RESUMO
PURPOSE: To assess whether the Modified 5 (mFI-5) and 11 (mFI-11) Factor Frailty Indices associate with postoperative mortality, complications, and functional benefit in supratentorial meningioma patients aged over 80 years. METHODS: Baseline characteristics were collected from eight centers. Based on the patients' preoperative status and comorbidities, frailty was assessed by the mFI-5 and mFI-11. The collected scores were categorized as "robust (mFI=0)", "pre-frail (mFI=1)", "frail (mFI=2)", and "significantly frail (mFI≥3)". Outcome was assessed by the Karnofsky Performance Scale (KPS); functional benefit was defined as improved KPS score. Additionally, we evaluated the patients' functional independence (KPS≥70) after surgery. RESULTS: The study population consisted of 262 patients (median age 83 years) with a median preoperative KPS of 70 (range 20 to 100). The 90-day and 1-year mortality were 9.0% and 13.2%; we recorded surgery-associated complications in 111 (42.4%) patients. At last follow-up within the postoperative first year, 101 (38.5%) patients showed an improved KPS, and 183 (69.8%) either gained or maintained functional independence. "Severely frail" patients were at an increased risk of death at 90 days (OR 16.3 (CI95% 1.7-158.7)) and one year (OR 11.7 (CI95% 1.9-71.7)); nine (42.9%) of severely frail patients died within the first year after surgery. The "severely frail" cohort had increased odds of suffering from surgery-associated complications (OR 3.9 (CI 95%) 1.3-11.3)), but also had a high chance for postoperative functional improvements by KPS≥20 (OR 6.6 (CI95% 1.2-36.2)). CONCLUSION: The mFI-5 and mFI-11 associate with postoperative mortality, complications, and functional benefit. Even though "severely frail" patients had the highest risk morbidity and mortality, they had the highest chance for functional improvement.
Assuntos
Fragilidade , Neoplasias Meníngeas , Meningioma , Complicações Pós-Operatórias , Humanos , Feminino , Masculino , Idoso de 80 Anos ou mais , Fragilidade/mortalidade , Fragilidade/complicações , Complicações Pós-Operatórias/mortalidade , Complicações Pós-Operatórias/epidemiologia , Meningioma/mortalidade , Meningioma/cirurgia , Neoplasias Meníngeas/mortalidade , Neoplasias Meníngeas/cirurgia , Neoplasias Supratentoriais/cirurgia , Neoplasias Supratentoriais/mortalidade , Avaliação de Estado de Karnofsky , Seguimentos , Estudos Retrospectivos , Prognóstico , Idoso FragilizadoRESUMO
PURPOSE: To assess the impact of individual surgeon experience on overall survival (OS), extent of resection (EOR) and surgery-related morbidity in elderly patients with glioblastoma (GBM), we performed a retrospective case-by-case analysis. METHODS: GBM patients aged ≥ 65 years who underwent tumor resection at two academic centers were analyzed. The experience of each neurosurgeon was quantified in three ways: (1) total number of previously performed glioma surgeries (lifetime experience); (2) number of surgeries performed in the previous five years (medium-term experience) and (3) in the last two years (short-term experience). Surgeon experience data was correlated with survival (OS) and surrogate parameters for surgical quality (EOR, morbidity). RESULTS: 198 GBM patients (median age 73.0 years, median preoperative KPS 80, IDH-wildtype status 96.5%) were included. Median OS was 10.0 months (95% CI 8.0-12.0); median EOR was 89.4%. Surgery-related morbidity affected 19.7% patients. No correlations of lifetime surgeon experience with OS (P = .693), EOR (P = .693), and surgery-related morbidity (P = .435) were identified. Adjuvant therapy was associated with improved OS (P < .001); patients with surgery-related morbidity were less likely to receive adjuvant treatment (P = .002). In multivariable testing, adjuvant therapy (P < .001; HR = 0.064, 95%CI 0.028-0.144) remained the only significant predictor for improved OS. CONCLUSION: Less experienced neurosurgeons achieve similar surgical results and outcome in elderly GBM patients within the setting of academic teaching hospitals. Adjuvant treatment and avoidance of surgery-related morbidity are crucial for generating a treatment benefit for this cohort.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Idoso , Humanos , Glioblastoma/patologia , Estudos Retrospectivos , Neoplasias Encefálicas/patologia , Procedimentos Neurocirúrgicos/métodos , Neurocirurgiões , Hospitais de EnsinoRESUMO
