Faculty Bibliography

Cerebral venous sinus thrombosis (CVST) requires anticoagulation to promote vessel recanalization. Current anticoagulation paradigms utilize plasma tests from peripheral venous/arterial samples for therapeutic monitoring. We describe a medically-refractory case of CVST in a 35-year-old woman later found to have JAK2 mutation and essential thrombocytosis. Despite therapeutic anticoagulation levels, worsening cerebral edema and progression to coma prompted endovascular treatment. Failed endovascular thrombectomy attempts led to placement of 2 separate indwelling microcatheters for continuous infusion of tissue plasminogen activator (tPA). Forty-hours of continuous-tPA in addition to systemic intravenous-heparin led to complete radiographic and clinical resolution of CVST. Whole blood coagulation testing using Rotational Thromboelastometry (ROTEM) from simultaneous samples taken intracranially (via cerebral microcatheters) and peripherally (via antecubital vein) all revealed prolonged intrinsic pathway activation clotting times consistent with heparin anticoagulation use. However, both intracranial ROTEM samples identified faster clotting times compared to the peripheral sample suggesting lower anticoagulation levels intracranially. Our findings were speculative and hypothesis generating as to whether this explained medical treatment failure. If there are coagulopathy differences at local sites of injury not adequately captured by peripheral blood draws, further investigation is required to identify better approaches to avoid under-treatment of similar cases.

Therapeutic hypothermia (TH) is a potent neuroprotectant for experimental ischemic stroke, but studies of TH for intracerebral hemorrhage (ICH) are emerging. We systematically reviewed the experimental literature to assess TH efficacy for ICH. We found 18 suitable papers; quality scores were moderately good. Compared with normothermia, TH reduced measures of edema (mean effect size (95% CI) -1.6873 (-2.3640, -1.0106), p < 0.0001) or blood-brain barrier leakage (p < 0.0001) and improved behavioral outcomes (p < 0.0001). There was no evidence of publication bias. In this meta-analysis of available preclinical studies of ICH, TH is potently effective for reducing perihematomal edema and for improving behavioral outcomes.

BACKGROUND:Non-vitamin K antagonist oral anticoagulant (NOAC) use has significantly reduced intracerebral hemorrhagic (ICH) risk compared with standard anticoagulant treatment. Hematoma expansion (HE) is a known predictor of mortality in warfarin-associated ICH. Little is known about HE in patients using NOACs. METHODS:We conducted a retrospective chart review of patients with ICH admitted to Cedars-Sinai Medical Center from October 2010 to June 2016. We identified patients with concomitant administration of an oral anticoagulant and collected data including evidence of HE on imaging and modified Rankin Scale (mRS) at discharge. We defined HE as relative (≥33% increase) or absolute expansion (≥12 mL). We compared outcomes of patients with and without HE. RESULTS:Out of 814 patients with ICH who were admitted, we identified 9 patients with recent NOAC use and 18 intentionally matched controls on warfarin. We found no significant differences in National Institutes of Health Stroke Scale or ICH score on presentation (median [interquartile range] 15 [5,21] versus 7 [1.25,19.5] [P = .41] and 2 [1,4] versus 1 [1,3] [P = .33]) between patients on NOACs and those on warfarin. Four out of the 9 patients on NOAC and 5 of the 18 patients on warfarin demonstrated HE, with no significant difference (P = .42). There were no significant differences in mRS on discharge between groups (P = .52). CONCLUSIONS:In our coagulopathic NOAC patient population, HE occurs within 6 hours in 44% of patients. This case series did not have sufficient statistical power to detect significant differences between the groups. To our knowledge, this is one of the largest case series reporting on HE with concomitant NOAC use.

