Neuro-Ophthalmologic Manifestations of Lymphocytic Hypophysitis

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Article initiated by:

Clement Anozie, Phillip H Keys

All contributors:

Andrew Go Lee, MD, Clement Anozie, Noor Laylani, M.D., Phillip H Keys, Samir Cayenne, Osama Al Deyabat, MBBS, Nagham Al-Zubidi, MD, Pamela Davila-Siliezar, MD, Osama Al Deyabat, MBBS

Assigned editor:

Osama Al Deyabat, MBBS

Review:

Assigned status Up to Date

 by Osama Al Deyabat, MBBS on October 17, 2024.

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Disease Entity

Hypophysitis refers to inflammation of the pituitary gland and can be classified as a primary or secondary disease. Lymphocytic Hypophysitis (LH) is a primary, autoimmune, and inflammatory lymphocytic process involving the pituitary gland and infundibulum that can result in hypopituitarism symptoms. These symptoms occur due to B and T cell infiltration of the gland and/or mass effect in the sella. Consequently, anterior and posterior pituitary hormone control is variable and often dysregulated. This results in a variety of endocrinologic presentations (e.g., central diabetes insipidus and hypo- or hyperprolactinemia or hypopituitarism).

While Hypophysitis can be classified by histology into lymphocytic, granulomatous, xanthomatous, and plasmacytic, LH can also be classified based on anatomy. Anatomical classifications include lymphocytic adeno-hypophysitis (LAH), lymphocytic infundibulo-neurohypophysitis (LIH), and lymphocytic pan-hypophysitis (LPH) based on the degree and location of pituitary involvement. Specific hormone dysregulation aligns with the area of pituitary involvement (i.e. central diabetes insipidus occurs with neuro- or pan-hypophysitis).

Epidemiology

LH has an annual incidence of about 1 in 9 million and approximately 0.4% of pituitary surgical cases. LH occurs more in women than men with a ratio of 2-4:1, likely due to its association with pregnancy. LH is most likely to occur in women during the end of pregnancy or the first few weeks after delivery.

Etiology/Risk factors

Hypophysitis is distinguished into two broad categories based on its etiology. Primary hypophysitis results from lymphocytic (primarily T cells) infiltration in the absence of a related immunologic insult. Inflammation resulting from secondary hypophysitis is often found in patients with other underlying conditions such as hemochromatosis, tuberculosis, syphilis, and sarcoidosis.

While the exact mechanisms of the development of LH are incompletely understood, LH is increasingly linked to autoimmune etiology due to its association with pregnancy and other autoimmune diseases. A family history of autoimmune disease, especially those associated with HLA DQ8 and DR3, has been shown to predispose patients to LH. In fact, the HLA-DQ8 and HLA-DR53 markers were present in 87% and 80% of patients with biopsy-proven lymphocytic hypophysitis. A relationship to pregnancy supports the diagnosis of LH but is not required. There is a peak in the incidence of LH in the 3rd trimester and it is two to four times more likely to affect women.

Pathophysiology

Much of the details of the pathophysiology of (primary) LH remain ill-defined. The general understanding involves an autoimmune process that leads to enlargement of the gland in the acute phase and fibrosis of the gland with varying severity depending on the extent/duration of inflammation. Thus, the pituitary inflammation and enlargement can lead to a variety of mass-effect symptoms such as headaches and temporal visual field defects as well as impede the gland’s ability to secrete hormones properly. Chronically, pituitary fibrosis as a result of sustained inflammation commonly leaves patients requiring hormonal supplementation.

The pathophysiology of LH can be determined through similar models of pituitary gland inflammation.

Nonspecific antibodies described against pituitary antigens are listed below:

• IgG4
• Anti-Pit-1
• PGSF1a & PGSF2
• TPIT
• α-enolase

Specifically, the pathophysiology of IgG4-mediated inflammation has been recognized as a key model for understanding the underlying causes of hypophysitis. New diagnostic testing of pituitary inflammatory conditions through non-invasive fluorodeoxyglucose-positive electron tomography (FDG-PET) has successfully recognized IgG4-related disease and has been translated to identify HLA markers such as DQ8 as being markedly elevated in patients with primary LH as compared to similar pituitary pathologies, showing promise for future screening.

