In mild disease, patients present with eyelid retraction. In fact, upper eyelid retraction is the most common ocular sign of Graves' orbitopathy. This finding is associated with lid lag on infraduction (Von Graefe's sign), eye globe lag on supraduction (Kocher's sign), a widened palpebral fissure during fixation (Dalrymple's sign) and an incapacity of closing the eyelids completely (lagophthalmos). Due to the proptosis, eyelid retraction and lagophthalmos, the cornea is more prone to dryness and may present with chemosis, punctate epithelial erosions and superior limbic keratoconjunctivitis. The patients also have a dysfunction of the lacrimal gland with a decrease of the quantity and composition of tears produced. Non-specific symptoms with these pathologies include irritation, grittiness, photophobia, tearing, and blurred vision. Pain is not typical, but patients often complain of pressure in the orbit. Periorbital swelling due to inflammation can also be observed.

- Eye signs in TED

In moderate active disease, the signs and symptoms are persistent and increasing and include myopathy. The inflammation and edema of the extraocular muscles lead to gaze abnormalities. The inferior rectus muscle is the most commonly affected muscle and patient may experience vertical diplopia on upgaze and limitation of elevation of the eyes due to fibrosis of the muscle. This may also increase the intraocular pressure of the eyes. The double vision is initially intermittent but can gradually become chronic. The medial rectus is the second-most-commonly-affected muscle, but multiple muscles may be affected, in an asymmetric fashion.

In more severe and active disease, mass effects and cicatricial changes occur within the orbit. This is manifested by a progressive exophthalmos, a restrictive myopathy that restricts eye movements and an optic neuropathy. With enlargement of the extraocular muscle at the orbital apex, the optic nerve is at risk of compression. The orbital fat or the stretching of the nerve due to increased orbital volume may also lead to optic nerve damage. The patient experiences a loss of visual acuity, visual field defect, afferent pupillary defect, and loss of color vision. This is an emergency and requires immediate surgery to prevent permanent blindness.

Graves ophthalmopathy (also known as thyroid eye disease (TED), dysthyroid/thyroid-associated orbitopathy (TAO), Graves' orbitopathy (GO)) is an autoimmune inflammatory disorder of the orbit and periorbital tissues, characterized by upper eyelid retraction, lid lag, swelling, redness (erythema), conjunctivitis, and bulging eyes (exopthalmos). It occurs most commonly in individuals with Graves' disease, and less commonly in individuals with Hashimoto's thyroiditis, or in those who are euthyroid.

It is part of a systemic process with variable expression in the eyes, thyroid, and skin, caused by autoantibodies that bind to tissues in those organs. The autoantibodies target the fibroblasts in the eye muscles, and those fibroblasts can differentiate into fat cells (adipocytes). Fat cells and muscles expand and become inflamed. Veins become compressed, and are unable to drain fluid, causing edema.

Annual incidence is 16/100,000 in women, 3/100,000 in men.

About 3–5% have severe disease with intense pain, and sight-threatening corneal ulceration or compression of the optic nerve. Cigarette smoking, which is associated with many autoimmune diseases, raises the incidence 7.7-fold.

Mild disease will often resolve and merely requires measures to reduce discomfort and dryness, such as artificial tears and smoking cessation if possible. Severe cases are a medical emergency, and are treated with glucocorticoids (steroids), and sometimes ciclosporin. Many anti-inflammatory biological mediators, such as infliximab, etanercept, and anakinra are being tried, but there are no randomized controlled trials demonstrating effectiveness.

The signs and symptoms of Graves' disease virtually all result from the direct and indirect effects of hyperthyroidism, with main exceptions being Graves' ophthalmopathy, goiter, and pretibial myxedema (which are caused by the autoimmune processes of the disease). Symptoms of the resultant hyperthyroidism are mainly insomnia, hand tremor, hyperactivity, hair loss, excessive sweating, shaking hands, itching, heat intolerance, weight loss despite increased appetite, diarrhea, frequent defecation, palpitations, muscle weakness, and skin warmth and moistness. Further signs that may be seen on physical examination are most commonly a diffusely enlarged (usually symmetric), nontender thyroid, lid lag, excessive lacrimation due to Graves' ophthalmopathy, arrhythmias of the heart, such as sinus tachycardia, atrial fibrillation, and premature ventricular contractions, and hypertension. People with hyperthyroidism may experience behavioral and personality changes, including: psychosis, mania, anxiety, agitation, and depression.

