Neurosarcoidosis presenting with hypopituitarism

Abstract

Hypothalamo-pituitary sarcoidosis is a rare manifestation of sarcoidosis, usually presenting alongside other symptoms of neurosarcoidosis. We describe the case of a 58-year-old man from Ghana who presented with progressive gait disturbance, cognitive dysfunction, hypothermia and bradycardia. He was found to have pituitary stalk thickening on imaging, and lymph node biopsy identified non-caseating granulomatous disease. Serology revealed gonadotropin deficiency, hypothyroidism and central adrenal insufficiency. Treatment with immunomodulatory therapy resulted in resolution of findings on imaging and improved cognition, though pituitary function never recovered. Treatment for his sarcoidosis unfortunately resulted in recurrent infections and avascular necrosis. Work-up, management and ongoing care required multidisciplinary cooperation between the admitting internal medicine team, infectious diseases, respirology, rheumatology, endocrinology and neurology.

Background

Sarcoidosis is a rare ‘multisystem disorder of unknown cause(s)’, characterised by the formation of non-caseating epithelioid granulomas in the affected organ sites.¹ Neurological manifestations occur in 5% of sarcoidosis cases.¹ Involvement of the hypothalamus, pituitary or infundibulum, referred to as hypothalamo-pituitary sarcoidosis, is seen in 9%–18% of neurosarcoidosis cases.^{2 3} Hypothalamo-pituitary sarcoidosis has various presentations and commonly manifests in conjunction with other symptoms indicating broader involvement of sarcoidosis. Commonly reported consequences of hypothalamo-pituitary sarcoidosis include diabetes insipidus, hyperprolactinaemia, gonadotropin deficiency and hypothyroidism.^{2 4 5} Treatment for sarcoidosis requires immunomodulatory therapy; however, the hormonal changes secondary to hypothalamo-pituitary involvement are often irreversible, requiring long-term hormone-replacement therapy.^{5 6} Long-term management requires monitoring with repeated laboratory studies and imaging, and close follow-up from multiple services including neurology, endocrinology and rheumatology.

Case presentation

A 58-year-old man from Ghana, previously healthy aside from previous hepatitis B infection with natural immunity, presented to our hospital in August 2016 with a 1-year history of progressive weakness, gait disturbance and increasing frequency of falls. He also had a 6-month history of dry cough. He was known to have a doctorate degree in his field, and be a high-functioning researcher, but was identified on preliminary examination to have cognitive dysfunction with a Montreal Cognitive Assessment score of 24/30. During his admission, he was noted to have hyponatraemia, bradycardia and hypothermia, with a temperature of approximately 34.5°C despite external warming.

Investigations

At time of presentation, our patient’s C reactive protein was elevated at 31.9 mg/L (normal <3.1 mg/L), with a normal ionised calcium of 1.17 mmol/L (normal range 1.10–1.30 mmol/L). Chest radiograph identified hilar fullness, prompting further investigation with CT of the chest. This revealed multiple enlarged and calcified mediastinal, hilar and intrapulmonary lymph nodes.

Investigation of our patient’s hypothermia and bradycardia revealed a low-normal thyroid-stimulating hormone of 0.49 mU/L (normal range 0.34–4.82 mU/L) in association with low triiodothyronine and thyroxine of 1.1 pmol/L and 7.2 pmol/L, respectively (normal range 3.5–6.5 pmol/L and 10.0–20.0 pmol/L, respectively). Morning cortisol was low at 56 nmol/L (normal range 120–620 nmol/L) and cosyntropin high-dose stimulation test resulted in an appropriate cortisol response. Adrenocorticotropic hormone was low at 2 pmol/L (normal <14 pmol/L). Testosterone was found to be very low at 1.07 nmol/L (normal range 10–38 nmol/L), in association with undetectable luteinising hormone levels and normal follicle-stimulating hormone levels. Prolactin and insulin-like growth factor 1 were both normal.

