Prospective Evaluation of Health Care Provider and Patient Assessments in Chemotherapy-Induced Peripheral Neurotoxicity.

BACKGROUND AND OBJECTIVE: There is no agreement on the gold standard for detection and grading of chemotherapy-induced peripheral neurotoxicity (CIPN) in clinical trials. The objective is to perform an observational prospective study to assess and compare patient-based and physician-based methods for detection and grading of CIPN. METHODS: Consecutive patients, aged 18 years or older, candidates for neurotoxic chemotherapy, were enrolled in the United States, European Union, or Australia. A trained investigator performed physician-based scales (Total Neuropathy Score-clinical [TNSc], used to calculate Total Neuropathy Score-nurse [TNSn]) and supervised the patient-completed questionnaire (Functional Assessment of Cancer Treatment/Gynecologic Oncology Group-Neurotoxicity [FACT/GOG-NTX]). Evaluations were performed before and at the end of chemotherapy. On participants without neuropathy at baseline, we assessed the association between TNSc, TNSn, and FACT/GOG-NTX. Considering a previously established minimal clinically important difference (MCID) for FACT/GOG-NTX, we identified participants with and without a clinically important deterioration according to this scale. Then, we calculated the MCID for TNSc and TNSn as the difference in the mean change score of these scales between the 2 groups. RESULTS: Data from 254 participants were available: 180 (71%) had normal neurologic status at baseline. At the end of the study, 88% of participants developed any grade of neuropathy. TNSc, TNSn, and FACT/GOG-NTX showed good responsiveness (standardized mean change from baseline to end of chemotherapy >1 for all scales). On the 153 participants without neuropathy at baseline and treated with a known neurotoxic chemotherapy regimen, we verified a moderate correlation in both TNSc and TNSn scores with FACT/GOG-NTX (Spearman correlation index r = 0.6). On the same sample, considering as clinically important a change in the FACT/GOG-NTX score of at least 3.3 points, the MCID was 3.7 for TNSc and 2.8 for the TNSn. CONCLUSIONS: MCID for TNSc and TNSn were calculated and the TNSn can be considered a reliable alternative objective clinical assessment if a more extended neurologic examination is not possible. The FACT/GOG-NTX score can be reduced to 7 items and these items correlate well with the TNSc and TNSn. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a patient-completed questionnaire and nurse-assessed scale correlate with a physician-assessed scale.

External validation of the Epilepsy Surgery Grading Scale in a Japanese cohort of patients with epilepsy.

The Epilepsy Surgery Grading Scale (ESGS) is a simple method to predict the likelihood of a patient with epilepsy proceeding to surgery and achieving seizure freedom. Usefulness of the ESGS has been confirmed in established epilepsy centres in the United States and Belgium for adult patients with drug-resistant focal epilepsy undergoing presurgical evaluation. However, the applicability of the ESGS has not yet been evaluated in a wider range of epilepsy patients that may reflect the general spectrum of epilepsy. The present study validated the ESGS in a Japanese epilepsy centre in which admission-based comprehensive epilepsy studies were indicated beyond presurgical evaluation. This single-centre retrospective study included adult patients with epilepsy admitted to the Epilepsy Monitoring Unit from 2010 to June 2019. Patients were classified as ESGS Grade 1 (most favorable), Grade 2 (intermediate), and Grade 3 (least favourable). Patients were grouped into three cohorts: all patients, patients with drug-resistant focal epilepsy, and patients who underwent resective epilepsy surgery. We assessed progression to surgery and seizure freedom at one year after surgery. Of the 1,158 total admissions, 670 patients met the inclusion criteria and formed the total cohort. Of these, 435 (64.9%) had drug-resistant focal epilepsy and 78 (11.6%) proceeded to resective surgery. Overall, progression to surgery was observed in 41.3%, 16.6%, and 4.8% of patients with Grade 1, 2, and 3, respectively. In the surgical cohort, seizure freedom was observed in 85.2%, 65.2%, and 31.3% of patients with Grade 1, 2, and 3, respectively. Our results indicate that the ESGS is effective in predicting whether a patient proceeds to epilepsy surgery and achieves seizure freedom even in the general population of epilepsy patients, regardless of type or resistance to antiepileptic drugs.

