Probable neurosarcoidosis presenting as acute on chronic otorrhoea: a difficult diagnosis

Abstract

An elderly African American woman presented to our clinic following 9 months of right-sided unilateral headache, otorrhoea and progressive hearing loss. Despite treatment with topical and oral antibiotics, her clinical condition worsened, and imaging showed mastoid coalescence with an associated subgaleal abscess. She underwent right mastoidectomy and was discharged 3 days later on broad-spectrum intravenous antibiotics despite negative operative cultures. Six weeks later, she was hospitalised with diplopia secondary to a right lateral rectus palsy. Imaging showed abscess resolution but progressive bony remodelling and enhancement of the lateral extending into anterior skull base. Chest CT demonstrated upper lobe predominant pulmonary micronodules, and mastoid biopsy on revision surgery was notable for non-caseating granulomas. Further extensive work-up could not identify an alternative cause, and a presumptive diagnosis of neurosarcoidosis was made. The patient was initiated on intravenous steroids, experienced symptomatic improvement and was thereafter transitioned to oral steroid taper on discharge.

Background

Sarcoidosis is an elusive disease of unknown cause characterised by granulomatous inflammation in affected organ systems; 90% of patients have pulmonary involvement at the time of diagnosis.¹ Patients who suffer from sarcoidosis frequently experience significant delays in diagnosis due the heterogenous clinical presentation and low sensitivity of ancillary investigations.² Definitive diagnosis is only achieved on discovery of non-caseating granulomas on neural biopsy; as such, the majority of patients are diagnosed with either ‘possible’ or ‘probable’ neurosarcoidosis according to the Zajicek criteria.³ Our patient case serves as an important teaching point for clinicians to always consider sarcoidosis when faced with otherwise common conditions that are prolonged and intractable to standard treatment.

Case presentation

An elderly African American woman presented to our outpatient otolaryngology clinic in February 2020 following 9 months of right-sided unilateral headache, otorrhoea and progressive hearing loss without significant vestibular symptoms. Prior to this, she was being seen at an outside location and had received prolonged courses of oral antibiotics, after which a diagnosis of chronic otomastoiditis was given. The patient had undergone CT and MRI of the brain days prior to presentation at our clinic; these images revealed complete opacification of the ipsilateral mastoid air cell system as well as complete opacification of the well-pneumatised petrous apex. Otomicroscopic exam demonstrated an intact tympanic membrane and a large amount of granulation tissue within the right external auditory canal, for which topical ciprofloxacin/dexamethasone ear drops were prescribed.

At her follow-up visit 2 weeks later, the patient endorsed progressive right otalgia, aural fullness and otorrhoea. In the context of previous imaging findings, the patient was hospitalised directly from clinic due to concern for possible petrous apicitis. Repeat imaging demonstrated coalescent mastoiditis with a subgaleal abscess (figure 1) and pachymeningeal enhancement in the ipsilateral cerebral hemisphere (figure 2). The patient was taken to the operating room for intact canal wall mastoidectomy, myringotomy with tympanostomy tube insertion and drainage of the subgaleal abscess. Her postoperative course was unremarkable, although all intraoperative cultures were negative. She was discharged 3 days later following placement of a peripherally inserted central catheter and initiation of daily intravenous vancomycin and cefepime. She noted improved otalgia at her postoperative follow-up visit.

Figure 1.

(A–D) Contrast-enhanced, axial plane, CT demonstrating coalescent mastoiditis with medial and lateral mastoid plate erosion (A–C) and associated subgaleal abscess (D).

Figure 2.

(A) Contrast-enhanced T1 fat saturated axial plane MRI demonstrating subperiosteal abscess. (B) Contrast-enhanced T1 fat saturated coronal plane MRI demonstrating ipsilateral cerebral hemisphere dural enhancement.

Six weeks following her initial hospitalisation, the patient presented to our emergency department in April 2020 with 1 day of diplopia. On examination, she was found to have a mild right abducens nerve (CN VI) palsy. Sensory, motor, coordination and gait examination were otherwise normal. The patient was admitted to the hospitalist service and maintained on her existing regimen of intravenous antibiotics. Repeat in-depth imaging was obtained and is reviewed below.

