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As neuropalliative care is better recognized and more widely utilized, there is as great a need for clinicians trained in the field as there is for disease-specific symptom management, advance care planning, and end-of-life care. In this manuscript, we describe potential career trajectories in neuropalliative care. For clinicians, this includes educational and training opportunities within primary neuropalliative care (integrating palliative care principles into usual neurology practice), specialty neuropalliative care (completing a hospice and palliative medicine fellowship), and hospice. We also describe considerations for establishing new clinical neuropalliative practices and highlight neuropalliative education and research as key areas for advancing the field., Competing Interests: None declared., (Thieme. All rights reserved.)

Background and Objectives: In a retrospective study evaluating the diagnostic approach of definitive neurological infections at a tertiary referral center, we assessed the time to diagnosis from presentation, number of diagnostic tests ordered, and modality of etiologic diagnosis., Methods: A total of 111 confirmed clinical cases of neurological infections from 2010-2018 were reviewed. Definitive neuroinfectious diagnoses were defined by positive cerebrospinal (CSF) polymerase chain reaction (PCR)/antigen, CSF culture, CSF antibody, serology, or pathology tests., Results: An etiologic diagnosis was determined at an average (SD) of 3.1 (5.9) days after presentation with an average (SD) of 27.7 (15.6) diagnostic tests ordered per workup.Viral neuro-infections were associated with lower intensive care unit (ICU) admission rates, shorter length of hospitalization, and fewer diagnostic tests ordered, as well as shorter time to definitive diagnosis ( P < .05). Longer hospitalizations were associated with immunosuppression status regardless of infectious etiology ( P < .001)., Discussion: Given the high morbidity and mortality of neuroinfectious disease, specifically meningitis and encephalitis, efficient diagnostic testing is imperative to facilitate the most appropriate clinical course of action with special attention to the specific patient population., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Introduction and Problem Statement: Neurologic disease is a leading cause of disability and death worldwide. As the global population ages, the burden of these diseases is expected to increase. Despite this increased clinical need, neurology trainees are seldom taught skills and concepts in palliative care. Education in Palliative and End-of-Life Care for Neurology (EPEC-N) is a publicly available neuropalliative care curriculum designed to be taught by both palliative care specialists and nonspecialists alike., Objectives: (1) To create a feasible curriculum in neuropalliative care using EPEC-N, (2) to improve learners' satisfaction with neuropalliative care training, and (3) to improve learners' confidence with neuropalliative care topics., Methods and Curriculum Description: Three academic centers implemented a neuropalliative care curriculum for neurology residents using EPEC-N modules. Each site selected 4 of the 26 topics. Instructor backgrounds varied by site and included neurology senior residents, fellows, and faculty; none had completed palliative care fellowship at the time of teaching. Teaching methods included lecture, case discussion, and role-play. To assess feasibility and acceptability of this curriculum, learners, instructors, and site leads completed postsession surveys., Results and Assessment Data: A total of 87 residents attended at least 1 didactic session, and 23 residents completed the evaluation survey. All 3 sites were able to successfully implement an evidence-based and subspecialist-approved neuropalliative care curriculum without relying on subspecialty instruction, despite variations in instructor background, curriculum format, and module selection. Learners overall expressed a positive experience with this curriculum, with most of the respondents indicating that each session was effective in improving their knowledge base, relevant to current practice, and provided in an effective teaching format. Site leads and instructors found the curriculum easy to use, in minimal need of modification, and helpful for delivering neuropalliative care education., Discussion and Lessons Learned: The EPEC-N curriculum was successfully implemented at 3 US sites, demonstrating feasibility, acceptability, and adaptability across institutions. Further research is needed to evaluate the effectiveness of this curriculum in improving neuropalliative care skills for neurologists and raising the standard of primary neuropalliative care., Competing Interests: The authors report no disclosures. Go to Neurology.org/NE for full disclosures., (© 2024 American Academy of Neurology.)

