Incidental neuronal intermediate filament inclusion pathology: unexpected biopsy findings in a 37‐year‐old woman with epilepsy
We present unexpected neuropathological findings in a 37‐year‐old woman who underwent surgery for removal of an epidermoid cyst. A first brain MRI at the age of 27 years (due to hyperprolactinaemia) showed a cystic lesion in the right prepontine region involving the cisterna ambiens with supratentorial extension. The lesion remained stable until she was 32 years, when it increased in size causing partial compression of the parahippocampal gyrus, midbrain peduncle and lateral pons (Figure 1). One year later, the patient started to present weekly seizures in the form of partial focal complex seizures. At that point, she had neither cognitive decline nor behavioural alterations, and she was independent for all daily activities. No family history of neurological or psychiatric disorders was known. She worked as a Catalan language teacher and no language problems were detected.
As her seizures turned refractory to treatment, she underwent surgical resection of the cyst at the age of 37, after obtaining written informed consent for surgery and for the use of tissue for research purposes, and ethical approval by the local ethics committee. By that time, mild cognitive impairment with mild memory alteration due to attention/recovery deficits in the visual sphere was detected on neuropsychological examination, and was likely attributed to the compression of the temporal pole by the lesion. During the resection of the cyst, the right temporal pole was removed in order to have appropriate access to the supratentorial portion of the cyst.
Histological examination confirmed the existence of an epidermoid cyst. The sample corresponding to the temporal lobe resection showed cerebral cortex with underlying white matter. There was mild superficial and subpial gliosis. At higher magnification many neurons harboured well‐delineated cytoplasmic inclusions in the form of eosinophilic fibrillar structures embedded in a clear halo, consistent with a ‘hyaline conglomerate’ type of inclusion (Figure 2B,C). There were also few basophilic inclusions and few of the ‘cherry spot’ type (Figure 2C, lower panel). Inclusions were strongly immunoreactive for neurofilaments [Dako, Glostrup, Denmark; mc, clone 2F11 which reacts against the 70 kDa (light) subunit of neurofilaments] (Figure 2F) and alpha‐internexin (Invitrogen, Carlsbad, CA, USA; mc, clone 2E3) (Figure 2D,E), but were negative for anti‐FUS antibodies (Sigma‐Aldrich HPA008784, St. Louis, MO, USA; and LifeSpan Biosciences, Seattle, WA, USA), transportin (Abcam, Cambridge, UK, clone D45) and TAF15 (TAFII68, Bethyl Laboratories Inc., Montgomery, TX, USA) (Figure 2G–I). They were variably and only faintly stained by anti‐ubiquitin (DAKO; pc) and anti‐p62 antibodies (BD Transduction Laboratories TM, NJ, USA; mc, clone 3/p62 lck ligand). There were no abnormal pTau (Thermo Scientific, Rockford, IL, USA; mc, clone AT8), TPD43 (Abnova, Taipei, Taiwan; mc, clone 2E2‐D3), Abeta (DAKO, mc, clone 6F/3D) or alpha‐synuclein (Novocastra, Newcastle, UK; mc, clone KM51) deposits. These features were consistent with those described in neuronal intermediate filament inclusion disease (NIFID).
NIFID is currently considered a clinicopathological entity among frontotemporal lobar degeneration (FTD) 1 associated with accumulations of neuronal intermediate filaments 2 and FET proteins (FUS, Ewing's sarcoma and TAF15) 4. Unfortunately, in our case, FUS and TAF15 remained negative, which could be in part explained by different protocols used for biopsy and post mortem brain fixation. However, a regular nuclear staining was observed using anti‐FUS antibodies. In 2014, Wong et al. 7 identified a novel heterozygous missense mutation in the PRKAR1B gene encoding the protein kinase A type I‐beta regulatory subunit in a family with FUS‐negative, alpha‐internexin‐positive neuronal inclusions. Sequencing of this gene in our patient disclosed no relevant mutations, but also a synonymous variant and three intronic variants, as described by Wong et al. in their article: intron 7, c.709‐16A>C [rs9330368, minor allele frequency (MAF) = 0.