Investigations

Brain MRI with gadolinium obtained during the patient’s initial hospitalisation in March 2020 demonstrated diffuse pachymeningeal enhancement in the right cerebral hemisphere. CT of the temporal bones demonstrated coalescent mastoiditis with destruction of the inner sigmoid plate and an associated subgaleal abscess. Cultures of right ear drainage obtained both in clinic preoperatively as well as intraoperatively at time of index surgery were negative for any growth whatsoever. Though pathology from the index surgery revealed non-specific inflammatory changes and patchy expression of S100 and CD1A, it was otherwise negative for significant IgG4 expression, BRAF gene mutation and vasculitic evidence. Serum antineutrophil cytoplasmic antibody (ANCA) levels were less than 1:40. Following hospital discharge in March 2020, fluorescent-treponemal antibody-absorption (FTA-ABS) test was found to be negative, and serum ACE levels were measured at 28 U/L (normal, 12–68 U/L).

On her presentation to the emergency department in April 2020, CT of the temporal bone revealed resolution of the abscess and expected petromastoid postoperative changes. MRI of the brain/temporal bone revealed new and progressive enhancement of the ipsilateral cavernous sinus, the ipsilateral jugular tubercle and the clivus with extension across the midline to the left side of the anterior skull base (figure 3). In addition, CT demonstrated enhancing soft tissue involving Dorello’s canal, through which CN VI runs. Given these progressive findings, there was radiological concern for granulomatous disease. Following admission to the hospitalist service, the infectious disease consultants recommended CT of the chest to evaluate for tuberculosis. This demonstrated numerous upper lobe predominant pulmonary micronodules in a random distribution and a dominant 1.5 cm subsolid right lower lobe nodule.

Figure 3.

Contrast-enhanced T1 fat saturated axial plane MRI demonstrating progression of enhancement from the lateral skull base to the anterior skull base (clivus) and extending across the midline to the contralateral side.

Cerebrospinal fluid (CSF) analysis showed clear fluid appearance with protein of 41 mg/dL, glucose of 63 mg/dL, white blood cell count of 1 cell/µL (66% lymphocytes and 8% neutrophils) and no malignant cells or oligoclonal bands. QuantiFERON-TB Gold (QFT) was negative, urine fungal antigens were negative and blood cultures did not result in growth of fungal or mycobacterial species. Serum myeloperoxidase and proteinase-3 antibodies were not detected.

The patient was taken back to the operating room on hospital day 6 for revision mastoidectomy, clival biopsy and biopsy of the nasal septum. All cultures were again negative. Tissue stains and molecular studies were non-specific but largely ruled out granulomatosis with polyangiitis (GPA, Wegener’s granulomatosis) and Langerhans cell histiocytosis (LCH). Finally, bronchoalveolar lavage and trans-bronchial biopsy performed on hospital day 10 were non-specific. Mastoid pathology was most significant for non-caseating granulomas, after which a diagnosis of neurosarcoidosis was made (figure 4).

Figure 4.

(A) Revision mastoidectomy biopsy. Mixed predominantly chronic inflammatory infiltrate composed of lymphocytes, histiocytes, few neutrophils and multinucleated giant cells. Note non-necrotising granulomas. H&E stain, ×100. (B) Revision mastoidectomy biopsy. Non-necrotising granuloma composed of epithelioid histiocytes and multinucleated giant cells. H&E stain, ×400.

