Joseph Safdieh

The varicella zoster virus vasculopathies: Clinical, CSF, imaging, and virologic features

Background: Varicella zoster virus (VZV) vasculopathy produces stroke secondary to viral infection of cerebral arteries. Not all patients have rash before cerebral ischemia or stroke. Furthermore, other vasculitides produce similar clinical features and comparable imaging, angiographic, and CSF abnormalities. Methods: We review our 23 published cases and 7 unpublished cases of VZV vasculopathy. All CSFs were tested for VZV DNA by PCR and anti-VZV IgG antibody and were positive for either or both. Results: Among 30 patients, rash occurred in 19 (63%), CSF pleocytosis in 20 (67%), and imaging abnormalities in 29 (97%). Angiography in 23 patients revealed abnormalities in 16 (70%). Large and small arteries were involved in 15 (50%), small arteries in 11 (37%), and large arteries in only 4 (13%) of 30 patients. Average time from rash to neurologic symptoms and signs was 4.1 months, and from neurologic symptoms and signs to CSF virologic analysis was 4.2 months. CSF of 9 (30%) patients contained VZV DNA while 28 (93%) had anti-VZV IgG antibody in CSF; in each of these patients, reduced serum/CSF ratio of VZV IgG confirmed intrathecal synthesis. Conclusions: Rash or CSF pleocytosis is not required to diagnose varicella zoster virus (VZV) vasculopathy, whereas MRI/CT abnormalities are seen in almost all patients. Most patients had mixed large and small artery involvement. Detection of anti-VZV IgG antibody in CSF was a more sensitive indicator of VZV vasculopathy than detection of VZV DNA (p < 0.001). Determination of optimal antiviral treatment and benefit of concurrent steroid therapy awaits studies with larger case numbers. GLOSSARY: EIA = enzyme immunoabsorbent assay; VZV = varicella zoster virus.

A Proposal for a Coordinated Effort for the Determination of Brainwide Neuroanatomical Connectivity in Model Organisms at a Mesoscopic Scale

In this era of complete genomes, our knowledge of neuroanatomical circuitry remains surprisingly sparse. Such knowledge is critical, however, for both basic and clinical research into brain function. Here we advocate for a concerted effort to fill this gap, through systematic, experimental mapping of neural circuits at a mesoscopic scale of resolution suitable for comprehensive, brainwide coverage, using injections of tracers or viral vectors. We detail the scientific and medical rationale and briefly review existing knowledge and experimental techniques. We define a set of desiderata, including brainwide coverage; validated and extensible experimental techniques suitable for standardization and automation; centralized, open-access data repository; compatibility with existing resources; and tractability with current informatics technology. We discuss a hypothetical but tractable plan for mouse, additional efforts for the macaque, and technique development for human. We estimate that the mouse connectivity project could be completed within five years with a comparatively modest budget.

Bacterial and fungal meningitis in patients with cancer

Objective: To analyze cases of bacterial and fungal meningitis in patients with cancer. Methods: Retrospective chart review from 1993 to 2004 was performed of patients with cancer at our institution who had positive CSF bacterial or fungal culture. Results: We identified 312 positive CSF cultures representing 175 unique presentations. Ninety-six cultures were deemed contaminants, leaving 79 cultures for analysis in 77 patients; 78% had prior neurosurgery. Organisms included 68% Gram-positive cocci, 10% Gram-positive bacilli, 14% Gram-negative bacilli, 7% Cryptococcus, and 1% C albicans. None had N meningitidis or H influenza. Two patients each had S pneumoniae or L monocytogenes. Five percent of presentations demonstrated the triad of fever, nuchal rigidity, and mental status changes. Seventy-five percent of presentations demonstrated CSF pleocytosis (≥10). Median CSF WBC count was 74 cells/mm3. CSF protein was elevated and glucose was depressed in 71%. In neutropenic patients (n = 6), 4 had 0 to 1 CSF WBC/mm3, and 2 had normal CSF. VP shunt infections were more likely to present with mental status changes. Thirty day mortality was 13%. Conclusions: Patients with cancer do not manifest symptoms of meningitis as often as patients without cancer and display a very different set of CSF organisms compared to a general population. The CSF inflammatory response is muted in patients with cancer with meningitis. Most patients with cancer with meningitis have had prior neurosurgery. Additionally, the organisms causing meningitis in the cancer population have shifted over time, with a decline in the organisms which typically infect immunocompromised hosts and an increase in Gram-positive infections.

The safety of levetiracetam

Levetiracetam is an antiepileptic drug approved for use as an adjunct agent in partial-onset seizures in adults and children aged ≥ 4 years. It was also approved as adjunctive therapy in the treatment of adults and adolescents aged ≥ 12 years with juvenile myoclonic epilepsy. A parenteral intravenous formulation has recently become available allowing for its use when oral administration is temporarily not feasible. Available literature has demonstrated and supported that levetiracetam has an acceptable safety profile and this review discusses the safety profile of levetiracetam, with attention to special populations. The most common adverse effects are somnolence, asthenia and dizziness, which usually appear early after initiation of levetiracetam therapy and generally resolve without medication withdrawal. The most serious adverse effects are behavioral in nature and are more common in children and in patients with a prior history of behavioral problems.

Review of levetiracetam, with a focus on the extended release formulation, as adjuvant therapy in controlling partial-onset seizures.