Thyroid storm is a severe form of thyrotoxicosis characterized by rapid and often irregular heart beat, high temperature, vomiting, diarrhea, and mental agitation. Symptoms may be unusual in the young, old, or pregnant. It is a medical emergency and requires hospital care to control the symptoms rapidly. Even with treatment, death occurs in 20% to 50%.

Hyperthyroidism may be asymptomatic or present with significant symptoms. Some of the symptoms of hyperthyroidism include nervousness, irritability, increased perspiration, heart racing, hand tremors, anxiety, difficulty sleeping, thinning of the skin, fine brittle hair, and muscular weakness—especially in the upper arms and thighs. More frequent bowel movements may occur, and diarrhea is common. Weight loss, sometimes significant, may occur despite a good appetite (though 10% of people with a hyperactive thyroid experience weight gain), vomiting may occur, and, for women, menstrual flow may lighten and menstrual periods may occur less often, or with longer cycles than usual.

Thyroid hormone is critical to normal function of cells. In excess, it both overstimulates metabolism and exacerbates the effect of the sympathetic nervous system, causing "speeding up" of various body systems and symptoms resembling an overdose of epinephrine (adrenaline). These include fast heart beat and symptoms of palpitations, nervous system tremor such as of the hands and anxiety symptoms, digestive system hypermotility, unintended weight loss, and (in "lipid panel" blood tests) a lower and sometimes unusually low serum cholesterol.

Major clinical signs include weight loss (often accompanied by an increased appetite), anxiety, heat intolerance, hair loss (especially of the outer third of the eyebrows), muscle aches, weakness, fatigue, hyperactivity, irritability, high blood sugar, excessive urination, excessive thirst, delirium, tremor, pretibial myxedema (in Graves' disease), emotional lability, and sweating. Panic attacks, inability to concentrate, and memory problems may also occur. Psychosis and paranoia, common during thyroid storm, are rare with milder hyperthyroidism. Many persons will experience complete remission of symptoms 1 to 2 months after a euthyroid state is obtained, with a marked reduction in anxiety, sense of exhaustion, irritability, and depression. Some individuals may have an increased rate of anxiety or persistence of affective and cognitive symptoms for several months to up to 10 years after a euthyroid state is established. In addition, those with hyperthyroidism may present with a variety of physical symptoms such as palpitations and abnormal heart rhythms (the notable ones being atrial fibrillation), shortness of breath (dyspnea), loss of libido, amenorrhea, nausea, vomiting, diarrhea, gynecomastia and feminization. Long term untreated hyperthyroidism can lead to osteoporosis. These classical symptoms may not be present often in the elderly.

Neurological manifestations can include tremors, chorea, myopathy, and in some susceptible individuals (in particular of Asian descent) periodic paralysis. An association between thyroid disease and myasthenia gravis has been recognized. The thyroid disease, in this condition, is autoimmune in nature and approximately 5% of patients with myasthenia gravis also have hyperthyroidism. Myasthenia gravis rarely improves after thyroid treatment and the relationship between the two entities is not well understood.

In Graves' disease, ophthalmopathy may cause the eyes to look enlarged because the eye muscles swell and push the eye forward. Sometimes, one or both eyes may bulge. Some have swelling of the front of the neck from an enlarged thyroid gland (a goiter).

