Hydrocephalus as the first presenting symptom of neurosarcoidosis in two patients: a diagnosis more forthcoming in the context of systemic disease

Abstract

Sarcoidosis is a multisystem disorder, characterised histologically by the presence of non-caseating epithelioid granulomas with exclusion of other granulomatous diseases. While the lungs and lymph nodes are affected in 90%, approximately 5% of patients have neurological involvement. The clinical manifestations of neurosarcoidosis (NS) are diverse, making diagnosis especially difficult in patients without known systemic disease. Hydrocephalus occurs in only 9% of patients with NS and although uncommon, is an important manifestation because it is associated with high morbidity and mortality. We report two cases of NS presenting with hydrocephalus, one as the first presentation of sarcoidosis and one in a patient with known multisystem sarcoidosis. The patient without systemic sarcoidosis posed the greater diagnostic challenge and followed a protracted course with multiple surgical interventions, progression of central nervous system inflammation and significant physical disability.

Background

Sarcoidosis is a multisystem granulomatous disorder of unknown aetiology that affects the lungs in over 90% of cases, but can affect a myriad of extrathoracic sites, such as the skin, eyes, lymph nodes and joints.¹ Neurological manifestations occur in 5%, though only 10%–19% of these have inflammation confined to the nervous system.¹

Any portion of the central or peripheral nervous system can be affected by this disease. The the most common signs of neurosarcoidosis (NS) are cranial neuropathies; around 50% present with unilateral facial nerve palsy,¹ which is often steroid-responsive or self-limiting.² Meanwhile NS can also manifest with optic neuropathy, meningeal infiltration, peripheral neuropathy, encephalopathy and even a myopathy. Communicating or non-communicating hydrocephalus occurs in approximately 9% of patients with NS.¹ Although uncommon, hydrocephalus is an important manifestation because it is associated with high morbidity and mortality.² Of all manifestations of NS, hydrocephalus has the worst long-term prognosis with a mortality rate of 75% and poor relapse free survival.³

The clinical manifestations of NS are diverse, making diagnosis especially difficult in patients without known systemic disease. We report two cases of NS presenting with hydrocephalus to highlight the challenge of diagnosing NS in the absence of a diagnosis of multisystem sarcoidosis, and the importance of prompt diagnosis and treatment to limit long-term disability.

Case 1

A 49-year-old man presented following 3 weeks of frontal headache, vomiting and vertigo. The headache was worst first thing in the morning and exacerbated by lying down and bending over. Neurological examination was normal. This occurred in the context of a recent diagnosis of systemic sarcoidosis. He had presented 9 months previously with exertional dyspnoea and complete heart block; prior to pacemaker insertion a cardiac MRI showed focal thickening and enhancement of the basal septum. There followed a high resolution CT of the chest demonstrating enlarged subcarinal, hilar and paratracheal lymph nodes. Histological confirmation of sarcoidosis had been made with biopsy of subcarinal and hilar nodes at endobronchial ultrasound.

A CT scan of the head revealed obstructive hydrocephalus and he underwent an endoscopic third ventriculostomy. At the time of surgery, the floor of the third and fourth ventricles appeared abnormal. Histological examination of the tissue supported NS. Cerebrospinal fluid (CSF) meanwhile was acellular, with normal protein, glucose and cytology. Serum and CSF levels of ACE were normal.

Outcome and follow-up

Immunotherapy was commenced in the form of prednisolone and azathioprine, and he has made an excellent recovery within 3 months of presentation with hydrocephalus.

Case 2

At age 34 years, our second case presented with headache and visual disturbance. This was attributed to acquired hydrocephalus, though no unifying cause was forthcoming. She was treated with endoscopic third ventriculostomy, resulting in resolution of her symptoms. However, 7 years later, she represented with headache and walking difficulties. Imaging revealed recurrence of her hydrocephalus and a web in the cerebral aqueduct (figure 1A); neurosurgical interventions in the ensuing 3 years would include insertion of a ventriculoperitoneal shunt, two shunt revisions and endoscopic fenestration of the third and fourth ventricles. Her headaches resolved, but over this period her mobility worsened and the dexterity in her hands started to deteriorate. Examination revealed a spastic tetraparesis, a symmetrical ataxia and reduced sensation up to the level of the mid-thighs. Repeat MRI after a more rapid progression, now 11 years after her first presentation, showed T2 hyperintensity in the cervical cord and contrast enhancing tissue in the foramen magnum (figure 1B and C), which would require decompression and laminectomy.

