Proton therapy for paediatric CNS tumours — improving treatment-related outcomes

Radiotherapy is an integral and highly effective aspect of the management of many paediatric CNS tumours, including embryonal tumours, astrocytic tumours and ependymal tumours. Nevertheless, continued improvements in long-term survivorship of such tumours means that radiotherapy-related toxicities that affect quality of life and overall functional status for survivors are increasingly problematic, and strategies that mitigate these adverse effects are needed. One such strategy is proton therapy, which has distinct advantages over conventional photon therapy and enables greater precision in the delivery of tumoricidal radiation doses with reduced irradiation of healthy tissues. These dose distribution advantages can translate into clinical benefits by reducing the risk of long-term adverse effects of radiotherapy, such as secondary malignancy, cognitive toxicity, endocrinopathy, hearing loss and vasculopathic effects. As the availability of proton therapy increases with the development of new proton centres, this treatment modality is increasingly being used in the management of paediatric CNS tumours. In this Review, we provide an introduction to the types of paediatric CNS tumours for which proton therapy can be considered, and discuss the available evidence that proton therapy limits toxicities and improves quality of life for patients. We will also consider uncertainties surrounding the use of proton therapy, evidence for its cost-effectiveness, and its future role in the management of paediatric CNS tumours.

Nature Reviews Neurology 2016

Zika Virus as an Emerging Global Pathogen Neurological Complications of Zika Virus

Importance  Zika virus (ZIKV) is an emerging arthropod-borne virus (arbovirus) in the genus Flavivirusthat has caused a widespread outbreak of febrile illness, is associated with neurological disease, and has spread across the Pacific to the Americas in a short period.

Observations  In this review, we discuss what is currently known about ZIKV, neuroimmunologic complications, and the impact on global human health. Zika virus spread across Africa and Asia in part owing to unique genomic evolutionary conditions and pressures resulting in specific human disease manifestations, complications, and pathogenesis. Recent data suggest that acute ZIKV infection in pregnant women may result in acute infection of fetal tissue and brain tissue, causing microcephaly and potentially severe debilitation of the infant or even death of the fetus. Cases of acute ZIKV are also associated with Guillain-Barré syndrome. With the increased number of cases, new complications such as ocular involvement and sexual transmission have been reported.

Conclusions and Relevance  Zika virus is an emerging viral pathogen with significant consequences on human health throughout the world. Ongoing research into this pathogen is urgently needed to produce viable vaccine and therapeutic options.

JAMA Neurology 2016

Neuropathologic Associations of Learning and Memory in Primary Progressive Aphasia

Importance  The dementia syndrome of primary progressive aphasia (PPA) can be caused by 1 of several neuropathologic entities, including forms of frontotemporal lobar degeneration (FTLD) or Alzheimer disease (AD). Although episodic memory is initially spared in this syndrome, the subtle learning and memory features of PPA and their neuropathologic associations have not been characterized.

Objective  To detect subtle memory differences on the basis of autopsy-confirmed neuropathologic diagnoses in PPA.

Design, Setting, and Participants  Retrospective analysis was conducted at the Northwestern Cognitive Neurology and Alzheimer’s Disease Center in August 2015 using clinical and postmortem autopsy data that had been collected between August 1983 and June 2012. Thirteen patients who had the primary clinical diagnosis of PPA and an autopsy-confirmed diagnosis of either AD (PPA-AD) or a tau variant of FTLD (PPA-FTLD) and 6 patients who had the clinical diagnosis of amnestic dementia and autopsy-confirmed AD (AMN-AD) were included.

Main Outcomes and Measures  Scores on the effortless learning, delayed retrieval, and retention conditions of the Three Words Three Shapes test, a specialized measure of verbal and nonverbal episodic memory.