Minor ocular (eye) signs, which may be present in any type of hyperthyroidism, are eyelid retraction ("stare"), extraocular muscle weakness, and lid-lag. In hyperthyroid "stare" (Dalrymple sign) the eyelids are retracted upward more than normal (the normal position is at the superior corneoscleral limbus, where the "white" of the eye begins at the upper border of the iris). Extraocular muscle weakness may present with double vision. In lid-lag (von Graefe's sign), when the patient tracks an object downward with their eyes, the eyelid fails to follow the downward moving iris, and the same type of upper globe exposure which is seen with lid retraction occurs, temporarily. These signs disappear with treatment of the hyperthyroidism.

Neither of these ocular signs should be confused with exophthalmos (protrusion of the eyeball), which occurs specifically and uniquely in hyperthyroidism caused by Graves' disease (note that not all exophthalmos is caused by Graves' disease, but when present with hyperthyroidism is diagnostic of Graves' disease). This forward protrusion of the eyes is due to immune-mediated inflammation in the retro-orbital (eye socket) fat. Exophthalmos, when present, may exacerbate hyperthyroid lid-lag and stare.

Thyroid-associated ophthalmopathy (TAO), or thyroid eye disease (TED), is the most common extrathyroidal manifestation of Grave's disease. It is a form of idiopathic lymphocytic orbital inflammation, and although its pathogenesis is not completely understood, autoimmune activation of orbital fibroblasts, which in TAO express the TSH receptor, is thought to play a central role.

Hypertrophy of the extraocular muscles, adipogenesis, and deposition of nonsulfated glycoaminoglycans and hyaluronate, causes expansion of the orbital fat and muscle compartments, which within the confines of the bony orbit may lead to dysthyroid optic neuropathy, increased intraocular pressures, proptosis, venous congestion leading to chemosis and periorbital edema, and progressive remodeling of the orbital walls. Other distinctive features of TAO include lid retraction, restrictive myopathy, superior limbic keratoconjunctivitis, and exposure keratopathy.

Severity of eye disease may be classified by the mnemonic: "NO SPECS":

- Class 0: No signs or symptoms

- Class 1: Only signs (limited to upper lid retraction and stare, with or without lid lag)

- Class 2: Soft tissue involvement (oedema of conjunctivae and lids, conjunctival injection, etc.)

- Class 3: Proptosis

- Class 4: Extraocular muscle involvement (usually with diplopia)

- Class 5: Corneal involvement (primarily due to lagophthalmos)

- Class 6: Sight loss (due to optic nerve involvement)

Typically the natural history of TAO follows Rundle's curve, which describes a rapid worsening during an initial phase, up to a peak of maximum severity, and then improvement to a static plateau without, however, resolving back to a normal condition.

Infiltrative ophthalmopathy is found in 5-10% of patients with Graves disease and resembles exophthalmos, except that the blurry or double vision is acquired because of weakness in the ocular muscles of the eye. In addition, there is no known correlation with the patient's thyroid levels. Exophthalmos associated with Grave's disease disappears when the thyrotoxicosis is corrected. Infiltrative ophthalmopathy at times may not be cured. Treatments consist of high dose glucocorticoids and low dose radiotherapy. The current hypothesis is that infiltrative ophthalmopathy may be autoimmune in nature targeting retrobulbar tissue. Smoking may also have a causative effect.

Pretibial myxedema is almost always preceded by the ocular signs found in Graves' disease.

It usually presents itself as a waxy, discolored induration of the skin—classically described as having a so-called "peau d'orange" (orange peel) appearance—on the anterior aspect of the lower legs, spreading to the dorsum of the feet, or as a non-localised, non-pitting edema of the skin in the same areas. In advanced cases, this may extend to the upper trunk (torso), upper extremities, face, neck, back, chest and ears.

The lesions are known to resolve very slowly. Application of petroleum jelly on the affected area could relieve the burning sensation and the itching. It occasionally occurs in non-thyrotoxic Graves' disease, Hashimoto's thyroiditis, and stasis dermatitis. The serum contains circulating factors which stimulate fibroblasts to increase synthesis of glycosaminoglycans.

