Chiefs’ Inquiry Corner – March 25th, 2019

March 25, 2019

Being an outstanding physician and lifelong learner requires stoking the flames of clinical curiosity.  In Chiefs’ Inquiry Corner (CIC) we attempt to succinctly answer actual clinical questions that have been raised on the wards and in the clinics of NYU’s teaching hospitals.  Our answers are not meant to be all encompassing or practice changing but rather to serve as springboards for further exploration.  For those of us with short attention spans, we hope CIC satisfies that craving for a morsel of knowledge in a digestible format.


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Herpes Simplex Virus (HSV) has become a common etiology of viral encephalitis in both immunocompromised as well as immunocompetent hosts. Prompt recognition of HSV encephalitis is crucial as a delay in treatment is associated with significant morbidity and mortality. Biopsy of the brain was previously the gold standard for the diagnosis of this condition, though has since fallen out of favor with the advent of the less invasive CSF polymerase chain reaction (PCR) – shown to have both high sensitivity as well as specificity in this diagnosis. Previous studies have suggested that patients are at low risk of HSV encephalitis when CSF wbc <5, CSF protein <50, the patient is older than 2 years old, and is immunocompetent – these are known are the “Reller Criteria,” and these thresholds have been shown to be extremely sensitive. A recently published multicenter, retrospective study examined 4,404 CSF samples in making a diagnosis of HSV encephalitis. In this cohort, 91 patients (2.1%) tested positive for HSV, 9 of whom were noted to have normal CSF WBC and protein (thereby not meeting the Reller criteria). These patients were noted to have clinical syndromes suggestive of encephalitis or meningoencephalitis, whereas clinical symptoms of meningitis were much more common in patients meeting the Reller criteria. Though this study has a number of limitations, including the use of different PCR assays between centers, it suggests that normal CSF cell and protein levels do not entirely rule out the possibility of a herpes simplex virus CNS infection. Therefore, we must maintain a high level of clinical suspicion in deciding whom to both test and treat for this potentially fatal condition.

References: Missing cases of HSV encephalitis  
High dose systemic methotrexate is a common treatment option in many leukemias, non-Hodgkin lymphomas, and osteosarcoma. Toxicity from high-dose methotrexate takes many forms – pulmonary, renal, and hepatic manifestations are some of the most well recognized. Systemic methotrexate has diverse neurologic toxicities: an acute form within 24 hours of treatment is characterized by transient mental status changes and in some cases seizures. A subacute form of toxicity develops between 2 and 16 days after treatment and is characterized by migrating focal ‘stroke-like’ symptoms which, in small studies, have been shown to correlate with restricted diffusion on diffusion-weighted MRI. A late stage manifestation of methotrexate neurotoxicity is leukoencephalopathy, characterized by diffuse white matter changes radiographically and progressive cognitive dysfunction clinically, which appear months to years after treatment. The mechanisms underpinning these toxicities are poorly understood and treatment options are limited; however small case series have shown a benefit in symptoms of subacute methotrexate neurotoxicity with dextromethorphan (which antagonizes NMDA receptors that are thought to be stimulated by methotrexate-mediated elevations in CNS homocysteine) and aminophylline (which is thought to counter methotrexate-mediated elevations in CNS adenosine).

References: Methotrexate Neurotoxicity  
Progressive Multifocal Leukoencephalopathy (PML) is an often fatal demyelinating disease of the central nervous system seen most commonly, but not exclusively, in patients with HIV infection and AIDS. The disease is caused by the polyomavirus JC (JCV), which asymptomatically infects >80% of the population and remains dormant in the kidneys and lymphoid tissue. In AIDS, patients who are immunocompromised from organ transplantation or hematological malignancy, and patients treated with the integrin inhibitor, natalizumab, JCV is able to reactivate in the central nervous system and cause a lytic infection of oligodendrocytes. PML classically presents with subacute progressive neurological deficits, including altered mental status, motor deficits, limb ataxia, gait ataxia, and visual symptoms. Seizures are common and the disease is usually progressive and fatal within a few months.

References: Progressive multifocal leukoencephalopathy