Endocrine and reproductive manifestations of sarcoidosis

N. Porter¹, H.L. Beynon² and H.S. Randeva¹

From the ¹Department of Medicine, Leicester Warwick Medical School, University of Warwick, Warwick, and ²Royal Free Hospital and UCL Medical School, London, UK

Introduction

Sarcoidosis is a multisystem protean disorder, characterized histologically by the presence of non-caseating epithelioid-cell granulomas in affected tissues. The aetiology of sarcoidosis remains unclear, although it is recognized as a disease of activated T lymphocytes. Sarcoidosis has an uneven distribution world-wide, with high prevalence rates in European countries such as Sweden and Denmark, compared to China or Japan. There is also geographical or community clustering of the disease. In the UK, for example, where the prevalence rate is 20 per 100 000,¹ the incidence increases from north to south, offering support for the idea that a transmissible agent may play a part in the aetiology of the condition. Interestingly, the incidence and clinical course of sarcoidosis varies in different racial groups living in the same geographical area. There is a 10-fold higher annual incidence in West Indian and Asian immigrants living in London than in the indigenous White population. Furthermore, in West Indian and Asian patients, full recovery appears less likely, and there is an increased incidence of extrathoracic disease.²

Onset is most commonly between the ages of 20 and 40 years, although sarcoidosis is occasionally reported in childhood and in the elderly. Although remarkably transient in some individuals, sarcoidosis may run a chronic course for others. There is a diverse range of possible presentations, with respiratory, ophthalmological and dermatological complications, for example. In this article, we outline the endocrine and reproductive manifestations of sarcoidosis.

	Vitamin D and calcium metabolism

The association between sarcoidosis and hypercalcaemia is seen in 5–10% of cases. Hypercalcaemia is usually transient in subacute sarcoidosis, but may fluctuate in chronic sarcoidosis, depending on disease activity.³ The underlying mechanism is thought to involve high circulating concentrations of 1,25-dihydroxyvitamin D₃ [1,25(OH)₂-D₃], produced by extrarenal 1-hydroxylation of vitamin D in alveolar macrophages and sarcoid granulomas.⁴ Production of 1,25(OH)₂-D₃ by alveolar macrophages is stimulated in a dose-response fashion by -interferon,⁵ and it is possible that the increased 1,25(OH)₂-D₃ production is a compensatory mechanism mounted by the immune system to inhibit the inflammatory process. Granulomatous production of parathyroid-hormone related protein (PTH-rP) may also play a role in abnormal calcium metabolism,⁴ where tissue necrosis factor-alpha (TNF-) and interleukin-6, produced by macrophages, increase PTH-rP gene expression.⁴ PTH-rP, the usual aetiological agent of humoral hypercalcaemia of malignancy, was reported in one series to be present in 85% of biopsies of granulomatous tissue from patients with sarcoidosis.⁶

The important targets of 1,25(OH)₂-D₃ are the intestinal epithelium and bone, where the hormone acts to increase intestinal calcium and phosphate absorption, increase osteoclastic recruitment and bone resorption, and modulate an increase in osteoblastic bone formation.⁷ Although hypercalcaemia has long been recognized as a complication of sarcoidosis, the presence of hypercalciuria is three times more common, occurring in approximately 40–50% of patients with sarcoidosis.⁷ The mechanism of hypercalciuria is multifactorial, including: (i) increased absorption of calcium with a high urinary calcium/creatinine ratio, associated with elevated serum 1,25(OH)₂-D₃ levels; (ii) resorption associated with extensive dissemination of sarcoidosis, including bones with high serum angiotensin-converting enzyme levels—osteopenia may occur and hypercalciuria persists on a calcium-poor diet—and (iii) association with osteoclast-activating factor, a bone resorbing substance, produced by activated lymphocytes and mononuclear cells and sarcoid granulomas. Figure 1 illustrates the causes of hypercalcaemia and hypercalciuria in sarcoidosis.

View larger version (20K): [in this window] [in a new window] Figure 1. Causes and consequences of abnormal calcium homeostasis in sarcoidosis. PTH-rP, parathyroid hormone (PTH) related protein; TNF-, tissue necrosis factor- ; IL-6, interleukin-6.

In patients with sarcoidosis, the production of 1,25(OH)₂-D₃ by granulomas is substrate-dependent. This is supported by the observation that hypercalcaemia in sarcoid patients who live in the northern hemisphere is usually more pronounced in the summer months, due to longer exposure to sunlight which increases the dermal production of vitamin D, in turn leading to increased hepatic production of 25-hydroxyvitamin D by the liver. Compared to normal subjects, the production of 1,25(OH)₂-D₃ in subjects with sarcoidosis is not regulated by calcium and parathyroid hormone, and may account for the characteristic finding of increased sensitivity to vitamin D in these patients.⁸ Of note, even though only around 50% of patients with active sarcoidosis are hypercalciuric, abnormal 1,25(OH)₂-D₃ metabolism has been described in some who are normocalciuric and normocalcaemic.⁹ Furthermore, hypercalcaemia complicating sarcoidosis most often results in suppression of parathyroid function.¹⁰ In contrast, an association with hyperparathyroidism is far less common, only having been reported in 50 cases of sarcoidosis in the past 40 years.¹⁰ Although mechanisms have been suggested to account for this combination of disorders, the frequency is so low that chance association cannot be excluded. However, in patients with clinical evidence of sarcoidosis and steroid-resistant hypercalcaemia, the diagnosis of concomitant primary hyperparathyroidism should be considered.

Abnormal calcium metabolism in sarcoidosis can lead to pancreatitis, nephrocalcinosis, nephrolithiasis, impaired renal function, renal failure and death,¹¹ highlighting the importance of diagnosing hypercalcaemia and hypercalciuria in these patients (Figure 1). Symptomatic hypercalcaemia presenting with dehydration, nephrogenic diabetes insipidus and altered conscious state is a rare but recognized complication of sarcoidosis. Furthermore, abnormal calcium metabolism may lead to osteopenia and osteoporosis. In addition to the well-documented increased risk of osteoporosis and fracture posed by corticosteroids^12–14 used in the treatment of sarcoidosis, there is some evidence that subjects with sarcoidosis may have a greater incidence of reduced bone density than the general population prior to commencing treatment.¹⁵ The institution of safe and effective bone protection therapy is necessary in individuals with sarcoidosis, who are often young and require a prolonged course of corticosteroids. Although primary prevention studies suggest that cholecalciferol is not entirely effective in preventing glucocorticoid-induced bone loss,¹⁶ it is well tolerated by patients, and can be used once hypercalcaemia has been excluded. Current available data indicate that bisphosphonates are the most effective agents for the primary and secondary prevention of glucocorticoid-induced osteoporosis.^17,18 It is therefore suggested that the use of bisphosphonates should be limited to patients who have a reduced bone mass before they begin to take corticosteroids, postmenopausal women and those who have shown significant loss of bone mass while receiving suitable hormone replacement (if required) and cholecalciferol.¹⁹ Of the bisphosphonates, alendronate appears to have the most favourable effects^17–19 and has also been successfully used in both men and premenopausal women with sarcoidosis.²⁰

