Atypical Presentation of Glioblastoma Multiforme

Background: Glioblastoma multiforme (GBM) is a highly malignant glial tumour classified by the World Health Organization (WHO) as a stage IV astrocytoma. It varies in shape and size and can be cystic, vascular and necrotic. It often appears as a ring-enhancing lesion on magnetic resonance imaging (MRI). The most common symptoms of GBM, such as headache, vomiting and seizures, are due to increased intracranial pressure. The objective of this case report is to describe an atypical presentation of GBM. Case Report: A 53-year-old woman of Italian origin presented with a 2-week history of lack of coordination in her hands and some difficulty in speech. Electromyography for assessment of her arms and cranial bulbar function was normal. However, 2 days later, the patient presented to the emergency department with progressive weakness in her left arm and leg as well as difficulty in speech. Mild left facial asymmetry was noted. A brain MRI revealed a right frontal mass. Stereotactic surgical resection was performed 2 days later, and biopsy confirmed the diagnosis of GBM. Although headache and other features of raised intracranial pressure are the most common initial symptoms of GBM, any atypical neurological or psychiatric presentation in an adult patient should raise suspicion for this tumour. Conclusion: Careful analysis of an adult with atypical signs and symptoms along with thorough review of radiological tests will facilitate early diagnosis of dangerous tumours such as GBM

NOS1AP is a novel molecular target and critical factor in TDP-43 pathology

Cappelli et al. reported that Nitric Oxide Synthase 1 Adaptor Protein is a co-regulated transcript of the TAR DNA-binding protein 43 kDa, reduced in amyotrophic lateral sclerosis and frontotemporal lobar degeneration patients with TAR DNA-binding protein 43 kDa pathology. Overall, their results highlight Nitric Oxide Synthase 1 Adaptor Protein as a novel druggable disease-relevant gene in TAR DNA-binding protein 43 kDa-related proteinopathies.Many lines of evidence have highlighted the role played by heterogeneous nuclear ribonucleoproteins in amyotrophic lateral sclerosis. In this study, we have aimed to identify transcripts co-regulated by TAR DNA-binding protein 43 kDa and highly conserved heterogeneous nuclear ribonucleoproteins which have been previously shown to regulate TAR DNA-binding protein 43 kDa toxicity (deleted in azoospermia-associated protein 1, heterogeneous nuclear ribonucleoprotein -Q, -D, -K and -U). Using the transcriptome analyses, we have uncovered that Nitric Oxide Synthase 1 Adaptor Protein mRNA is a direct TAR DNA-binding protein 43 kDa target, and in flies, its modulation alone can rescue TAR DNA-binding protein 43 kDa pathology. In primary mouse cortical neurons, we show that TAR DNA-binding protein 43 kDa mediated downregulation of Nitric Oxide Synthase 1 Adaptor Protein expression strongly affects the NMDA-receptor signalling pathway. In human patients, the downregulation of Nitric Oxide Synthase 1 Adaptor Protein mRNA strongly correlates with TAR DNA-binding protein 43 kDa proteinopathy as measured by cryptic Stathmin-2 and Unc-13 homolog A cryptic exon inclusion. Overall, our results demonstrate that Nitric Oxide Synthase 1 Adaptor Protein may represent a novel disease-relevant gene, potentially suitable for the development of new therapeutic strategies

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Atypical Presentation of Glioblastoma Multiforme

Background: Glioblastoma multiforme (GBM) is a highly malignant glial tumour classified by the World Health Organization (WHO) as a stage IV astrocytoma. It varies in shape and size and can be cystic, vascular and necrotic. It often appears as a ring-enhancing lesion on magnetic resonance imaging (MRI). The most common symptoms of GBM, such as headache, vomiting and seizures, are due to increased intracranial pressure. The objective of this case report is to describe an atypical presentation of GBM. Case Report: A 53-year-old woman of Italian origin presented with a 2-week history of lack of coordination in her hands and some difficulty in speech. Electromyography for assessment of her arms and cranial bulbar function was normal. However, 2 days later, the patient presented to the emergency department with progressive weakness in her left arm and leg as well as difficulty in speech. Mild left facial asymmetry was noted. A brain MRI revealed a right frontal mass. Stereotactic surgical resection was performed 2 days later, and biopsy confirmed the diagnosis of GBM. Although headache and other features of raised intracranial pressure are the most common initial symptoms of GBM, any atypical neurological or psychiatric presentation in an adult patient should raise suspicion for this tumour. Conclusion: Careful analysis of an adult with atypical signs and symptoms along with thorough review of radiological tests will facilitate early diagnosis of dangerous tumours such as GBM. LEARNING POINT: An adult patient with symptoms that do not conform to a neurological condition should be investigated for a brain tumour.Careful history taking and examination are essential for reaching the correct diagnosis as soon as possible.Meticulous review of radiological images in order to detect subtle changes in brain anatomy is essential

