Tractament dels gliomes malignes: estat actual*

Els gliomes malignes (astrocitoma anaplàstic i glioblastoma multiforme)són els tumors dels sistema nerviós més freqüents després dels meningiomes. La seva incidència, l'ocurrència en l'edat mitjana de vida, així com la considerable morbiditat que produeixen fan dels gliomes malignes un problema mèdic i social important. El tractament actual dels gliomes malignes no és, ni de bon tros, óptim. En les dues últimes dècades el seu pronòstic s'ha intentat millorar mitjançant el tractament combinat amb cirurgia, radioteràpia (RT) i quimioteràpia. L'eficàcia dels diferents tractaments ha estat avaluada en treballs clínics randomitzats i ben dissenyats...

Antibody-Mediated Encephalitis

Antibody-mediated encephalitides constitute a group of inflammatory brain diseases that are characterized by prominent neuropsychiatric symptoms and are associated with antibodies against neuronal cell-surface proteins, ion channels, or receptors (Table 1).1 Common clinical features include a change in behavior, psychosis, seizures, memory and cognitive deficits, abnormal movements, dysautonomia, and a decreased level of consciousness. There are, however, no systemic manifestations other than autonomic dysfunction, and this group of diseases is separable from traditional autoimmune disorders such as systemic lupus erythematosus, which may affect the nervous system. Also separate from this group of antibody-mediated encephalitides are several disorders, some of which are paraneoplastic, such as cerebellar degeneration,2 neuromyelitis optica,3 and stiff-person spectrum diseases,4 that are associated with antibodies against neuronal or glial cell-surface antigens but that are rarely associated with the aforementioned symptoms. The antibody-mediated encephalitides occur in person

Macroglobulinemia de Waldenström

La malaltia de Waldenström és una entitat poc freqüent, de la qual hi ha poques sèries, i que es defineix com una neoplàsia limfoproliferativa amb secreció monoclonal de macroglobulines. Ambdós criteris poden matisar-se, encara que les manifestacions clíniques predominants solen referir-se al component secretor, el qual necessàriament ha de pertànyer al grup d'immunoglobulines M, amb exclusió d'altres entitats similars amb components monoclonals d'altra naturalesa..

Carbonic anhydrase-related protein VIII antibodies and paraneoplastic cerebellar degeneration

Paraneoplastic cerebellar degeneration (PCD) is a common cause of subacute cerebellar ataxia caused by widespread loss of the Purkinje cells of the cerebellum. PCD diagnosis can be confirmed by detection of onconeural antibodies that may also indicate the underlying tumour type 1. Most onconeural antibodies associated with PCD recognize intracellular antigens in Purkinje cells 2. These antigens are supposed to induce, besides the antibody synthesis, an antigen‐specific cytotoxic T‐cell attack that probably is responsible of the Purkinje cell death and limited response to treatment 3, 4. The most common onconeural antibody in PCD is the Yo antibody that associates with breast and ovarian cancer 4. In a previous case report, we identified a new antibody, targeting the intracellular Purkinje cell protein carbonic anhydrase‐related protein VIII (CARP VIII), in a patient with PCD and melanoma 5. We provide further evidence for the association of CARP VIII antibodies with PCD by demonstrating a second patient with these antibodies, who had an ovarian adenocarcinoma and developed cerebellar ataxia

The Diagnostic Value of Onconeural Antibodies Depends on How They Are Tested

Detection of onconeural antibodies is important because establishes a definitive diagnosis of paraneoplastic neurological syndrome (PNS). The recommended method for diagnosis of onconeural antibodies is by immunohistochemistry on rodent brain sections and confirmation of results by immunoblot. However, in many diagnostic laboratories samples are only tested with commercial line blots. In this study we inquired whether this change in diagnostic methodology (line blot alone vs. combined immunohistochemistry and line blot) would affect the results. Among 439 samples examined by immunohistochemistry and a commercial line blot (Euroimmun, Lübeck, Germany) 96 (22%) were positive by line blot, and their clinical information was reviewed. Onconeural antibodies were detected by both assays in 46/96 (48%) patients (concordant group) whereas 50 (52%) were only positive by line blot (discordant group). In the concordant group 42/46 (91%) patients had a definite diagnosis of PNS whereas in the discordant group only 4/50 (8%) had PNS (p < 0.00001). None of the 14 patients with ZIC4 antibodies and 1/13 (8%) with Yo antibodies demonstrated only by line blot had PNS. These findings show a robust diagnostic value of combined diagnostic techniques, and both should be used to demonstrate onconeural antibodies, If antibody testing is performed only with line blot assay, positive bands should be confirmed by rodent brain immunohistochemistry. For ZIC4 or Yo antibody testing, line blot positivity with negative immunohistochemistry has no diagnostic significance, and for the rest of onconeural antibodies the predictive diagnostic value is low

