Recovery of auditory evoked response attentional gain modulation following the first psychotic episode indexes improvements in symptom severity.

Attentional control of auditory N100/M100 gain is reduced in individuals with first-episode psychosis (FEP). Persistent problems with executive modulation of auditory sensory activity may impact multiple aspects of psychosis. As a follow-up to our prior work reporting deficits in attentional M100 gain modulation in auditory cortex, we examined changes in M100 gain modulation longitudinally, and further examined relationships between auditory M100 and symptoms of psychosis. We compared auditory M100 in auditory sensory cortex between 21 FEP and 29 matched healthy participants and between timepoints separated by 220 ± 100 days. Magnetoencephalography data were recorded while participants alternately attended or ignored tones in an auditory oddball task. M100 was measured as the average of 80-140 ms post-stimulus in source-localized evoked responses within bilateral auditory cortex. Symptoms were assessed using the PANSS and PSYRATS. M100 amplitudes, attentional modulation of M100 amplitudes, and symptom severity all improved in FEP over time. Further, improvement in M100 modulation correlated with improvements in negative symptoms (PANSS) as well as physical, cognitive, and emotional components of hallucinations (PSYRATS). Conversely, improvements in the overall size of the M100, rather than the difference between active and passive M100 amplitudes, were related to worsening of positive symptoms (PANSS) and physical components of hallucinations. Results indicate a link between symptoms (particularly auditory hallucinations) and auditory cortex neurophysiology in FEP, where auditory attention and auditory sensation have opposed relationships to symptom change. These findings may inform current models of psychosis etiology and could provide nonpharmaceutical avenues for early intervention.

Functional connectivity and gray matter deficits within the auditory attention circuit in first-episode psychosis.

Background: Selective attention deficits in first episode of psychosis (FEP) can be indexed by impaired attentional modulation of auditory M100. It is unknown if the pathophysiology underlying this deficit is restricted to auditory cortex or involves a distributed attention network. We examined the auditory attention network in FEP. Methods: MEG was recorded from 27 FEP and 31 matched healthy controls (HC) while alternately ignoring or attending tones. A whole-brain analysis of MEG source activity during auditory M100 identified non-auditory areas with increased activity. Time-frequency activity and phase-amplitude coupling were examined in auditory cortex to identify the attentional executive carrier frequency. Attention networks were defined by phase-locking at the carrier frequency. Spectral and gray matter deficits in the identified circuits were examined in FEP. Results: Attention-related activity was identified in prefrontal and parietal regions, markedly in precuneus. Theta power and phase coupling to gamma amplitude increased with attention in left primary auditory cortex. Two unilateral attention networks were identified with precuneus seeds in HC. Network synchrony was impaired in FEP. Gray matter thickness was reduced within the left hemisphere network in FEP but did not correlate with synchrony. Conclusion: Several extra-auditory attention areas with attention-related activity were identified. Theta was the carrier frequency for attentional modulation in auditory cortex. Left and right hemisphere attention networks were identified, with bilateral functional deficits and left hemisphere structural deficits, though FEP showed intact auditory cortex theta phase-gamma amplitude coupling. These novel findings indicate attention-related circuitopathy early in psychosis potentially amenable to future non-invasive interventions.

Attentional M100 gain modulation localizes to auditory sensory cortex and is deficient in first-episode psychosis.

Selective attention is impaired in first-episode psychosis (FEP). Selective attention effects can be detected during auditory tasks as increased sensory activity. We previously reported electroencephalography scalp-measured N100 enhancement is reduced in FEP. Here, we localized magnetoencephalography (MEG) M100 source activity within the auditory cortex, making novel use of the Human Connectome Project multimodal parcellation (HCP-MMP) to identify precise auditory cortical areas involved in attention modulation and its impairment in FEP. MEG was recorded from 27 FEP and 31 matched healthy controls (HC) while individuals either ignored frequent standard and rare oddball tones while watching a silent movie or attended tones by pressing a button to oddballs. Because M100 arises mainly in the auditory cortices, MEG activity during the M100 interval was projected to the auditory sensory cortices defined by the HCP-MMP (A1, lateral belt, and parabelt parcels). FEP had less auditory sensory cortex M100 activity in both conditions. In addition, there was a significant interaction between group and attention. HC enhanced source activity with attention, but FEP did not. These results demonstrate deficits in both sensory processing and attentional modulation of the M100 in FEP. Novel use of the HCP-MMP revealed the precise cortical areas underlying attention modulation of auditory sensory activity in healthy individuals and impairments in FEP. The sensory reduction and attention modulation impairment indicate local and systems-level pathophysiology proximal to disease onset that may be critical for etiology. Further, M100 and N100 enhancement may serve as outcome variables for targeted intervention to improve attention in early psychosis.