Acropachy or thyroid acropachy refers to a dermopathy associated with Graves' disease. It is characterized by soft-tissue swelling of the hands and clubbing of the fingers. Radiographic imaging of affected extremities typically demonstrates periostitis, most commonly the metacarpal bones. The exact cause is unknown, but it is thought to be caused by stimulating auto-antibodies that are implicated in the pathophysiology of Graves' thyrotoxicosis. There is no effective treatment for acropachy.

Since it is closely associated with Graves' disease, it is associated with other manifestations of Graves' disease, such as Graves' ophthalmopathy and thyroid dermopathy.

Hereditary acropachy (also known as "isolated congenital nail clubbing") may be associated with HPGD.

There are suggestions in the medical literature that treatment with radioactive iodine for Graves' hyperthyroidism may be a trigger for pretibial myxedema which would be consistent with radioiodine ablation causing or aggravating ophthalmopathy, a condition which commonly occurs with pretibial myxedema and is believed to have common underlying features.

Other known triggers for ophthalmopathy include thyroid hormone imbalance, and tobacco smoking, but there has been little research attempting to confirm these are also risk factors for pretibial myxedema.

Hyperthyroidism occurs in about 0.2-0.4% of all pregnancies. Most cases are due to Graves’ disease although less common causes (e.g. toxic nodules and thyroiditis) may be seen. Clinical assessment alone may occasionally be inadequate in differentiating hyperthyroidism from the hyperdynamic state of pregnancy. Distinctive clinical features of Graves’ disease include the presence of ophthalmopathy, diffuse goitre and pretibial myxoedema. Also, hyperthyroidism must be distinguished from gestational transient thyrotoxicosis, a self-limiting hyperthyroid state due to the thyroid stimulatory effects of beta-hCG . This distinction is important since the latter condition is typically mild and will not usually require specific antithyroid treatment. Red cell zinc may also be useful in differentiating the two. Hyperthyroidism due to Graves’ disease may worsen in the first trimester of pregnancy, remit in later pregnancy, and subsequently relapse in the postpartum.

Measurement of the degree of exophthalmos is performed using an exophthalmometer.

Most sources define exophthalmos/proptosis as a protrusion of the globe greater than 18 mm.

The term exophthalmos is often used when describing proptosis associated with Graves' disease.

Proptosis is the anterior displacement of the eye from the orbit. Since the orbit is closed off posteriorly, medially and laterally, any enlargement of structures located within will cause the anterior displacement of the eye. Swelling or enlargement of the lacrimal gland causes inferior medial and anterior dislocation of the eye. This is because the lacrimal glands are located superiorly and laterally in the orbit.

Uncontrolled hyperthyroidism in pregnancy is associated with an increased risk of severe pre-eclampsia and up to a four-fold increased risk of low birth weight deliveries. Some of these unfavourable outcomes are more marked in women who are diagnosed for the first time in pregnancy. A recent study has also shown that already high normal maternal FT4 levels are associated with a decrease in child IQ and gray matter and cortex volumes, similar to the effects of hypothyroidism.

Uncontrolled and inadequately treated maternal hyperthyroidism may also result in fetal and neonatal hyperthyroidism due to the transplacental transfer of stimulatory TSH receptor antibodies (TRAbs). Clinical neonatal hyperthyroidism occurs in about 1% of infants born to mothers with Graves’ disease. Rarely neonatal hypothyroidism may also be observed in the infants of mothers with Graves’ hyperthyroidism. This may result from transplacental transfer of circulating maternal anti-thyroid drugs, pituitary-thyroid axis suppression from transfer of maternal thyroxine.

Affected individuals typically present with sudden painful proptosis, redness, and edema. Proptosis will vary according to the degree of inflammation, fibrosis, and mass effect. Occasionally, ptosis, chemosis, motility dysfunction (ophthalmoplegia), and optic neuropathy are seen. In the setting of extensive sclerosis there may be restriction, compression, and destruction of orbital tissue. Symptoms usually develop acutely (hours to days), but have also been seen to develop over several weeks or even months.Malaise, headaches, and nausea may accompany these symptoms. Other unusual presentations described include cystoid macular edema, temporal arteritis, and cluster headaches.

