The annual incidence of LYH may be estimated at one case per 9 million. Data from 4 large patient analyses (905-2500 people) indicate that LYH is seen in less than 1% (0.88-0.24%) of all surgical pituitary specimens. In 2012, Kalra et al. indicated that the number of children under 18 years old with LYH was greater than 96 in the literature. The incidence in children was much lower compared to approximately 460 adults with autoimmune hypophysitis. In contrast to adults (more female patients were identified with a female-to-male ratio of 8:1) no significant sex predilection was seen among children.
Concurrent autoimmune conditions were reported in 20-50% of cases of LYH in adults. The most common association was observed with autoimmune thyroid disease, reported in 15-25% of LYH cases, i.e. 70-80% of cases with an associated autoimmune disease. Chronic autoimmune thyroiditis constituted about 75%, while Graves' disease and subacute thyroiditis were reported less frequently. Autoimmune adrenalitis was reported in 5-7% of cases (15-25% of patients with an associated autoimmune condition), while pernicious anaemia and type 1 diabetes were seen in 2% of cases. Associated autoimmune disorders occurred in 7 out of 96 children, with an incidence of 7% as compared to 20-50% in adults.
The clinical presentation of LYH is variable and comprises 4 categories of symptoms: sellar compression, hypopituitarism, CDI, and hyperprolactinaemia. In adults with LYH, 96% have PST and 72% have CDI.
The symptoms of sellar compression, represented by headache and visual disturbances, are the most common and usually the initial complaints in LAH. Headache is the result of the distortion of the dura mater and diaphragma sellae by the expanding pituitary mass. However, a recent study showed that pituitary volume did not correlate with its severity. Headache is observed more often in patients with LAH (53%) than in those with LINH (13%). Visual abnormalities include visual field defects, decreased acuity, and diplopia, which are secondary to the compression of the optic chiasm by a pituitary mass expanding upward or laterally to the cavernous sinus. Visual disturbances are described in 43% of LAH and seldom in LINH, i.e. only in 3%. The other most common symptoms are due to a partial or complete deficit of the anterior pituitary hormones. CDI is another of the most common problems, which may be attributed either to direct immune destruction or to the compression of the posterior lobe and infundibular stem. CDI is the cardinal feature of LINH (98%) and may be very rare in LAH (1%). CDI may be masked in the presence of a coexisting glucocorticoid deficit because it opposes the action of antidiuretic hormone (ADH) at several levels. Glucocorticoids inhibit the secretion of ADH from the neurons of the paraventricular nucleus and suppress the synthesis of aquaporin 2, an ADH-dependent water channel expressed in the renal collecting tubules. The manifestations of hyperprolactinaemia, mainly represented by amenorrhoea and galactorrhoea, are the least common. Hyperprolactinaemia results from stalk compression, with the resulting decrease in dopamine delivery to the anterior pituitary. The inflammatory process may directly destroy the lactotrophs, inducing the release of prolactin (PRL) into the general circulation. Headache, visual disturbances, hypocortisolism, and hypothyroidism are more common in LAH than in LINH or LPH. In contrast, CDI suggests LINH, a condition in which other presenting symptoms, such as visual disturbances, hypocortisolism, hypogonadism, and hyperprolactinaemia are rare.
A presumptive diagnosis of LYH may be made based on clinical, laboratory, and imaging studies, but the definitive confirmation requires a pituitary biopsy.
Antibodies against pituitary protein and vasopressin-secreting hypothalamic cells may be found in patients with LYH. They may be measured with indirect immunofluorescence, immunoblotting, or enzyme-linked immunosorbent assay (ELISA). However, the specificity and sensitivity of pituitary antibodies is poor, as they were found in various pituitary diseases such as Cushing's disease, pituitary adenoma, empty sella syndrome, as well as in other autoimmune diseases, such as type 1 diabetes mellitus, Hashimoto's thyroiditis, and Graves' disease. A retrospective analysis of 379 patients with LYH conducted by Caturegli et al. revealed that antibodies against pituitary protein were detected in 10-80% of patients depending on the form of LYH and the method used (they were more often confirmed in immunoblotting).