Antibody repertoire in paraneoplastic cerebellar degeneration and small cell lung cancer

The goal of this study is to determine whether patients with paraneoplastic cerebellar degeneration (PCD) and small-cell lung cancer (SCLC) have a specific repertoire of antibodies, if SOX1 antibodies (SOX1-ab) can predict the presence of SCLC, and if antibodies to cell surface antigens occur in this syndrome. Antibody analysis was done using immunohistochemistry on rat brain, immunoblot with recombinant antigens, screening of cDNA expression libraries, and immunolabeling of live neurons in 39 patients with PCD and SCLC. VGCC-ab were measured by RIA, and SOX1-ab, Hu-ab, and ZIC4-ab by immunoblot. Lambert-Eaton myastenic syndrome (LEMS) was present in 10 of 23 patients with electrophysiological studies. At least one antibody was detected in 72% of patients. The individual frequencies were: 49% SOX1-ab, 44% VGCC-ab, 31% Hu-ab, and 13% ZIC4-ab. SOX1-ab occurred in 76% of patients with VGCC-ab and 27% of those without VGCC-ab (p = 0.0036). SOX1-ab were not found in 39 patients with sporadic late-onset cerebellar ataxia, 23 with cerebellar ataxia and glutamic acid decarboxylase antibodies, and 73 with PCD and cancer types other than SCLC (31 without onconeural antibodies, 25 with Yo-ab , 17 with Tr-ab). Five patients (13%) had antibodies against unknown neuronal cell surface antigens but none of them improved with immunotherapy. One serum immunoreacted against the axon initial segment of neurons and another serum against ELKS1, a protein highly expressed in the cerebellum that interacts with the beta4-subunit of the VGCC. In conclusion, 72% of patients with PCD and SCLC had one or more antibodies that indicate the presence of this tumor. In these patients, VGCC-ab and SOX1-ab occur tightly associated. SOX1-ab are predictors of SCLC in ataxia patients with a specificity of 100% and sensitivity of 49%. Unlike limbic encephalitis with SCLC, antibodies to cell surface antigens other than VGCC-ab, are infrequent and do not predict response to treatment

Clinical significance of Kelch-like protein 11 antibodies

Objective: To report the clinical and oncologic associations of antibodies against Kelch-like protein 11 (KLHL11-ab), recently suggested as biomarkers of a paraneoplastic brainstem cerebellar syndrome associated with testicular seminoma, and to determine the value of immunohistochemistry as a screening technique. Methods: Studies included 432 sera or CSF from 329 patients with paraneoplastic (157) or autoimmune neurologic syndromes (172); 63 with neurologic symptoms and benign teratomas; 28 with small-cell lung cancer, and 12 healthy subjects. KLHL11-abs were examined using a cell-based assay (CBA) with HEK293 cells transfected with a human KLHL11 clone. The CBA specificity was confirmed by immunoprecipitation. All positive samples were examined by immunohistochemistry on rat brain sections. Results: KLHL11-abs were detected in 32 patients by CBA, and patients' antibodies immunoprecipitated KLHL11. Using rat brain immunohistochemistry, only 7 samples (22%) were positive. Patients' median age was 28 years (range 9-76 years), and 16 (50%) were women. Tumors were identified in 23/32 (72%) patients, including 14 teratomas and 7 seminomas or mixed germ cell tumors. Thirteen (41%) patients had cerebellar ataxia (7) or encephalitis with brainstem cerebellar symptoms (6), 7 (22%) anti-NMDA receptor (NMDAR) encephalitis (5 with ovarian teratoma), 5 (16%) opsoclonus-myoclonus, 3 (9%) limbic encephalitis, and 4 (12%) diverse neurologic symptoms (3 with benign teratomas). Concurrent autoantibodies occurred in 14 (44%) patients (7 anti-NMDAR, 6 Ma2, and 1 Hu). Conclusions: KLHL11-abs associate with a spectrum of syndromes and tumors wider than those previously reported; 44% of patients have concurrent neuronal antibodies, some of them (anti-NMDAR) pathogenically relevant. Brain immunostaining is not useful for routine screening of KLHL11-abs