Management of abnormal calcium homeostasis includes measurement of serum calcium and albumin in order to estimate the ionized calcium level, 24-h urine collection for calcium excretion and creatinine clearance, and an abdominal ultrasound investigation performed to exclude urolithiasis or nephrocalcinosis. Treatment of the hypercalcaemia and/or hypercalciuria in sarcoidosis (Table 1) is aimed at reducing intestinal calcium absorption and 1,25(OH)₂-D₃ synthesis. It is accepted practice that all patients be advised to minimize their exposure to sunlight, avoid a diet rich in vitamin D and maintain a fluid intake of > 21/day.²¹

View this table: [in this window] [in a new window] Table 1 Treatment of abnormal calcium homeostasis in sarcoidosis

Prednisolone 20–40 mg daily is the drug of choice, because of its effectiveness in rapidly restoring normocalcaemia. Corticosteroids reduce gastrointestinal calcium absorption and inhibit osteoclast function^22,23 because of their effects on the endogenous production of 1,25(OH)₂-D₃.⁷ Corticosteroids are potent inhibitors of 1-hydroxylase in macrophages,⁵ and down-regulate interleukin-2 and -interferon,⁵ resulting in reduced PTHrP production by macrophages. Prednisolone therapy causes a relatively swift decrease in serum calcium within 2–4 days. A reduction in urinary calcium excretion rate soon follows, within 7–10 days. Once the calcium abnormality is brought under control, prednisolone dosage can be reduced over a period of 4–6 weeks. If hypercalcaemia associated with sarcoidosis fails to resolve on corticosteroid therapy, primary hyperparathyroidism should be excluded.

Ketoconazole is now considered an appropriate second-line treatment in hypercalcaemic sarcoidosis when oral steroids are ineffective or contraindicated.^19,24 Ketoconazole is an imidazole antifungal agent that inhibits cytochrome P450-linked hydroxylation of 1,25(OH)₂-D₃. Although the literature supporting the use of ketoconazole in combination with corticosteroids is limited to isolated case reports,^21,25 it has been our experience that the addition of ketoconazole results in the dose of corticosteroids being significantly reduced in all patients and ceased in some. It should be noted that ketoconazole has no role for any other manifestation of sarcoidosis. Chloroquine and hydroxychloroquine also cause inhibition of 25(OH)D₃-1-hydroxylase,^26,27 and can be considered for patients who are intolerant of ketoconazole or who develop abnormal liver function tests. Methotrexate and azathioprine are frequently used as adjuvant therapy for sarcoidosis, and help to control hypercalcaemia by reducing the granuloma burden.

	Pituitary and hypothalamus

About 5% of patients with sarcoidosis have clinical involvement of the nervous system;²⁸ however, the incidence of subclinical and undiagnosed neurosarcoidosis (NS) is much higher.²⁹ Although its involvement in NS is uncommon, the hypothalamus is the most frequently involved of all the endocrine glands. Sarcoidosis, like other granulomatous diseases, infections, and metastatic tumours, commonly leads to an infiltrative process in the hypothalamo-hypophyseal region,³⁰ resulting in neuroendocrinological dysfunction,³¹ whereas a primary pituitary defect and an empty sella occur rarely.³² Earlier studies of post-mortem findings in patients with hypopituitarism complicated by sarcoidosis, assumed that pituitary destruction was the cause of hormone loss.³³ However, subsequent reports, demonstrated pituitary responsiveness to synthetic hypothalamic releasing factors in patients with sarcoidosis and hypopituitarism, concluding that hypothalamic insufficiency is the major cause for hypopituitarism in these patients.³⁴

Polyuria and polydipsia are common presenting features of hypothalamic involvement, due either to diabetes insipidus or a disordered control of thirst; the syndrome of inappropriate secretion of anti-diuretic hormone (SIADH) has also been reported.^35,36 In a study by Stuart et al.,³⁵ polydipsia and polyuria were more often primarily due to thirst dysregulation, with adequate endogenous ADH, than to true diabetes insipidus. There has been a report of chronic hypernatraemia and hypovolaemia in a patient with hypothalamic sarcoidosis who did not complain of thirst.³⁷ Neuroendocrinological dysfunction also includes hyperprolactinaemia, which normalizes after treatment of sarcoidosis, and is reported to occur in 3–32% of patients;³⁸ however, other endocrinopathies, including a hypothalamic syndrome, occur in <> with NS.³⁹ Table 2 illustrates the clinical features of hypothalamo-pituitary sarcoidosis.

View this table: [in this window] [in a new window] Table 2 Clinical features of hypothalamo-pituitary sarcoid

Complete loss of the counter-regulatory response to glucose has been described in hypothalamic sarcoidosis.⁴⁰ Given that hypothalamic sarcoidosis can lead to secondary hypothyroidism, hypoadrenalism, and growth hormone insufficiency/deficiency,⁴¹ the counter-regulatory response to hypoglycaemia, namely an increase in catecholamines, glucagon, cortisol and growth hormone, is impaired. The specific region of the hypothalamus responsible for triggering the release of such counter-regulatory hormones during hypoglycaemia has been shown in rat models to be in the ventromedial region.⁴⁰ Sarcoid invasion of the satiety centre in the ventral median nucleus of the hypothalamus may also lead to morbid obesity.⁴² In addition to the above abnormalities, other manifestations attributed to hypothalamic sarcoidosis include marked somnolence, often preceded or followed by insomnia,⁴³ extreme variations in body temperature⁴⁴ and marked personality changes.⁴⁵

The diagnosis of NS ideally requires evidence of systemic disease, a compatible clinical or neuroradiological picture of sarcoidosis and histological confirmation of non-caseating granulomas.²⁹ In patients with NS, the chest X-ray is abnormal in only 30% of cases at presentation, whereas >90% of patients with sarcoidosis have an abnormality. The imaging procedure of choice for hypothalamo-pituitary sarcoid is contrast-enhanced magnetic resonance imaging (MRI), which can also be used to follow therapeutic response.^46,47 Cerebrospinal fluid examination, gallium scanning, serum angiotensin converting enzyme (SACE) and CSF angiotensin converting enzyme (CACE) may be of help in supporting the diagnosis, but lack both sensitivity and specificity.⁴⁶

In about 50% of patients with NS, CSF examination reveals characteristic but non-specific abnormalities such as increased protein and a mild pleocytosis, mostly lymphocytes; hypoglycorrhachia is occasionally seen.⁴⁸ Normal results of CSF analysis do not exclude hypothalamo-pituitary sarcoidosis. SACE and CACE are helpful in supporting the diagnosis of NS in only a small group of patients. In particular, SACE is often normal in isolated NS; elevation is usually associated with active pulmonary disease. Elevated SACE and CACE, the latter elevated in 50% of patients with NS, reflect an activated disease state, with a sensitivity from 50–86%⁴⁹ and 80%,⁵⁰ respectively. Elevation of CSF lysozyme and ß₂ microglobulin have been reported in some patients with NS,⁵¹ but are less specific than elevation of ACE.⁵² Determination of CSF lymphocyte subpopulations (increased T4:T8), oligoclonal bands and IgG index have been used to diagnose and differentiate NS from other diseases, such as multiple sclerosis, but lack specificity.⁵³ If the diagnosis remains in doubt, biopsy of the lesion is indicated to establish the diagnosis.⁴⁶ It is important to realize that pituitary sarcoid may mimic pituitary tumours³⁴ and can present with classical bitemporal hemianopia and other field defects which may respond well to high-dose immunosuppressive therapy. Table 3 illustrates the possible investigations and treatment modalities of hypothalamo-pituitary sarcoidosis.