The authors of a case series presenting LAH reported that MRI studies showed an enlarging pituitary mass in 75-90% of patients. Even in cases with CDI, in which the initial scan was normal, repeated imaging evaluations performed months later might reveal a mass-like image. Heinze and Bercu published a review of 63 patients in which they reported a post-contrast enhancement of the lesion in 70%. Honegger et al. reported a tongue-like extension toward the hypothalamus as a characteristic finding of LAH. A diffuse thickening of the pituitary stalk is a very characteristic MRI feature in patients with LINH. Its greater diameter was found to exceed 3.5 mm at the level of the median eminence of the hypothalamus. The normal smooth tapering of the infundibular stalk is lost, and a varying degree of asymmetry may exist. Marked gadolinium enhancement of the stalk is quite common, extending even into the lower hypothalamus. The loss of the usual neurohypophyseal "bright spot" was also commonly reported. However, it should be kept in mind that this MRI sign may be absent in 10% of normal subjects. Extensive pituitary inflammatory changes were reported in LINH, extending upwards to the suprasellar area and affecting the optic pathway, or laterally to the cavernous sinuses, with thickening of the pituitary stalk, enlargement of the neurohypophysis, or lack of the neurohypophyseal bright spot on the normal neurohypophysis on MRI. Histopathology remains the gold standard for the diagnosis of LYH. The infiltration of the pituitary gland with lymphocytes, with the predominance of T cells and particular CD4 cells is the defining pathological feature of LYH. Plasma cells, eosinophils, macrophages, histiocytes, and neutrophils are also present. Fibrosis and rare necrosis may be reported in pathological specimens.
LINH should be suspected as a cause of PST when we observe: an acute onset of CDI with headache and mass-effect symptoms; isolated, early or disproportionate disruption of ACTH or TSH secretion, disproportionate disruption of anterior pituitary function for the magnitude of the changes on MRI; the presence of other autoimmune conditions and/or positive autoantibodies, including thyroid peroxidase antibodies, antinuclear antibodies, antiparietal cells, adrenal antibodies, and anti-smooth muscle antibodies; the presence of antipituitary antibodies in the serum; lymphocytic pleocytosis in the CSF; and characteristic MRI findings (diffuse thickening of the pituitary stalk with or without enhancement after gadolinium, loss of the normal posterior "bright spot" on T1-weighted images).
Currently, the treatment of LYH is only symptomatic. It includes reducing the size of the pituitary/stalk mass and/or replacing the defective endocrine function. Mass reduction may be achieved via pituitary surgery, immunosuppressive drugs, or radiotherapy. Glucocorticoids should be used as the first line of treatment, rather than surgery. Glucocorticoids may be effective for treating LYH, both as anti-inflammatory agents to reduce the size of the pituitary mass or the thickened stalk, and as the replacement of defective adrenal function. Prednisone, hydrocortisone, and methylprednisolone were the most commonly used glucocorticoids. In the case of patients with poor response to glucocorticoids, other immunosuppressive drugs, such as azathioprine, methotrexate, or cyclosporine A, may be used. Surgery should be performed only in the presence of serious and progressive deficits of visual field, visual acuity, ocular movements, or increased intracranial pressure, not responsive to pharmacological treatment. Radiotherapy (conventional fractionated external-beam radiotherapy, Gamma Knife radiosurgery) should be limited to cases with severe mass-effect symptoms, those who show poor response, or those who are poor candidates for high doses of glucocorticosteroids and/or surgery. However, it is important to mention the findings of some authors, e.g. Caturegli et al., who reported that LYH resolved spontaneously without any treatment in 11 patients (3%).