SIRT1 inactivation switches reactive astrocytes to an antiinflammatory phenotype in CNS autoimmunity.

Astrocytes are highly heterogeneous in their phenotype and function, which contributes to CNS disease, repair, and aging; however, the molecular mechanism of their functional states remains largely unknown. Here, we show that activation of sirtuin 1 (SIRT1), a protein deacetylase, played an important role in the detrimental actions of reactive astrocytes, whereas its inactivation conferred these cells with antiinflammatory functions that inhibited the production of proinflammatory mediators by myeloid cells and microglia and promoted the differentiation of oligodendrocyte progenitor cells. Mice with astrocyte-specific Sirt1 knockout (Sirt1-/-) had suppressed progression of experimental autoimmune encephalomyelitis (EAE), an animal model of CNS inflammatory demyelinating disease. Ongoing EAE was also suppressed when Sirt1 expression in astrocytes was diminished by a CRISPR/Cas vector, resulting in reduced demyelination, decreased numbers of T cells, and an increased rate of IL-10-producing macrophages and microglia in the CNS, whereas the peripheral immune response remained unaffected. Mechanistically, Sirt1-/- astrocytes expressed a range of nuclear factor erythroid-derived 2-like 2 (Nfe2l2) target genes, and Nfe2l2 deficiency shifted the beneficial action of Sirt1-/- astrocytes to a detrimental one. These findings identify an approach for switching the functional state of reactive astrocytes that will facilitate the development of astrocyte-targeting therapies for inflammatory neurodegenerative diseases such as multiple sclerosis.

Systemic Immune Bias Delineates Malignant Astrocytoma Survival Cohorts.

Patients with grade III anaplastic astrocytomas (AA) separate into survival cohorts based on the presence or absence of mutations in isocitrate dehydrogenase (IDH). Progression to glioblastoma (GBM), morphologically distinguishable by elevated microvascular proliferation, necrosis, and cell division in tumor tissues, is considerably more rapid in IDH wild-type tumors such that their diagnosis as AA is relatively rare. More often initially presenting as GBM, these contain higher numbers of tumor-associated macrophages (TAMs) than most AA, and GBM patients also have higher levels of circulating M2 monocytes. TAM and M2 monocytes share functional properties inhibitory for antitumor immunity. Yet, although there is a wealth of data implicating TAM in tumor-immune evasion, there has been limited analysis of the impact of the circulating M2 monocytes. In the current study, immune parameters in sera, circulating cells, and tumor tissues from patients with primary gliomas morphologically diagnosed as AA were assessed. Profound differences in serum cytokines, glioma extracellular vesicle cross-reactive Abs, and gene expression by circulating cells identified two distinct patient cohorts. Evidence of type 2-immune bias was most often seen in patients with IDH wild-type AA, whereas a type 1 bias was common in patients with tumors expressing the IDH1R132H mutation. Nevertheless, a patient's immune profile was better correlated with the extent of tumor vascular enhancement on magnetic resonance imaging than IDH mutational status. Regardless of IDH genotype, AA progression appears to be associated with a switch in systemic immune bias from type 1 to type 2 and the loss of tumor vasculature integrity.

Pitch and Duration Mismatch Negativity are Associated With Distinct Auditory Cortex and Inferior Frontal Cortex Volumes in the First-Episode Schizophrenia Spectrum.

BACKGROUND: Pitch and duration mismatch negativity (pMMN/dMMN) are related to left Heschl's gyrus gray matter volumes in first-episode schizophrenia (FESz). Previous methods were unable to delineate functional subregions within and outside Heschl's gyrus. The Human Connectome Project multimodal parcellation (HCP-MMP) atlas overcomes this limitation by parcellating these functional subregions. Further, MMN has generators in inferior frontal cortex, and therefore, may be associated with inferior frontal cortex pathology. With the novel use of the HCP-MMP to precisely parcellate auditory and inferior frontal cortex, we investigated relationships between gray matter and pMMN and dMMN in FESz. METHODS: pMMN and dMMN were measured at Fz from 27 FESz and 27 matched healthy controls. T1-weighted MRI scans were acquired. The HCP-MMP atlas was applied to individuals, and gray matter volumes were calculated for bilateral auditory and inferior frontal cortex parcels and correlated with MMN. FDR correction was used for multiple comparisons. RESULTS: In FESz only, pMMN was negatively correlated with left medial belt in auditory cortex and area 47L in inferior frontal cortex. Duration MMN negatively correlated with the following auditory parcels: left medial belt, lateral belt, parabelt, TA2, and right A5. Further, dMMN was associated with left area 47L, right area 44, and right area 47L in inferior frontal cortex. CONCLUSIONS: The novel approach revealed overlapping and distinct gray matter associations for pMMN and dMMN in auditory and inferior frontal cortex in FESz. Thus, pMMN and dMMN may serve as biomarkers of underlying pathological deficits in both similar and slightly different cortical areas.