Figure 1.

Neurosarcoidosis (NS) presenting with hydrocephalus (case 2). After representing with headache, vomiting and visual disturbance, 7 years after a third ventricle ventriculostomy, hydrocephalus was demonstrated to have recurred (A). Multiple neurosurgical interventions (see text) were undertaken and while her headache resolved, she developed a progressive tetraparesis. Repeat imaging, now 11 years after her first presentation, demonstrated an area of T2 hyperintensity extending inferiorly from the foramen magnum to the body of C2 (B). Further, post-contrast T1-weighted images highlighted leptomeningeal enhancement (C). This tissue was biopsied and histological examination (D) demonstrated numerous epithelioid granulomas with multinucleated giant cells, in keeping with a diagnosis of NS.

Histological examination of this tissue showed granulomatous change consistent with sarcoidosis (figure 1D). She had no evidence of extraneural inflammation: her history revealed no systemic symptoms, while imaging of her body, a vasculitic screen and a CSF examination were all normal.

Outcome and follow-up

She was commenced on prednisolone and mycophenolate mofetil and achieved 9 months of stability. However, she relapsed 1 year later, necessitating admission for intravenous methylprednisolone. Immunotherapy has been escalated to cyclophosphamide, and while her hand function has normalised, she is still unable to mobilise independently.

Discussion

As the clinical manifestations of NS are so diverse, the diagnosis is especially challenging in those without known systemic disease.¹ Here, we highlight that NS was readily identified in a patient with multisystem involvement (case 1). In case 2, over a decade elapsed between first presentation with hydrocephalus and NS diagnosis. During this period, she developed progressive disability that has been refractory to first-line immunotherapy.

In the rare instances of isolated NS, the diagnosis is infrequently considered unless imaging is suggestive; it is often not made until neural biopsy. Histological confirmation of granulomatous disease at an accessible extraneural site can support diagnosis of ‘probable NS’ without the need for central nervous system (CNS) biopsy and is generally preferable where possible.¹ However, in patients with isolated NS, as the CSF and MRI features are non-specific, biopsy is necessary for definitive diagnosis.¹

Efforts should be made to diagnose NS promptly and with a high degree of certainty because swift immunotherapy may be necessary to prevent irreversible neuronal damage. There are no guidelines for management of NS, but corticosteroids are widely accepted as first-line and methotrexate, hydroxychloroquine, leflunomide and infliximab should be considered.

We identified a small number of case reports where hydrocephalus was the first manifestation of NS, including cases mimicking idiopathic normal pressure hydrocephalus.⁴ In a patient without a diagnosis of sarcoidosis but evidence of bilateral hilar lymphadenopathy on chest X-ray, the initial management of hydrocephalus with insertion of a ventriculoperitoneal shunt (which occurred 2 weeks after symptom onset and then required revision), did not improve symptoms.³ Steroids were then commenced and symptoms resolved in 3 weeks.³ The authors noted that if steroids had been commenced earlier, shunt insertion may not have been necessary.³ This is supported by the outcome seen in case 1. One report described a patient recently diagnosed with pulmonary sarcoidosis who was found to have a contrast enhancing lesion in the cerebral aqueduct causing non-communicating hydrocephalus.⁵ This patient underwent endoscopic third ventriculostomy and NS was confirmed histologically. Symptoms resolved following surgery and no steroids or immunosuppressive agents were commenced. Our case 2 achieved 7 years of remission following endoscopic third ventriculostomy, but omission of steroids and/or immunosuppression during subsequent progression of CNS inflammation is likely to have worsened her prognosis. Finally, the potential for misdiagnosis of tuberculosis has been highlighted, especially in populations where this is endemic.⁶ In all cases, it is important to exclude CNS infection before commencing steroids or immunotherapy.

Learning points.

• Neurological involvement is uncommon in sarcoidosis, occurring in 5% of patients and does present, rarely, in the absence of multisystem disease.

• Hydrocephalus is an important manifestation of neurosarcoidosis (NS) because it is associated with high morbidity and mortality.

• Diagnosis of NS in the absence of multisystem involvement can be a challenge, and as MRI and CSF features are non-specific, a tissue diagnosis should be considered.

• Where possible, diagnosis should be made promptly because delay in treatment with immunotherapy may cause irreversible neuronal damage.