Results  The PPA-FTLD (n = 6), PPA-AD (n = 7), and AMN-AD (n = 6) groups did not differ by demographic composition (all P > .05). The sample mean (SD) age was 64.1 (10.3) years at symptom onset and 67.9 (9.9) years at Three Words Three Shapes test administration. The PPA-FTLD group had normal (ie, near-ceiling) scores on all verbal and nonverbal test conditions. Both the PPA-AD and AMN-AD groups had deficits in verbal effortless learning (mean [SD] number of errors, 9.9 [4.6] and 14.2 [2.0], respectively) and verbal delayed retrieval (mean [SD] number of errors, 6.1 [5.9] and 12.0 [4.4], respectively). The AMN-AD group had additional deficits in nonverbal effortless learning (mean [SD] number of errors, 10.3 [4.0]) and verbal retention (mean [SD] number of errors, 8.33 [5.2]), which were not observed in the PPA-FTLD or PPA-AD groups (all P < .005).

Conclusions and Relevance  This study identified neuropathologic associations of learning and memory in autopsy-confirmed cases of PPA. Among patients with clinical PPA syndrome, AD neuropathology appeared to interfere with effortless learning and delayed retrieval of verbal information, whereas FTLD-tau pathology did not. The results provide directions for future research on the interactions between limbic and language networks.

JAMA Neurology 2016

The Association of Chemotherapy-Induced Peripheral Neuropathy Symptoms and the Risk of Falling

Importance  Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of neurotoxic chemotherapy resulting in pain, sensory loss, and decreased quality of life. Few studies have prospectively examined the relationship between sensory neuropathy symptoms, falls, and fall-related injuries for patients receiving neurotoxic chemotherapy.

Objective  To determine the association between the symptoms of CIPN and the risk of falls for patients receiving neurotoxic chemotherapy.

Design, Setting, and Participants  In this secondary analysis of a prospective study, 116 patients with breast, ovarian, or lung cancer who were beginning neurotoxic chemotherapy with a taxane or platinum agent were recruited from oncology clinics. These patients would call a novel automated telephone system daily for 1 full course of chemotherapy. The telephone system (SymptomCare@Home) used a series of relevant CIPN questions to track symptoms on a 0 to 10 ordinal scale and contained a questionnaire about falls. Those reporting a numbness and tingling severity score of 3 or greater for at least 10 days were considered to have significant CIPN symptoms and were compared with those patients who did not. Data analysis was performed in November 2015.

Exposure  Chemotherapy with a neurotoxic taxane or platinum agent.

Main Outcomes and Measures  Patient-reported falls or near falls and fall-related injuries. The hypothesis was generated after data collection but prior to data analysis.

Results  Of the 116 patients who started neurotoxic chemotherapy (mean [SD] age was 55.5 [11.9] years, and 109 [94.0%] were female), 32 met the predetermined criteria for CIPN symptoms. The mean duration of follow-up was 62 days, with 51 telephone calls completed per participant. Seventy-four falls or near falls were reported. The participants with CIPN symptoms were nearly 3 times more likely to report a fall or near fall than the participants without CIPN symptoms (hazard ratio, 2.67 [95% CI, 1.62-4.41]; P < .001). The participants with CIPN symptoms were more likely than the participants without CIPN symptoms to obtain medical care for falls (8 of 32 participants with CIPN symptoms [25.0%] vs 6 of 84 participants without CIPN symptoms [7.1%]; P = .01).

Conclusions and Relevance  These findings suggest that the sensory symptoms of CIPN are an indicator of an increased risk of falling and an increased use of health care resources. This study demonstrates the utility of a novel telephone-based system to track neuropathy symptoms. Careful monitoring and coaching of patients receiving neurotoxic chemotherapy for new sensory symptoms may facilitate more effective fall prevention strategies.

JAMA Neurology 2016

Pregnancy outcome following maternal exposure to pregabalin may call for concern

Objective: To investigate pregnancy outcomes following maternal use of pregabalin.