Intradural extramedullary capillary hemangioma of the cauda equina: case report of a rare spinal tumor.

INTRODUCTION: Intradural extramedullary capillary hemangiomas of the cauda equina are exceedingly rare, with only 20 previous cases reported. In the adult population, these tumors are rare and can arise in the central and peripheral nervous systems from the dura or spinal nerve roots. Intradural capillary hemangiomas of the cauda equina can yield symptoms such as lower extremity weakness, pain, and bladder and bowel dysfunction. The clinical symptomology and surgical management of this rare spinal lesion are reviewed in this case report. CASE PRESENTATION: A 50-year-old male presented with progressive bilateral lower extremity weakness for 2 years, with recent bladder and bowel dysfunction. On physical exam, strength was symmetrically impaired in both lower extremities. Pre-operative magnetic resonance imaging (MRI) of the lumbar spine demonstrated a gadolinium-enhanced intradural lesion at the L4 level. Laminectomy was performed and the lesion was resected. Histopathological analysis determined that the tumor demonstrated features consistent with a capillary hemangioma. DISCUSSION: Clinically, patients with capillary hemangiomas of the cauda equina present with space-occupying compressive deficits, including progressive low back and lower extremity pain, motor deficits, paresthesias, sensory loss, and bowel and bladder dysfunction. Acute presentation can transpire following a hemorrhagic episode, although this is more associated with cavernous rather than capillary hemangiomas. Our patient demonstrated non-acute, progressive weakness, and late-onset bladder and bowel dysfunction. This report demonstrates that this rare lesion should be included in the differential diagnosis of cauda equina lesions.

Rapidly progressive ACTH-dependent Cushing's disease masquerading as ectopic ACTH-producing Cushing's syndrome: illustrative case.

BACKGROUND: Cushing's disease (CD) remains a challenging condition to diagnose and treat. This case study highlights the challenges of diagnosing CD when faced with discrepant clinical, biochemical, and radiological findings. OBSERVATIONS: A 62-year-old man presented with rapid evolution of symptoms, including depression, fatigue, and extreme muscle atrophy, which resulted in the patient being a wheelchair user over the course of a few months. His rapid clinical course in conjunction with hypercortisolemia in the setting of a pituitary macroadenoma involving the cavernous sinus, two large pulmonary nodules, and urine-free cortisol levels in the thousands suggested an aggressive ectopic adrenocorticotropic hormone (ACTH) source. After extensive testing ruled out CD from an ectopic source and because of the patient's abrupt clinical deterioration, the authors concluded that the source was likely an aggressive pituitary adenoma. Therefore, the authors performed an endonasal transsphenoidal approach for resection of the pituitary adenoma involving the cavernous sinus, and the patient was scheduled for radiosurgery to control tumor progression. LESSONS: Although extremely high levels of cortisol and ACTH are associated with ectopic Cushing's syndrome, they may also indicate an aggressive form of CD. Suspicion should be maintained for hypercortisolemia from a pituitary source even when faced with discrepant information that may suggest an ectopic source.

Parahippocampal area three gray matter is reduced in first-episode schizophrenia spectrum: Discovery and replication samples.

Early course schizophrenia is associated with reduced gray matter. The specific structures affected first and how deficits impact symptoms and cognition remain unresolved. We used the Human Connectome Project multimodal parcellation (HCP-MMP) to precisely identify cortical areas and investigate thickness abnormalities in discovery and replication samples of first-episode schizophrenia spectrum individuals (FESz). In the discovery sample, T1w scans were acquired from 31 FESz and 31 matched healthy controls (HC). Thickness was calculated for 360 regions in Freesurfer. In the replication sample, high-resolution T1w, T2w, and BOLD-rest scans were acquired from 23 FESz and 32 HC and processed with HCP protocols. Thickness was calculated for regions significant in the discovery sample. After FDR correction (q < .05), left and right parahippocampal area 3 (PHA3) were significantly thinner in FESz. In the replication sample, bilateral PHA3 were again thinner in FESz (q < .05). Exploratory correlation analyses revealed left PHA3 was positively associated with hallucinations and right PHA3 was positively associated with processing speed, working memory, and verbal learning. The novel use of the HCP-MMP in two independent FESz samples revealed thinner bilateral PHA3, suggesting this byway between cortical and limbic processing is a critical site of pathology near the emergence of psychosis.