BACKGROUND: Stereoelectroencephalography (SEEG) allows the identification of deep-seated seizure foci and determination of the epileptogenic zone (EZ) in drug-resistant epilepsy (DRE) patients. We evaluated the accuracy and treatment-associated morbidity of frameless VarioGuide® (VG) neuronavigation-guided depth electrode (DE) implantations. METHODS: We retrospectively identified all consecutive adult DRE patients, who underwent VG-neuronavigation DE implantations, between March 2013 and April 2019. Clinical data were extracted from the electronic patient charts. An interdisciplinary team agreed upon all treatment decisions. We performed trajectory planning with iPlan® Cranial software and DE implantations with the VG system. Each electrode's accuracy was assessed at the entry (EP), the centre (CP) and the target point (TP). We conducted correlation analyses to identify factors associated with accuracy. RESULTS: The study population comprised 17 patients (10 women) with a median age of 32.0 years (range 21.0-54.0). In total, 220 DEs (median length 49.3 mm, range 25.1-93.8) were implanted in 21 SEEG procedures (range 3-16 DEs/surgery). Adequate signals for postoperative SEEG were detected for all but one implanted DEs (99.5%); in 15/17 (88.2%) patients, the EZ was identified and 8/17 (47.1%) eventually underwent focus resection. The mean deviations were 3.2 ± 2.4 mm for EP, 3.0 ± 2.2 mm for CP and 2.7 ± 2.0 mm for TP. One patient suffered from postoperative SEEG-associated morbidity (i.e. conservatively treated delayed bacterial meningitis). No mortality or new neurological deficits were recorded. CONCLUSIONS: The accuracy of VG-SEEG proved sufficient to identify EZ in DRE patients and associated with a good risk-profile. It is a viable and safe alternative to frame-based or robotic systems.
Assuntos
Eletroencefalografia , Epilepsia/cirurgia , Neuronavegação , Técnicas Estereotáxicas , Adulto , Eletrodos Implantados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Morbidade , Neuronavegação/efeitos adversos , Período Pós-Operatório , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVES: Demographic changes will lead to an increase in old patients, a population with significant risk of postoperative morbidity and mortality, requiring neurosurgery for meningiomas. This multicenter study aims to report neurofunctional status after resection of patients with supratentorial meningioma aged 80 years or older, to identify factors associated with outcome, and to validate a previously proposed decision support tool. METHODS: Neurofunctional status was assessed by the Karnofsky Performance Scale (KPS). Patients were categorized in poor (KPS ≤40), intermediate (KPS 50-70), and good (KPS ≥80) preoperative subgroups. Volumetric analyses of tumor and peritumoral brain edema (PTBE) were performed; volumes were scored as small (<10 cm 3 ), medium (10-50 cm 3 ), and large (>50 cm 3 ). RESULTS: The study population consisted of 262 patients, and the median age at surgery was 83.0 years. The median preoperative KPS was 70; 117 (44.7%) patients were allotted to the good, 113 (43.1%) to the intermediate, and 32 (12.2%) to the poor subgroup. The median tumor and PTBE volumes were 30.2 cm 3 and 27.3 cm 3 ; large PTBE volume correlated with poor preoperative KPS status ( P = .008). The 90-day and 1-year mortality rates were 9.0% and 13.2%, respectively. Within the first postoperative year, 101 (38.5%) patients improved, 87 (33.2%) were unchanged, and 74 (28.2%) were functionally worse (including deaths). Each year increase of age associated with 44% (23%-70%) increased risk of 90-day and 1-year mortality. In total, 111 (42.4%) patients suffered from surgery-associated complications. Maximum tumor diameter ≥5 cm (odds ratio 1.87 [1.12-3.13]) and large tumor volume (odds ratio 2.35 [1.01-5.50]) associated with increased risk of complications. Among patients with poor preoperative status and large PTBE, most (58.3%) benefited from surgery. CONCLUSION: Patients with poor preoperative neurofunctional status and large PTBE most often showed postoperative improvements. The decision support tool may be of help in identifying cases that most likely benefit from surgery.