A non-contrast CT of the head and lumbar puncture were completed as preliminary work-up for our patient’s gait and cognitive changes. The initial CT of the head (figure 1) report noted two calcified extra-axial lesions adjacent to the superior sagittal sinus and the inferior aspect of the left tentorium cerebelli. On retrospective review with neuroradiology, the initial images were also suspicious for pituitary stalk thickening. Lumbar puncture showed a pleocytosis, primarily lymphocytic, with low glucose and high protein. The cerebrospinal fluid ACE level was normal, bacterial and fungal cultures had no growth, and cryptococcus PCR, venereal disease research laboratory and acid-fast bacillus were all negative.

Figure 1.

On non-contrast-enhanced head CT (coronal reformat) completed at time of presentation, there is suspicion of a thickened pituitary stalk (arrow).

For improved characterisation, a CT of the head with contrast was ordered, which identified a 5 mm enhancing soft tissue mass at the infundibulum of the pituitary stalk with homogeneous enhancement and additional nodular leptomeningeal enhancement (figure 2). MRI of the head (figure 3) and spinal cord identified diffuse, nodular and linear leptomeningeal and dural thickening and enhancement in the supratentorial and infratentorial compartments and surrounding the cervical and thoracic cord down to the level of the conus, with several foci of cord signal abnormality.

Figure 2.

Coronal contrast-enhanced head CT shows mass-like thickening and enhancement of the pituitary stalk (arrow) and several areas of patchy and nodular leptomeningeal enhancement (arrowheads).

Figure 3.

Sagittal contrast-enhanced MRI demonstrates mass-like enhancement of the pituitary stalk (white arrow), extensive leptomeningeal enhancement in the posterior fossa with ‘sugar-coating’ of the cerebellum (arrowheads) and thick dural-based enhancement in the anterior cranial fossa (black arrow).

A hilar lymph node biopsy revealed small histiocytic granulomas, with comment consistent with sarcoidosis.

Differential diagnosis

The primary differential diagnosis prior to the biopsy was sarcoidosis versus tuberculosis. Both of these processes would have explained the calcified lymph nodes in the chest, and the leptomeningeal thickening and enhancement on brain and spinal cord imaging. In addition, both conditions are known to infiltrate the pituitary stalk and gland, resulting in hypopituitarism.

Treatment

After results from the hilar lymph node biopsy returned, a diagnosis of probable sarcoidosis was made. For treatment, rheumatology initiated treatment with prednisone and azathioprine. For his hypopituitarism, endocrinology started replacement with levothyroxine, prednisone and testosterone.

Outcome and follow-up

At time of discharge from physical rehabilitation, our patient’s cognition had improved significantly, and he was able to ambulate independently.

A follow-up MRI completed 4 months after the initial MRI showed significant improvement (figure 4); the infundibulum and pituitary were midline and normal in calibre, and the leptomeningeal thickening and enhancement were nearly imperceptible. Despite this regression, the patient unfortunately did not recover any pituitary function. He continues to require thyroid, cortisol and testosterone replacement.

Figure 4.

Follow-up MRI reveals significant improvement with normalisation of pituitary stalk morphology (white arrow). Supratentorial and infratentorial leptomeningeal and dural lesions have also improved. There are a few areas of residual leptomeningeal enhancement in the posterior fossa (arrowhead) and mild dural thickening in the anterior cranial fossa (black arrow).

Our patient’s sarcoidosis was well controlled on a maintenance regimen of prednisone and azathioprine for 2 years. Due to increasing liver enzymes, his azathioprine was substituted with mycophenolate mofetil. Infliximab was also added for recurrent lesions seen on MRI of the brain.

As a result of his prednisone use, our patient unfortunately developed bilateral hip avascular necrosis. In addition, he has had multiple admissions over the last 3 years for infection, complicated by significant hypothermia, bradycardia and hypotension. It is unclear whether this is secondary to inadequate stress response, hypothyroidism, autonomic thermodysregulation secondary to sarcoidosis, or, most likely, a combination of these factors.

Our patient is still alive, approximately 4 years post-diagnosis. He is actively followed by neurology, rheumatology and endocrinology.

