Acute porphyrias - A neurological perspective.

Acute hepatic porphyrias (AHP) can cause severe neurological symptoms involving the central, autonomic, and peripheral nervous system. Due to their relative rarity and their chameleon-like presentation, delayed diagnosis and misdiagnosis are common. AHPs are genetically inherited disorders that result from heme biosynthesis enzyme deficiencies and comprise four forms: acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and ALA-dehydratase porphyria (ALADP). Depending on the clinical presentation, the main differential diagnoses are Guillain-Barré syndrome and autoimmune encephalitis. Red flags that could raise the suspicion of acute porphyria are neurological symptoms starting after severe (abdominal) pain, in association with reddish urine, hyponatremia or photodermatitis, and the presence of encephalopathy and/or axonal neuropathy. We highlight the diagnostic difficulties by presenting three cases from our neurological intensive care unit and give a comprehensive overview about the diagnostic findings in imaging, electrophysiology, and neuropathology.

Midlevel visual deficits after strokes involving area human V4.

We present the results of 51 stroke patients with free central visual fields of which about half suffer from clear deficits of midlevel vision undetected by standard clinical tests. These patients yield significantly elevated thresholds for detection and/or discrimination between forms defined by motion, colour, or line orientation ('texture'). As demonstrated by voxel-based lesion-symptom mapping (VLSM) the underlying lesions involve mainly area human V4 (hV4) located in the posterior third of the fusiform gyrus and extending into the lingual gyrus. Patient's detection thresholds correlate only very weakly between the submodalities tested, indicating partly separate neural networks on mid-level vision for colour, motion, and texture detection. Correlations are far stronger for form discrimination tasks, indicating partly shared mechanisms for even simple form discrimination of distinct visual submodalities. We conclude that deficits of visual perception are far more common after strokes in visual brain areas than is apparent in clinical practice. Our results further clarify the functional organization of midlevel visual cortical areas.

Daratumumab treatment for therapy-refractory anti-CASPR2 encephalitis.

The anti-CD38 antibody daratumumab is approved for treatment of refractory multiple myeloma and acts by depletion of plasma cells and modification of various T-cell functions. Its safety, immunological effects and therapeutic potential was evaluated in a 60-year old patient with life-threatening and treatment-refractory anti-CASPR2 encephalitis requiring medical care and artificial ventilation in an intensive care unit. His autoimmune dysfunction was driven by exceptional high anti-CASPR2 autoantibody titers combined with an abnormally increased T-cell activation. As he remained unresponsive to standard and escalation immunotherapies (methylprednisolone, plasma exchange, immunoadsorption, immunoglobulins, rituximab and bortezomib), therapy was escalated to 13 cycles of 16 mg/kg daratumumab. During the treatment period, clinical, radiological, histological and laboratory findings, including quantification of autoreactive and protective antibody levels and FACS-based immune phenotyping, were analyzed. Daratumumab treatment was associated with significant clinical improvement, substantial reduction of anti-CASPR2 antibody titers, especially in CSF, decrease of immunoglobulin levels and protective vaccine titers, as well as normalization of initially increased T-cell activation markers. However, the patient died of Gram-negative septicemia in a neurorehabilitation center. In conclusion, our findings suggest that daratumumab induces not only depletion of autoreactive long-lived plasma cells associated with improvements of neurological sequelae, but also severe side effects requiring clinical studies investigating efficacy and safety of anti-CD38 therapy in antibody-driven autoimmune encephalitis.

Bortezomib for treatment of therapy-refractory anti-NMDA receptor encephalitis.

OBJECTIVE: We assessed the therapeutic potential of the plasma-cell-depleting proteasome inhibitor bortezomib in severe and therapy-refractory cases of anti-NMDA receptor (anti-NMDAR) encephalitis. METHODS: Five severely affected patients with anti-NMDAR encephalitis with delayed treatment response or resistance to standard immunosuppressive and B-cell-depleting drugs (corticosteroids, IV immunoglobulins, plasma exchange, immunoadsorption, rituximab, cyclophosphamide) who required medical treatment and artificial ventilation on intensive care units were treated with 1-6 cycles of 1.3 mg/m2 bortezomib. Occurrence of adverse events was closely monitored. RESULTS: Bortezomib treatment showed clinical improvement or disease remission, which was accompanied by a partial NMDAR antibody titer decline in 4 of 5 patients. With respect to disease severity, addition of bortezomib to the multimodal immunosuppressive treatment regimen was associated with an acceptable safety profile. CONCLUSIONS: Our study identifies bortezomib as a promising escalation therapy for severe and therapy-refractory anti-NMDAR encephalitis. CLASSIFICATION OF EVIDENCE: This retrospective case series provides Class IV evidence that bortezomib reduces antibody titers and improves the clinical course of patients with severe anti-NMDAR encephalitis.

Adult hemophagocytic lymphohistiocytosis causing multi organ dysfunction in a patient with multiple autoimmune disorders: when the immune system runs amok.

We report a case of several autoimmune disorders eventually presenting as severe multi organ dysfunction syndrome caused by adult hemophagocytic lymphohistiocytosis (HLH). Clinical and laboratory tests might lead to fatal misinterpretation without awareness of its diagnostic evaluation, as HLH shares common features with sepsis and immune-mediated systemic inflammatory response syndromes.

Neurological and neuropsychological characteristics of occipital, occipito-temporal and occipito-parietal infarction.

Neuropsychological deficits after occipital infarction are most often described in case studies and only a small sample of studies has attempted to exactly correlate the anatomical localization of lesions with associated neuropsychological symptoms. The present study investigated a large number of patients (N = 128) in order to provide an overview of neurological and neuropsychological deficits after occipital, occipito-temporal and occipito-parietal infarction. A particular approach of the study was to define exact anatomical correlates of neuropsychological dysfunction by using voxel-based lesion-symptom mapping (VLSM) in 61 patients. In addition to a visual field defect and phosphenes, patients often reported anomia, difficulties in reading and memory deficits. Visual disorders, such as achromatopsia, akinetopsia or prosopagnosia, were rarely reported by the patients. Memory and visual disorders were diagnosed efficiently using simple clinical screening tests, such as the Rey-Osterrieth Complex Figure Test for immediate recall, the Demtect and the Lang Stereo Test. Visual field defects, reading disorders and the perception of phosphenes were associated primarily with lesions of the calcarine sulcus. Anomia and memory deficits were related to lesions of the occipital inferior gyrus, the lingual gyrus and hippocampus, as well as to lesions of principal white matter tracts.

Specificity of fast perceptual learning in shape localisation tasks based on detection versus form discrimination.

Perceptual learning is defined as a long-lasting improvement of perception as a result of experience. Here we examined the role of task on fast perceptual learning for shape localisation either in simple detection or based on form discrimination in different visual submodalities, using identical stimulus position and stimulus types for both tasks. Thresholds for each submodality were identified by four-alternative-forced-choice tasks. Fast perceptual learning occurred for shape detection-based on luminance, motion and color differences but not for texture differences. In contradistinction, fast perceptual learning was not evident in shape localisation based on discrimination. Thresholds of all submodalities were stable across days. Fast perceptual learning seems to differ not only between different visual submodalities, but also across different tasks within the same visual submodality.