Assuntos
Edema Encefálico , Neoplasias Meníngeas , Meningioma , Neoplasias Supratentoriais , Humanos , Idoso de 80 Anos ou mais , Meningioma/patologia , Neoplasias Meníngeas/patologia , Estudos Retrospectivos , Neoplasias Supratentoriais/cirurgia , Neoplasias Supratentoriais/complicações , Edema Encefálico/etiologia , Resultado do TratamentoRESUMO
BACKGROUND: Spinal surgery has to address the challenge of a dramatic increase of the growing number of older persons. The purpose of the present study was to project the numbers of surgically treated degenerative spine disease (DSD) in Austria from 2017 until 2080 to provide potential future scenarios that the Austrian Health system might have to face. METHODS: Current numbers on demographic information from Austria as well as population projections for 2017-2080 were obtained from Statistics Austria (STAT). A lower/main/upper scenario reflecting low/main/high growth and ageing scenarios deducted from fertility, life expectancy and immigration calculations was used. Information on prevalence of surgically treated DSD was obtained from the Austrian Spine Register. RESULTS: The population in Austria (evaluated in 2017) was 8.78 millions and is estimated to evolve to 7.86/10.0/13.1 millions by 2080. The total number of surgically treated DSD recorded in the Spine Register was 9300 and was estimated to be 9300/11200/13700 in 2080. The number of subjects with surgically treated DSD were expected to increase in the age-strata (main scenario), 100% corresponds to the number in each age and gender stratum: 0-40 years by (male/female) 2%/2%, 40-50 years -7%/-7%, 50-59 years -11%/-9%, 60-69 years 21%/16%, 70-79 years 51%/31%, 80-89 years 211%/129% and 90+years 698%/411%. CONCLUSIONS: Total numbers of subjects with DSD in Austria will increase from 2017 to 2080. The increase will be substantial in those aged 80+ and those aged 90+. The assumptions of this analysis were taken conservatively. Hence, the future socio-economic burden to society might be greater as projected by the study.
Assuntos
Doenças da Coluna Vertebral , Humanos , Masculino , Feminino , Idoso , Idoso de 80 Anos ou mais , Áustria/epidemiologia , Doenças da Coluna Vertebral/epidemiologia , Doenças da Coluna Vertebral/cirurgia , Projetos de Pesquisa , PrevisõesRESUMO
Background: It was proposed that network topology is altered in brain tumor patients. However, there is no consensus on the pattern of these changes and evidence on potential drivers is lacking. Objectives: We aimed to characterize neurooncological patients' network topology by analyzing glial brain tumors (GBTs) and brain metastases (BMs) with respect to the presence of structural epilepsy. Methods: Network topology derived from resting state magnetoencephalography was compared between (1) patients and controls, (2) GBTs and BMs, and (3) patients with (PSEs) and without structural epilepsy (PNSEs). Eligible patients were investigated from February 2019 to March 2021. We calculated whole brain (WB) connectivity in six frequency bands, network topological parameters (node degree, average shortest path length, local clustering coefficient) and performed a stratification, where differences in power were identified. For data analysis, we used Fieldtrip, Brain Connectivity MATLAB toolboxes, and in-house built scripts. Results: We included 41 patients (21 men), with a mean age of 60.1 years (range 23-82), of those were: GBTs (n = 23), BMs (n = 14), and other histologies (n = 4). Statistical analysis revealed a significantly decreased WB node degree in patients versus controls in every frequency range at the corrected level (p1-30Hz = 0.002, pγ = 0.002, pß = 0.002, pα = 0.002, pθ = 0.024, and pδ = 0.002). At the descriptive level, we found a significant augmentation for WB local clustering coefficient (p1-30Hz = 0.031, pδ = 0.013) in patients compared to controls, which did not persist the false discovery rate correction. No differences regarding networks of GBTs compared to BMs were identified. However, we found a significant increase in WB local clustering coefficient (pθ = 0.048) and decrease in WB node degree (pα = 0.039) in PSEs versus PNSEs at the uncorrected level. Conclusion: Our data suggest that network topology is altered in brain tumor patients. Histology per se might not, however, tumor-related epilepsy seems to influence the brain's functional network. Longitudinal studies and analysis of possible confounders are required to substantiate these findings.