Oxaliplatin- and docetaxel-induced polyneuropathy: clinical and neurophysiological characteristics.

The aim of this study was to evaluate the presence and characterization of chemotherapy-induced neuropathy (CIPN) and neuropathic pain 5 years after adjuvant chemotherapy with docetaxel or oxaliplatin. Patients from an ongoing prospective study, who had received adjuvant chemotherapy with docetaxel or oxaliplatin in 2011 to 2012 were invited to participate. The patients underwent a thorough examination with interview, neurological examination, questionnaires, assessment tools, nerve conduction studies (NCS), quantitative sensory testing, MScan motor unit number estimation (MUNE), and corneal confocal microscopy (CCM). Patients were divided into no, possible, probable, and confirmed CIPN. Out of the 132 eligible patients, 63 agreed to participate: 28 had received docetaxel and 35 had received oxaliplatin. Forty-one percent had confirmed CIPN, 34% possible or probable CIPN, and 22% did not have CIPN. The CIPN was characterized mainly by sensory nerve fiber loss, with a more pronounced large fiber than small fiber loss but also some motor fiber loss identified on NCS and MUNE. In general, patients had mild neuropathy with relatively low scores on assessment tools and no association with mood and quality of life. CCM was not useful as a diagnostic tool. Of the patients with probable or confirmed CIPN, 30% experienced pain, which was most often mild, but still interfered moderately with daily life in 20% to 25% and was associated with lower quality of life. In conclusion CIPN was confirmed in 41% 5 years after chemotherapy. The neuropathy was generally mild, but in patients with neuropathic pain it was associated with lower quality of life.

Routine diagnostics for neural antibodies, clinical correlates, treatment and functional outcome.

OBJECTIVE: To determine frequencies, interlaboratory reproducibility, clinical ratings, and prognostic implications of neural antibodies in a routine laboratory setting in patients with suspected neuropsychiatric autoimmune conditions. METHODS: Earliest available samples from 10,919 patients were tested for a broad panel of neural antibodies. Sera that reacted with leucine-rich glioma-inactivated protein 1 (LGI1), contactin-associated protein-2 (CASPR2), or the voltage-gated potassium channel (VGKC) complex were retested for LGI1 and CASPR2 antibodies by another laboratory. Physicians in charge of patients with positive antibody results retrospectively reported on clinical, treatment, and outcome parameters. RESULTS: Positive results were obtained for 576 patients (5.3%). Median disease duration was 6 months (interquartile range 0.6-46 months). In most patients, antibodies were detected both in CSF and serum. However, in 16 (28%) patients with N-methyl-D-aspartate receptor (NMDAR) antibodies, this diagnosis could be made only in cerebrospinal fluid (CSF). The two laboratories agreed largely on LGI1 and CASPR2 antibody diagnoses (κ = 0.95). The clinicians (413 responses, 71.7%) rated two-thirds of the antibody-positive patients as autoimmune. Antibodies against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), NMDAR (CSF or high serum titer), γ-aminobutyric acid-B receptor (GABABR), and LGI1 had ≥ 90% positive ratings, whereas antibodies against the glycine receptor, VGKC complex, or otherwise unspecified neuropil had ≤ 40% positive ratings. Of the patients with surface antibodies, 64% improved after ≥ 3 months, mostly with ≥ 1 immunotherapy intervention. CONCLUSIONS: This novel approach starting from routine diagnostics in a dedicated laboratory provides reliable and useful results with therapeutic implications. Counseling should consider clinical presentation, demographic features, and antibody titers of the individual patient.

Myasthenia Gravis Impairment Index: Sensitivity for Change in Generalized Muscle Weakness.