Pediatric IOI accounts for about 17% of cases idiopathic orbital inflammation. The most common sign is proptosis, but redness and pain are also experienced. Presentation varies slightly compared to adults with bilateral involvement, uveitis, disc edema and tissue eosinophilia being more common in this population. The presence of uveitis generally implies a poor outcome for pediatric IOI. Bilateral presentation may have a higher incidence of systemic disease.

An attack often begins with muscle pain, cramping, and stiffness. This is followed by weakness or paralysis that tends to develop rapidly, usually in late evening or the early hours of the morning. The weakness is usually symmetrical; the limb muscles closer to the trunk (proximal) are predominantly affected, and weakness tends to start in the legs and spread to the arms. Muscles of the mouth and throat, eyes, and breathing are usually not affected, but occasionally weakness of the respiratory muscles can cause life-threatening respiratory failure. Attacks typically resolve within several hours to several days, even in the absence of treatment. On neurological examination during an attack, flaccid weakness of the limbs is noted; reflexes are usually diminished, but the sensory system is unaffected. Mental status is not affected.

Attacks may be brought on by physical exertion, drinking alcohol, or eating food high in carbohydrates or salt. This may explain why attacks are more common in summer, when more people drink sugary drinks and engage in exercise. Exercise-related attacks tend to occur during a period of rest immediately after exercise; exercise may therefore be recommended to abort an attack.

There may be symptoms of thyroid overactivity, such as weight loss, a fast heart rate, tremor, and perspiration; but such symptoms occur in only half of all cases. The most common type of hyperthyroidism, Graves' disease, may additionally cause eye problems (Graves' ophthalmopathy) and skin changes of the legs (pretibial myxedema). Thyroid disease may also cause muscle weakness in the form of thyrotoxic myopathy, but this is constant rather than episodic.

Although these blocking antibodies may be confined to one of the larger muscles responsible for moving the face or appendages or for breathing, about 90% of MG patients eventually have eye involvement. The most common symptoms are double vision (diplopia) and eyelid drooping (ptosis), whereas the pupil is always spared. Diplopia occurs when MG affects a single extraocular muscle in one eye, limiting eye movement and leading to double vision when the eye is turned toward the affected muscle. Ptosis occurs when the levator palpebrae superioris (the muscle responsible for eyelid elevation) is affected on one or both sides, leading to eyelid drooping. Although these symptoms may not be readily apparent in well-rested patients, weakness can usually be induced with exercise of the commonly affected muscles (e.g. by having the patient look upward for about 60 seconds).

In 75% of MG cases, the initial manifestation is in the eye. Within 2 years, 80% of patients with ocular onset of MG will progress to involve other muscle groups, thereby developing generalized MG. If MG is confined to the ocular muscles for more than 3 years, there is a 94% likelihood that the symptoms will not worsen or generalize.

Aside from asymmetric ptosis (which becomes worse with fatigue, sustained upgaze, and at the end of the day) and variable limitation of extraocular muscles/diplopia, other clinical signs of ocular MG include gaze-evoked nystagmus (rapid, involuntary, oscillatory motion of the eyeball) and Cogan’s lid twitch (upper lid twitch present when patient looks straight ahead after looking down for 10–15 seconds).

Individuals with the disease present with upper abdominal pain (epigastric), at times accompanied by nausea, vomiting, loss of appetite, edema, and weight loss. A small amount of gastrointestinal bleeding may occur, which is typically due to superficial mucosal erosions; large volume bleeding is rare. 20% to 100% of patients, depending on time of presentation, develop a protein-losing gastropathy accompanied by low blood albumin and edema.

Symptoms and pathological features of Ménétrier disease in children are similar to those in adults, but disease in children is usually self-limited and often follows respiratory infection.