View this table: [in this window] [in a new window] Table 3 Investigation and treatment of Hypothalamo-pituitary sarcoid (HPS)

If the diagnosis is certain, corticosteroids remain the mainstay of treatment of NS. Corticosteroids effectively suppress the elevated CD4-CD8 (T4-T8) lymphocyte ratio, decrease interleukin-2 production, and inhibit collagen synthesis, all of which occur at the sites of active disease.⁵⁴ Treatment is usually prolonged, exposing the patient to significant steroid-related side-effects. Those unresponsive, or who have a primary contraindication to corticosteroid therapy, often require higher doses, either orally or using pulsed methylprednisolone. In these patients adjuvant or alternative treatment with radiotherapy and/or immunosuppressive agents may be necessary. Azathioprine, cyclosporin, chloroquine and cyclophosphamide have all been tried, with variable success.^55–57 There are very few data on the efficacy of immunomodulatory therapy in NS, and no prospective data are available. Certain authors recommend methotrexate⁵⁸ or hydroxychloroquine⁵⁹ as first-line steroid-sparing agents, whilst others opt for cyclosporine and azathioprine.⁵⁴

	Thyroid

Sarcoid granuloma in the thyroid was first described in 1938.⁶⁰ The thyroid is an uncommon site of the disease, with clinically evident involvement of the thyroid gland infrequently reported in the literature, although its incidence was approximately 4% in some autopsy series.^61,62 Middle-aged women are most frequently affected, and in most cases peripheral or intrathoracic lymphadenopathy is observed.

Hypothyroidism has been noted in patients with sarcoidosis.⁶³ Hypothyroidism, caused through extensive infiltration by epithelioid granulomas, may be present for some time before the diagnosis of sarcoidosis is made, as illustrated by Brun et al.,⁶⁴ where the patient was hypothyroid for 3 years before the diagnosis of sarcoidosis was made. There may be (symmetrical or asymmetrical) painless thyroid enlargement with or without fixation to deep tissues of the neck. The association of hyperthyroidism and sarcoidosis has also been described.⁶³ This observation was made in patients undergoing thyroidectomy for hyperthyroidism, and at autopsy in patients who had previously had surgery for hyperthyroidism. There is no evidence or reason to suggest that sarcoidosis of the thyroid gland predisposes to hyperthyroidism. Unilateral or bilateral proptosis, as seen in patients with hyperthyroidism/Graves disease, may occur in patients with sarcoidosis who do not have endocrine exophthalmos; retro-orbital infiltration by sarcoid tissue being the probable pathogenesis. Other associations of sarcoid and the thyroid include goitre, sarcoid thyroiditis, Hashimotos thyroiditis, de Quervains thyroiditis, painful thyroid enlargement, Hurthle cell hyperplasia⁶² and thyroid carcinoma.⁶⁵ Diagnosis and therapeutic management prove difficult when thyroid carcinoma and sarcoidosis co-exist.

The relationship between the presence of sarcoid granulomas in the thyroid gland and clinical thyroid disease is not known, and a cause-effect relationship has not been established. Scadding⁶⁶ stated that sarcoidosis rarely, if ever results in the functional derangement of the thyroid, while Karlish and MacGregor⁶⁷ reported a prevalence of overt thyroid disease in sarcoidosis in 3.6%, with the majority being autoimmune in aetiology. A study by Papadopoulos et al.,⁶⁸ reported an overall frequency of thyroid autoimmunity of 17% with a 10% frequency of clinical autoimmune thyroid disease, the latter with a histological/cytological appearance of the thyroid, pointing to a genuine autoimmune process rather than to sarcoid dissemination.

	Adrenal glands

Involvement of the adrenal glands rarely occurs in sarcoidosis. The functional status of the adrenal gland in patients with sarcoidosis has nearly always been normal when evaluated after stimulation with exogenous ACTH, with the exception of patients with secondary adrenal failure due to hypothalamic-pituitary infiltration by sarcoid granulomas.⁴¹ When there is sarcoid involvement, the adrenal gland is replaced by dense fibrosis, leading to adrenal insufficiency, but patients respond well to glucocorticoid and mineralocorticoid replacement. However, sarcoidosis of the adrenal gland has also been described as leading to an adrenal crisis⁶⁷ and death.⁶⁹ Both caseating and non-caseating epithelioid granulomas have been reported at autopsy in patients with coexisting sarcoidosis and tuberculosis. Finally, the association between sarcoidosis and Addison’s disease is unusual, but when it occurs it is likely to be as a result of autoimmunity.⁶⁸

	Pancreas

Sarcoid involvement of the pancreas is extremely rare. In a Japanese review of 663 562 autopsies,⁷⁰ 212 cases of sarcoidosis were noted; pancreatic granulomas were found in 2.1% of patients in whom the cause of death was related to sarcoid, and in 1.3% of patients in whom the cause of death was unrelated to sarcoid. Epithelioid granulomas occurring in the pancreas or peripancreatic lymph nodes may produce symptoms related to parenchymal infiltration or common bile duct obstruction. Acute pancreatitis most often occurs in young individuals (18–47 years) and with variable amylase levels at presentation.⁷¹ In some patients there is associated hypercalcaemia, which may also cause pancreatitis. Chronic pancreatitis without a true obstructive pancreatic mass has been reported twice.⁷¹ Isolated sarcoidosis of the pancreas most often presents as a pancreatic head mass, and symptoms include abdominal pain (50%), weight loss (44%) and obstructive jaundice (44%). Given that sarcoidosis of the pancreas is rare, it is important to note that it often mimics pancreatic cancer. In those patients who have a history of sarcoidosis, the diagnosis should be considered, but the possibility of carcinoma of the pancreas must be ruled out.

Noguchi et al. reported a patient with pancreatic exocrine deficiency and sarcoidosis.⁷² In their report, levels of pancreatic enzymes paralleled changes in the levels in activity of sarcoid lesions in the liver and lungs, as well as the ACE and lysozyme levels; the pancreatic enzymes were reduced by corticosteroid therapy, leading to the conclusion that the pancreatic impairment was due to sarcoidosis. Diabetes mellitus is an unlikely complication of pancreatic sarcoidosis, but is frequently seen in patients as a complication of corticosteroid therapy. Interestingly, necrobiosis lipoidica, a characteristic finding of diabetes mellitus has been reported in patients with sarcoidosis.⁶³ The significance of this finding, and whether there is a possible cause-effect relationship, has not been determined.