INTRODUCTION: The recently developed Myasthenia Gravis Impairment Index (MGII) is a promising measure as it has less floor effects and a higher relative efficiency in its responsiveness to treatment effect compared to other MG measures. This study aimed at validating the MGII in a Dutch cohort of MG patients and analyzing the sensitivity of MGII compared to MG-ADL for changes in generalized weakness. METHODS: We analyzed (generalized items of; -gen) MGII, quantitative myasthenia gravis (QMG), Myasthenia Gravis Activities of Daily Living (MG-ADL), EQ-5D visual analog, Myasthenia Gravis Composite (MGC) and ACTIVLIM (an ADL questionnaire focusing on generalized weakness) scores in a prospective cohort of 99 MG patients. We investigated correlations between MGII and other outcome measures. We used a generalized linear model to assess whether MGIIgen had an additional sensitivity on top of MG-ADLgen for changes (Δ) in QMGgen in individual patients. RESULTS: MGII had a lower floor effect (4%) compared to QMG (6%), MG-ADL (11%) and MGC (16%). MGII correlated well with QMG (r = 0.68), MG-ADL (r = 0.83) and MGC (r = 0.74). As expected, the correlations with EQ visual analog and ACTIVLIM were lower (r = - 0.57 and - 0.48). ΔMGIIgen had an additional value on top of ΔMG-ADLgen in the prediction of ΔQMGgen (B = 0.54, p = 0.01). DISCUSSION: The MGII score was cross-culturally validated in a Dutch cohort of MG patients. MGII had a higher sensitivity for generalized weakness than MG-ADL.

Comparing two models of performance validity assessment in patients with Parkinson's disease who are candidates for deep brain stimulation surgery.

Utility of standalone and embedded performance validity tests (PVTs) as well as the decision-making algorithms used to reach clinical conclusions about credible and noncredible performance can be population specific. To better understand PVT utility in Parkinson's disease candidates for deep brain stimulation (DBS) we present on two aims: 1) establishing the frequency data of below-criterion responding for the Medical Symptom Validity Test and three embedded PVTs in a sample of 47 patients with Parkinson's disease, and 2) comparing the efficacy of two models for clinical-decision making regarding noncredible performance. Consistent with expectations from previous studies and desired specificity values, our retrospective analysis indicated that in this sample of presumably well-motived patients, the rate of below-criterion responding was less than 10% for all PVTs administered. Regarding our model comparison, we compared a typical PVT battery that required administration of a standalone measure in all cases against a recently proposed low risk algorithm that attempts to lower testing burden by relying more heavily on embedded PVTs with administration of a standalone measure only in the event of below-criterion performance on an embedded indicator. Results suggest that for patients with Parkinson's disease judged to be at limited risk for noncredible performance, a low risk PVT model may prove both more efficient and less prone to error than a more typical model. Implications for clinical decision-making are discussed, as are limitations of the study and its generalizability.

The use, misuse and abuse of paraneoplastic panels in neurological disorders. A retrospective study.

OBJECTIVES: The field of paraneoplastic neurological syndromes PNS has grown exponentially with the increased identification of associated antibodies. Testing for these antibodies is commonly done in "panels" to increase sensitivity, and these panels have become a routine test on CSF samples obtained for a variety of clinical indications. Excessive testing has raised concerns about the correct utilization of these panels. Our study investigates the appropriateness of use of paraneoplastic panel in an academic, tertiary-care medical center. PATIENTS AND METHODS: We retrospectively reviewed charts of all patients who had autoimmune paraneoplastic panel testing in one year period. We collected date on demographics, clinical presentations and ancillary testings on all reviewed charts. Then, we devised an algorithm based on available data to define cases where testing had been unnecessary or likely unnecessary. RESULTS: We collected 60 cases that had undergone autoimmune paraneoplastic testing serum and/or CSF. Testing was unnecessary in 10 cases (16%), in which presentations had a definitive confirmatory tests. Testing was unlikely necessary in 11 cases (18%), in which all ancillary testing was normal in 6 cases, and presentation was not compatible with any known syndrome in 5 cases. Collectively, paraneoplastic panel testing was of extremely low yield on more than one third of the cases where where w testing was done. CONCLUSION: Our results adds to the growing concerns about the utilization of paraneoplastic panels, and the urgent need for enhanced screening and establishing a framework that can guide neurologists on when testing can have a sufficient yield to warrant it. Such framework should be built using diagnostic algorithms based on risk, clinical manifestations, characterization of autoantibodies and their associations.

