
• Vigorous towel drying after an accidental, very brief water exposure may help to prevent the Schistosoma parasite from penetrating the skin. However, do not rely on vigorous towel drying alone to prevent schistosomiasis.
• Repeated doses of artesunate or artemether (6 mg/kg every 1 or 2 weeks) appear to provide chemoprophylactic protection against infection with S.japonicum after episodic exposure.

Medical therapy

The mainstay of treatment for schistosomiasis is pharmacotherapy. Praziquantel is the drug of choice in treating schistosomiasis. Corticosteroids should be administered in addition to praziquantel in patients with symptoms due to neuro-schistosomiasis and patients with severe Katayama fever. The goals of treatment of schistosomiasis are to eradicate the helminth and correct any sequelae of infection.

Antimicrobial Regimen

• 1. Schistosoma mansoni, S. haematobium, S. intercalatum

• Preferred regimen: Praziquantel 40 mg/kg per day PO in qd or bid for one day
• Alternative regimen (1): Oxamniquine 20 mg/kg PO single dose
• Alternative regimen (2): Artemisinin no dose is established yet
• Alternative regimen (3): Mefloquine 250 mg PO single dose
• Note: There is no benefit in associating the alternative therapies to Praziquantel.
• Note: Praziquantel is not effective against larval/egg stages of the disease.

• 2. S. japonicum, S. mekongi

• Preferred regimen: Praziquantel 60 mg/kg per day PO bid for one day
• Alternative regimen (1): Artemisinin no dose is established yet
• Alternative regimen (2): Mefloquine 250 mg PO single dose
• Note: There is no benefit in associating the alternative therapies to Praziquantel.

• 3. Katayama Fever

• Preferred regimen: Prednisone 20-40 mg/day PO for 5 days, THEN Praziquantel
• Note: Praziquantel should be used after 4-6 weeks of exposure, because it cannot kill the larvae stages of the Schistosoma. Praziquantel should be used after acute schistosomiasis syndrome symptoms have resolved always together with corticosteroids, only when ova are detected in stool or urine samples.

Praziquantel

• Praziquantel is first-line therapy for infection with all five Schistosoma species (S.japonicum, S.mansoni, S.intercalatum, S.mekongi, and S.haematobium).
• Praziquantel is also used as part of mass chemotherapy campaigns in endemic areas to decrease individual worm burden so as to reduce community transmission.
• Inexpensive
• Not effective against immature schistosomes (schistosomules)
• Not useful for treatment of cercarial dermatitis (ie, cutaneous schistosomiasis or swimmer's itch) caused by transient, self-limited infection withAustrobilharziaspecies
• Very well tolerated; adverse effects are usually mild and transient and do not require treatment.
• Women who are breastfeeding should not breastfeed on the day of treatment
• Rifampin significantly reduces the bioavailability of praziquantel and, thus, should be discontinued 4 weeks before treatment
• Schistosome eggs may take weeks to pass out of the intestinal and bladder wall; therefore, egg passage continues for approximately a month after treatment

Corticosteroids

• Corticosteroids are indicated as an adjunctive treatment (in addition to praziquantel) in patients with symptoms due to:
  • Neuro-schistosomiasis (transverse myelitis, seizures, or other symptoms of increased intracranial pressure)
  • Patients presenting with severe Katayama fever
• Corticosteroids help to alleviate acute allergic reactions and mass effects caused by excessive granulomatous inflammation in the CNS.

Artemisinin compounds

• Artemisinin compounds are employed in the eradication of migrating schistosome larvae in recently infected patients.
• Artemether also may provide chemoprophylactic protection against S.mansoniandS haematobium.

Medical therapy

The mainstay of treatment for Addison's disease is pharmacotherapy which is replacement of deficient hormones. Medical management of Addison's disease can be discussed under two categories

• Acute management ( Addison's crisis)
• Chronic management

Acute management

The main stay of treatment includes glucocorticosteroids and supportive therapy

Goals

• Normalization of blood pressure and volume status
• Supplementation of adequate glucocorticoids plus mineralocorticoid.

Supportive therapy

• Maintain airway, breathing, and circulation, and refer immediately to tertiary care center for intravenous corticosteroids.
• If the patient has pre filled syringes (emergency kit) and presents with Addisonian crisis while far from a hospital, an intramuscular injection should be given and the patient transferred to the nearest emergency room for intravenous normal saline and intravenous hydrocortisone.
• Normal saline 0.9% or 5% dextrose in normal saline should be administered to correct hypotension and dehydration.
• It is usually necessary to administer 1 L rapidly and a further 2 to 4 L over the first 24 hours, to correct hypotension.
• Careful monitoring of BP, fluid status, and serum sodium and potassium levels should be maintained.

Pharmocotherapy

• Dexamethasone should be given to patients with suspected Addisonian crisis prior to any laboratory measurements.
• Intravenous hydrocortisone is used to treat Addisonian crisis following dexamethasone.
• In addition, fludrocortisone is needed for mineralocorticoid replacement.

Adult

• Preferred regimen (1): Dexamethasone IV 2-8 mg/dose q12h followed by a Oral 0.5 mg maintenance dose.
• Preferred regimen (1): Hydrocortisone 100 mg bolus immediately; followed by either 100 mg q8h (or) 300 mg q24 by continuous infusion for 2 to 3 days; then 100 to 150 mg q24h and taper to 75 mg/d before switching to oral maintenance dose
  • Note: Maintenance dose 10 mg in the morning, 5 mg around noon, and 5 mg in the afternoon (or) 10 to 15 mg in the morning and 5 to 10 mg in the afternoon.

Pediatric

Preferred regimen (1): Hydrocortisone 1 to 2 mg/kg/dose bolus immediately; followed by 25 to 150 mg/d, given in divided doses every 6 to 8 hours (in infants and young children)or150 to 250 mg/d given in divided doses every 6 to 8 hours (in older children).

Chronic management

The main stay of treatment includes glucocorticosteroids and mineralocorticoids.

Goals

• Adequate daily supplementation of glucocorticoid and mineralocorticoid to mimic normal physiology. This should aim to maintain normal blood pressure, blood glucose, and fluid volume, and instill a sense of well-being in the patient
• Advise patients on medication for minor illness (febrile illness or emesis) to double or triple their usual dose of glucocorticoid. In case of severe illness, they should inject themselves with a large dose of glucocorticoid and seek immediate medical attention
• If patients are monitored to normalize ACTH level, they are almost invariably overtreated with glucocorticoid resulting in iatrogenic Cushing syndrome. Monitoring is primarily based on clinical features
• Ensure that patients are aware that they must be vigilant in maintaining their therapeutic regimen

Precautions

• All patients with known Addison disease should have an emergency plan in place for corticosteroid supplementation (oral or intramuscular), to be implemented if significant illness occurs
• Immediate action is needed for the signs of Addisonian crisis in a known Addison disease patient
• If the patient has pre filled syringes (emergency kit) and presents with Addisonian crisis while far from a hospital, an intramuscular injection should be given and the patient transferred to the nearest emergency room for intravenous normal saline and intravenous hydrocortisone.
• In an undiagnosed patient who requires immediate corticosteroid treatment, dexamethasone may be given as it does not interfere with ACTH stimulation testing.