Ophthalmologic Manifestations

Two primary etiologies of symptoms are implicated in the LH disease process: hormone dysregulation from immune infiltration of the hormone-secreting cells and enlargement of the pituitary gland leading to mass effect on surrounding structures in and near the sella. Ophthalmologic manifestations of LH stem from the mass effect of pituitary inflammation and enlargement. LH most frequently presents as headache and visual disturbances.

Visual disturbances occur in anywhere from 15-52% of patients with primary hypophysitis and are most common in lymphocytic adeno-hypophysitis in comparison to lymphocytic infundibuloneurohypophysitis or lymphocytic pan-hypophysitis.

• Chiasmal syndrome* – 15%

• Ocular motor paresis with diplopia – 7%
  • Linked to lateral expansion into the cavernous sinus with compression of the cranial nerves III, IV, and VI

• Anisocoria from Horner syndrome or CN III palsy

• Decrease in visual acuity – 16%

• Visual field defects – 34%; including optic nerve defects, junctional visual field loss, bitemporal hemianopsia and optic tract visual field defects (e.g., homonymous hemianopsia)

Diagnosis/Diagnostic procedures

A definitive diagnosis of LH is made with a pituitary biopsy usually acquired via a trans-sphenoidal approach. Without a biopsy, the diagnosis is made on a basis of exclusion.

As LH commonly presents as symptoms of hypopituitarism +/- mass effect-related headaches and visual disturbances, the initial workup includes evaluation of pituitary hormone evaluation. A personal or family history of autoimmune disease can be supportive. Additionally, evaluating for an undiagnosed autoimmune disease should also be done (inflammatory markers such as CRP, ESR, lupus antibodies, etc).

In addition to clinical and laboratory information, imaging studies can be useful in guiding diagnosis. Historically, imaging has reliably been used to detect pituitary enlargement and was unsuccessful in distinguishing between pituitary adenomas and other causes of pituitary enlargement such as hypophysitis. After many cases of misdiagnoses and unnecessary surgeries, Gutenberg et al. developed a highly sensitive and specific scoring system able to aid in distinguishing pituitary adenomas from lymphocytic hypophysitis.

Differential diagnosis

Differential diagnosis is broad but can include:
Pituitary adenomas Primary hypophysitis of other histologic makeup Secondary hypophysitis Pituitary apoplexy Sheehan’s syndrome Pituitary metastases Physiologic pituitary hypertrophy

Management

An appropriate approach to treatment is supportive therapy, which has been shown to allow radiographic improvement in most patients. Other options include pituitary surgery in the form of either gross total resection or partial resection, glucocorticoid therapy, or immunosuppressive agents such as methotrexate. Stereotactic radio-surgery or fractionated radiotherapy is not common and associated with refractory disease.

Non-operative management is the preferred treatment.

As trans-sphenoidal surgery (TSS) is associated with secondary pituitary dysfunction and less overall improvement in disease regression compared to conservative therapy, it is generally indicated only in cases with severe headaches or cranial nerve deficits unresponsive to medical therapy. When performed, TSS is reliable in allowing for both Sellar decompression and providing an opportunity for histologic analysis and diagnosis. Endocrinopathies are not expected to significantly improve with TSS.

Clinicians should be aware that inflammatory lesions can occur in the pituitary gland. The radiographic features of LH including infundibulum involvement may allow a clinical diagnosis to be made and empiric treatment (e.g., corticosteroids) to be initiated but other cases require histologic confirmation. The endocrinologic manifestations can be life-threatening and should be managed urgently. The neuro-ophthalmologic manifestations of LH include afferent (visual loss) and efferent (diplopia, anisocoria, ptosis).