Sarcoidosis is an auto-inflammatory, granulomatous disorder of unknown aetiology, with multi-organ involvement, hilar lymphadenopathy, and pulmonary interstitial infiltrations being the most common manifestations. Furthermore, it affects the eyes, skin, liver, and spleen. Sarcoidosis may also involve any area of the CNS: the meninges, ventricles, cerebellar hemisphere, white matter of the frontal lobe, adjacent brain or spinal cord parenchyma, pituitary stalk, pituitary, hypothalamus, thalamus, optic nerve and chiasm, cranial nerves such as the facial, auditory, and vestibulocochlear nerve.
The incidence of clinically recognized sarcoidosis in children is 0.22-0.29/100,000 children per year, and gradually increases with age to a small peak in teenagers at 13-15 years of age. However, adults aged 45-55 years are most often affected, with half of them being older than 55 years of age at the time of diagnosis. Neurosarcoidosis was reported in 5-10% of adults with systemic sarcoidosis and was seldom recognized in children. Isolated neurosarcoidosis is very rarely diagnosed. According to the English sources, a total of 54 children and adolescents were diagnosed with neurosarcoidosis, and only 9 children with isolated neurosarcoidosis. The average age of onset was 12 years (3 months - 18 years).
General symptoms of sarcoidosis are fatigue, weight loss, fever, persistent cough, skin changes (subcutaneous infiltrates, erythema nodosum, lupus pernio), eye lesions (uveitis, retinal changes, conjunctival nodules), and peripheral lymphadenopathy.
The manifestations of neurosarcoidosis include seizures, headache, vomiting, somnolence, cranial neuropathies (common: VII, II, infrequent: III, IV, VI, V, VIII), pituitary and hypothalamic dysfunction, cerebellar signs, neuropsychological deficits, myelopathy, and peripheral neuropathy. Granulomatous masses that involve the hypothalamus and pituitary gland cause the following: diabetes insipidus, growth and sexual maturation failure, and syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hypothalamic-pituitary involvement accounts for 6-9% of all neurosarcoidosis cases. Endocrine investigations mostly identify GH, gonadotropin and thyrotropin deficiency, CDI in over half of cases, and - the least frequently - corticoadrenal insufficiency. Convulsions are the most common symptom of neurosarcoidosis in children, while cranial neuropathies, especially in nerve VII, are the most common after puberty and in adults.
Neurosarcoidosis is a diagnosis of exclusion. There is no single diagnostic test for sarcoidosis. Diagnosis is achieved by the combination of history, examination, CNS MRI, CSF analysis, gallium-67 scintigraphy, 18F-FDG PET/CT, and biopsy. The MRI features of neurosarcoidosis include diffuse leptomeningeal thickening and enhancement, focal dural or brain parenchymal enhancement with or without mass effect, periventricular radial vascular enhancement, and enhancement, enlargement, or atrophy of the cranial nerves or enlargement of the pituitary stalk. Criteria for the paediatric diagnosis of neurosarcoidosis have not been established, although most clinicians use the classification scheme (definitive-probable-possible) by Zajicek et al.. Anaemia, leukopaenia, and eosinophilia are commonly seen on blood counts. Hypercalcaemia and/or hypercalciuria occur in up to 10% and 40% of children, respectively, because a sarcoid macrophage is able to synthesize 1,25-dihydroxyvitamin D. Angiotensin-converting enzyme (ACE) is a biomarker of sarcoidosis. ACE levels are elevated in sarcoidosis because of the activation of monocytes, which are the precursors to the epithelioid cells that form granulomas. ACE is not specific for sarcoidosis. However, it is elevated in the serum of 68-88% of patients with systemic disease and in the CSF of 24-55% of patients with neurosarcoidosis. It should be noted that other disease processes that have also shown elevated serum ACE levels include tuberculosis, lung cancer, Hodgkin lymphoma, and cirrhosis of the liver. Normal serum/CSF ACE level cannot exclude the diagnosis of sarcoidosis. However, an elevated CSF ACE level should prompt further neurosarcoidosis evaluation.