Unbiased high-throughput sequencing (HTS) has enabled new insights into the diversity of agents implicated in central nervous system (CNS) infections. The addition of positive selection capture methods to HTS has enhanced the sensitivity while reducing sequencing costs and the complexity of bioinformatic analysis. Here we report the use of virus capture-based sequencing for vertebrate viruses (VirCapSeq-VERT) and bacterial capture sequencing (BacCapSeq) in investigating CNS infections. Thirty-four samples were categorized: (1) patients with definitive CNS infection by routine testing; (2) patients meeting clinically the Brighton criteria (BC) for meningoencephalitis; (3) patients with presumptive infectious etiology highest on the differential. RNA extracts from cerebrospinal fluid (CSF) were used for VirCapSeq-VERT, and DNA extracts were used for BacCapSeq analysis. Among 8 samples from known CNS infections in group 1, VirCapSeq and BacCapSeq confirmed 3 expected diagnoses (42.8%), were negative in 2 (25%), yielded an alternative result in 1 (11.1%), and did not detect 2 expected negative pathogens. The confirmed cases identified HHV-6, HSV-2, and VZV while the negative samples included JCV and HSV-2. In groups 2 and 3, 11/26 samples (42%) were positive for at least one pathogen; however, 27% of the total samples (7/26) were positive for commensal organisms. No microbial nucleic acids were detected in negative control samples. HTS showed limited promise for pathogen identification in presumed CNS infectious diseases in our small sample. Before conducting larger-scale prospective studies to assess the clinical value of this novel technique, clinicians should understand the benefits and limitations of using this modality., (© 2023. The Author(s) under exclusive licence to The Journal of NeuroVirology, Inc.)

Objectives: Early presentation and workup for acute infectious (IE) and autoimmune encephalitis (AE) are similar. This study aims to identify routine laboratory markers at presentation that are associated with IE or AE., Methods: This was a multi-center retrospective study at three tertiary care hospitals in New York City analyzing demographic and clinical data from patients diagnosed with definitive encephalitis based on a confirmed pathogen and/or autoantibody and established criteria for clinical syndromes., Results: Three hundred and thirty-three individuals with confirmed acute meningoencephalitis were included. An infectious-nonbacterial (NB) pathogen was identified in 151/333 (45.40%), bacterial pathogen in 95/333 (28.50%), and autoantibody in 87/333 (26.10%). NB encephalitis was differentiated from AE by the presence of fever (NB 62.25%, AE 24.10%; p < 0.001), higher CSF white blood cell (WBC) (median 78 cells/μL, 8.00 cells/μL; p < 0.001), higher CSF protein (76.50 mg/dL, 40.90 mg/dL; p < 0.001), lower CSF glucose (58.00 mg/dL, 69.00 mg/dL; p < 0.001), lower serum WBC (7.80 cells/μL, 9.72 cells/μL; p < 0.050), higher erythrocyte sedimentation rate (19.50 mm/HR, 13.00 mm/HR; p < 0.05), higher C-reactive protein (6.40 mg/L, 1.25 mg/L; p = 0.005), and lack of antinuclear antibody titers (>1:40; NB 11.54%, AE 32.73%; p < 0.001). CSF-to-serum WBC ratio was significantly higher in NB compared to AE (NB 11.3, AE 0.99; p < 0.001). From these findings, the association of presenting with fever, CSF WBC ≥50 cells/μL, and CSF protein ≥75 mg/dL was explored in ruling-out AE. When all three criteria are present, an AE was found to be highly unlikely (sensitivity 92%, specificity 75%, negative predictive value 95%, and positive predictive value 64%)., Interpretations: Specific paraclinical data at initial presentation may risk stratify which patients have an IE versus AE., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Depression is a leading cause of disease burden, yet current therapies fully treat <50% of affected individuals. Increasing evidence implicates epigenetic mechanisms in depression and antidepressant action. Here we examined a possible role for the DNA dioxygenase, ten-eleven translocation protein 1 (TET1), in depression-related behavioral abnormalities. We applied chronic social defeat stress, an ethologically validated mouse model of depression-like behaviors, and examined Tet1 expression changes in nucleus accumbens (NAc), a key brain reward region. We show decreased Tet1 expression in NAc in stress-susceptible mice only. Surprisingly, selective knockout of Tet1 in NAc neurons of adult mice produced antidepressant-like effects in several behavioral assays. To identify Tet1 targets that mediate these actions, we performed RNAseq on NAc after conditional deletion of Tet1 and found that immune-related genes are the most highly dysregulated. Moreover, many of these genes are also upregulated in the NAc of resilient mice after chronic social defeat stress. These findings reveal a novel role for TET1, an enzyme important for DNA hydroxymethylation, in the brain's reward circuitry in modulating stress responses in mice. We also identify a subset of genes that are regulated by TET1 in this circuitry. These findings provide new insight into the pathophysiology of depression, which can aid in future antidepressant drug discovery efforts.

