PMC7424063_01
Imaging, electroencephalography (EEG) and neuropsychological findings. (A) The magnetic resonance imaging produced unsuspicious findings. (B) An [18F]fluorodeoxyglucose positron emission tomography (FDG PET) examination at baseline revealed no relevant regional metabolic abnormality suggestive of inflammation. Upper row: Transaxial FDG PET images (voxel-wise FDG uptake normalized to whole brain uptake), lower row: 3D surface projections of regions with decreased FDG uptake (colour-coded Z-score, compared to age-matched healthy controls; minor, linear-shaped areas of hypometabolism were judged to be non-specific partial volume effects due to atrophy). The cerebral FDG PET scan was performed as part of the whole-body PET/CT scan 50 min after injection of 340 MBq FDG (Vereos Digital PET/CT, Philips Healthcare, The Netherlands). (C) The routine EEG revealed marginal intermittent, rhythmic, and generalized slowing. (D) The independent component analyses showed sharp spikes in component 4, arc-shaped theta (sometimes delta waves) in component 5, and intermittent rhythmic, generalized delta activity (IRDAs) in component 6. (E) Rate of IRDAs during initial treatment: Under benzodiazepines (EEG 1, 3 and 4) the IRDA activity appeared to be low, after the steroid pulse the IRDA rate increased significantly, during plasma exchange they were reduced again, in the two follow-up EEGs directly after initial treatment and half a year later under rituximab the IRDA activity decreased overall, whereas without valproate the IRDAs were increased again after hyperventilation. EEG 1 was performed with a medication of lorazepam, amisulpride, and olanzapine; EEG 2 with valproate (lamotrigine in low dose) and amisulpride; EEG 3 with clobazam, valproate (lamotrigine in low dose), and amisulpride; EEG 4 with clobazam (low dose), valproate (lamotrigine in low dose), and amisulpride; EEG 5 with valproate (lamotrigine in low dose), amisulpride; after steroid pulse treatment, with still 40 mg methylprednisolone orally; EEG 6 with valproate (reduced), lamotrigine, amisulpride, still 10 mg methylprednisolone and after 4 cycles of plasma exchange; EEG 7 with valproate (low dose), lamotrigine, amisulpride, with still 10 mg methylprednisolone orally; EEG 8 follow up (a half year later) with lamotrigine and amisulpride. (F) Measures of attentional performance during the course of the disease (t2 was performed at six-months follow-up).
fpsyt-11-00627-g001.jpg
PMC7424063_01_fpsyt-11-00627-g001.jpg
f1
The structural brain MRI was normal ( Figure 1 ). The independent component analyses (ICA) revealed sharp waves (component 4) and intermittent rhythmic delta activity (IRDA, component 5 + 6,  Figure 1 ). An FDG PET examination of his brain showed no relevant regional hypermetabolism (suggestive of active inflammation) or hypometabolism (as a possible sequel of inflammation or degeneration) aside from mild relative striatal hypermetabolism, compatible with ongoing neuroleptic medication ( Figure 1 ). Of the three different IRDA components visible before valproate ( Figure 1 ), only one single left frontal component was still visible in the ICA after valproate. A complete neuropsychological testing was possible for the first-time half a year after initiation of immunosuppressive treatment, showing ongoing deficits in alertness and working memory and particularly in divided attention and set shifting ( Figure 1 , t2). The follow-up MRI was unchanged, and CSF autoantibody testing showed reduced titers of the anti-neuronal autoantibody, although still clearly detectable.  Figure 1  illustrates the course of the EEG slowing (IRDAs) under treatment and after a 6-months follow-up period.
The "tissue-based assay" using indirect immunofluorescence screening on unfixed brain sections of rodents identified antibody binding to granule cells in the granule cell layer of the cerebellum (above) and to neurites of hippocampal interneurons (below). Autoantibodies in the cerebrospinal fluid showed a "somatodendritic staining pattern" (arrows point to dendritic processes on hippocampal interneurons in stratum lacunosum moleculare), but also to cell nuclei, reflecting antinuclear antibodies (ANAs). In a control cerebrospinal fluid sample of the hippocampus (downright) there was no comparable signal. The cerebrospinal fluid material was used undiluted. ML, molecular layer; GCL, granule cell layer; WM, white matter.
fpsyt-11-00627-g002.jpg
PMC7424063_01_fpsyt-11-00627-g002.jpg
f2
ANA pattern ( Figure 2 ). A complete neuropsychological testing was possible for the first-time half a year after initiation of immunosuppressive treatment, showing ongoing deficits in alertness and working memory and particularly in divided attention and set shifting ( Figure 1 , t2).