The analysis of the CSF may show pleocytosis (> 5 white blood cells) with slight lymphocytosis (10-100 cells per microl), slightly elevated protein (> 50 mg/dl) in 76% of samples, slightly decreased glucose (< 50 mg/dl) in 51% of samples and increased immunoglobulins with oligoclonal banding. However, CSF abnormalities are not specific to neurosarcoidosis, and normal CSF results were obtained in more than a third of cases. A retrospective review of the Mayo Clinic record system revealed that oligoclonal banding was present in the spinal fluid of 18% of patients.
Kidd et al. presented 6 patients with hypothalamic involvement of neurosarcoidosis in MR imaging. Stalk enlargement was reported in 2 of those patients.
In a case of HPR involvement, a whole-body gallium or FDG-PET scan can show other lesions that are more accessible for biopsy.
Biopsy still provides the strongest evidence for this disease. The diagnosis of sarcoidosis is confirmed by demonstrating a typical noncaseating granuloma on a biopsy specimen.
No established treatment guidelines exist for neurosarcoidosis. High-dose corticosteroids, particularly oral prednisone, are widely used and are often effective in the treatment of sarcoidosis. If corticosteroid therapy is unsuccessful, second-line immunosuppressants are administered, e.g. methotrexate, azathioprine, mycophenolate mofetil, and leflunomide. More recently, third-line agents, including tumour necrosis factor inhibitors, i.e. infliximab or adalimumab, have been indicated in the treatment. Infliximab was dentified as an effective treatment option for patients, including those who had previously been refractory to other immunosuppressants.
Pituitary tuberculosis should also be considered in the differential diagnosis of PST. The incidence of tubercular hypophysitis is 0.5-4% of all intracranial lesions. 25-30% of tubercular hypophysitis cases reported in the literature had previous or active tuberculosis. Primary pituitary tuberculosis caused by Mycobacterium tuberculosis is a sporadic condition, and only 106 cases were reported from 1924 to 2019. It mainly affects young adults with the median age being 35 years (from 5 to 60). Several cases of children with pituitary tuberculosis were also reported, especially in endemic countries.
Headache (85.2%), somnolence, visual disturbances (48.1%), low-grade fever (14.8%), and vomiting are common clinical symptoms. Anterior pituitary insufficiency (51.9%), hyperprolactinaemia (27.6%), and CDI are common endocrine dysfunctions in pituitary tuberculosis. The presence of CDI is one of the key features in distinguishing pituitary tuberculoma from pituitary adenoma.
It is difficult to differentiate inflammatory lesions from those of pituitary adenoma clinically and radiologically. In MRI, pituitary tuberculosis usually presents the features suggestive of a sellar and suprasellar mass, and it may be very difficult to differentiate between pituitary tuberculoma and adenoma. The thickening and nodularity of the pituitary stalk are also considered to be signs of pituitary tuberculoma. However, this finding is non-specific; it is also seen in other inflammatory conditions like sarcoidosis or lymphocytic hypophysitis.
The following tests should be performed in patients with a suspected tuberculous aetiology of PST: tuberculin skin test, QuantiFERON-TB test (sensitivity 92.6%), and chest X-ray/computed tomography (CT). CSF examination may reveal moderate pleocytosis (100-300 mm3), increased protein level (100-400 mg/dl), and decreased glucose level (< 40 mg/dl). The samples do not always stain for acid-fast bacilli and Mycobacterium spp. when tested with polymerase chain reaction (PCR) method. The definitive confirmation of the diagnosis requires a histopathological examination, which reveals necrotizing granulomatous inflammation, staining for acid-fast bacilli (not usually demonstrable from pathological tissue), and the PCR of Mycobacterium spp. in DNA extracted from the tissue.