Levetiracetam is a second-generation antiepileptic drug (AED) with a unique chemical structure and mechanism of action. The extended release formulation of levetiracetam (Keppra XR™; UCB Pharma) was recently approved by the Food and Drug Administration for adjunctive therapy in the treatment of partial-onset seizures in patients 16 years of age and older with epilepsy. This approval is based on a double-blind, randomized, placebo-controlled, multicenter, multinational trial. Levetiracetam XR allows for once-daily dosing, which may increase compliance and, given the relatively constant plasma concentrations, may minimize concentration-related adverse effects. Levetiracetam’s mode of action is not fully elucidated, but it has been found to target high-voltage, N-type calcium channels as well as the synaptic vesicle protein 2A (SV2A). Levetiracetam has nearly ideal pharmacokinetics. It is rapidly and almost completely absorbed after oral ingestion, is <10% protein-bound, demonstrates linear kinetics, is minimally metabolized through a pathway independent of the cytochrome P450 system, has no significant drug–drug interactions, and has a wide therapeutic index. The most common reported adverse events with levetiracetam XR were somnolence, irritability, dizziness, nausea, influenza, and nasopharyngitis. Levetiracetam XR provides an efficacious and well-tolerated treatment option for adjunctive therapy in the treatment of partial-onset seizures.

Varicella zoster virus meningitis with hypoglycorrhachia in the absence of rash in an immunocompetent woman

We report varicella-zoster virus (VZV) meningitis in a healthy adult woman with no antecedent rash and with hypoglycorrhachia. Cerebrospinal fluid (CSF) examination revealed the presence of VZV DNA, anti-VZV immunoglobulin G (IgG) antibody, and intrathecal production of anti-VZV IgG antibody.

Ommaya reservoir infections: A 16-year retrospective analysis

OBJECTIVES Ommaya reservoirs (OmR) are used in the treatment of cancer yet risk factors and outcome of infection are not well characterized. We therefore examined our experience with this device. METHODS Using administrative databases, we identified all patients with OmR in situ between 1993 and 2008 at Memorial Sloan-Kettering Cancer Center. Charts were reviewed for laboratory, demographic, and clinical information. RESULTS During the study period, 616 patients with OmRs received care at MSKCC comprising 462,467 Ommaya-days. 34 patients with OmR infection were identified (5.5% of patients, 0.74 infections per 10,000 Ommaya-days). 32% of infections occurred within 30 days of OmR placement. Most (74%) OmR infections occurring after 30 days post-placement were associated with OmR access in the preceding 30 days. Recovered organisms included coagulase-negative staphylococci (56%) and Propionibacterium acnes (24%). 70% of patients had fever and/or headache and 69% had cerebrospinal fluid pleocytosis. 50% of patients had the reservoir removed during treatment of the infection. CONCLUSIONS OmR infection occurs in one of every 20 persons with the device. A third of the infections appear related to OmR placement while the remainder may occur at any time and usually are associated with recent reservoir access. Treatment often includes device removal.

PBL 2.0: enhancing problem-based learning through increased student participation

Abstract Purpose : The purpose of this study was to test a new problem-based learning (PBL) method to see if it reinvigorated the learning experience. Method : A new PBL format called PBL 2.0, which met for 90 min two times per week, was introduced in 2009 into an 11-week integrated neuroscience course. One hundred second-year medical students, divided into 10 groups of 10, who had completed their first year of medical school using a traditional PBL format, participated in PBL 2.0. Students were prohibited from using computers during the first session. Learning objectives were distributed at the end of the first day to the small groups, and students were assigned to pairs/trios responsible for leading an interactive discussion on specific learning objectives the following day. Student-led ‘lectures’ were prohibited. All students were responsible for learning all of the learning objectives so that they could participate in their discussions. Results : One hundred and six students were surveyed and 98 submitted answers (92% response). The majority of groups adhered to the new PBL method. Students invested more time preparing the learning objectives. Students indicated that the level of interaction among students increased. The majority of students preferred the new PBL format. Conclusions : PBL 2.0 was effective in increasing student interaction and promoting increased learning.

Recurrent, alternating Tolosa-Hunt syndrome.

A 24-year-old woman presented with right face pain and blurry vision. Examination revealed right pupil-sparing third nerve palsy and decreased sensation in the second and third divisions of the right trigeminal nerve. MRI demonstrated right cavernous sinus enhancement. Infectious, rheumatologic, and neoplastic evaluation was negative, and the patient was diagnosed with Tolosa-Hunt syndrome. Corticosteroid therapy resulted in resolution of all symptoms. Ten months later, the patient developed left face pain and double vision with a left third nerve palsy on examination. MRI revealed an enhancing left cavernous sinus. High-dose corticosteroid therapy again led to resolution of symptoms. This case demonstrates that Tolosa-Hunt syndrome can rarely recur on the contralateral side. MRI of this presentation has not been previously reported in the literature.

The evaluation and management of bacterial meningitis: current practice and emerging developments.

Background and Objective:Bacterial meningitis is a serious neurologic illness with significant morbidity and mortality if not recognized and treated promptly and appropriately. The presentation and management are influenced by host factors and the pathogenic organism; the purpose of this review is to highlight those differences and to survey the literature on current practices and emerging developments in evaluation and management. Review Summary:Clinicians must have a high index of suspicion for bacterial meningitis. The classic symptoms of bacterial meningitis are fever, neck stiffness, altered mental status, and headache. Certain patient populations, such as the young and the immunocompromised, may have a blunted presentation, and for these patients, clinicians must have an especially low threshold for obtaining a lumbar puncture. When bacterial meningitis is suspected, antibiotic therapy should be initiated as soon as possible because early treatment is associated with a better outcome. In addition, the use of the corticosteroid dexamethasone has been shown to be helpful as an adjuvant therapy in specific clinical situations. New adjuvant therapies are being developed to lower the high rate of complications that currently occur in patients with bacterial meningitis. Conclusions:Recent studies have altered the evaluation and management of bacterial meningitis. In addition, they have elucidated the mechanisms through which bacterial meningitis causes complications and have identified new targets for treatment.