Ocular adnexal manifestations of neuroendocrine neoplasms: a case report and a major review.

PURPOSE: To describe a patient with orbital neuroendocrine neoplasm (NEN)/carcinoid tumor and to review the clinical presentation, systemic work-up, histopathologic features, and outcome of all previously reported ocular adnexal (OA) NENs. METHODS: A systematic literature review. PubMed/MEDLINE and Google Scholar databases were searched for all well-documented cases of OA NENs. RESULTS: Final analysis yielded 94 patients with OA NENs, 50 females (53%) and 44 (47%) males with an average age of 63 years (range 14-86). Of 91 patients with known information, the most common presenting signs were proptosis (56/91, 61%) and visual disturbances (42/91, 47%), induced by a mass most commonly associated with an extraocular muscle (49/63, 78%). The majority of tumors (88/94, 94%) were metastases, most commonly from the gastrointestinal tract (52/88, 59%). OA NEN metastasis presented following detection of primary tumor in 73/94 (78%) patients (median time to metastasis 36 months, range 0-288 months) and as an initial manifestation of disease in 15/94 (16%) patients (median time to primary detection 18 months, range 1-108 months). Systemic work-up included extra-OA NEN biopsy (37/54, 69%), multimodal imaging (42/54, 78%), and other laboratory studies (32/54, 59%). Resection with or without adjuvant chemotherapy, radiotherapy, and biologics was the most common intervention for OA NENs (36/82, 44%). Of 67 patients with available follow-up, the median survival was 108 months (95% CI 55-161 months) and the absolute 5-year survival rate was 68%. CONCLUSIONS: OA NENs are almost exclusively metastases and can precede detection of primary tumor by many months, requiring appropriate diagnostic work-up.

A dual effect of ursolic acid to the treatment of multiple sclerosis through both immunomodulation and direct remyelination.

Current multiple sclerosis (MS) medications are mainly immunomodulatory, having little or no effect on neuroregeneration of damaged central nervous system (CNS) tissue; they are thus primarily effective at the acute stage of disease, but much less so at the chronic stage. An MS therapy that has both immunomodulatory and neuroregenerative effects would be highly beneficial. Using multiple in vivo and in vitro strategies, in the present study we demonstrate that ursolic acid (UA), an antiinflammatory natural triterpenoid, also directly promotes oligodendrocyte maturation and CNS myelin repair. Oral treatment with UA significantly decreased disease severity and CNS inflammation and demyelination in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Importantly, remyelination and neural repair in the CNS were observed even after UA treatment was started on day 60 post immunization when EAE mice had full-blown demyelination and axonal damage. UA treatment also enhanced remyelination in a cuprizone-induced demyelination model in vivo and brain organotypic slice cultures ex vivo and promoted oligodendrocyte maturation in vitro, indicating a direct myelinating capacity. Mechanistically, UA induced promyelinating neurotrophic factor CNTF in astrocytes by peroxisome proliferator-activated receptor γ(PPARγ)/CREB signaling, as well as by up-regulation of myelin-related gene expression during oligodendrocyte maturation via PPARγ activation. Together, our findings demonstrate that UA has significant potential as an oral antiinflammatory and neural repair agent for MS, especially at the chronic-progressive stage.

ATRX Mutations in Pineal Parenchymal Tumors of Intermediate Differentiation.

Pineal parenchymal tumors are rare neoplasms, ranging from WHO Grade I to IV. There are few studies characterizing the molecular profiles of these tumors. ATRX alterations are strongly associated with the presence of the alternative lengthening of telomeres (ALT) phenotype, and within the central nervous system they tend to occur in subsets of gliomas, including those with IDH, NF1, or histone (H3 K27M or G34) mutations. Here, we identified ATRX frameshift mutations by next generation sequencing associated with corresponding protein loss in 2 cases of pineal parenchymal tumors of intermediate differentiation (PPTID) developing in a 21-year-old woman and a 64-year-old man. In contrast, we identified partial ATRX loss in 1 pineoblastoma, among 14 pineal parenchymal tumors of various grades (6 pineoblastomas, 4 pineocytomas, and 4 PPTID) using tissue microarrays; ALT was absent in these cases. Evaluating the cBioPortal database, an ATRX mutation was identified in one (of 3 total) PPTIDs analyzed. Thus, ATRX mutations associated with protein loss and ALT develop in a small subset of pineal parenchymal tumors and may be limited to those with intermediate differentiation. The clinical significance of these alterations requires further study.