Evaluation and validation of sustained upgaze combined with the ice-pack test for ocular myasthenia gravis in Asians.

The accuracy of the ice-pack test for diagnosing myasthenia gravis (MG) has been reported to be excellent, however, the sensitivity is low in patients with mild ptosis which is common in Asians who have absent or low double eyelid folds. Herein, we performed the ice-pack test after sustained upgaze and tested its validity for diagnosing MG. The study included 30 newly diagnosed MG patients with ptosis (median age 47 years, range 2-87 years) and 30 controls with ptosis other than MG (median age 58 years, range 5-83 years). All MG patients initially presented with ptosis and/or diplopia; 26 patients had purely ocular MG while 4 patients progressed to generalized MG. All patients performed the new ice-pack test after sustained upgaze for 2 min. The ice-pack test was judged positive if there was an improvement of at least 2 mm of margin reflex distance compared to the level of ptosis before (conventional ice-pack test) or after (new ice-pack test) sustained upgaze. Subgroup analysis was performed according to the level of ptosis. The conventional test showed 43.3% sensitivity and 100% specificity for diagnosing MG, while the new ice-pack test achieved 73.3% sensitivity and 96.7% specificity, respectively. In patients with mild ptosis, the sensitivity and specificity for diagnosing MG were 27.8% and 100% by the conventional test, and 72.2% and 96.7% by the new ice-pack test, respectively. The new ice-pack test combined with sustained upgaze was more sensitive for diagnosing MG, particularly in patients with mild ptosis which is common in Asians.

Diagnostic Accuracy of Procalcitonin for Early Aspiration Pneumonia in Critically Ill Patients with Coma: A Prospective Study.

BACKGROUND: Early diagnostic orientation for differentiating pneumonia from pneumonitis at the early stage after aspiration would be valuable to avoid unnecessary antibiotic therapy. We assessed the accuracy of procalcitonin (PCT) in diagnosing aspiration pneumonia (AP) in intensive care unit (ICU) patients requiring mechanical ventilation after out-of-hospital coma. METHODS: Prospective observational 2-year cohort study in a medical-surgical ICU. PCT, C-reactive protein (CRP) and white blood cell count (WBC) were measured at admission (H0) and 6 h (H), H12, H24, H48, H96, and H120 after inclusion. Lower respiratory tract microbiological investigations performed routinely in patients with aspiration syndrome were the reference standard for diagnosing AP. Performance of PCT, CRP, and WBC up to H48 in diagnosing AP was compared based on the areas under the ROC curves (AUC) and likelihood ratios (LR+ and LR-) computed for the best cutoff values. RESULTS: Of 103 patients with coma, 45 (44%) had AP. Repeated PCT assays demonstrated a significant increase in patients with AP versus without AP from H0 to H120. Among the three biomarkers, PCT showed the earliest change. ROC-AUC values were poor for all three biomarkers. Best ROC-AUC values for diagnosing AP were for CRP at H24 [0.73 (95%CI 0.61-0.84)] and PCT at H48 [0.73 (95%CI 0.61-0.84)]. LR+ was best for PCT at H24 (3.5) and LR- for CRP and WBC at H24 (0.4 and 0.4, respectively). CONCLUSIONS: Early and repeated assays of PCT, CRP, and WBC demonstrated significant increases in all three biomarkers in patients with versus without AP. All three biomarkers had poor diagnostic performance for ruling out AP. Whereas PCT had the fastest kinetics, PCT assays within 48 h after ICU admission do not help to diagnose AP in ICU patients with coma.