Decreased medial prefrontal cortex (mPFC) neuronal activity is associated with social defeat-induced depression- and anxiety-like behaviors in mice. However, the molecular mechanisms underlying the decreased mPFC activity and its prodepressant role remain unknown. We show here that induction of the transcription factor ΔFosB in mPFC, specifically in the prelimbic (PrL) area, mediates susceptibility to stress. ΔFosB induction in PrL occurred selectively in susceptible mice after chronic social defeat stress, and overexpression of ΔFosB in this region, but not in the nearby infralimbic (IL) area, enhanced stress susceptibility. ΔFosB produced these effects partly through induction of the cholecystokinin (CCK)-B receptor: CCKB blockade in mPFC induces a resilient phenotype, whereas CCK administration into mPFC mimics the anxiogenic- and depressant-like effects of social stress. We previously found that optogenetic stimulation of mPFC neurons in susceptible mice reverses several behavioral abnormalities seen after chronic social defeat stress. Therefore, we hypothesized that optogenetic stimulation of cortical projections would rescue the pathological effects of CCK in mPFC. After CCK infusion in mPFC, we optogenetically stimulated mPFC projections to basolateral amygdala or nucleus accumbens, two subcortical structures involved in mood regulation. Stimulation of corticoamygdala projections blocked the anxiogenic effect of CCK, although no effect was observed on other symptoms of social defeat. Conversely, stimulation of corticoaccumbens projections reversed CCK-induced social avoidance and sucrose preference deficits but not anxiogenic-like effects. Together, these results indicate that social stress-induced behavioral deficits are mediated partly by molecular adaptations in mPFC involving ΔFosB and CCK through cortical projections to distinct subcortical targets.

We report psychometric results of the Behavioural Activity Rating Scale (BARS) using data from three Phase III clinical trials of intramuscular ziprasidone in acutely agitated patients with psychosis (Studies 1 and 2) or in stable psychotic patients (Study 3). Convergent validity and divergent validity were assessed with baseline data from Studies 1 and 2 in subjects with acute agitation. To investigate convergent validity, we sought Pearson and Spearman correlation of BARS scores with scores on the Clinical Global Impression of Severity (CGI-S) Scale and a predefined cluster of agitation-related items from the Positive and Negative Syndrome Scale (PANSS). For divergent validity, we sought Pearson and Spearman correlation between BARS scores and a predefined cluster of PANSS items measuring negative symptoms. Discriminant validity was investigated with the help of subjects with moderate psychopathology (Study 3). Wilcoxon rank-sum and two-sample t tests determined whether mean (or median) BARS scores differed between subjects with acute agitation (Studies 1 and 2) and moderate psychopathology (Study 3). Responsiveness to treatment effect and rater reliability were also evaluated. In Study 2, Pearson correlation coefficients of BARS scores with PANSS agitation items and CGI-S were moderate (convergent validity) and statistically significant (P<0.005). The correlation between BARS scores and PANSS negative component scores was low (divergent validity). Treatment effect size was larger for BARS than for PANSS agitation items and CGI-S (responsive to treatment differences). Virtually perfect inter- and intra-rater reliability was achieved. Study 1 produced similar results. BARS showed psychometrically valid properties for measurement of behavioral activity in acutely agitated patients with psychosis.