	Reproductive system

Male
The frequency of genitourinary sarcoidosis in men is <> in clinically diagnosed cases, and 5% in autopsy studies.⁷³ It has been reported to be 10 times more frequent in Black men,⁷³ in parallel with the increased incidence of sarcoidosis in this group. Sarcoid granulomas have been found in order of decreasing frequency in the epididymis, testis and prostate gland, with only rare involvement of the spermatic cord, scrotum and penis. Initial presentation can include an asymptomatic, painless mass in the scrotum, acute epididymo-orchitis and testicular swelling (Table 4). A hypoechogenic lesion on ultrasound is a recognized feature of testicular sarcoid.⁷⁴

View this table: [in this window] [in a new window] Table 4 Sarcoidosis of the reproductive system

Testicular sarcoidosis as a presenting feature is rare and few reports exist of sarcoid affecting the body of the testis without concomitant epididymal involvement. The average age of patients with genitourinary sarcoidosis is 31 years, which coincides with the peak occurrence of testicular malignancy, so a high index of suspicion for malignancy must be maintained. The incidence of testicular malignancy is low in the Black population, with only 1.2–3.5% of all testicular tumours found in Black patients. The effect of genitourinary sarcoidosis on fertility has not been studied, but it is reasonable to assume that the fibrosis and occlusion of the ductus epididymis seen in this disease could cause oligospermia and infertility.⁷⁵ Leydig cell dysfunction may alter secondary sexual characteristics; however, glucocorticoids are effective in reducing sarcoid-testicular mass and improving gonadal function.

Female
The main significance of sarcoidosis of the genital tract is its differentiation from other lesions, especially tuberculosis. The most common site of involvement of the female reproductive system is the uterus. Sarcoidosis of the uterus is most often diagnosed in the endometrium, because this tissue is amenable to sampling via curettage. In almost all reported cases of uterine sarcoidosis in which the entire uterus was examined after hysterectomy, granulomas were found in the myometrium as well as the endometrium.⁷⁶ The frequency with which sarcoidosis is found in the various portions of the uterus appears to reflect sampling bias rather than a true reflection of distribution. Occasionally, when some other pathological process occurring in the cervix serves to focus attention on this tissue, this portion of the uterus is found to be involved. Sarcoidosis cases involving fallopian tubes and the ovary have also been reported.⁷⁷

Clinical manifestations include amenorrhoea, menorrhagia, metrorrhagia, post menopausal bleeding and erosion of the cervix (Table 4). Sarcoidosis of the uterus is usually discovered during the investigation of abnormal uterine bleeding in patients with known sarcoid elsewhere. Involvement of the peritoneum with sarcoid has been reported as causing an elevated CA125 with appearances at operation similar to those of metastatic cancer.⁷⁸ Women with uterine sarcoidosis suffer little, if any, detrimental effect with regard to their ability to become pregnant and carry pregnancies to term, and delivery of a healthy baby can occur despite the presence of granulomas in the placenta.⁷⁷ Corticosteroids have been used in the treatment of uterine sarcoidosis with improvement in clinical outcome.

	Endocrine autoimmunity

Autoimmune disease and sarcoidosis may be related, and the association between sarcoidosis and autoimmune thyroid disease has long been recognized. The frequency and type of endocrine autoimmunity was examined in a series of 89 Swedish patients with sarcoidosis by Papadopoulos et al.⁶⁸ The study found that 19.2% of the patients with sarcoidosis had clinical or serological evidence of endocrine autoimmunity. Two patients had Addison’s disease, both with polyglandular autoimmune syndrome type II; evidence of thyroid autoimmunity was found in 13 patients, eight with clinical autoimmune thyroid disease (two with Graves disease and six with autoimmune thyroiditis), of whom two had PGA syndrome type III, and five with isolated positive thyroid serology; two patients had diabetes mellitus and one had premature ovarian failure. Addison’s disease, clinical autoimmune thyroid disease and polyglandular autoimmune syndrome type II were significantly more common compared with the general population. Complex immunological and genetic mechanisms might explain the association of sarcoidosis and autoimmune diseases, and further studies are needed to define the significance of these findings.

	Conclusions

Sarcoidosis is a relatively common multisystem disease characterized by epithelioid granulomas. Endocrine gland involvement leads to a diverse range of presentations. Hypercalcaemia and hypercalciuria result primarily from the synthesis of 1,25 hydroxyvitamin-D₃ in sarcoid granulomas. Involvement of the pituitary and hypothalamus can cause diabetes insipidus, SIADH, disordered control of thirst, morbid obesity and impaired secretion of anterior pituitary hormones. Thyroid dysfunction occurs in sarcoidosis and this may be due to an autoimmune process rather than sarcoid dissemination. Testicular sarcoid can present as a painless mass in the scrotum or acute epididymo-orchitis and may cause oligospermia and infertility. Involvement of the female reproductive tract may cause menstrual abnormalities.

	Footnotes

Address correspondence to Dr H.S. Randeva, Molecular Medicine Research Group, Biomedical Research Institute, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL. e-mail: hrandeva@bio.warwick.ac.uk

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40. Fery F, Plat L, Van De Bourne P, Cogan E, Mockel J. Impaired Counterregulation of Glucose in a Patient with Hypothalamic Sarcoidosis. N Engl J Med 1999; 340:852–7.[Free Full Text]

41. Veseky D, Maldonono A, Levey G. Partial Hypopituitarism and Possible Hypothalamic Involvement In Sarcoidosis. Am J Med 1977; 62:425–30.[CrossRef][ISI][Medline]

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44. Jefferson M. Sarcoidosis of the nervous system. Brain 1957; 80:540–56.[Free Full Text]

45. Gjerse A, Kjerulif-Jensen K. Hypothalamic lesion caused by Boek’s sarcoid. J Clin Endocrinol 1950; 10:1602–8.[Medline]

46. Randeva HS, Davison R, Chamoun V, Bouloux PM-G. Isolated neurosarcoidosis—a diagnostic enigma: Case report and discussion. Endocrine 2002; 17:241–7.[CrossRef][ISI][Medline]

47. Sherman JL, Stern BJ. Sarcoidosis of the CNS: comparison of unenhanced and enhanced MRI images. Am J Radiol 1990; 155:1293–301.[Abstract/Free Full Text]

48. Gaines JD, Eckman PB, Remington JS. Low CSF glucose level in sarcoidosis involving the central nervous system. Arch Intern Med 1970; 125:333–6.[CrossRef][ISI][Medline]

49. Schultz T, Miller WC, Bedrossian CW. Clinical application of measurement of angiotensin converting enzyme level. JAMA 1979; 242:439–41.[Abstract]

50. Oksanen V, Fyhrquist F, Somer H, Gronhagen-Riska C. Angiotensin converting enzyme in cerebrospinal fluid: a new assay. Neurology 1985; 35:1220–3.[Abstract/Free Full Text]

51. Oksanen V, Gronhagen-Riska C, Tikanoja S, Somer H, Fyhrquist F. Cerebrospinal fluid lysozyme and ß₂-microglobulin in neurosarcoidosis. J Neurol Sci 1986; 73:79–87.[CrossRef][ISI][Medline]

52. Selroos O, Klockars M. Relation between clinical stage of sarcoidosis and serum values of angiotensin converting enzyme and beta₂-microglobulin. Sarcoidosis 1987; 4:13–17.[Medline]