The effect of the percutaneous endoscopic gastrostomy (PEG) tube placement on the quality-of-life of ALS patients and their caregivers

Background: Dysphagia is one of the most important complications, together with respiratory insufficiency, encountered in ALS. The presence of dysphagia exposes patients to malnutrition, dehydration and aspiration pneumonia. Because of this, most ALS patients have a Percutaneous Endoscopic Gastrostomy (PEG) placed (1,2). It remains unclear how this procedure impacts the quality-of-life (QoL) of ALS patients and their caregivers (3). Objectives: The objective of this prospective qualitative study is to determine how the placement of a PEG tube effects the QoL of ALS patients and their caregivers. Results: In total, 14 patients and their caregivers participated. Measurements were taken prior to PEG placement and at weeks 4 and 12 after placement: Assessment included Hospital Anxiety and Depression Score (HADS) (patient and caregiver), caregiver burden scale (CBS, caregivers) and SWAL-QoL (patients). Paired t-tests and signed rank tests were utilized to compare the measures between the different time points. The overall testing level was set at 0.05, with no adjustments for multiple testing. SAS 9.4 was used to perform all data analyses. Analysis was performed of available responses. Patients and caregivers had no significant change of anxiety or depression scores between the different time points as measured by HADS. There was a significant increase in caregiver burden between week 4 and week 12 (p=0.004), as measured by the CBS. The comparisons between baseline and the other 2 time points showed no significant changes. Patient\u27s general health as measured by Swallowing-Quality-of-Life (SWAL-QoL) decreased significantly between weeks 4 and 12 (p=0.031). However, no other measures within the SWAL-QoL were significant at the 0.05 level. Discussion and conclusions: This pilot study shows that it is feasible to assess patients and their caregivers\u27 quality-of-life and caregiver burden during the time of PEG placement. Findings suggest that patients and their caregivers adjust well to PEG placement, as there is no significant difference in anxiety and depression in patients or caregivers after PEG placement. PEG placement may not have any benefits on the quality-of-life issues related to dysphagia; however, caregivers reported a significant increase in caregiver burden after placement. More extensive studies are required to assess the true impact of dysphagia and placement of nutritional devices

Value of terminal latency index and sensory electrophysiology in idiopathic and diabetic chronic inflammatory demyelinating polyradiculoneuropathy

Objectives: To evaluate sensory electrophysiology, terminal latency index (TLI), and treatment response in idiopathic and diabetic chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Methods: We performed a retrospective review of 147 patients with CIDP who underwent electrodiagnostic evaluation (January 2000–December 2015). Eighty-nine patients fulfilled electrophysiological criteria described by the Ad hoc Subcommittee of the American Academy of Neurology and Albers et al. Fifty-eight patients were divided into idiopathic (N = 40) and diabetic (N = 18) groups. These groups were compared for age, sex, cerebrospinal fluid protein, response to treatment, sensory response abnormalities, and TLI measurements using chi-square tests for binary and categorical variables and using t-tests and mixed-effects models for continuous variables. Results: The difference in abnormal rates of sensory responses was significant for the sural nerve, with the idiopathic group having a lower rate than the diabetic group (80% vs. 100%, p \u3c 0.001). No group differences in the TLI measurements were significant. Conclusions: Sural sensory responses may have some value in differentiating idiopathic CIDP from diabetic CIDP. Larger prospective studies are needed to confirm our findings. Significance: Our study suggests that abnormal sural sensory potentials may have some significance in differentiating idiopathic CIDP from diabetic CIDP

Terminal latency index (TLI) and sensory electrophysiology in paraproteinemic chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)