Thyrotoxic periodic paralysis (TPP) is a condition featuring attacks of muscle weakness in the presence of hyperthyroidism (overactivity of the thyroid gland). Hypokalemia (a decreased potassium level in the blood) is usually present during attacks. The condition may be life-threatening if weakness of the breathing muscles leads to respiratory failure, or if the low potassium levels lead to cardiac arrhythmias (irregularities in the heart rate). If untreated, it is typically recurrent in nature.

The condition has been linked with genetic mutations in genes that code for certain ion channels that transport electrolytes (sodium and potassium) across cell membranes. The main ones are the L-type calcium channel α1-subunit and potassium inward rectifier 2.6; it is therefore classified as a channelopathy. The abnormality in the channel is thought to lead to shifts of potassium into cells, under conditions of high thyroxine (thyroid hormone) levels, usually with an additional precipitant.

Treatment of the hypokalemia, followed by correction of the hyperthyroidism, leads to complete resolution of the attacks. It occurs predominantly in males of Chinese, Japanese, Vietnamese, Filipino, and Korean descent. TPP is one of several conditions that can cause periodic paralysis.

Idiopathic orbital inflammatory (IOI) disease, or orbital pseudotumor, refers to a marginated mass-like enhancing soft tissue involving any area of the orbit. It is the most common painful orbital mass in the adult population, and is associated with proptosis, cranial nerve (Tolosa–Hunt syndrome), uveitis, and retinal detachment. Idiopathic orbital inflammatory syndrome, also known as orbital pseudotumor, was first described by Gleason in 1903 and by Busse and Hochhmein. It was then characterized as a distinct entity in 1905 by Birch-Hirschfeld. It is a benign, nongranulomatous orbital inflammatory process characterized by extraocular orbital and adnexal inflammation with no known local or systemic cause. Its diagnosis is of exclusion once neoplasm, primary infection and systemic disorders have been ruled-out. Once diagnosed, it is characterized by its chronicity, anatomic location or histologic subtype.

Idiopathic orbital inflammation has a varied clinical presentation depending on the involved tissue. It can range from a diffuse inflammatory process to a more localized inflammation of muscle, lacrimal gland or orbital fat. Its former name, orbital pseudotumor, is derived due to resemblance to a neoplasm. However, histologically it is characterized by inflammation. Although a benign condition, it may present with an aggressive clinical course with severe vision loss and oculomotor dysfunction.

Ocular myasthenia gravis (MG) is a disease of the neuromuscular junction resulting in hallmark variability in muscle weakness and fatigability. MG is an autoimmune disease where anomalous antibodies are produced against the naturally occurring acetylcholine receptors in voluntary muscles. MG may be limited to the muscles of the eye (ocular MG), leading to abrupt onset of weakness/fatigability of the eyelids or eye movement. MG may also involve other muscle groups (generalized MG).

Ménétrier disease (also known as hypoproteinemic hypertrophic gastropathy; named after a French physician Pierre Eugène Ménétrier, 1859–1935), is a rare, acquired, premalignant disease of the stomach characterized by massive gastric folds, excessive mucous production with resultant protein loss, and little or no acid production. The disorder is associated with excessive secretion of transforming growth factor alpha (TGF-α).

The more common features of the disease are summarized in the acronym POEMS:

Papilledema (swelling of the optic disc) often but not always due to increased intracranial pressure) is the most common ocular sign of POEMS syndrome, occurring in ≥29% of cases. Less frequent ocular findings include cystoid macular edema, serous macular detachment, infiltrative orbitopathy, and venous sinus thrombosis.

Pulmonary disease/ Polyneuropathy: The lungs are often affected at more severe stages of the illness, although since by then physical exertion is usually limited by neuropathy, shortness of breath is unusual. Pulmonary hypertension is the most serious effect on the lungs, and there may also be restriction of chest expansion or impaired gas exchange.

Organomegaly: The liver may be enlarged, and less often the spleen or lymph nodes, though these organs usually function normally.

Edema: Leakage of fluid into the tissues is a common and often severe problem. This may take several forms, including dependent peripheral edema, pulmonary edema, effusions such as pleural effusion or ascites, or generalized capillary leakage (anasarca).