Differential diagnosis

The patient’s clinical picture on initial presentation, including subjective history of chronic otorrhoea and evidence of opacification of the mastoid and middle ear cells on CT and MRI, was most consistent with chronic suppurative otitis media. However, despite initial improvement following appropriate surgery and prolonged course of antibiotics, her cranial nerve palsy and progressive skull base remodelling in association with pulmonary lesions on chest CT prompted evaluation for alternative diagnoses. The differential diagnosis for granulomatous conditions causing otorrhoea, pachymeningitis and pulmonary nodules includes various infectious, neoplastic and autoimmune aetiologies which are reviewed below.^{4 5}

Chronic middle ear infections secondary to Mycobacterium tuberculosis may manifest as clear, odourless otorrhoea and hearing loss. However, cultures of tissue samples obtained intraoperatively were negative for growth of acid-fast bacilli, and QFT was negative, suggesting against the diagnosis of tuberculosis.⁶ Otosyphilis, or inner ear infection by Treponema pallidum, represents a potential cause of hearing loss, but our patient lacked the classic stigmata to suggest late-stage syphilis, and FTA-ABS testing was negative.⁶ Though fungi may rarely cause infections of the middle ear, tissue stains and cultures of right ear drainage were negative for fungal growth.⁶

Neoplastic conditions such as lymphoma or leptomeningeal carcinomatosis may rarely involve the middle ear and mastoid, manifesting as otorrhoea and hearing loss. However, these conditions would be expected to present with multiple neurological deficits due to mass effect or other symptoms of malignancy such as fever and weight loss.⁷ LCH may result in granulomatous changes within the middle ear, manifesting as otorrhoea and conductive hearing loss due to soft tissue infiltration. Nonetheless, LCH predominantly presents in children and young adults; moreover, histological and imaging findings were not consistent with the classic presentation of LCH.⁸

GPA is a small-vessel vasculitis known to cause concurrent pachymeningitis, otorrhoea and hearing loss.⁹ Our patient, however, did not exhibit elevated serum ANCA levels or necrotising granulomas on biopsy of the middle ear and nasal septum. Previous reports have identified IgG4-related disease as an elusive cause of chronic otorrhoea and aural fullness.¹⁰ However, IgG4 levels were not elevated in tissue biopsy or serum samples, effectively ruling out the diagnosis.¹¹ The diagnosis of sarcoidosis as it applies to our patient is discussed further below.

Treatment

The patient was initially treated with prolonged courses of oral antibiotics including ciprofloxacin and sulfamethoxazole/trimethoprim as well as ototopical medications (ofloxacin and dexamethasone). After her symptoms progressed despite medical therapy, she underwent intact canal wall mastoidectomy with incision and drainage of the subgaleal abscess and myringotomy with tympanostomy tube placement. Following surgery, she was discharged with intravenous vancomycin and cefepime as well as the same ototopical medications for 6 weeks.

Given further radiological progression as outlined above, these medications were maintained on hospital admission but discontinued on hospital day 4 as it was felt she did not have a bacterial infection. She then underwent revision mastoidectomy and after her microbiological studies and laboratory findings ruled out tuberculosis, she was treated with high-dose intravenous corticosteroids and placed on a prolonged steroid taper on discharge.

Outcome and follow-up

The patient was last seen approximately 2.5 months after her index surgery. She endorsed complete resolution of her otorrhoea, otalgia and headache; however, she described only mild improvement in the right-sided lateral rectus palsy. Otomicroscopic exam revealed a patent tympanostomy tube and no signs of infection. She is undergoing a prolonged corticosteroid taper per the consulting rheumatologists.

Discussion

Sarcoidosis may affect the central nervous system in 5%–15% of affected patients; however, few cases have reported direct involvement of the mastoid and middle ear as the initial manifestation of the disease.^{12 13} Neurosarcoidosis most often presents as cranial neuropathy or headache, both of which were seen in our patient at a later point in her disease course.² MRI abnormalities are common, and dural involvement is reported in up to 34% of patients.¹⁴ Though elevated serum ACE levels are often included as part of the initial diagnostic work-up, prior literature has demonstrated a sensitivity of only 41.4% and false-positive rate of 10%, suggesting a limited role in clinical practice.¹⁵ Similarly, CSF analysis may demonstrate pleocytosis and elevated oligoclonal immunoglobulin bands; however, these findings are found in only 58% and 63% of patients, respectively.^{2 14} As such, our patient’s normal serum ACE level and unremarkable CSF analysis do not independently suggest against the diagnosis of neurosarcoidosis.