Discussion

Sarcoidosis is a chronic multisystem non-caseating granulomatous disease of unknown aetiology, affecting between 10 and 20 per 100 000 of the population.⁷ Neurosarcoidosis is clinically evident in only 5% of systemic sarcoidosis cases.^{1 3 7} There are three levels of diagnostic certainty outlined by the Neurosarcoidosis Consortium Consensus Group for diagnosis of neurosarcoidosis: possible, probable and definite. Our patient met criteria for ‘probable’ neurosarcoidosis based on ‘clinical presentation and diagnostic evaluation suggestive of neurosarcoidosis’, in association with ‘pathological confirmation of systemic granulomatous disease consistent with sarcoidosis’.¹

Neurosarcoidosis most commonly presents with cranial nerve palsy or headache, affecting 55% and 32% of patients with neurosarcoidosis, respectively, in a meta-analysis of 1088 patients.⁷ Aseptic meningitis has also been reported as a common presentation of neurosarcoidosis.² Gait disturbance, as seen in our patient, is relatively common among patients with neurosarcoidosis, affecting 28%, whereas hypopituitarism is more rare, affecting 9%–18%.^{3 7} The relatively high involvement of the hypothalamo-pituitary axis in neurosarcoidosis has been hypothesised to be due to its proximity to the basal meninges, which are preferentially involved.³ Isolated hypothalamo-pituitary sarcoidosis was rare; it was seen in zero patients in a cohort of nine, and two patients out of a cohort of twenty-four.^{6 8} Concurrent pulmonary involvement was most common, and other neurological involvement was identified in 58%–77% of cases.^{6 8}

Common manifestations of hypothalamo-pituitary sarcoidosis include diabetes insipidus, hyperprolactinaemia and hypopituitarism, especially in lesions involving the pituitary stalk due to involvement of the neurohypophyseal and hypophyseal portal systems.⁹ In keeping with known patterns of hypopituitarism, hypogonadism is the most common manifestation of anterior pituitary involvement, followed by hypothyroidism, then adrenal insufficiency.⁵ In the two largest studies evaluating the hormonal consequences of hypothalamo-pituitary sarcoidosis, panhypopituitarism was present in between 13% and 44% of affected patients.⁸ Hypothermia has been infrequently described. Two case reports have hypothesised hypothalamic involvement as the cause, though in our patient’s case, hypothermia may also have been explained by hypothyroidism.^{10 11}

Common findings on MRI for patients with hypothalamo-pituitary sarcoidosis include infiltrative lesions of the hypothalamus and/or pituitary gland, and infiltrative lesions or thickening or enhancement of the pituitary stalk.⁶ Lesions in the hypothalamic-pituitary axis are seen on imaging in approximately 18% of neurosarcoidosis, though symptoms from these lesions are less common.³

A review including 42 patients with hypothalamo-pituitary sarcoidosis identified high-dose glucocorticoid therapy to achieve induction in more than 90% of cases, with subsequent steroid-sparing immunomodulatory therapy in 57% of patients.⁵ The most common steroid-sparing therapies reported were methotrexate and mycophenolate mofetil.⁵ A large retrospective study assessing the outcomes of 234 patients with neurosarcoidosis on various immunomodulatory therapies identified hydroxychloroquine, cyclophosphamide and infliximab to be associated with the lowest HRs for relapse of any kind and neurological relapse, whereas azathioprine was associated with the highest HR for relapse.¹² Infection was a significant side effect of corticosteroid therapy, and was seen in 7% of patients.¹²

Regression of central nervous system lesions with steroid treatment is commonly reported, with improvement or resolution in greater than 50% of cases, though hormonal recovery was seen in only 10%–20%.^{5 6 8} In fact, progressive pituitary dysfunction was more common than recovery, and seen in 21%–55% of patients.^{6 8} Mortality was described in approximately 10% of cases of hypothalamo-pituitary neurosarcoidosis.⁵

Learning points.

• Sarcoidosis has many presentations: consider sarcoidosis on the differential in new presentations of hypopituitarism, or when infiltrative lesions of the infundibulum/hypothalamus/pituitary gland are identified.

• Hypothalamo-pituitary complex involvement should be considered in patients with a diagnosis of neurosarcoidosis, given its prevalence of up to 18%, even if lesions are not clearly identified on preliminary imaging.

• Hypopituitarism often persists or progresses despite regression of lesions involving the hypothalamus/infundibulum/pituitary gland on imaging after immunomodulatory therapy.

• Attempt steroid-sparing therapy in symptomatic patients who relapse on reduced doses of steroids; the complications of steroid use are significant and can be disabling.