The 2016 World Health Organization classification of tumours of the central nervous system.

The 2016 WHO classification of tumours of the central nervous system represents the new paradigm among the specialists in the brain tumours and proposes a new approach combining histopathological and molecular features into diagnosis named 'integrated diagnosis'. The aim of this challenge is to overstep the interobserver variability of diagnosis based on previous classifications in order to ensure homogenous biological entities with a more accurate clinical significance. Over the last two decades, several molecular aberrations into gliomagenesis were highlighted and then confirmed as emerging biomarkers through prognostic stratification. In particular, IDH1/IDH2 genes mutations, 1p/19q codeletion and mutations in genes encoding histone H3 variants drastically changed the knowledge about diffuse gliomas inducing the WHO working group to consider the phenotype-genotype approach. In the present review, the historical development of the diagnosis of brain tumours from the 3D spatial configuration to the integration of multidisciplinary data up to recent molecular alterations is discussed. At the national level, the RENOCLIP network (supported by the National Cancer Institute) contributes to improve the standardization of histological diagnosis and the facilitation of access to molecular biology platforms for the detection of genetic aberrations necessary for integrated diagnosis. Importantly, the French POLA cohort allowed to test the clinical impact of the new criteria introduced by 2016 WHO classification of CNS tumours confirming the high accuracy in predicting clinical behaviour for diffuse gliomas.

A Validation Study of the International Consensus Diagnostic Criteria for Neuroleptic Malignant Syndrome.

BACKGROUND: Neuroleptic malignant syndrome requires prompt recognition for effective management, but there are no established diagnostic criteria. This is the first validation study of recently published international expert consensus (IEC) diagnostic criteria, which include priority points assigned on the basis of the importance of each criterion for making a diagnosis of neuroleptic malignant syndrome. METHODS: Data were extracted from 221 archived telephone contact reports of clinician-initiated calls to a national telephone consultation service from 1997 to 2009; each case was given a total priority point score on the basis of the IEC criteria. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, (DSM-IV-TR) research criteria, in original form and modified to accept less than "severe" rigidity, served as the primary diagnostic reference standard. Consultants' diagnostic impressions were used as a secondary reference standard. Receiver operating characteristic curve analysis was used to optimize the priority point cutoff score with respect to the reference standards. RESULTS: Area under the receiver operating characteristic curve ranged from 0.715 (95% confidence interval, 0.645-0.785; P = 1.62 × 10) for consultant diagnoses to 0.857 (95% confidence interval, 0.808-0.907; P < 5 × 10) for modified DSM-IV-TR criteria. The latter was associated with 69.6% sensitivity and 90.7% specificity. CONCLUSIONS: Agreement was best between IEC criteria with a cutoff score of 74 and modified DSM-IV-TR criteria (sensitivity, 69.6%; specificity, 90.7%); this cutoff score demonstrated the highest agreement in all comparisons. Consultant diagnoses showed much better agreement with modified, compared with original, DSM-IV-TR criteria, suggesting that the DSM-IV-TR criterion of "severe" rigidity may be more restrictive than what most knowledgeable clinicians use in practice.

Diagnostic criteria for Menière's disease.

This paper presents diagnostic criteria for Menière's disease jointly formulated by the Classification Committee of the Bárány Society, The Japan Society for Equilibrium Research, the European Academy of Otology and Neurotology (EAONO), the Equilibrium Committee of the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) and the Korean Balance Society. The classification includes two categories: definite Menière's disease and probable Menière's disease. The diagnosis of definite Menière's disease is based on clinical criteria and requires the observation of an episodic vertigo syndrome associated with low- to medium-frequency sensorineural hearing loss and fluctuating aural symptoms (hearing, tinnitus and/or fullness) in the affected ear. Duration of vertigo episodes is limited to a period between 20 minutes and 12 hours. Probable Menière's disease is a broader concept defined by episodic vestibular symptoms (vertigo or dizziness) associated with fluctuating aural symptoms occurring in a period from 20 minutes to 24 hours.