Methods: This multicenter, observational prospective cohort study compared pregnancy outcomes in women exposed to pregabalin with those of matched controls (not exposed to any medications known to be teratogenic or to any antiepileptic drugs). Teratology Information Services systematically collected data between 2004 and 2013.

Results: Data were collected from 164 exposed pregnancies and 656 controls. A significantly higher major birth defect rate in the pregabalin group was observed after exclusion of chromosomal aberration syndromes, and when cases with exposure during first trimester of pregnancy were analyzed separately (7/116 [6.0%] vs 12/580 [2.1%]; odds ratio 3.0, 95% confidence interval 1.2–7.9, p = 0.03). The rate of live births was lower in the pregabalin group (71.9% vs 85.2%, p < 0.001), primarily due to a higher rate of both elective (9.8% vs 5.0%, p = 0.02) and medically indicated (5.5% vs 1.8%, p = 0.008) pregnancy terminations. In the Cox proportional cause specific hazards model, pregabalin exposure was not associated with a significantly higher risk of spontaneous abortion.

Conclusions: This study demonstrated a signal for increased risk of major birth defects after first trimester exposure to pregabalin. However, several limitations such as the small sample size, differences across groups in maternal conditions, and concomitant medication exposure exclude definitive conclusions, so these results call for confirmation through independent studies.

Neurology 2016

Applying the HIV-associated neurocognitive disorder diagnostic criteria to HIV-infected youth

Objective: The aim of this study was to apply the HIV-associated neurocognitive disorders (HAND) criteria for diagnosing HAND in HIV-infected adults, in a cohort of HIV-infected youth to thus establish whether this system is able to detect a spectrum of neurocognitive disorders (ND) in HIV-infected youth.

Methods: We used a comprehensive pediatric neurocognitive battery, an assessment of functional competence, and the American Academy of Neurology system for diagnosing ND in a cross-sectional study of HIV-infected youth (n = 86) and HIV-negative controls (n = 34) to establish whether this system could detect a spectrum of ND in HIV-infected youth (6–16 years).

Results: Compared to a well-matched control group of HIV-negative youth, HIV-infected youth performed significantly more poorly on tests of Verbal IQ, Full Scale IQ, processing speed, finger tapping, verbal memory, expressive language, cognitive flexibility, and inhibition. HIV-infected youth were also more likely to have impaired total competence on the Child Behavior Checklist. Using the criteria for HAND, we found that 45.35% of the 86 HIV-infected youth could be diagnosed with an ND. Furthermore, youth with HIV encephalopathy (HIVE) were 9.4 times more likely to have a diagnosis of a major ND compared to HIV-infected youth without HIVE.

Conclusions: The HAND criterion designed for adults was able to identify youth with important functional cognitive impairments who do not fit criteria for HIVE and would therefore not have been identified otherwise. This has major clinical implications regarding the importance of managing HIV-infected youth.

Neurology 2016

Extracellular vesicles in neurodegenerative disease — pathogenesis to biomarkers

To develop effective disease-modifying therapies for neurodegenerative diseases, reliable markers of diagnosis, disease activity and progression are a research priority. The fact that neurodegenerative pathology is primarily associated with distinct subsets of cells in discrete areas of the CNS makes the identification of relevant biomarker molecules a challenge. The trafficking of macromolecules from the CNS to the cerebrospinal fluid and blood, mediated by extracellular vesicles (EVs), presents a promising source of CNS-specific biomarkers. EVs are released by almost all cell types and carry a cargo of protein and nucleic acid that varies according to the cell of origin. EV output changes with cell status and reflects intracellular events, so surface marker expression can be used to identify the cell type from which EVs originate. EVs could, therefore, provide an enriched pool of information about core neuropathogenic, cell-specific processes. This Review examines the current knowledge of the biology and function of EVs, discusses the evidence for their involvement in the pathogenesis of neurodegenerative diseases, and considers their potential as biomarkers of disease.

Nature Reviews Neurology 2016