John P. Betjemann

In Reply We thank Estol for his interest in our Viewpoint¹ discussing the call for neurologists to accept the challenge of diagnosing and managing hypertension to prevent neurologic disease. We applaud their efforts to study hypertension within their health system, in particular the effort made to change the culture of young neurologists by educating them on the importance of measuring blood pressure. Identify all potential conflicts of interest that might be relevant to your comment. Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued. Err on the side of full disclosure. If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response. Not all submitted comments are published. Please see our commenting policy for details.

This Viewpoint advocates for neurologists to address hypertension, including providing preventive care.

Multiple forms of status epilepticus exist (absence, focal, nonconvulsive) but generalized convulsive status epilepticus is most common and represents a neurological emergency. Two double-blind, randomized clinical trials (published 2001 and 2012) demonstrated the efficacy of benzodiazepines for the prehospital treatment of generalized convulsive status epilepticus.^1,2

Importance: Identifying infectious causes of subacute and chronic meningitis can be challenging. Enhanced, unbiased diagnostic approaches are needed. Objective: To present a case series of patients with diagnostically challenging subacute and chronic meningitis in whom metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF), supported by a statistical framework generated from mNGS sequencing of non-infectious patients and environmental controls, identified a pathogen. Design: Case series. Using mNGS data from the CSF of 94 non-infectious neuroinflammatory cases and 24 water and reagent controls, we developed and implemented a weighted scoring metric based on z-scores at the species and genus level for both nucleotide and protein databases to prioritize and rank mNGS results. We performed mNGS on total RNA extracted from CSF of patients with subacute or chronic meningitis and highlight seven cases representing a diverse array of pathogens. Setting: A multi-center study of mNGS pathogen discovery in patients with suspected neuroinflammatory conditions. Participants: Patients with diagnostically challenging subacute or chronic meningitis enrolled in a research study of mNGS performed on CSF. Intervention: mNGS was performed on total RNA extracted from CSF (0.25-0.5 mL). A weighted z-score was used to filter out environmental contaminants and facilitate efficient data triage and analysis. Main Outcomes: 1) Pathogens identified by mNGS and 2) ability of a statistical model to prioritize, rank, and simplify mNGS results. Results: mNGS identified parasitic worms, fungi and viruses in seven subjects: Taenia solium (n=2), Cryptococcus neoformans , human immunodeficiency virus-1, Aspergillus oryzae , Histoplasma capsulatum , and Candida dubliniensis . Evaluating mNGS data with a weighted z-score based scoring algorithm effectively separated bona fide pathogen sequences from spurious environmental sequences. Conclusions and Relevance: mNGS of CSF identified a diversity of microbial pathogens in patients with diagnostically challenging subacute or chronic meningitis, including a case of subarachnoid neurocysticercosis that defied diagnosis for one year, the first case of CNS vasculitis caused by Aspergillus oryzae , and the fourth reported case of Candida dubliniensis meningitis. Filtering metagenomic data with a scoring algorithm greatly clarified data interpretation and highlights the difficulties attributing biological significance to organisms that may be present in control samples used for metagenomic sequencing studies. Key Points: Question: How can metagenomic next-generation sequencing of cerebrospinal fluid be leveraged to aid in the diagnosis of patients with subacute or chronic meningitis? Findings: Metagenomic next-generation sequencing identified parasitic worms, fungi and viruses in a case series of seven subjects. A database of water-only and healthy patient controls enabled application of a z-score based scoring algorithm to effectively separate bona fide pathogen sequences from spurious environmental sequences. Meaning: Our scoring algorithm greatly simplified data interpretation in a series of patients with a wide range of challenging infectious causes of subacute or chronic meningitis identified by metagenomic next-generation sequencing.

Status epilepticus represents a relatively common neurologic emergency, with an annual incidence ranging from 10 to 41 per 100 000 persons.^1-5 Generalized convulsive status epilepticus is both the most serious and most common type of status epilepticus, representing 45% to 74% of cases.^2,5 As many as 30% of patients ultimately diagnosed as having epilepsy will initially present with status epilepticus.^2,6 While the overall case fatality associated with status epilepticus approaches 20%, an individual’s mortality risk depends largely on the underlying etiology; acute symptomatic causes (eg, ischemic stroke, intracerebral hemorrhage, acute traumatic brain injury, and hypoxic and anoxic brain injury) are associated with a higher case fatality than are more chronic etiologies (eg, alcohol abuse, preexisting epilepsy, and remote effects of stroke and trauma).^4,7-11