The clinical features of this case demonstrate the particular challenge associated with establishing a diagnosis of neurosarcoidosis, as demonstrated in the most recent consensus diagnostic criteria.¹⁶ ‘Definite’ neurosarcoidosis requires demonstration of non-caseating granulomas on neural biopsy; as such our patient would be defined as a case of probable neurosarcoidosis given her suggestive clinical presentation, pathological granuloma confirmation and imaging findings. The same authors state that patients with probable neurosarcoidosis can safely be considered to have the disease and be treated as such, as occurred with our patient.¹⁶

Corticosteroids remain the gold standard for treatment of sarcoidosis. Most patients tend to achieve remission or stable disease on initiation of steroids; thus, minimising delays in diagnosis is essential for achieving an optimal outcome.² Our case highlights the importance of keeping sarcoidosis on the differential for a patient with a common clinical presentation refractory to standard treatment or unexplained symptoms in multiple organ systems.

Patient’s perspective.

1. What would you say was the most painful part of this process?

How you felt before the first surgery? How you felt after the first surgery? How you felt before the second surgery? How you felt after the second surgery? “Before the first surgery was the most painful. I had constant pounding pain in the right side of the head that would not go away. Despite this, the drainage from the right ear was the inciting event that made me go to the doctor. The pain was markedly improved after the first surgery, but it did start to come back prior to Dr Matsuoka opening up the incision at follow-up.”

2. Would you say that your occupation prior to retirement (registered nurse) had any effect on your ability to cope with and/or understand the disease process and treatment choices?

“It had a lot to do with it, because I was able to understand that there is no quick diagnosis for some things. Medicine is always evolving, and I understood that there are always new things happening or being learned. For that reason, my prior occupation helped tremendously. Knowing what I know as a former nurse also helps me realize that my medical issue is not yet over, but I am prepared for that.”

3. Distracting activities: You had to be in the hospital without any visitors and a decreased ability to move around because of COVID. What did you do to distract yourself?

Were there particular people you spoke with on the phone most? If so, who were they, and why?“I did not actually think about it very much until getting home, at which point it dawned on me that I had not had visitors the entire time as they were not allowed. I personally was not as bothered by it since I already live alone, but I did feel bad for all of the other patients who were in fact hospitalized with COVID, who may have died without having family be able to see them. Listening to music was helpful and streaming church services was good – this helped maintain continuity with my normal activities outside of the hospital.”

4. Has this process affected you emotionally?

If so, how? Spiritually? If so, how?“If it was not for my faith, I could not have handled it. What I came here for (ear drainage) apparently was not what I was in actuality to be in the hospital for (this turned out to be a hard to understand and diagnosis process). My faith allowed me to be comfortable with what ever happened, and it was a re-affirmation of faith for me.”

5. Since being discharged from the hospital, have your activities of daily living had to change?

If so, how? What modifications have you had to make to them?“The biggest thing is the persistent deficit in the right eye because I cannot walk up and down stairs or walk in a straight line as easy as I used to. I wear the eye patch sometimes but don’t particularly like it. If I do not close the right eye I cannot see well, but I have improved somewhat in that I can now see with the right eye open as long as I tilt my head a certain way. The steroids seem to have made my blood pressure lower and because of my prior nursing career I am able to monitor it better.”

6. Is there any one thing you would like shared with us and the medical community at large that might read this?

“Trust in your doctors, be comfortable with the doctors and any members of the team because this trust makes a big difference. The first impression is the most important interaction because you size them up right then. You have to have the understanding that your doctor is going to listen to you and that you are both on even footing. You don’t have to agree but you do have to listen to one another and take the other’s opinion seriously.”

Learning points.

• The diagnosis of sarcoidosis should always be considered in a patient with a clinical presentation refractory to first-line therapy or unexplained multiorgan systemic disease.

• The differential diagnosis for granulomatous conditions causing pachymeningitis, otorrhoea and pulmonary lesions includes various infectious, neoplastic and autoimmune etiologies.

• Elevated serum ACE testing only carries a 41% sensitivity for the detection of sarcoidosis; therefore, a negative result cannot independently rule out the diagnosis.