A 57-year-old man first presented to our hospital in 2014 due to progressive hearing and visual loss over the previous 3 years. Except for a history of recurrent anterior uveitis of both eyes and secondary glaucoma on the left, his past medical history was unremarkable. On examination, vision on the right eye was intact but on the left eye he could only distinguish light and darkness. Hearing was impaired on both sides (left>right). The remaining neurological exam was normal and he denied having any headache or nausea.
Brain MRI showed retroclival and tentorial pachymeningeal gadolinium enhancement as well as enhanced cranial nerves V, VII, and VIII. There were no further imaging signs of intracranial hypotension, such as venous engorgement or subdural collection. CSF analysis revealed a marked lymphocytic pleocytosis (844 cells/microL; ref. <5/microL) and increased lactate (34.4 mg/dL; ref. <22 mg/dL). Blood-brain barrier permeability was disturbed as evidenced by an elevated CSF protein (1485 mg/L; ref. 150-450 mg/L) and albumin quotient (QAlb = 21.4; ref. <4.07 based on QAlb = (4+age)/15). Reiber diagrams revealed an intrathecal IgG and IgA synthesis (15% and 39%, respectively). Soluble interleukin-2 receptor was elevated in CSF (287 IU/mL; ref. <50 IU/mL).
Extensive rheumatologic studies, including ANA screening, rheumatoid factor, antineutrophil cytoplasmic antibodies and HLA-B27 genotyping, remained negative. Serum immunoglobulin G subclasses 1-4, CD4/8 ratio in blood and CSF, serum angiotensin converting enzyme and serum soluble interleukin-2 receptor were normal. M. tuberculosis CSF PCR and interferon-gamma release assay of peripheral blood were negative.
Thoracic and abdominal-pelvic CT scan was normal. Dural biopsy obtained from right parietal burr-hole surgery showed typical dense connective tissue with low density of cells. There were no signs of inflammation, no granulomas, or signs of vasculitis and M. tuberculosis PCR from biopsy was negative. As known causes of HP could not be identified at this timepoint, a diagnosis of iHP was made.
Treatment was initiated with a pulsed intravenous methylprednisolone followed by oral prednisolone and oral methotrexate (up to 20 mg/week). Methotrexate had to be interrupted due to severe lymphocytopenia. Oral prednisolone was maintained throughout the years (2-20 mg/d). Despite treatment with various further immunosuppressants (for synopsis, see Fig. 1), symptoms slowly worsened over the years and inflammatory markers remained elevated.
In 2020, he was blind in the left eye and visual acuity was 0.4 in the right one. He had received a cochlea implant left in 2017 and audiogram revealed a severe sensorineural hearing impairment in the right ear. No further neurological signs were present. Furthermore, he was depressed and expressed suicidal thoughts due to loss of autonomy. His partner noted he was increasingly suspicious of strangers.
After informed consent, an Ommaya reservoir was implanted and treatment with 40 mg cytarabine, 15 mg methotrexate and 4 mg dexamethasone initiated and instilled 4 times over 2 weeks. At the fifth and last treatment session, dexamethasone was left out due to suspected corticosteroid-induced psychosis.
During the course of intrathecal treatment, CSF cell count and lactate levels decreased (Fig. 2a). Furthermore, an 18-plex immunoassay of CSF detected several cytokines before treatment (IL-6, IL-10, IL-17A, IL-27, TNF-alpha, GM-CSF) that were not present in CSF of 3 control patients with neurodegenerative diseases (Fig. 2c). After treatment, CSF levels of the pro-inflammatory, profibrotic cytokines IL-6 and IL-10 decreased. In addition, follow-up cerebral MRI 3 months after intraventricular chemotherapy showed reduced meningeal enhancement (Fig. 2b), as far as comparable due to artifacts after cochlear implantation in the posttreatment images. At a follow-up visit 3 months after treatment interruption, audiogram revealed an unchanged hearing impairment. Visual impairment at clinical examination also remained static.
Over the first weeks of intraventricular treatment, the patient developed psychotic symptoms (hallucinations, delusion, fear), necessitating medication with haloperidol and risperidone as well as a 2-day stay in a closed psychiatric ward. Corticosteroid-induced psychosis was suspected and intrathecal treatment consecutively discontinued. Ommaya reservoir infection was excluded through negative CSF cultures and viral/bacterial PCRs. There were no signs of toxic encephalopathy on cerebral MRI. At last follow-up - 4 months after the last treatment session - psychiatric symptoms had regressed to the initial (pretreatment) status.
Six months after the last intrathecal chemotherapy, the patient died of a large embolic stroke. Cerebral autopsy revealed pronounced chronic inflammatory changes around the brainstem and basal leptomeninges as well as prominent fibrotic changes of the residual tissue and distinct meningeal proliferation. Inflammatory changes included granulomatous formations without necrosis and mixed infiltrations with clusters of lymphocytes, plasma cells, macrophages and eosinophilic granulocytes, typical of sarcoidosis (Fig. 3). Based on the postmortem histopathological findings, a final diagnosis of neurosarcoidosis with secondary HP was made. The remainder of the body was not examined for systemic sarcoidosis, as the patient's life partner (and appointed representative by the patient) only consented for cerebral autopsy.