Potential role of CSF cytokine profiles in discriminating infectious from non-infectious CNS disorders.

Current laboratory testing of cerebrospinal fluid (CSF) does not consistently discriminate between different central nervous system (CNS) disease states. Rapidly distinguishing CNS infections from other brain and spinal cord disorders that share a similar clinical presentation is critical. New approaches focusing on aspects of disease biology, such as immune response profiles that can have stimulus-specific attributes, may be helpful. We undertook this preliminary proof-of-concept study using multiplex ELISA to measure CSF cytokine levels in various CNS disorders (infections, autoimmune/demyelinating diseases, lymphomas, and gliomas) to determine the potential utility of cytokine patterns in differentiating CNS infections from other CNS diseases. Both agglomerative hierarchical clustering and mixture discriminant analyses revealed grouping of CNS disease types based on cytokine expression. To further investigate the ability of CSF cytokine levels to distinguish various CNS disease states, non-parametric statistical analysis was performed. Mann-Whitney test analysis demonstrated that CNS infections are characterized by significantly higher CSF lP-10/CXCL10 levels than the pooled non-infectious CNS disorders (p = 0.0001). Within the infection group, elevated levels of MDC/CCL22 distinguished non-viral from viral infections (p = 0.0048). Each disease group of the non-infectious CNS disorders independently showed IP-10/CXCL10 levels that are significantly lower than the infection group [(autoimmune /demyelinating disorders (p = 0.0005), lymphomas (p = 0.0487), gliomas (p = 0.0294), and controls (p = 0.0001)]. Additionally, of the non-infectious diseases, gliomas can be distinguished from lymphomas by higher levels of GRO/CXCL1 (p = 0.0476), IL-7 (p = 0.0119), and IL-8 (p = 0.0460). Gliomas can also be distinguished from autoimmune/demyelinating disorders by higher levels of GRO/CXCL1 (p = 0.0044), IL-7 (p = 0.0035) and IL-8 (p = 0.0176). Elevated CSF levels of PDGF-AA distinguish lymphomas from autoimmune/demyelinating cases (p = 0.0130). Interrogation of the above comparisons using receiver operator characteristic analysis demonstrated area under the curve (AUC) values (ranging from 0.8636-1.0) that signify good to excellent utility as potential diagnostic discriminators. In conclusion, our work indicates that upon formal validation, measurement of CSF cytokine levels may have clinical utility in both identifying a CNS disorder as infectious in etiology and, furthermore, in distinguishing viral from non-viral CNS infections.

Poststroke exercise is as effective as skilled rehabilitation: Effects in young and aged mice.

Stroke is a leading cause of long-term disability, though current rehabilitative strategies fail to yield complete recovery. Focused training of the impaired limb improves functional outcome in rodents, but these strategies require intensive training that is difficult to practice in humans. Because aerobic exercise has been found to induce beneficial changes in the brain, it is a promising rehabilitative strategy after stroke. The current study investigated the effect of voluntary poststroke aerobic exercise on functional outcome in young and aged mice. Mice were trained on a skilled reaching task before receiving focal ischemic stroke and being subdivided into 3 different groups for rehabilitative training: traditional skilled reach rehabilitation, aerobic exercise, and control procedures. Both young and aged mice benefited from aerobic exercise after stroke, though the behavioral profile somewhat differed. Aerobic exercise in young mice yielded poststroke performance levels that were equivalent to preinjury levels. In aged mice, aerobic exercise accelerated improvement in motor performance without an effect on the absolute level of performance compared with controls. Our results suggest that aerobic exercise may be an effective alternative or adjunctive rehabilitative strategy after stroke. Potential mechanisms of this effect need to be further investigated. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Cerebral Amyloidoma Resulting from Central Nervous System Lymphoplasmacytic Lymphoma: A Case Report and Literature Review.