Rationale: Intramuscular (IM) conventional antipsychotics and/or benzodiazepines are effective in the short-term treatment of acutely agitated psychotic patients but may be associated with adverse effects. A short-acting IM formulation of the novel antipsychotic, ziprasidone, which may offer advantages over conventional agents, has been developed., Objective: To compare ziprasidone IM 2 mg (n=38) and 20 mg (n=41) in the acute control and short-term management of agitated psychotic patients., Methods: A prospective, randomized, double-blind, 24-h study assessed efficacy using the Behavioral Activity Rating Scale (BARS) and the PANSS. The BARS is a validated rating scale for the assessment of treatment response in acute agitation associated with psychosis. Following the initial dose, three more doses could be given 4 h apart if needed during the 24-h period., Results: The mean BARS score had decreased 15 min after the first 20 mg IM dose and was statistically significantly lower than the 2 mg group at 30 min post-dose. The improvement with the 20 mg dose increased until 2 h, and was maintained until at least 4 h post-dose (P<0.001). Two hours after the first injection, almost all of the patients receiving ziprasidone 20 mg were BARS responders compared with just one-third of those receiving 2 mg ziprasidone (P<0.001). The calming effect of ziprasidone was also evident by the significant reduction in PANSS agitation items (P<0.05) and CGI-severity at 4 h (P=0.008). Both ziprasidone doses were very well tolerated. Ziprasidone IM 20 mg was not associated with EPS, dystonia, akathisia, respiratory depression or with excessive sedation., Conclusions: Ziprasidone IM 20 mg substantially and significantly reduced the symptoms of acute agitation in patients with psychotic disorders. Ziprasidone 20 mg IM was very well tolerated and produced no dystonia or akathisia.

Many anti-psychotic medications produce marked weight gain. In this study, we estimate the expected impact of degrees of antipsychotic-induced weight gain on selected mortality rate and incidence rates of impaired glucose tolerance (IGT) and hypertension (HTN) among US adults. Using raw data from 5209 respondents from the Framingham Heart Study's public use data set and national statistics on population demographics, we estimated the expected effect of weight gain on number of deaths and incident cases of IGT and HTN for a 10-year period commencing in 1999. Results indicated that the estimated deleterious effects of weight gain were greater for people with higher BMIs at baseline, for greater degrees of weight gain, for men than women, and for older than younger persons. Because there is a 'U-shaped' relation between BMI and mortality rate, small to moderate weight gains among people with baseline BMIs less than 23 were predicted to decrease mortality rates, whereas weight gains among people with baseline BMIs above that level were expected to increase mortality rates. However, the relations of IGT and HTN with BMI are monotonically increasing. Thus, the anticipated effect of weight gain on IGT and HTN is deleterious regardless of baseline BMI. Because it is unclear whether the beneficial effects of the atypical agents on, for example, reducing suicide mortality, outweigh the putative increase in mortality due to weight gain, we estimate the beneficial effects due to decreased death from suicide with the potential deleterious effects due to a 10-kg weight gain. We found that 492 suicide deaths per 100,000 schizophrenic patients would be prevented over 10 years with the use of clozapine compared to 416 additional deaths due to antipsychotic induced weight gain. Although this estimate is rather crude and should be seen only as offering a sense of the likely situation, results suggest that the lives saved via clozapine may essentially be offset by the deaths due to weight gain. As we discuss, it is not possible to provide definitive estimates of the effect of antipsychotic-induced weight gain on health and mortality, but our findings suggest that the magnitude of weight gains induced by many antipsychotic agents is likely to have important deleterious effects on mortality and health.

The effects of disease states and therapeutic drugs on the QT interval have been extensively studied in an attempt to understand the relationship between QT and the risk of torsade de pointes and sudden cardiac death. Differences in heart rate correction methods, electrocardiogram lead placement, and other internal (eg, genetic, physiologic) and external (eg, food, time of day) factors have confounded the interpretation of this relationship. A comprehensive review of the epidemiologic literature suggests that the corrected QT interval (QTc) is an important but imprecise marker of cardiovascular disease. The association between QTc prolongation and mortality has been identified in patients with cardiac disease but is unclear in patients without cardiac disease. Drug-related prolongation of QTc can clearly increase the risk of torsade de pointes, but this arrhythmia is rarely associated with a QTc of less than 500 ms. It also appears that noncardiac drugs that are associated with QTc prolongation are not identical in their proarrhythmic capacities and that increased exposure via clinically significant drug interactions is a major contributor to the liability of noncardiac drug-induced arrhythmia. Recognition of the aforementioned variables in conjunction with careful QTc measurements assists in establishing a more precise benefit-risk ratio for a specific drug therapy or for arrhythmia risk associated with various pathophysiologic or genetic states.

