Cluster-like headache and a cystic hypothalamic tumour as first presentation of sarcoidosis

Introduction

Sarcoidosis is a granulomatous, multisystem inflammatory disease of unknown cause. The prevalence is low, estimated at about 10–50 per 100,000. The disease is spread worldwide, affecting all races and ethnicities, being most common in North-European Caucasians and Afro-Americans of West-African descent (1–3). The pathogenesis is ill-understood, yet is thought to be a complex interaction between genetic predisposition, environmental exposure and certain infectious agents (2). The pathological hallmark of sarcoidosis is the presence of non-caseating granulomas on histology, consisting of clusters of centrally organised epitheloid histiocytes and macrophages, outlined by lymphocytes (1,2). Sarcoidosis is often diagnosed in adults in their third and fourth decade (1,2). It is estimated that 5–15% of sarcoidosis patients have clinical involvement of the nervous system, but post-mortem studies suggest that neurosarcoidosis is diagnosed in only half of the patients during life (2). Neurosarcoidosis often presents early in the course of disease with a large variety of symptoms and signs (4–6). Common symptoms are visual loss, facial nerve palsy and headache. Cranial neuropathy (up to 75%), parenchymal brain lesions (50%) and leptomeningeal involvement (10–20%) are the most common findings on neurological and radiological examination (1,5,6). In this report we describe a new clinical presentation of sarcoidosis with a probably related extraordinary cystic lesion.

Case report

A 31-year-old man was referred to the neurologist because of severe headaches. A diffuse headache had started gradually 2 months before. After 2 weeks this headache was accompanied by attacks of severe headache, starting at night, and lasting for about an hour. These attacks were concentrated around and behind the right eye and temple, and started with tearing of the right eye and drooping of the right eyelid. There was no conjunctival injection or rhinorrhoea and no photo- or phonophobia. These attacks occurred up to three times a night, without a distinct diurnal pattern. The patient described these attacks as ‘the worst pain ever experienced’. The attacks usually ended with nausea and eventually vomiting. Sumatriptan prescribed by his general practitioner lessened the pain only moderately, for about 15 minutes. During these attacks, the patient felt restless, could not lay down quiet or sit still. Posture was of no influence on the intensity. The patient had no history of headache and medical history was further unremarkable. He did not smoke and alcohol consumption was occasional. Family history was negative for headache. At first visit to the neurologist, the headache, including the attacks, had disappeared for 3 days. Blood pressure, neurological examination and ophthalmoscopy were normal. Cluster headache was considered, and MRI-brain was performed. The MRI-scan revealed a multicystic, contrast enhancing lesion in the right hypothalamus (Figure 1), accompanied by oedema and some enlargement of the lateral ventricles. MRI findings were further unremarkable. Histological examination from a stereotactic biopsy revealed a non-caseating, granulomatous process concordant with sarcoidosis, as shown in Figure 2. Polymerase chain reaction tests (PCR) for Mycobacterium were negative. OPEN IN VIEWER

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Figure 2.

Two slices of the pathohistological sample, showing the typical distribution of a non-caseating epitheloid granuloma, within the normal brain tissue. The centre is filled with pale-nucleate histiocytes, whereas the granuloma is outlined by lymphocytes with a clear-purple round nucleus. There are no signs of atypia or malignant degeneration.

Serum ACE level was increased (118 U/l; normal: 8–52 U/l), and serum-lysozyme was normal. Serum ANCA-tests and serum β-HCG were both negative. ¹⁸F-FDG positron electron tomography (PET) showed increased metabolism in the cerebral lesion and in lymph nodes of mediastinum and both lung hili. A diagnosis of sarcoidosis was made and treatment was started with prednisone at a low dose of 20 mg once daily. Lumbar puncture was not performed, as these findings were considered sufficient for the diagnosis of sarcoidosis. The patient had had no headache or headache attacks since his first visit to the neurology department.

On follow-up at 2 months and 7 months MRI showed gradual regression of the lesion. Because of serious weight gain and behavioural changes, the dosage of prednisone was continued at this low dose and gradually tapered off.

Discussion

In this case report the patient presented with a diffuse headache, after a few weeks accompanied by severe headache attacks at night. These attacks were described as severe unilateral pain in the trigeminal nerve area, lasting for about an hour and accompanied by autonomic features like ptosis and lacrimation and by restlessness. These symptoms are characteristic for cluster headache. MRI of the brain showed a multicystic tumorous lesion in the right hypothalamus, at the side of the headache attacks.

The pathophysiology of cluster headache and other trigemino-autonomic cephalalgias (TACs) has not yet been elucidated. The pain afferents from the ocular branch of the trigeminal nerve might stimulate by a reflex mechanism the superior salivatory nucleus (SSN) in the brainstem, leading to unilateral lacrimation through the parasympathetic branches of the facial nerve. It is also hypothesised that the SSN is directly stimulated by the hypothalamus. The hypothalamus is probably also the origin of the signs of unilateral sympathetic dysfunction like ptosis and miosis (7). The hypothalamus seems to play a central role in the complex regulatory system of TACs, although its role as the primary causative agent in these headaches is still disputed (7–10).

We hypothesise that our patient had cluster headache induced by the hypothalamic neurosarcoidosis lesion. Although parenchymal brain lesions can occur in any region of the cerebrum and cerebellum, neurosarcoidosis has a preference (up to 15%) for the base of the brain, in particular the hypothalamic and pituitary region causing endocrinological problems (1). The concept of a structural lesion causing TACs has been investigated previously. A 2007 database research review (11) found 31 case reports of patients with TACs and a structural lesion. Tumours in that review were mostly adenomas located in the pituitary gland. Other structural lesions were meningiomas, aneurysms of the right or left carotid arteries, arteriovenous malformations and two separated cases of a gangliocytoma and a nasopharynx carcinoma respectively (12,13). To our knowledge, lesions solely confined to the hypothalamus associated with TACs and cluster-like headaches have not been reported so far, even though lesions originating in its vicinity and compressing the hypothalamus, or other structures of the above described regulatory system, the so-called pain matrix (9,10), have been described (11,14). We cannot rule out that the finding of neurosarcoidosis in the hypothalamus is a coincidental diagnosis. The patient’s headache attacks persisted for about 4 weeks and disappeared completely a few days before the visit to a neurologist, being typical for new-onset idiopathic cluster headache in a 31-year-old man. The initial diffuse headache in our patient may be attributed to the mass lesion and concurrent oedema. Accompanying hydrocephalus of the lateral ventricles by some blockade of either one or both foramina of Monro may also have contributed. The gradual regression of the hypothalamic lesion, the low dose prednisone treatment, but also the natural course of cluster headache may explain why attacks did not recur so far or evolve into a chronic disorder.

A peculiar aspect of the present case was the cystic mass on MRI. Cystic masses in neurosarcoidosis have only been described occasionally and presumably are formed in the same way as in pulmonary cavitary sarcoidosis, i.e. by ischemic necrosis (15,16).

In conclusion, this case report demonstrates the relevance of neuroimaging in new-onset cluster headache (17). The hypothalamus presumably is the central key in the pathogenesis of cluster headache, but a hypothalamic lesion in new-onset cluster headache has not been reported until now. In addition, a cystic contrast enhancing brain tumour may be the first presentation of sarcoidosis.

Clinical implications

Sarcoidosis is a granulomatous multisystem disease with a complex, multivariate aetiology of unknown origin with a wide variety of presenting symptoms.