53. Li CY, Yam LT. Cytologic and immunohistochemical studies of cerebrospinal fluid in meningeal sarcoidosis. Acta Cytologica 1992; 36:963–7.[ISI][Medline]

54. Agbogu BN, Stern BJ, Sewell C, Yang G. Therapeutic considerations in patients with refractory neurosarcoidosis. Arch Neurol 1995; 52:875–9.[ISI][Medline]

55. Stem BJ, Schonfeld SA, Sewell C, Krumholz A, Scott P, Belendiuk G. The treatment of neurosarcoidosis with cyclosporine. Arch Neurol 1992; 49:1065–72.[CrossRef][ISI][Medline]

56. Sharma OP. Neurosarcoidosis. A personal perspective based on the study of 37 patients. Chest 1997; 112:220–8.[CrossRef][ISI][Medline]

57. Lower EE, Broderick JP, Brott TG, Baughman RP. Diagnosis and management of neurological sarcoidosis. Arch Intern Med 1997; 157:1864–8.[CrossRef][ISI][Medline]

58. Lower EE, Baughmann RP. Prolonged use of methotrexate for sarcoidosis. Arch Intern Med 1995; 155:846–51.[CrossRef][ISI][Medline]

59. Sharma OP. Effectiveness of Chloroquine and Hydroxychloroquine in treating selected patients with sarcoidosis with neurological involvement. Arch Neurol 1998; 85:1248–54.

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61. Maycock RL, Bertrand P, Morrison CDE. Manifestations of sarcoidosis: analysis of 145 patients with a review of nine series selected from the literature. Am J Med 1963; 35:67–89.[CrossRef][ISI][Medline]

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67. Karlish AJ, MacGregor GA. Sarcoidosis, thyroiditis and Addisons disease. Lancet 1970; ii:330–3.

68. Papadopoulos K, Hornblad Y, Liljebladh H, Hallengren B. High Frequency of Endocrine Autoimmunity in Patients with sarcoidosis. Eur J Endocrinol 1996; 134:331–6.[Abstract/Free Full Text]

69. Maycock RL, Bertrand P, Morrison CE, et al. Manifestations of sarcoidosis: analysis of 145 patients with a review of nine series selected from the literature. Am J Med 1963; 35:67–87.[CrossRef][ISI][Medline]

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74. Metcalfe MS, Rees Y, Morgan P, O’Reilly K, Sandu DPS. Sarcoidosis presenting as a testicular mass. Br J Urol 1998; 82:769–70.[CrossRef][ISI][Medline]

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Treatments Hypertension - How to Cure High Blood Pressure

Thousands of high blood pressure sufferers will search the internet this month for 'treatments hypertension'. They are looking for simple and effective way to naturally cure high blood pressure. However, most patients will be unsuccessful and return to their life of medication.

Is there a way to naturally cure hypertension? Yes and in this article you will teach you how to cure high blood pressure with a 7 secrets that pharmaceutical companies do not want you to know.

How to Cure High Blood Pressure Naturally

Unfortunately, most Americans are under the assumption that the only treatment for high blood pressure is medication. Even with tons of research studies pointing to simple ways to normalize your score naturally, we seem to believe the propaganda that medication is the only way to cure our ailments.

In the case of high blood pressure, there are numerous ways to normalize your score using drug-free remedies. Here are a few tips to get you started!

1. Your diet is obviously very important to the reversal of high blood pressure. One of the most important things you can do is reduce your sodium intake to at least 2,300 mg of day, which is about the equivalent of a teaspoon of salt. Start looking at the labels.

2. Your diet should have plenty of grains, fruits, vegetables, nuts, seeds, fish, poultry and dried beans. Avoid processed and fast foods because of the amount of sodium and preservatives in each.

3. Living a simpler live is always better. Some simple lifestyle changes that can reduce stress and normalize blood pressure are as follows: getting at least 8 hours of sleep, waking up at 6 AM, practicing breathing exercises, meditate or pray for at least 20 minutes a day, cut out the alcohol and cigarettes.

4. Researchers at Duke University found that getting more potassium could lower blood pressure by as many as 20 points for people most at risk for high blood pressure. Try to supplement at least the daily recommended allowance at 4,700 milligrams.

5. Herbal therapy may also be a great option for you. For instance, garlic is one herb that has been shown to lower cholesterol which will in turn lower high blood pressure. We recommend you supplement this herb in cloves but capsules will also work.

6. Flushing your body of cholesterol and plaque will help lower your cholesterol and help lower your high blood pressure. You can do this by drinking plenty of water. You should drink at least 12 glasses of water a day to benefit from this. You may also wish to get at least 5-7 servings of fruits and vegetables which will also flush cholesterol and plaque. Make it a goal to only drink water as your beverage in a month.

7. Finally, the hawthorn herb is a widely used remedy in Europe to treat cardiovascular problems. Both the berries and flowers of the hawthorn plant are used in herbal preparations to make the heart and cardiovascular systems work more efficient. Hawthorn widens the blood vessels and will naturally normalize hypertension in weeks while accompanied with simple lifestyle changes.

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Diabetes Natural Treatments - Vitamin for Diabetes?

Thousands of people search the internet each day for diabetes natural treatments. Most of these people do not want to be on insulin medication the rest of their lives. And many of these diabetics cannot afford the cost of expensive insulin.

Whatever your reason, rest assured that you can reverse diabetes naturally and eventually cure the disease completely. In this article, you will learn 3 important vitamins and supplements your body needs to repair and create new cells that accept insulin.

Let me explain!

Why Diabetes Natural Treatments Work?

The main reason diabetes can be reversed and cured is because your body is composed of trillions of cells. And a typical diabetic's cells are resistant to insulin. Therefore, they need insulin to keep their blood sugar normal.

However, scientists have discovered that your body is capable of making new cells that are not resistant to insulin. Since diabetes is a disease that is predominantly caused by a poor nutrition plan and unhealthy lifestyle, it is possible to reverse diabetes with a better diet, better supplements and exercise.

In this article, you will learn what supplements are essential for making new cells that are not resistant to insulin.

Supplements - Vitamin for Diabetes

1. The the first tip is not a vitamin, it is still important to remember when curing diabetes. Your diet should compromise less carbohydrates and more protein. Protein is needed because it is essential for repairing the cell membrane of cells

2. A chromium and vanadium supplement will assist in the regulation of blood sugar. Chromium works to make insulin more effective to cells. Vanadium will actually do the job of insulin and transport sugar (energy) to the cells.

3. Zinc is another supplement you may want to try. Zinc can help the blood sugar get into the cells and make the insulin work better.

4. Two important vitamins should be part of all diabetes natural treatments. Vitamin C and vitamin E will help the body convert the sugar into used energy by the cells. In some studies, vitamin E improved the body's response to insulin.

5. You may also wish to supplement a quality multivitamin and amino acid supplement. Both have been show to benefit in rebuilding healthier cells and help with weight control.

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Case 6-2009 — A 37-Year-Old Woman with Vertigo, Facial Weakness, and a Generalized Seizure

Didier Cros, M.D., R. Gilberto Gonzalez, M.D., Ph.D., and Eugene J. Mark, M.D.