This study assessed the efficacy of ziprasidone for the treatment of schizoaffective disorder. Data were taken from subsets of patients with schizoaffective disorder, derived from two separate double-blind, placebo-controlled, parallel-group, multicenter studies. A total of 115 hospitalized patients with an acute episode of schizoaffective disorder were randomly assigned to receive either fixed oral doses of ziprasidone 40 mg/day (N = 16), 80 mg/day (N = 18), 120 mg/day (N = 22), 160 mg/day (N = 25), or placebo (N = 34) for 4 to 6 weeks. Mean baseline-to-endpoint changes in Brief Psychiatric Rating Scale (BPRS) total, BPRS Core, Clinical Global Impressions Severity scale (CGI-S), BPRS Depressive, BPRS Manic, and Montgomery-Asberg Depression Rating Scale total scores were compared between the placebo and ziprasidone groups. Neurological (Simpson-Angus, Barnes Akathisia, Abnormal Involuntary Movement Scale [AIMS]) and other side effects were also assessed. Significant dose-related improvements on all primary efficacy variables (BPRS total, BPRS Core, CGI-S) and for BPRS Manic items were observed with ziprasidone treatment in a combined analysis of data from both studies (p < or = 0.01). Ziprasidone 160 mg/day was significantly more effective than placebo in improving mean BPRS total, BPRS Core, BPRS Manic, and CGI-S scores (p < 0.05). At 120 mg/day, ziprasidone was significantly more effective than placebo in improving mean CGI-S scores (p < 0.05). The incidence of individual adverse events was generally low in all treatment groups and was not dose-related. In addition, no significant differences were observed between baseline-to-endpoint mean changes in Simpson-Angus and AIMS scores with placebo or ziprasidone 40 to 160 mg/day. These results suggest that ziprasidone may have efficacy in the treatment of affective as well as psychotic symptoms of schizoaffective disorder, with a low side-effect burden.

Background: There is a clear need for effective, well-tolerated intramuscular (i.m.) agents for the acute control of agitated psychotic patients. Currently used agents, including conventional antipsychotics and/or benzodiazepines, may be associated with distressing side effects such as extrapyramidal side effects and excessive sedation., Objective: The objective of this study was to evaluate the efficacy and tolerability of the rapid-acting i.m. formulation of the novel antipsychotic ziprasidone in the treatment of inpatients with psychosis and acute agitation (DSM-IV diagnoses)., Method: In a 24-hour, double-blind, fixed-dose clinical trial, patients were randomly assigned to receive up to 4 injections (every 2 hours p.r.n.) of 2 mg (N = 54) or 10 mg (N = 63) of ziprasidone i.m. The Behavioral Activity Rating Scale measured behavioral symptoms at baseline and the response to treatment up to 4 hours after the first i.m. injection., Results: Ziprasidone i.m., 10 mg, rapidly reduced symptoms of acute agitation and was significantly more effective (p < .01) than the 2-mg dose up to 4 hours after the first injection. Patients were calmed but not excessively sedated, and over half were classed as responders 2 hours after the 10-mg dose. No acute dystonia or behavioral disinhibition was reported. One patient who received the 10-mg dose experienced the extrapyramidal side effect akathisia., Conclusion: Ziprasidone i.m., 10 mg, is rapidly effective and well tolerated in the short-term management of the agitated psychotic patient. Comparison with a study of identical design comparing 2-mg with 20-mg doses in patients with similar levels of psychopathology suggests that efficacy with 10 mg or 20 mg of ziprasidone i.m. is significant and dose related.

In this double-blind study, patients with an acute exacerbation of schizophrenia or schizoaffective disorder were randomized to receive either ziprasidone 80 mg/day (n = 106) or 160 mg/day (n = 104) or placebo (n = 92), for 6 weeks. Both doses of ziprasidone were statistically significantly more effective than placebo in improving the PANSS total, BPRS total, BPRS core items, CGI-S, and PANSS negative subscale scores (p < .05). Ziprasidone 160 mg/day significantly improved depressive symptoms in patients with clinically significant depression at baseline (MADRS > or = 14, over-all mean 23.5) (p < .05) as compared with placebo. The percentage of patients experiencing adverse events was similar in each treatment group, and resultant discontinuation was rare. The most frequent adverse events associated with ziprasidone were generally mild dyspepsia, nausea, dizziness, and transient somnolence. Ziprasidone was shown to have a very low liability for inducing movement disorders and weight gain. The results indicate that ziprasidone is effective and well tolerated in the treatment of the positive, negative, and depressive symptoms of an acute exacerbation of schizophrenia or schizoaffective disorder.