RESUMO
Background: Penetrating brain injury (PBI) is a heterogeneous condition with many variables. Few data exist on civilian PBI. In some publications, PBI differentiation between low-velocity injury (LVI) and high-velocity injury (HVI) is made, but exact definitions are not given yet. The incidence of PBI depends heavily on the country of origin. Furthermore, captive bolt pistol (CBP) injuries represent a rare type of LVI and almost no reports exist in the human medical literature. Treatment of PBI has been controversially discussed due to high morbidity and mortality with results varying considerably between series. Prognostic factors are of utmost importance to identify patients who presumably benefit from treatment. Methods: A retrospective, single-center analysis of a consecutive patient series was performed from September 2005 to May 2018. We included all patients with PBI who reached our hospital alive and received any neurosurgical operative procedure. Results: Of 24 patients, 38% died, 17% had an unfavourable outcome, and 46% had a favourable outcome. In total, 58% of patients with PBI were self-inflicted. Leading causes of injury were firearms, while captive bolt pistols were responsible for 21% of injuries. LVI represented 54%, and HVI represented 46%. The outcome in HVI was significantly worse than that in LVI. A favourable outcome was achieved in 69% of LVI and 18% of HVI. Low GCS and pathological pupillary status at admission correlated significantly with an unfavourable outcome and death. Conclusions: PBI is a heterogeneous injury with many variables and major geographical and etiological differences. Differentiation between LVI and HVI is crucial for decision-making and predicting outcomes. In patients presenting with object trajectories crossing the midline, no favourable outcome could be achieved. Nevertheless, in total, a favourable outcome was possible in almost half of the patients who succeeded in surgery.
RESUMO
Here, we report on a patient presenting with two histopathologically distinct gliomas. At the age of 42, the patient underwent initial resection of a right temporal oligodendroglioma IDH mutated 1p/19q co-deleted WHO Grade II followed by adjuvant radiochemotherapy with temozolomide. 15 months after initial diagnosis, the patient showed right hemispheric tumor progression and an additional new left frontal contrast enhancement in the subsequent imaging. A re-resection of the right-sided tumor and resection of the left frontal tumor were conducted. Neuropathological work-up showed recurrence of the right-sided oligodendroglioma with features of an anaplastic oligodendroglioma WHO Grade III, but a glioblastoma WHO grade IV for the left frontal lesion. In depth molecular profiling revealed two independent brain tumors with distinct molecular profiles of anaplastic oligodendroglioma IDH mutated 1p/19q co-deleted WHO Grade III and glioblastoma IDH wildtype WHO grade IV. This unique and rare case of a patient with two independent brain tumors revealed by in-depth molecular work-up and epigenomic profiling emphasizes the importance of integrated work-up of brain tumors including methylome profiling for advanced patient care.
Assuntos
Astrocitoma , Neoplasias Encefálicas , Glioblastoma , Glioma , Oligodendroglioma , Astrocitoma/patologia , Biologia , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Cromossomos Humanos Par 1 , DNA , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/terapia , Glioma/patologia , Humanos , Isocitrato Desidrogenase/genética , Metilação , Mutação , Oligodendroglioma/diagnóstico , Oligodendroglioma/genética , Oligodendroglioma/terapiaRESUMO
This case of severe phenotype-genotype mismatch brain tumor morphologically mimicking benign ganglioglioma emphasizes the urgent need for advanced molecular profiling in brain tumor diagnosis in the era of sophisticated molecular profiling.