Presentation of Case

Dr. Sang-Woo (Steve) Han (Neurology): A 37-year-old woman was seen in the emergency department of this hospital because of a seizure. Four months earlier, episodes of vertigo began to occur several times a week that lasted up to several hours and were associated with nausea and vomiting. She was evaluated in the emergency department of another hospital; meclizine was prescribed, and she was instructed to follow up with her primary care physician. During the next 3 months, she had episodes of vertigo several times per week that were associated with tinnitus, diminished hearing, a sense of fullness in her right ear, and difficulty walking.

The results of otoscopic and audiographic examinations by an otolaryngologist were normal, with no cranial-nerve deficits; a diagnosis of endolymphatic hydrops was made, and a low-salt diet was recommended. Five weeks before admission, computed tomographic (CT) scanning of the sinuses revealed mild mucosal thickening of the maxillary sinuses with mild inflammatory changes in the ethmoid sinus. Triamterene and hydrochlorothiazide were begun and meclizine was continued, with partial relief of symptoms. One month before admission, magnetic resonance imaging (MRI) of the brain showed a focus of enhancement, 2 mm in diameter, in the deep right internal auditory canal, a finding consistent with an intracanalicular schwannoma, and several foci of hyperintensity on T₂-weighted images in the frontal white matter and subinsular cortex bilaterally, findings consistent with nonspecific gliosis. Formal vestibular testing with electrocochleography and otolaryngology follow-up were scheduled.

Approximately 2 weeks later (2 weeks before admission), the patient awoke one morning with right-sided facial weakness. Three days before admission, another episode of dizziness occurred. On the morning of admission, the patient's daughter found her on a couch, unresponsive, with shaking extremities and drooling. The movements lasted approximately 5 minutes. Emergency medical services were called, and the patient was taken to the emergency department of another hospital. On arrival, the patient had regained consciousness; she recalled fatigue and a disturbance in balance immediately before the seizure but no headache.

On examination, the patient was agitated, confused, and fearful. The temperature was 37.1°C, the blood pressure 114/78 mm Hg, the pulse 122 beats per minute, the respiratory rate 22 breaths per minute, and the oxygen saturation 97% while the patient was breathing ambient air. The height was 157.5 cm, and the weight 44.5 kg. She was able to follow simple commands; her speech was garbled. There was a right facial droop; the deep-tendon reflexes were 3+ throughout, and spasticity and clonus were evident in the right leg. A complete blood count; levels of serum glucose, electrolytes, calcium, potassium, and magnesium; and liver- and renal-function tests were normal. An electrocardiogram showed sinus tachycardia. Lorazepam and phenytoin were administered intravenously. CT of the head, without the administration of contrast material, showed no intracerebral hemorrhage. After the CT scan, the patient had severe pain in the left hip, and morphine sulfate and additional lorazepam were given. She was transferred to this hospital by ambulance approximately 7 hours after her arrival at the other hospital.

The patient's mother reported that the patient had recently had a headache, ear pain, and left hip pain and that her appetite had been poor. There was a history of a febrile seizure in childhood. Six years earlier, she had had a traumatic fracture of the left hip; 3 years after that, a total hip replacement was performed because of osteonecrosis. She had had a tonsillectomy, a cone biopsy of the cervix, and cesarean sections. Amenorrhea had developed 18 months earlier. A test for human immunodeficiency virus (HIV) had been negative. She was of native Alaskan heritage and had been adopted as an infant. Her children were healthy; there was no information about her other biologic relatives. She was single, lived with her three children, and worked in sales. She drank alcohol daily, smoked cigarettes, and did not use illicit drugs. She had possible allergies to codeine and penicillin. Medications included meclizine, triamterene, and hydrochlorothiazide.

On examination, the patient was initially somnolent but arousable; she later became agitated, belligerent, and uncooperative. The temperature was 36.6°C, the blood pressure 95/64 mm Hg, the pulse 100 beats per minute, the respiratory rate 16 breaths per minute, and the oxygen saturation 97% while the patient was breathing ambient air. Her affect ranged from angry to tearful. She was oriented to self but not to place or time. Dentition was poor; the abdomen was soft with diffuse mild tenderness, and the remainder of the general physical examination was normal. Her speech was fluent. There was asymmetry in the facial muscles, with right-sided weakness. The pupils were reactive; the extraocular movements were intact, with horizontal nystagmus and saccadic breakdown of pursuit, without ptosis. Hearing was intact; the tongue protruded in the midline, and there was mild dysarthria. Other cranial-nerve functions and attention, memory, and ability to make calculations could not be assessed. There was limitation of movement in the left leg because of hip pain; motor strength was otherwise normal. The arms and legs were hyperreflexic; plantar reflexes were extensor. Posture, stance, stride, and arm swing were markedly impaired. She walked with her feet inverted and on her toes, with small steps.

The complete blood count; levels of serum electrolytes, glucose, bilirubin, and protein; and liver- and renal-function tests were normal. Serum and urine pregnancy testing was negative. Analysis of the urine was normal except for a toxicology screening, which was positive for opiates. Radiographs of the chest, hip, pelvis, and foot were normal. MRI of the brain, performed after the administration of lorazepam, was limited by motion-related artifacts but revealed hyperintensities of the medial temporal lobes on T₂-weighted and fluid-attenuated inversion recovery (FLAIR) images bilaterally and in the posterior gyri recti, more prominently on the left side than on the right. There was nearly complete opacification of the right maxillary sinus. She was admitted to the Neurology Service.

During the first 3 days, the patient remained agitated, belligerent, and confused, requiring the use of leather physical restraints. Phenytoin, magnesium, acyclovir, folate, thiamine, a transdermal nicotine patch, and dalteparin were administered. Lorazepam and olanzapine were given for agitation, and hydromorphone and morphine sulfate as needed for pain. On the third hospital day, the patient was evaluated by a psychiatrist. She was somnolent and confused and not oriented to place or time, with poor memory. She was easily distracted, with slurred and slowed speech and tangential thought. The C-reactive protein level was 23.2 mg per liter (normal range, <8.0);> rate, electrolyte levels, and electroencephalography were normal. Olanzapine was discontinued and haloperidol administered.

On the fourth hospital day, her mental status improved and the restraints were removed; she was pleasant and engaged, with linear thought, recall of three of three objects at 5 minutes, and knowledge of past presidents. Extraocular movements were intact, and there was no nystagmus. There was weakness of the right lower facial muscles and increased extensor tone in both legs, the ankles were plantar flexed, and the feet were inverted. Motor strength was normal, although it was difficult to fully assess in the left leg because of hip pain. The sensory examination was normal. There was hyperreflexia in the arms and legs and sustained clonus in the left ankle, and the plantar reflexes were extensor. The gait was abnormal because of hypertonia, with circumduction of the left leg to avoid dragging the foot.

A lumbar puncture was performed (Table 1). Cytologic examination of the fluid revealed increased lymphocytes, which were predominantly mature-appearing. A tuberculin skin test was negative. Flow cytometry showed T cells with a CD4:CD8 ratio of 3:4. Repeated MRI revealed extensive, multifocal regions of nodular enhancement involving the leptomeninges and ependyma, along the lenticulostriate vessels, hippocampi, and optic nerves bilaterally, within the left rectus gyrus, along the optic chiasm and pituitary stalk, and within the right internal auditory canal. Hyperintensities of the mesial temporal lobes and left rectus gyrus were again noted on T₂-weighted and FLAIR images. Magnetic resonance angiography of the head and neck were normal.

View this table: [in this window] [in a new window] Table 1. Results of Cerebrospinal Fluid Analysis.

On the seventh hospital day, MRI of the spine revealed enhancing leptomeningeal nodules involving the cervical spinal cord and conus medullaris, as well as parenchymal involvement in the cervical spinal cord. CT scanning of the chest, abdomen, and pelvis showed bilateral hilar and mediastinal lymphadenopathy, slight thickening of the bronchial walls, and small retroperitoneal and mesenteric lymph nodes. The antinuclear-antibody (ANA) test was positive at 1:320 in a speckled pattern. Serum levels of thyrotropin, prolactin, and follicle-stimulating hormone were normal, and a rapid plasma reagin test was negative. Acyclovir and dalteparin were stopped.

A transbronchial biopsy of the lung on the 12th day revealed mild nonspecific interstitial fibrosis without evidence of granulomas or cancer. The patient was discharged later that day at her request, pending the results, and was readmitted 3 days later. Biopsies of the dura and brain were performed the next day; pathological examination of the biopsy specimens revealed normal cortex and meninges. The serum level of angiotensin-converting enzyme (ACE) was 36 U per liter (normal range, 7 to 46).

A diagnostic procedure was performed.

Differential Diagnosis

Dr. Didier Cros: This previously healthy 37-year-old woman had a 4-month history of neurologic manifestations, including vertigo, nausea, facial weakness, bilateral pyramidal syndrome, and a seizure, which were suggestive of multifocal pathology in the nervous system, and long-standing amenorrhea that may indicate endocrine dysfunction. She was afebrile and HIV-negative. May we review the radiologic studies?

Dr. R. Gilberto Gonzalez: Attempts at MRI of the brain on admission were marred by motion artifact, despite sedation. Repeated MRI on hospital day 4 (Figure 1A and 1B) showed extensive signal abnormalities and abnormal enhancement involving the leptomeninges, the ependyma, and the parenchyma in both a linear and nodular pattern. There was thickening and diffuse linear and nodular enhancement of the pituitary stalk. MRI of the spine on day 7 (Figure 1C) revealed involvement of the entire spine by the enhancing abnormality, with both leptomeningeal enhancement and linear and nodular enhancement of the spinal cord parenchyma; most prominent in the upper cervical area was the nodular enhancement of the cervical spinal cord. Chest CT performed the same day revealed pretracheal and bilateral hilar lymphadenopathy (Figure 1D).

View larger version (125K): [in this window] [in a new window] Figure 1. Radiologic Images. An axial T1-weighted MRI of the brain obtained after the administration of contrast material (Panel A) reveals extensive, multifocal regions of enhancement involving all intracranial compartments, including the brain parenchyma (arrowhead), ependyma (arrow, bottom left), and leptomeninges (arrow, top right). A sagittal image of the brain (Panel B) shows enhancement involving the corpus callosum (upper row of arrows), with a coating of abnormal contrast enhancement and linear and nodular extension from the surface into the body of the corpus callosum, as well as coating of the ventral surface of the brain stem (bottom three arrows). There is thickening and enhancement of the pituitary stalk (arrowhead). A sagittal T1-weighted MRI scan of the cervical spine obtained after the administration of contrast material (Panel C) shows enhancing leptomeningeal nodules involving the surface of the cervical spinal cord, as well as parenchymal involvement (arrow). CT of the chest (Panel D) shows enlarged hilar lymph nodes (arrows).

Dr. Cros: A large number of disorders may affect the leptomeninges and the brain and spinal cord parenchyma and may ensheath the cranial nerves and spinal roots. The documentation of mediastinal and hilar lymphadenopathy in this patient helps to focus the differential diagnosis. I participated in the care of this patient, and our considerations included neoplastic, infectious, and inflammatory and granulomatous disorders.

Neoplastic Disorders

Metastases of systemic cancer were a concern at the time of presentation, even though there was no known malignant condition in this patient. Breast, lung, and gastrointestinal cancers, melanoma, and lymphomas account for the majority of primary tumors that metastasize to the meninges. In the absence of known cancer, and with the normal results of the clinical examination of skin and breasts and of the chest, abdominal, and pelvic CT scans, the suspicion of a systemic lymphoma affecting the intrathoracic lymph nodes was heightened. Primary central nervous system (CNS) lymphoma was also considered, since leptomeningeal involvement occurs in 40% of patients with primary CNS lymphoma and is the initial presentation in about 8% of patients.^1,2

Examination of the cerebrospinal fluid is central to the diagnosis of meningeal carcinomatosis. The spinal fluid was obtained by lumbar puncture, which is optimal for the assessment of possible malignant infiltration, since the cauda equina is often affected by the pathologic process. False negative results may occur if cerebrospinal fluid is obtained from an unaffected compartment of the subarachnoid space. Cytologic examination in this case revealed no malignant cells, and flow cytometry showed no evidence of lymphoma.

Infectious Disorders

A number of infectious diseases may affect the leptomeninges. Tuberculosis has a predilection for the leptomeninges of the base of the brain and frequently affects the cranial nerves, causing a vasculitis of the penetrating arteries that may result in strokes and also causing obstruction to the flow of cerebrospinal fluid that results in hydrocephalus. Although rare (fewer than 200 cases per year in the United States), tuberculosis of the CNS should be diagnosed promptly, since the prognosis remains poor despite efficacious medications. Examination of the cerebrospinal fluid revealed no acid-fast bacilli, but this examination should be repeated if clinical suspicion is high. In this patient, the diagnostic suspicion was lessened by the chronicity, absence of fever, normal sedimentation rate, absence of cavitary lesions in the lungs, and negative purified-protein-derivative tuberculin test.

Syphilis was also considered, since early neurosyphilis may result in a pathologic pattern similar to that documented by the results of imaging and cerebrospinal fluid examination in this patient. Florid leptomeningeal inflammation causes multiple cranial neuropathies, infectious vasculitis with possible stroke, and hydrocephalus. Parenchymal involvement in the brain and spinal cord may result from the development of syphilitic gumma. This diagnosis was ruled out by the nonreactive serum rapid plasma reagin test and by a Venereal Disease Research Laboratory test of cerebrospinal fluid.

Neuroborreliosis may cause clinical patterns similar to those of syphilis, including meningitis and encephalomyelitis, which may be more common with the strains of borrelia in Europe than with those in North America.³ In fact, the pathological resemblance of meningovascular syphilis and neuroborreliosis has been documented.⁴ Primary infection with borrelia is much more common than syphilis, particularly in New England. Neurologic manifestations develop in 15% of patients with Lyme disease and include cranial neuropathies, painful radiculopathies, and lymphocytic meningitis. Generalized neuropathy indistinguishable from the Guillain–Barré syndrome may be seen. In this patient, testing for antibodies and for borrelia DNA by polymerase chain reaction was negative, ruling out Lyme disease.