Limitations of a commercial assay as diagnostic test of autoimmune encephalitis

Detection of neuronal surface antibodies (NSAb) is important for the diagnosis of autoimmune encephalitis (AE). Although most clinical laboratories use a commercial diagnostic kit (Euroimmun, Lübeck, Germany) based on indirect immunofluorescence on transfected cells (IIFA), clinical experience suggests diagnostic limitations. Here, we assessed the performance of the commercial IIFA in serum and CSF samples of patients with suspected AE previously examined by rat brain immunohistochemistry (Cohort A). Of 6213 samples, 404 (6.5%) showed brain immunostaining suggestive of NSAb: 163 (40%) were positive by commercial IIFA and 241 (60%) were negative. When these 241 samples were re-assessed with in-house IIFA, 42 (18%) were positive: 21 (9%) had NSAb against antigens not included in the commercial IIFA and the other 21 (9%) had NSAb against antigens included in the commercial kit (false negative results). False negative results occurred more frequently with CSF (29% vs 10% in serum) and predominantly affected GABABR (39%), LGI1 (17%) and AMPAR (11%) antibodies. Results were reproduced in a separate cohort (B) of 54 AE patients with LGI1, GABABR or AMPAR antibodies in CSF which were missed in 30% by commercial IIFA. Patients with discordant GABABR antibody results (positive in-house but negative commercial IIFA) were less likely to develop full-blown clinical syndrome; no significant clinical differences were noted for the other antibodies. Overall, NSAb testing by commercial IIFA led to false negative results in a substantial number of patients, mainly those affected by anti-LG1, GABABR or AMPAR encephalitis. If these disorders are suspected and commercial IIFA is negative, more comprehensive antibody studies are recommende

The diagnosis of anti-LGI1 encephalitis varies with the type of immunodetection assay and sample examined

Detection of Leucine-rich glioma inactivated 1 (LGI1) antibodies in patients with suspected autoimmune encephalitis is important for diagnostic confirmation and prompt implementation of immunomodulatory treatment. However, the clinical laboratory diagnosis can be challenging. Previous reports have suggested that the type of test and patient's sample (serum or CSF) have different clinical performances, however, there are no studies comparing different diagnostic tests on paired serum/CSF samples of patients with anti-LGI1 encephalitis. Here, we assessed the clinical performance of a commercial and an in house indirect immunofluorescent cell based assays (IIF-CBA) using paired serum/CSF of 70 patients with suspected anti-LGI1 encephalitis and positive rat brain indirect immunohistochemistry (IIHC). We found that all (100%) patients had CSF antibodies when the in house IIF-CBA was used, but only 88 (83%) were positive if the commercial test was used. In contrast, sera positivity rate was higher with the commercial test (94%) than with the in house assay (86%). If both serum and CSF were examined with the commercial IIFA-CBA, 69/70 (98.5%) patients were positive in at least one of the samples. These findings are clinically important for centers in which rat brain IIHC and in house IIFA-CBA are not available. Moreover, the observation that all patients with anti-LGI1 encephalitis have antibodies in CSF is in line with the concept that these antibodies are pathogenic.Copyright © 2022 Muñoz-Sánchez, Planagumà, Naranjo, Couso, Sabater, Guasp, Martínez-Hernández, Graus, Dalmau and Ruiz-García

Pregnancy outcomes in anti-NMDA receptor encephalitis: Case series

To report the effects of anti-NMDA receptor (NMDAR) encephalitis in pregnant patients and their babies.We studied a retrospective cohort of patients who developed anti-NMDAR encephalitis during pregnancy or became pregnant while recovering from the encephalitis. In addition, we reviewed the English literature between 2010 and 2019 related to this topic.We studied 11 patients; 6 developed anti-NMDAR encephalitis during pregnancy, and 5 became pregnant while recovering. There were no obstetrical complications, but 6 (55%) babies were premature. Ten newborns were healthy, and 1 (9%) developed transient respiratory distress. Nine infants had assessable follow-up (median 18 months; range, 7-96 months), and all showed normal development. We identified 21 cases in the English literature. Obstetrical complications occurred in 7 (33%) pregnancies. Two patients died of septic shock (1 baby successfully delivered), another 2 had miscarriages, and in 2, the pregnancy was terminated. Sixteen babies (76%) were delivered, 9 (56%) premature. At birth, 13/16 (81%) newborns were healthy, 2/16 (13%) had transient neurologic or respiratory symptoms, and 1 (6%) died of brain edema. Follow-up (median 12 months; range, 6-36 months) was reported for 8 children: 7 (88%) showed normal development and behavior, and 1 (13%) cortical dysplasia. Immunotherapy was used during pregnancy in 7 (64%) of our patients and 18 (86%) of the reported cases, including rituximab in 4 cases, without adverse effects.Patients who develop anti-NMDAR encephalitis during pregnancy or become pregnant during recovery often have obstetrical complications, but most of the newborns are healthy and appear to have normal development.Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology