Acute anti-Ma2 paraneoplastic encephalitis associated to pembrolizumab: a case report and review of literature

Abstract

Anti-Ma2 encephalitis is a rare neurological disorder with a predominant involvement of brainstem, limbic and diencephalic structures. Although an unspecific encephalopathy is the usual form of presentation, acute-onset neurologic symptoms and other atypical manifestations have been described and account for the challenging diagnosis of this entity. Despite being usually detected as a paraneoplastic syndrome in patients with early-stage tumors or without a previous history of malignancy, a growing concern has arisen from several cases reported in metastatic patients under treatment with immune checkpoint inhibitors. We report what to our knowledge is the first known case of anti-Ma2 encephalitis associated to pembrolizumab and presenting as an acute-onset focal neurological syndrome, consisting on acute global aphasia, right upper limb paresia, hypoacusia, sleep disorder, decreased conscious level and a motor focal status that was refractory to anticonvulsant therapy. A brain MRI scan showed a focal alteration of the cortical-subcortical signal on the left parietal lobe. CSF study found a significant hyperproteinorrhachia and electroencephalography showed lateralized periodic discharges (LPDs), suggestive of a diffuse encephalopathy. A positive result for anti-Ma2 antibodies was obtained both in blood and CSF samples through indirect immune-fluorescence (IFI) and later confirmed by western-blot technique. Our patient obtained a mild response to steroid therapy and a significant improvement after the administration of intravenous immunoglobulins. The hypothesis that checkpoint inhibitors may trigger the expression of previously subclinical paraneoplastic events, through the strengthening of cytotoxic T cells-mediated immune response, is supported by our finding of preexisting anti-Ma2 antibodies in preserved blood samples obtained before the initiation of pembrolizumab in our patient. Further research is needed to reveal if the detection of onconeural antibodies prior to a treatment with checkpoint inhibitors may be used as a predictive biomarker of neurologic immune-related high-grade toxicity.

Keywords: Anti-Ma2; case report; checkpoint inhibitors; encephalitis; paraneoplastic.

Figure 1

Images from brain MRI at diagnosis. Arrows point at a triangular focal alteration of the cortical-subcortical signal that can be observed on the left parietal lobe, associated to a slimming of the cortex and a mild ampliation of the adjacent subarachnoid space, hyperintense in FLAIR (A,B) and T2 (C) sequences, and hypointense in T1 sequence (D). The diffusion-weighted magnetic resonance imaging (DWI) technique shows a cortical restricted diffusion in this same area (E,F). Correlation with apparent diffusion coefficient (ADC) and exponential apparent diffusion coefficient (eADC) maps is shown in (G) and (H) respectively.

Figure 2

Detection of anti-Ma2 antibodies. (A) Indirect immunofluorescence demonstrating presence of anti-Ma2 Abs from the peripheral blood sample of our patient. Anti-Ma2 Abs are shown in cerebellar dentate nucleus Purkinje cells, with a high uptake in the neuronal nucleolus. (Magnification times: 40×/0.75). (B) Western blot analysis revealing a high intensity band corresponding to the anti-Ma2 antibody, with a quantitative value of expression of 95 UA/100.

Figure 3

Chronological timeline. The figure shows the changes in steroid therapy dosage and the most important events of the case. PDN, prednisone; MPS, methylprednisolone; IVIg, intravenous immunoglobulins; Abs, antibodies.