Objective: To differentiate sensory electrophysiology, TLI and treatment response in patients with paraproteinemic CIDP. Background: Low TLI has been reported as a useful electrophysiological marker for MAG-CIDP. To our knowledge comparison of sensory electrophysiology and TLI of paraproteinemic CIDP subgroups have not been previously reported. Design/Methods: Retrospective review (January 2000-December 2015) of 89 patients with CIDP fulfilling electrophysiological criteria (AAN ad hoc subcommittee and Albers and colleagues).CIDP patients with diabetes(n=18) were excluded. 71 patients were divided into idiopathic (n=40) and paraproteinemic CIDP (n=31). Paraproteinemic CIDP subgroups: MAG (8), non-MAG(8) and IgG(15) were compared to idiopathic CIDP (40). These groups were compared for demographics, history of cancer, CSF protein, sensory conductions, TLI measurements and response to treatment using chi-square tests for binary and categorical variables and t-tests for continuous measures. Results: There was a higher proportion of females in idiopathic-CIDP compared to non-MAG-CIDP (50% vs 13%). Idiopathic group having a higher proportion of patients on monotherapy (59% vs 50%) and combination therapy (38% vs 17%) compared to non-MAG. Higher mean CSF protein compared to MAG-CIDP(p=0.001) was seen in the idiopathic. The difference between idiopathic and IgG-CIDP was significant for overall Rx response (p=0.025) and Rx response in patients with follow-up(p=0.01). For both variables, patients in the idiopathic group had a higher proportion of patients on combination therapy and lower proportion of no treatment offered compared to patients in the IgG-CIDP. 50% of non-MAG-CIDP patients had a history of cancer vs 0% of MAG-CIDP. None of the other differences were significant. There were no group differences in sensory electrophysiology and TLI. Conclusions: Sensory electrophysiology and TLI may have no value in differentiating paraproteinemic CIDP. CSF protein is higher in idiopathic CIDP compared to MAG-CIDP. Idiopathic-CIDP has a higher proportion of females compared to non-MAG-CIDP and a higher proportion of patients on combination therapy compared to IgG-CIDP. Cancer screening should be considered in patients with non-MAG-CIDP

Does electrophysiology and treatment response differ in idiopathic vs diabetic chronic inflammatory demyelinating polyneuropathy (CIDP)?

Introduction: Sensory electrophysiology and Terminal latency index (TLI) differences have been described in various CIDP sub-groups. Objective: Evaluate electrophysiology, TLI and treatment response in idiopathic and diabetic CIDP. Methods: Retrospective review of 147 patients with CIDP who underwent electrodiagnostic evaluation (January 2000-December 2015). 89 patients fulfilled electrophysiological criteria described by Ad hoc subcommittee of American Academy of Neurology (AAN) and Albers et al. We excluded patients (31) with acute inflammatory demyelinating neuropathy, hereditary sensorimotor neuropathy, vasculitis and polyneuropathy with paraproteinemia. 58 patients were divided into idiopathic (40) and diabetic (18) groups. These groups were compared for age, sex, history of cancer, CSF protein, response to treatment, sensory response abnormalities and TLI measurements using chi-square tests for binary and categorical variables and t-tests for continuous measures. All testing was at the alpha=0.05 level. Results: Group differences for age, sex, history of cancer, CSF protein and treatment response were not significant. Comparing TLI values in measurable responses, the difference between the two groups for tibial TLI was significant (p=0.012), with idiopathic group having a lowermean as compared to the diabetic. TLI values differences formedian, ulnar and peroneal nerves were not significant. The difference in abnormal rates of sensory responses was significant for the sural nerve with the idiopathic group having a lower rate compared to the diabetic group (80% vs 100%, p\u3c0.05). No differences were noted for the ulnar, median and radial nerves. Conclusion: Tibial TLI and sural sensory responses have some value in differentiating the two groups. Larger prospective studies are needed to confirm our findings

General Characteristics of Edaravone Use in the Natural History of ALS and Other Motor Neuron Disorders Consortium Dataset (NeuroBANK™)

Objective: To report percentage and general information on patients receiving edaravone in the clinics members of ALS Natural History Study Consortium. Background: The ALS Natural History Study protocol was developed with the goal of sharing longitudinal natural history data from several ALS multidisciplinary clinics participating in the ALS Natural History Consortium. Edaravone was approved by the FDA in May 2018 as a new treatment for ALS. There is not yet much data available regarding edaravone use in the United States. We report on edaravone use in our clinics since its approval. Design/Methods: All patients followed regularly in seven multidisciplinary ALS clinics are being offered participation in the study. Consenting participants are assigned a Neurological Global Unique Identifier (NeuroGUID), and a predefined clinical dataset is captured in NeuroBANK™. All medications, including edaravone, are recorded. The dataset will be queried for edaravone use, duration of use, and selected clinical and demographic information. Results: As July of 2018, 105 of 419 consented PALS had received edaravone. Ten PALS were not included due to incomplete data. Of the remaining 95, 61 are male, 34 are female, and age range is from 37 to 82 years. Sixteen PALS (17%) have stopped edaravone, on average after 2.6 months of onset of treatment (range:treatment). Average ALSFRS-R score of all patients on edaravone was 33.6, and of the patients that discontinued the medication was 29.8. Enrollment has accelerated since that time and updated results, vital capacity slopes, and data for the aggregate population through March 2019 will be reported at the meeting. Conclusions: The ALS Natural History Study Consortium provides an opportunity to participating sites to aggregate heterogeneous patient population, and to provide usage and efficacy information on concomitant medications, including post-marketing review of approved drugs as edaravone