Endocrinopathy: In women, amenorrhea, and in men, gynecomastia, erectile dysfunction and testicular atrophy, are common early symptoms due to dysfunction of the gonadal axis. Other hormonal problems occurring in at least a quarter of patients include type 2 diabetes, hypothyroidism, and adrenal insufficiency.

Monoclonal paraprotein: In most cases a serum myeloma protein can be detected, although this is not universal. This may represent IgG or IgA, but the light chain type is almost always lambda. This is in contrast to most paraproteinemic neuropathies, in which the paraprotein is usually an IgM antibody.

Skin changes: A very wide variety of skin problems have been reported in association with POEMS syndrome. The most common is non-specific hyperpigmentation. The fingernails may be clubbed or white. There may be thickening of the skin, excess hair or hair in unusual places (hypertrichosis), skin angiomas or hemangiomas, or changes reminiscent of scleroderma.

The diagnosis of POEMS syndrome is based on meeting its two mandatory criteria, meeting at least one of its 3 other major criteria, and meeting at least one of its 6 minor criteria. These criteria are:

- Mandatory major criteria

- Plasma cell dyscrasia: This is evidenced by 1) the presence of a serum myeloma protein, typically an IgG or IgA isotype (occurs in nearly 100% of cases; in >95% of instances the myeloma proteins contain a λ chain that is restricted to either of two V lambda 1 subfamily members viz., IGLV1-40*01 and IGLV1-44*01 (see V lambda family); 2) any, but often a small, increase above the normal value of <1.5% in the percentage of nucleated bone marrow cells that are clonal plasma cells (occurs ~67% of cases); and/or 3) presence of a plasma cell tumor (i.e. plasmacytoma) usually in bone (occurs in ~33% of cases).

- Polyneuropathy: The nerve damage is usually symmetrical, located in distal extremities, and due to the nerve losing its fatty myelin coating and axonal damage. Neurons of the Sensory, motor and autonomic nervous systems are all affected. The typical symptoms are therefore numbness, tingling, and weakness in the feet, later affecting the legs and hands. Pain is unusual, but the weakness may eventually become severe and disabling. The autonomic neuropathy may cause excessive sweating and erectile dysfunction; hormonal changes may also contribute to the latter. It is usually the symptoms of neuropathy which prompt a person with POEMS syndrome to seek medical attention.

- Other major criteria

- Castleman disease: The lymphoproliferative disorder Castleman disease associated with POEMS syndrome is multicentric and occurs in ~15 of cases. It is characterized by a morphology in lymph nodes termed angiofollicular lymph node hyperplasia; an overly activate immune system; excessive production of cytokines including particularly IL-6 and to lesser extents, proliferation of immune B cells and T cells, enlarged lymph nodes, enlarged liver and spleen, capillary leak syndrome, anasarca, evidence of extravascular fluid overload, and organ failure. Patients with Castleman disease without a plasma cell dyscrasia and peripheral neuropathy but having other signs and symptoms of POEMS syndrome can be classified as a Castleman disease variant of POEMS syndrome.

- Sclerotic bone lesions: These lesions consist of plasma cell tumors encased within or associated with abnormally dense bone structures; in different studies, they have been observed to occur in 27% to 97% of cases.

- Elevated VEGF: VEGF is a cytokine that stimulates angiogenesis (i.e. capillary formation), increases capillary permeability, and contributes to polyneuropathy. It is elevated in almost all cases of POEMS syndrome and has become a clinically useful marker for the syndrome's presence, severity, and response to treatment. However, its role in mediating the symptoms of this disease are unclear. A second cytokine, IL-12, is similar to VEGF in being highly correlated with the disease activity level in POEMS syndrome.

- Minor criteria

- Organomegaly: Enlargement spleen, liver, and/or lymph nodes occurs in 45% to 85% of cases.

- Extravascular volume overload: Ascites, pleural effusions, pericardial effusions, and/or lower extremity edema occur in 27% to 89% of cases.