Cerebral amyloidomas are rare cerebral mass lesions often associated with significant morbidity. Cerebral amyloid accumulation can be the result of a number of disease states and it is crucial for proper patient care to identify the pathogenic process leading to amyloidoma formation. Low grade clonal B-cell processes are one cause of cerebral amyloidomas. We report a case of an 87-year-old woman who presented with a lymphoplasmacytic lymphoma associated cerebral amyloidoma complicated by cerebral hemorrhage, discuss the proper workup of this disease entity, and present a review of the literature on this topic.

Spheno-Orbital Meningiomas: An Analysis Based on World Health Organization Classification and Ki-67 Proliferative Index.

PURPOSE: To evaluate the clinical behavior of spheno-orbital meningiomas with regard to World Health Organization (WHO) tumor grade and Ki-67, a cellular marker of proliferation. METHODS: A retrospective review over a 16-year period of the demographic, clinical, radiographic, and surgical data of all patients with spheno-orbital meningioma who underwent surgical resection. Tumor specimens were examined histologically using the current WHO 2016 classification and immunohistochemically using Ki-67/MIB-1 monoclonal antibody. RESULTS: Thirty-eight patients met all inclusion criteria: 78.9% of tumors were WHO grade I with a mean Ki-67 of 3.76, and 93% of patients were clinically stable at last follow up; 10.5% of lesions were WHO grade II (atypical) with a mean Ki-67 of 14.93, and 10.5% of lesions were WHO grade III (anaplastic) with a mean Ki-67 of 58.3. All grade II and III meningiomas exhibited an aggressive clinical course. There were statistically significant correlations between disease clinical progression and WHO tumor grade (p < 0.001), between disease clinical progression and Ki-67 (p < 0.001), and between increasing Ki-67 index and higher WHO grade (p < 0.001). For WHO grade I lesions, a Ki-67 of ≥3.3 correlated with recurrence (p = 0.0256). Overall, disease-specific mortality occurred in 5 (13%) patients. CONCLUSIONS: Ki-67 index is a valuable marker to use in conjunction with WHO grade to predict meningioma behavior, particularly in histologically borderline lesions, and possibly to identify a subset of WHO grade I tumors at risk of recurrence. This combination of methods can aid in tailoring treatment and surveillance strategies.

Thoracic spinal osteochondroma: A rare presentation of spinal cord compression.

Osteochondromas are the most common benign bone tumor typically seen in the appendicular skeleton and are rarely found in the spine. We present a case of an osteochondroma of the spine presenting with spinal cord compression. 27-year-old male presented with lower extremity weakness and paresthesia, decreased lower extremity sensation, and decreased proprioception. MRI showed a heterogeneous mass with minimal peripheral enhancement and without restricted diffusion. CT demonstrated a calcified mass extending from the left facet joint of T11-T12 with medial extension, resulting in severe central canal stenosis and cord compression. The patient underwent surgical resection with pathology demonstrating an osteochondroma.

Human parechovirus and enterovirus initiate distinct CNS innate immune responses: Pathogenic and diagnostic implications.

BACKGROUND: Human parechovirus (HPeV) and enterovirus (EV) cause a range of human diseases including serious CNS infections. Little is known regarding the immune response to HPeV meningitis compared to EV meningitis or how the immune response to HPeV reflects its pathogenesis. OBJECTIVE: To characterize the innate immune response to HPeV CNS infection in order to increase our understanding of HPeV pathogenesis and possibly help identify HPeV in the clinical setting. STUDY DESIGN: CSF samples from 13 patients with HPeV meningitis, 7 patients with EV meningitis, and 11 patients negative for CNS infections were analyzed for chemokines/cytokines using multiplex ELISA assays. RESULTS: CSF levels of the majority of cytokines/chemokines analyzed were significantly higher in patients with EV meningitis (EV group) compared to patients with HPeV meningitis (HPeV group) and controls. In the HPeV group, a small number of cytokine/chemokine levels were higher than controls; however, these levels were either significantly lower or not significantly different compared to the EV group. IL-6 levels were lower in HPeV than in both EV and controls. CONCLUSIONS: The immune response to HPeV CNS infection differs from that of EV. Distinct patterns of cytokine/chemokine expression in HPeV infections suggest HPeV-mediated modulation of the immune response. HPeV disrupts the interferon cascade and seems to interfere with early inflammatory signaling. Although HPeV elicits a predominantly muted immune reaction, a partial, general infectious-type cytokine/chemokine response does occur. Beyond providing insight into HPeV pathogenesis, the identified cytokine/chemokine profile may aid in early detection of HPeV infection.