Case definition for progressive multifocal leukoencephalopathy following treatment with monoclonal antibodies.

BACKGROUND: Novel immunosuppressive/modulating therapies with monoclonal antibodies (MABs) have been associated with progressive multifocal leukoencephalopathy (PML), a potentially fatal disease of the brain caused by the JC virus. Taking the complex diagnostic testing and heterogeneous clinical presentation of PML into account, an agreed case definition for PML is a prerequisite for a thorough assessment of PML. OBJECTIVE/METHODS: A working group was established to develop a standardised case definition for PML which permits data comparability across clinical trials, postauthorisation safety studies and passive postmarketing surveillance. The case definition is designed to define levels of diagnostic certainty of reported PML cases following treatment with MABs. It was subsequently used to categorise retrospectively suspected PML cases from Germany reported to the Paul-Ehrlich-Institute as the responsible national competent authority. RESULTS: The algorithm of the case definition is based on clinical symptoms, PCR for JC virus DNA in cerebrospinal fluid, brain MRI, and brain biopsy/autopsy. The case definition was applied to 119 suspected cases of PML following treatment with MABs and is considered to be helpful for case ascertainment of suspected PML cases for various MABs covering a broad spectrum of indications. Even if the available information is not yet complete, the case definition provides a level of diagnostic certainty. CONCLUSIONS: The proposed case definition permits data comparability among different medicinal products and among active as well as passive surveillance settings. It may form a basis for meaningful risk analysis and communication for regulators and healthcare professionals.

Using a Virtual Classroom environment to describe the attention deficits profile of children with Neurofibromatosis type 1.

The objectives of this study were to describe the nature of the attention deficits in children with Neurofibromatosis type 1 (NF1) in comparison with typically developing (TD) children, using the Virtual Classroom (VC), and to assess the utility of this instrument for detecting attention deficits. Twenty-nine NF1 children and 25 age-and gender-matched controls, aged 8-16, were assessed in a VC. Parents' ratings on the Conners' Parent Rating Scales-Revised: Long (CPRS-R:L) questionnaire were used to screen for Attention Deficit-Hyperactivity Disorder (ADHD). Significant differences were found between the NF1 and the control groups on the number of targets correctly identified (omission errors) and the number of commissions (commission errors) in the VC, with poorer performance by the NF1 children (p < 0.005). Significant correlations were obtained between the number of targets correctly identified, the number of commission errors, and the reaction time. Significant correlations were also found between the total correct hits and the cognitive problems/inattention scale, as well as two other indexes of the CPRS-R:L: the DSM-IV Symptoms Subscale and the ADHD Index. The VC results support the hypothesis that NF1 is marked by inattention and impulsivity and that participants with NF1 are more inattentive (omission errors) and impulsive (commission errors) than normal controls. The VC appears to be a sensitive and ecologically valid assessment tool for use in the diagnosis of attention deficits among children with NF1.

[Neurosurgery: achievements and challenges].

Neurosurgery is one of the most dynamic and fast-developing medical sciences aimed at studying a wide range of diseases and lesions of the nervous system with constant improvement of methods of their diagnosis and surgical treatment. With the routine clinical use of computed tomography, positron emission tomography, magnetic resonance imaging the possibilities of revealing structural, metabolic and functional changes in the brain in different types of pathology have significantly enlarged. Today, methods of neurovisualization are widely used for preoperative modeling and intraoperative navigation. Also, these methods permit to study the fundamental aspects of brain functioning in health and pathology at the organ, tissue, cellular and molecular levels. In the last decades, the spectrum of neurosurgical methods including microsurgical, endoscopic, stereotactic, radiosurgical, reconstructive and other technologies was extended and diver-