- Endocrinopathy: Gynecomastia occurs in 12% to 18% of cases; endocrine abnormalities involving the regulation of gonadotrophins, adrenal gland corticosteroids, and prolactin occur in 55% to 89%, 16% to 33%, and 55 to 20% of cases, respectively. Diabetes and hypothyroidism also occur in 3% to 36% and 9% to 67%, respectively, of cases but are not considered to be criteria for the presence of POEMS syndrome because of their frequent occurrence in the general population.

- Skin changes: Skin changes occur in 68% to 89% of POEMS syndrome patients. These changes most commonly are hyperpigmentation and/or hypertrichosis (abnormal amount of hair growth over the body) but less commonly include glomeruloid hemangioma, signs or symptoms of Hypervolemia (e.g. edema and ascites), acrocyanosis (blue discoloration of the extremities due to blood flow abnormalities), flushing, and/or white nails.

- Papilledema: Papilledema (swelling of retinal optical discs) occurs in 29% to 64% of cases. Papilledema in POEMS syndrome patients may occur with or without visual disturbances, increased intracranial pressure, or changes in cerebral spinal fluid protein levels.

- Thrombocytosis/polycythemia: Thrombocytosis (increase in blood platelet count) and polycythemia (increase in red blood cells) occurs 54% to 88% and 12% to 19%, respectively, of POEMS syndrome patients and may be may underlying causes of these patients to experience thrombosis events.

Sarcoidosis is a systemic disease of unknown cause that results in the formation of non-caseating granulomas in multiple organs. The prevalence is higher among blacks than whites by a ratio of 20:1. Usually the disease is localized to the chest, but urogenital involvement is found in 0.2% of clinically diagnosed cases and 5% of those diagnosed at necropsy. The kidney is the most frequently affected urogenital organ, followed in men by the epididymis. Testicular sarcoidosis can present as a diffuse painless scrotal mass or can mimic acute epididymo-orchitis. Usually it appears with systemic manifestations of the disease. Since it causes occlusion and fibrosis of the ductus epididymis, fertility may be affected. On ultrasound, the hypoechogenicity and ‘infiltrative’ pattern seen in the present case are recognized features. Opinions differ on the need for histological proof, with reports of limited biopsy and frozen section, radical orchiectomy in unilateral disease and unilateral orchiectomy in bilateral disease. The peak incidence of sarcoidosis and testicular neoplasia coincide at 20–40 years and this is why most patients end up having an orchiectomy. However, testicular tumours are much more common in white men, less than 3.5% of all testicular tumours being found in black men. These racial variations justify a more conservative approach in patients of descent with proven sarcoidosis elsewhere. Careful follow-up and ultrasonic surveillance may be preferable in certain clinical settings to biopsy and surgery, especially in patients with bilateral testicular disease.

Two main approaches to genitourinary sarcoidosis have been proposed. Based on the marked relationship between testicular cancer and sarcoidosis, orchiectomy is recommended, even if evidence of sarcoidosis in other organs is present. By contrast, others consider immediate orchiectomy as being quite aggressive because of several factors associated with a benign diagnosis, as well as the involvement of the epididymis or vas deferens and bilateral testicular involvement. If the malignant diagnosis is established by exploration and intraoperative ultrasound-guided biopsy, orchiectomy is performed in cases of diffuse involvement of a testis. Spontaneous resolution has been reported in 50% to 70% of patients with active sarcoidosis. If the diagnosis is not established unequivocally, immunosuppressive agents (frequently steroids) will resolve the inflammation in patients who wish to salvage their fertility; and in those with severely advanced disease, after careful consideration.

A new approach has been proposed recently, based on the absence of evidence for malignant transformation in pathologically confirmed benign diagnosed testicular sarcoidosis, and it involves the open exploration of both testes, with resection of the largest lesion (on the right tunica). In this technique, patient was not given steroids after the operation. Nevertheless, careful follow-up may be preferred to medication or surgery in certain clinical settings.