OBJECTIVE:To determine a neuro-anatomic cause for central neuropathic pain (CNP) observed in multiple sclerosis (MS) patients. METHODS:Parallel clinical and neuro-anatomical studies were performed. A clinical investigation of consecutively acquired MS patients with and without CNP (i.e. cold allodynia or deep hyperesthesia) within a single MS center was pursued. A multivariate logistic regression model was used to assess the relationship between an upper central thoracic spinal cord focus to central pain complaints. To identify the hypothesized autonomic interneurons with bilateral descending projections to lumbosacral sensory neurons, retrograde single- and double-labeling experiments with CTb and fluorescent tracers were performed in three animal species (i.e. rat, cat, and monkey). RESULTS:Clinical data were available in MS patients with (n = 32; F:23; median age: 34.6 years (interquartile range [IQR]: 27.4-45.5)) and without (n = 30; F:22; median age: 36.6 years [IQR: 31.6-47.1]) CNP. The value of a central focus between T1-T6 in relation to CNP demonstrated a sensitivity of 96.9% (95% confidence interval [CI]: 83.8-99.9) and specificity of 83.3% (95% CI: 65.3-94.4). A significant relationship between CNP and a centrally located focus within the thoracic spine was also observed (odds ratio [OR]: 155.0 [95% CI lower limit: 16.0]; P < 0.0001, two-tailed Fisher exact test). In all animal models, neurons with bilateral descending projections to the lumbosacral superficial dorsal horn were concentrated in the autonomic intermediomedial nucleus surrounding the mid-thoracic central canal. INTERPRETATION/CONCLUSIONS:Our observations provide the first evidence for the etiology of CNP. These data may assist with the development of refined symptomatic therapies and allow for insights into unique pain syndromes observed in other demyelinating subtypes.

We recently observed a reliable phenotypic difference in the inflammatory pain sensitivity of a congenic mouse strain compared to its background strain. By constructing and testing subcongenic strains combined with gene-expression assays, we provide evidence for the candidacy of the Yy1 gene - encoding the ubiquitously expressed and multifunctional Yin Yang 1 transcription factor - as responsible. To confirm this hypothesis, we used a Cre/lox strategy to produce mutant mice in which Yy1 expression was ablated in Nav 1.8-positive neurons of the dorsal root ganglion. These mutants also displayed reduced inflammatory pain sensitivity on the formalin test. Further testing of pain-related phenotypes in these mutants revealed robustly increased sensitivity to systemic and spinal (but not supraspinal) morphine analgesia, and greatly increased endogenous (swim stress-induced) opioid analgesia. None of the known biological roles of Yin Yang 1 were suggestive of such a phenotype, and thus a novel player in pain modulatory systems has been identified.

Quantitative trait locus mapping of chemical/inflammatory pain in the mouse identified the Avpr1a gene, which encodes the vasopressin-1A receptor (V1AR), as being responsible for strain-dependent pain sensitivity to formalin and capsaicin. A genetic association study in humans revealed the influence of a single nucleotide polymorphism (rs10877969) in AVPR1A on capsaicin pain levels, but only in male subjects reporting stress at the time of testing. The analgesic efficacy of the vasopressin analog desmopressin revealed a similar interaction between the drug and acute stress, as desmopressin inhibition of capsaicin pain was only observed in nonstressed subjects. Additional experiments in mice confirmed the male-specific interaction of V1AR and stress, leading to the conclusion that vasopressin activates endogenous analgesia mechanisms unless they have already been activated by stress. These findings represent, to the best of our knowledge, the first explicit demonstration of analgesic efficacy depending on the emotional state of the recipient, and illustrate the heuristic power of a bench-to-bedside-to-bench translational strategy.

It is widely appreciated that there is significant inter-individual variability in pain sensitivity, yet only a handful of contributing genetic variants have been identified. Computational genetic mapping and quantitative trait locus analysis suggested that variation within the gene coding for the beta3 subunit of the Na+,K+-ATPase pump (Atp1b3) contributes to inter-strain differences in the early phase formalin pain behavior. Significant strain differences in Atp1b3 gene expression, beta3 protein expression, and biophysical properties of the Na+,K+ pump in dorsal root ganglia neurons from resistant (A/J) and sensitive (C57BL/6J) mouse strains supported the genetic prediction. Furthermore, in vivo siRNA knockdown of the beta3 subunit produced strain-specific changes in the early phase pain response, completely rescuing the strain difference. These findings indicate that the beta3 subunit of the Na+,K+-ATPase is a novel determinant of nociceptive sensitivity and further supports the notion that pain variability genes can have very selective effects on individual pain modalities.