Inflammatory and Granulomatous Disorders

In Wegener's granulomatosis, meningitis may occasionally be the initial clinical presentation,⁵ although peripheral and cranial neuropathies are the most common neurologic manifestations. Wegener's granulomatosis generally affects the upper and lower airways and the kidneys. The normal sedimentation rate and the absence of lung lesions in this patient argued against this diagnosis, as did a sensitive and specific test for antineutrophil cytoplasmic antibodies, which was negative.

The possibility of systemic lupus erythematosus (SLE) was discussed, since the ANA test was positive at 1:320. Leptomeningeal involvement and myelopathy can be seen in patients with lupus, albeit rarely.⁶ Other neuropsychiatric manifestations in SLE include stroke, transient ischemic attacks, seizures, psychosis, cognitive disorders and dementia, and delirium⁷; this patient had many of these manifestations at the time of her admission. Primary neurologic presentations of SLE occur in 24% of cases,⁶ usually in patients with a positive ANA test and anti–double-stranded DNA antibody.

Other inflammatory disorders were also considered. Rheumatoid arthritis can cause CNS disease, but this usually occurs in patients with severe rheumatoid arthritis with a positive rheumatoid factor.⁸ Sjögren's syndrome on rare occasions causes meningoencephalitis, but the autoantibodies correlating with Sjögren's syndrome were absent.

Neurosarcoidosis

A diagnosis of neurosarcoidosis was considered most likely, in view of both the pattern of CNS involvement documented by MRI and the mediastinal and hilar lymphadenopathy. Neurosarcoidosis is a chronic granulomatous disease that varies in incidence around the world and among racial and ethnic groups — in the United States, the adjusted annual incidence among blacks is about three times as high as that among whites.⁹ I am not aware of reports of the incidence in Inuits. The disease involves patients of all ages but most commonly is seen in young adults, such as this patient. Sarcoidosis most commonly affects the lungs, eyes, and skin. According to autopsy studies, the nervous system is affected in up to 25% of patients,¹⁰ but only about half these patients have clinical neurologic manifestations.² About 40% of patients with neurosarcoidosis have previously diagnosed sarcoidosis in another organ, most commonly the chest or anterior uvea, unlike our patient.^11,12 Cranial neuropathies, particularly optic and facial neuropathies, are the most common manifestation of neurosarcoidosis and are seen in 30 to 40% of patients with neurosarcoidosis. Spinal cord and meningeal involvement, seen in this patient, are also common.¹² Rarely, psychosis may occur, as seen in this patient.

Findings on brain MRI typically include multiple white-matter lesions, with or without meningeal enhancement, but a single parenchymal lesion, an optic-nerve lesion, or spinal cord lesions may be seen or the findings may be normal.¹¹ Involvement of the hypothalamus, pituitary, or both occasionally occurs in patients with neurosarcoidosis, as it did in this patient, and may have been responsible for the amenorrhea noted in this patient.^1,12 ACE is produced by sarcoid granulomas, and the serum level is elevated in 60% of patients with sarcoidosis. A normal serum ACE level, as seen in this patient, does not eliminate this possibility of sarcoidosis. The sensitivity and specificity of ACE levels in the cerebrospinal fluid are unknown.

The diagnosis of neurosarcoidosis should be confirmed by microscopical examination of a biopsy specimen. Since noncaseating granulomas are not pathognomonic of sarcoidosis, the pattern of neurologic and organ involvement should be consistent with sarcoidosis, and alternative diagnoses should be ruled out. The diagnosis of neurosarcoidosis is considered definite if granulomas are seen on biopsy specimens of the brain or meninges, and probable if the pathological evidence is obtained on non-CNS tissue such as the lung or lymph nodes. In this patient, after the lung biopsy showed no evidence of granulomas or cancer, we elected to perform a biopsy of the brain and meninges, since in a patient with this constellation of clinical findings, detection of a noncaseating granuloma in the brain would have secured a diagnosis of sarcoidosis and ruled out other diagnoses. The results of examination of the biopsy specimens of the brain and meninges were normal; therefore, the natural target of our examination became the mediastinal nodes.

Dr. Didier Cros's Diagnosis

Neurosarcoidosis.

Pathological Discussion

Dr. Eugene J. Mark: Mediastinoscopy with biopsies of several enlarged lymph nodes was performed. On histopathological examination, compact, non-necrotizing granulomas occupied approximately 80% of the lymph-node tissue (Figure 2A). The lymph node had areas of sclerosis (Figure 2B), and the hyaline collagen was wrapped around individual granulomas. All the granulomas were histologically similar, which has been described as a feature of the granulomas in sarcoidosis, as distinct from granulomas due to mycobacterial or fungal infection.^13,14 Special staining and cultures of the biopsy specimens of the lymph nodes were negative for microorganisms. The combination of the histopathological, clinical, and radiographic findings indicates a diagnosis of sarcoidosis.^13,14

View larger version (106K): [in this window] [in a new window] Figure 2. Biopsy Specimen of a Mediastinal Lymph Node (Hematoxylin and Eosin). Numerous granulomas occupy a majority of the node (Panel A). Three granulomas are surrounded by dense collagen (Panel B). A conchoidal body — a large, concentric calcification also known as a Schaumann body, which is a frequent finding in granulomas of sarcoidosis — is subtotally replacing a granuloma (Panel B, inset).

The distribution of granulomas in sarcoidosis differs somewhat in various organ systems. In the lung, the granulomas are preferentially distributed along lymphatic pathways.^15,16,17 In the CNS, the granulomas of sarcoidosis preferentially involve the meninges, as was the case with this patient. They can also involve the ependyma with extension into the choroid plexus and form nodules and tumorous masses that may extend into the underlying parenchyma.^18,19

Dr. Nancy Lee Harris (Pathology): Dr. Sheth, will you tell us about your care and follow-up of this patient?

Dr. Kevin N. Sheth (Neurology): When the patient first arrived, she was floridly psychotic, and it took several days for us to obtain a thorough history and physical examination. It was not clear whether her altered mental state was due to neurosarcoidosis, a postictal phenomenon, or a reaction to lorazepam. After the diagnosis of sarcoidosis was established, we began treatment with high-dose prednisone. She had a dramatic response, with resolution of her vertigo and gradual resolution of her neurologic symptoms; phenytoin was discontinued. Several months after beginning treatment with prednisone, her menstrual periods resumed. Eight months after she was discharged from the hospital, she had residual hyperreflexia, but her strength and gait were normal; prednisone was discontinued.

Anatomical Diagnosis

Neurosarcoidosis.

Dr. Gonzalez reports receiving lecture fees from Bayer and General Electric. No other potential conflict of interest relevant to this article was reported.

Source Information

From the Department of Neurology (D.C.); the Division of Neuroradiology, Department of Radiology (R.G.G.); and the Department of Pathology (E.J.M.), Massachusetts General Hospital; and the Departments of Neurology (D.C.), Radiology (R.G.G.), and Pathology (E.J.M.), Harvard Medical School.

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