Surgery is not indicated in tuberculous hypophysitis except for obtaining biopsies to confirm the diagnosis. Antitubercular drugs that cross the blood-brain barrier are administered to patients for 9-24 months depending on the clinical and imaging outcome. A significant reduction in size was reported as early as 2 months after treatment, usually with a complete resolution of sellar mass at the end of the regimen. The improvement of endocrinological status and even eliminated panhypopituitarism were reported in some patients. In cases such as tubercular hypophysitis, early diagnosis is very important given that panhypopituitarism may be eliminated in clinical terms following an effective anti-tuberculosis treatment. A delayed diagnosis may lead to permanent endocrine dysfunction.
Considering the causes of PST described above, Table 1 presents tests used in the diagnostic process of PST in children.
After PST imaging in MRI, diagnostic tests should be planned, taking into account the history and physical examination data. First- and second-line tests may be distinguished.
The first-line tests used in the diagnosis of patients with PST include: complete blood count, ESR, ALAT, ASPAT, GGTP, urea level, creatinine, INR, APTT, blood electrolytes; 1,25-dihydroxyvitamin D; serum ACE, QuantiFERON, tuberculin test; antipituitary antibodies, anti-vasopressin antibodies, systemic autoantibodies; endocrine tests assessing the function of the anterior and posterior pituitary gland, serum tumour markers ( beta-hCG, alpha-FP); imaging tests (chest X-ray, skeletal radiograph, abdominal ultrasound), and neurological and ophthalmic examination.
If first-line tests are inconclusive, it is possible to use the so-called second-line tests in selected cases, depending on the clinical presentation. These tests include the following: tumour markers in CSF, ACE in CSF, the detection of Mycobacterium spp. by PCR in CSF, and immunoglobulin G4 (IgG4) in the serum. Imaging tests of the second line are whole-body imaging with MRI, gallium 67-scintigraphy, 18F-FDG PET/MRI, or PET/CT. It is crucial when LCH or sarcoidosis is suspected because it might detect extracranial lesions not otherwise identified, which may be biopsied.
In 2021, the British national recommendations for diagnosing children and adolescents with PST, CDI, or both, developed by specialists under the auspices of paediatric endocrinology and oncology societies, were published. According to the recommendation mentioned above, a routine CSF examination for acid-fast bacilli is not recommended due to the sporadic occurrence of pituitary tuberculosis in children. Nonetheless, it should be considered in exposed patients or those at a high risk. Likewise, due to the sporadic diagnosis of neurosarcoidosis as the cause of PST in children and adolescents, the authors do not recommend routine ACE in the CSF, unless neurosarcoidosis is strongly suspected. Because IgG4-related hypophysitis seldom affects a child or young person, routine measurement of IgG4 concentrations is not currently advisable.
The indications for and timing of endoscopic pituitary biopsy in children and young people are controversial. Biopsy should be performed in a specialist pituitary neurosurgical unit with perioperative endocrine support on-site to reduce the risk of complications. According to the British recommendations of 2021, pituitary biopsy should be considered only in markedly thickened (>= 6.5-7 mm) or enlarging stalk with additional visual or endocrine deficits, which continue to pose a worrying diagnostic dilemma after repeated tests. Histopathological examination is conclusive in most cases. However, it is important to remember that histological findings compatible with a lymphocytic inflammatory process may represent the first sign of a host reaction to occult germinoma, which requires a repeated biopsy. In the case of CDI, a repeated brain MRI and investigation of beta-hCG tumour marker in the serum and CSF should be performed every 3-6 months during the first 3 years after the onset of CDI (the frequency depending on the presence of a progressively enlarging pituitary stalk), to rapidly establish a diagnosis before the developed large tumour triggers visual and neurological symptoms. Subsequently, MRI should be performed every year for the following 2 years and every 2-5 years thereafter, depending on the size and evolution of the lesion. Therefore, the follow-up strategy should be individually adapted.