RESUMO
Non-convulsive SE (NCSE) is characterized by altered consciousness with or without slight motor manifestations or other phenomena such as aphasia, sensory, auditory, emotional, gustatory or other symptoms. A 69-year-old right-handed man developed the sudden onset of apraxia in his right arm. On admission, the patient was alert and well oriented. In his past medical history, an intracerebral hematoma (ICH) in the left temporo-parietal area was noted occurred five years before the current admission. An electroencephalography (EEG) showed rhythmic theta-delta activity with fluctuating frequency between 1.5 and 5â¯Hz in the left centro-parieto-temporal area, which promptly responded to the intravenous injection of 2â¯mg clonazepam and 1000â¯mg levetiracetam. Apraxia resolved completely and the EEG demonstrated intermittent non-rhythmic delta-theta slowing in the left temporo-parietal area. A cranial CT scan showed residual cystic encephalomalacia in the left temporo-parietal area due to the previous ICH. An MRI exhibited an old parenchymal defect in the left temporo-parietal area with a residual hemosiderin rim on the susceptibility weighted imaging (SWI) and no diffusion restriction on the diffusion weighted image (DWI). NCSE presented with right arm apraxia in our patient with a post-hemorrhagic residual parenchymal defect in the left temporo-parietal area.
RESUMO
Here, we report on a 28-year old male patient presenting with neck and shoulder pain, dysesthesia of all four limbs and hypesthesia of both hands, without motor deficits. Magnetic resonance imaging showed an intradural, intramedullary mass of the cervical spinal cord of 6.4 cm length and 1.7 cm diameter. The patient underwent surgical resection. Histological and immunohistochemical evaluation showed pleomorphic glial tumor cells, mitoses, calcifications, and atypical ganglioid cells compatible with the morphology of anaplastic ganglioglioma (WHO Grade III). Extensive molecular workup revealed H3F3A K27M, TERT C228T and PDGFRα Y849C mutations indicating poor prognosis. The H3F3A K27M mutation assigned the tumor to the molecular group of diffuse midline glioma (WHO Grade IV). Epigenome-wide methylation profiling confirmed the methylation class of diffuse midline glioma. Thus, this is a very rare case of malignant glioma with H3 K27M genotype phenotypically mimicking anaplastic ganglioglioma. This case emphasizes the importance of comprehensive morphological and molecular workup including methylome profiling for advanced patient care.
Assuntos
Genótipo , Glioma/genética , Glioma/patologia , Histonas/genética , Neoplasias da Medula Espinal/genética , Neoplasias da Medula Espinal/patologia , Adulto , Vértebras Cervicais , Imagem de Difusão por Ressonância Magnética , Ganglioglioma , Glioma/diagnóstico por imagem , Humanos , Masculino , Neoplasias da Medula Espinal/diagnóstico por imagemRESUMO
OBJECTIVE: To assess the prognostic profile, clinical outcome, treatment-associated morbidity, and treatment burden of elderly patients with glioblastoma (GBM) undergoing microsurgical tumor resection as part of contemporary treatment algorithms. METHODS: We retrospectively identified patients with GBM ≥65 years of age who were treated by resection at 2 neuro-oncology centers. Survival was assessed by Kaplan-Meier analyses; log-rank tests identified prognostic factors. RESULTS: The study population included 160 patients (mean age, 73.1 ± 5.1 years), and the median contrast-enhancing tumor volume was 31.0 cm3. Biomarker analyses revealed O(6)-methylguanine-DNA methyltransferase-promoter methylation in 62.7% and wild-type isocitrate dehydrogenase in 97.5% of tumors. The median extent of resection (EOR) was 92.3%, surgical complications were noted in 10.0% of patients, and the median postoperative hospitalization period was 8 days. Most patients (60.0%) received adjuvant radio-/chemotherapy. The overall treatment-associated morbidity was 30.6%. The median progression-free and overall survival were 5.4 months (95% confidence interval [CI], 4.6-6.4 months) and 10.0 months (95% CI, 7.9-11.7 months). The strongest predictors for favorable outcome were patient age ≤73.0 years (P = 0.0083), preoperative Karnofsky Performance Status Scale score ≥80% (P = 0.0179), postoperative modified Rankin Scale score ≤1 (P < 0.0001), adjuvant treatment (P < 0.0001), and no treatment-associated morbidity (P = 0.0478). Increased EOR did not correlate with survival (P = 0.5046), but correlated significantly with treatment-associated morbidity (P = 0.0031). CONCLUSIONS: Clinical outcome for elderly patients with GBM remains limited. Nonetheless, the observed treatment-associated morbidity and treatment burden were moderate in the patients, and patient age and performance status remained the strongest predictors for survival. The risks and benefits of tumor resection in the age of biomarker-adjusted treatment concepts require further prospective evaluation.