A double-blind, placebo-controlled, multicenter study, was performed to evaluate the efficacy and safety of ziprasidone in 139 patients with an acute exacerbation of schizophrenia or schizoaffective disorder. Patients were randomized to receive ziprasidone 40 mg/day, 120 mg/day or placebo for 28 days. Ziprasidone 120 mg/day was significantly more effective than placebo in improving the BPRS total, CGI-S. BPRS depression cluster and BPRS anergia cluster scores (all P < 0.05). Similarly, the percentages of patients classified as responders on the BPRS (> or = 30% reduction) and the CGI improvement (score < or = 2) were significantly greater with ziprasidone 120 mg/day compared with placebo (P < 0.05). The number of patients who experienced an adverse event was similar in all three treatment groups, and discontinuation due to adverse events was rare (five of 91 ziprasidone-treated patients). The most frequently reported adverse events, that were more common in either ziprasidone group than in the placebo group, were dyspepsia, constipation, nausea and abdominal pain. There was a notably low incidence extrapyramidal side-effects (including akathisia) and postural hypotension and no pattern of laboratory abnormalities or apparent weight gain. Ziprasidone-treated patients were not clinically different from placebo-treated patients on the Simpson-Angus Rating scale, Barnes Akathisia scale and AIMS assessments. These results indicate that ziprasidone 120 mg/day is effective in the treatment of the positive, negative and affective symptoms of schizophrenia and schizoaffective disorder with a very low side-effect burden.

The central nucleus of the rat amygdala (CeA) contains many corticotropin releasing factor (CRF) immunoreactive neurons. Previous studies have demonstrated that these CRF neurons project to brain stem regions responsible for modulation of autonomic outflow. Calcitonin gene-related peptide (CGRP) terminals overlap the distribution of CRF cell bodies in the CeA. These CGRP terminals mainly originate from cell bodies that are located in the pontine parabrachial nucleus. The present study examined the possibility that CRF cell bodies are innervated by CGRP terminals. The results suggest that over 35% of the CRF neurons in the CeA are contacted by CGRP terminals as judged by the indiscernible distances between the terminals and cell bodies and or dendrites. In addition, a dual-labeled electron microscopic technique demonstrates that CGRP terminals form synaptic contacts with CRF cell bodies and dendrites. This suggests that CGRP neurons in the parabrachial nucleus can modulate the activity of CRF amygdaloid brain stem efferents. Previous studies have shown that CRF, when administered into the central nervous system, produces increases in heart rate, blood pressure, and plasma catecholamines. CGRP administration into the amygdala has been shown to have a similar effect on the autonomic nervous system. It is, therefore, possible that CGRP could exert these effects via an amygdaloid CRF pathway.

1. Reflex effects mediated by knee joint afferent neurons were tested using the electrically evoked monosynaptic reflex in motoneurons innervating muscles which act about the knee. 2. Joint afferents were excited using small extension movements of the knee, stimuli which have been shown to be effective in activating a large fraction of the myelinated fibers in joint nerves. Because of the variability of reflex responses observed by others under similar experimental conditions, experimental control and data collection were done automatically under computer control. Large numbers of trials were presented in random sequence, and the resulting data were sorted and averaged. 3. Positive feedback was observed in both knee extensor (vasti) and knee flexor (posterior biceps-semitendinosus (PB-ST)) motoneuron populations. Vasti motoneurons were excited, and PB-ST motoneurons were inhibited by knee extensions when the posterior articular nerve (PAN) was intact; these effects were lost or substantially reduced when the PAN was cut. 4. Using knee extension stimuli, no reliable reflex effects were observed which could be attributed to afferents in medial articular nerve.

With the widespread use of serum VDRL testing and penicillin therapy, the prominence of syphilis as an occult cause of neurologic disease has receded. Recent statistics from the Centers for Disease Control, Atlanta, reflect an increase in cases of primary syphilis, promising that more cases of neurosyphilis will arise to confound the unwary clincian. We studied an unusual case of neurosyphilis and developed a rational basis for antibiotic treatment of this condition.