Assuntos
Neoplasias Encefálicas/cirurgia , Glioblastoma/cirurgia , Procedimentos Neurocirúrgicos , Idoso , Idoso de 80 Anos ou mais , Áustria , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Feminino , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Resultado do TratamentoRESUMO
BACKGROUND: The rate of intracranial aneurysm remnants/recurrences after microsurgical clipping varies widely. The optimal management for these patients remains a matter of debate. Repeat surgery in particular bears a high risk of periprocedural complications due to anatomical distortion from prior procedures. This study aims to evaluate the risk-benefit profile of flow-diverter stents in these patients. METHODS: The patient database of our neurovascular centre was queried to identify patients with clipped aneurysms who subsequently underwent endovascular treatment with intraluminal flow-diverter stents. The outcome analysis consisted of an assessment of clinical parameters (modified Rankin scale) and the post-interventional angiographic occlusion status (according to the Raymond-Roy occlusion classification). RESULTS: Six patients underwent endovascular treatment with flow-diverter stents of recurrent aneurysms after clipping. Treatment was necessary in two patients due to progressive neurological deficits, and due to angiographic proof of an increasing aneurysm size in the other four patients. Median aneurysm size was 0.45 cm. All patients had a prior history of subarachnoid haemorrhage. The time from primary clipping to recurrence was 10.6 years. Complete radiological aneurysm occlusion was feasible in five out of six cases. Two patients who had experienced pre-interventional neurological deficits showed a complete remission of symptoms on last follow-up. No periprocedural morbidity or mortality was recorded and no patient required retreatment within the median follow-up. CONCLUSION: This case series suggests that endovascular treatment with flow-diverter stents of aneurysm remnants after previous microsurgical clipping is a feasible treatment concept with a low-risk profile, which might prevent the treatment burden and risks of repeat surgery.
Assuntos
Aneurisma Roto/cirurgia , Procedimentos Endovasculares/métodos , Aneurisma Intracraniano/cirurgia , Stents , Adulto , Aneurisma Roto/diagnóstico por imagem , Angiografia Digital , Angiografia Cerebral , Estudos de Viabilidade , Feminino , Humanos , Aneurisma Intracraniano/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/uso terapêutico , Recidiva , Reoperação , Estudos Retrospectivos , Resultado do TratamentoRESUMO
[This corrects the article DOI: 10.7759/cureus.3741.].
RESUMO
Introduction Local treatment concepts are in high demand in the salvage treatment of recurrent brain metastases. Still, their risks and benefits are scarcely characterized. In this study, we analyzed the outcome and risk-/benefit-ratio of salvage CyberKnife (Accuray Incorporated, Sunnyvale, California, US) radiosurgery in the treatment of recurrent brain metastases after whole brain radiotherapy (WBRT). Materials and methods Seventy-six patients with 166 recurrent brain metastases and a multimodal pretreatment were retrospectively investigated. All patients underwent salvage CyberKnife radiosurgery (single fraction, reference dose: 17-22 Gy). Study endpoints were post-recurrence survival (PRS) after salvage treatment as well as local and distant tumor control rates. Central nervous system (CNS) toxicity was assessed according to the toxicity criteria of the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer (RTOG/EORTC)). Results The population was homogenous regarding its demographic parameters. All patients had a history of WBRT prior to salvage CyberKnife radiosurgery. PRS was 13.3 months (10.4 - 16.2 months), one-year local and distant tumor control rates were 87% (95% CI: 75-99) and 38% (95% CI: 23-52), respectively. Eighteen patients suffered from RTOG/EORTC grade I/II toxicity. No toxicity-related risk factors were identified. Discussion This study found indicative survival and tumor control rates as well as a favorable risk/benefit ratio regarding radiotoxicity in salvage CyberKnife radiosurgery. These results point to a proactive therapeutic strategy based on appropriate patient selection instead of therapeutic nihilism.