Absence of Cerebrospinal Fluid Pleocytosis in Encephalitis.

BACKGROUND: Early diagnosis of encephalitis involves identifying signs of neuroinflammation, including cerebrospinal fluid (CSF) pleocytosis. However, absence of CSF pleocytosis in encephalitis has been described, most notably in autoimmune encephalitis. We examined clinical characteristics and outcomes associated with the absence or presence of CSF white blood cell pleocytosis (≥ 5 cells/µL), to inform timely diagnosis and management of encephalitis. METHODS: This retrospective study compares initial CSF profiles in 597 adult patients with all-cause encephalitis. RESULTS: Of the 597 patients, 446 (74.7%) had CSF pleocytosis while 151 (25.3%) did not. CSF pleocytosis occurred more commonly in infectious cases (200/446, 44.8%), along with 59 (13.2%) autoimmune cases, comprised chiefly of anti-NMDAR encephalitis (37/59, 62.7%). Notably, the group without pleocytosis was comprised of similar proportions of infectious (47/151, 31.1%) and autoimmune (38/151, 25.92%; p>0.05) encephalitis. Among those with infectious encephalitis, 47/247 (19%) had absent pleocytosis, including 18/76 (23.7%) with HSV-1 encephalitis. The absence of pleocytosis was associated with a decreased rate of acyclovir administration (47.7% in patients without pleocytosis vs. 71.1% in patients with pleocytosis, p<0.001). Despite pleocytosis being associated with some measures of clinical severity at admission such as a Full Outline of UnResponsiveness (FOUR) score ≤14, it was not associated with mortality or prolonged hospitalization. CONCLUSION: CSF pleocytosis is an important criterion for encephalitis diagnosis, but 25.3% of patients with all-cause encephalitis and 23.7% of those with HSV-1 encephalitis exhibit absence of pleocytosis on initial LP. Acyclovir initiation should not be delayed in the absence of pleocytosis in patients with suspected encephalitis.

Development and Validation of a Risk Score for Predicting ICU Admission in Adults with New-Onset Encephalitis.

BACKGROUND: Timely intensive care unit (ICU) admission for patients with encephalitis is associated with better prognosis. Therefore, our aim was to create a risk score predicting ICU admission in adults with encephalitis, which could aid in optimal management and resource allocation. METHODS: We initially identified variables that would be most predictive of ICU admission among 372 patients with encephalitis from two hospital systems in Houston, Texas (cohort 1), who met the International Encephalitis Consortium (IEC) criteria from 2005 to 2023. Subsequently, we used a binary logistic regression model to create a risk score for ICU admission, which we then validated externally using a separate cohort of patients from two hospitals in Baltimore, Maryland (cohort 2), who met the IEC criteria from 2006 to 2022. RESULTS: Of 634 patients with encephalitis, 255 (40%) were admitted to the ICU, including 45 of 113 (39.8%) patients with an autoimmune cause, 100 of 272 (36.7%) with an infectious cause, and 110 of 249 (44.1%) with an unknown cause (p = 0.225). After conducting a multivariate analysis in cohort 1, we found that the presence of focal neurological signs, new-onset seizure, a Full Outline of Unresponsiveness score ≤ 14, leukocytosis, and a history of chronic kidney disease at admission were associated with an increased risk of ICU admission. The resultant clinical score for predicting ICU admission had an area under the receiver operating characteristic curve (AUROC) of 0.77 (95% confidence interval [CI] 0.72-0.82, p < 0.001). Patients were classified into three risk categories for ICU admission: low risk (score 0, 12.5%), intermediate risk (scores 1-5, 49.5%), and high risk (scores 6-8, 87.5%). External validation in cohort 2 yielded an AUROC of 0.76 (95% CI 0.69-0.83, p < 0.001). CONCLUSIONS: ICU admission is common in patients with encephalitis, regardless of etiology. Our risk score, encompassing neurologic and systemic factors, may aid physicians in decisions regarding intensity of care for adult patients with encephalitis upon hospital admission.

Emerging shadows: HHV-8-associated encephalitis unveiled in a solid organ transplant recipient.

Human herpesviruses (HHVs) cause a wide variety of central nervous system (CNS) infections including meningitis and encephalitis. While HHV-8 is not typically associated with neurological diseases, several studies have indicated a relationship, such as secondary central nervous system (CNS) metastases and a few isolated cases of HHV-8 encephalitis in acquired immunodeficiency syndrome (HIV). However, it has not been previously linked to encephalitis in solid organ transplantation (SOT). This case presents the first-ever instance of HHV-8 encephalitis in a SOT recipient. Our case highlights the association of HHV-8-related diseases, such as post-transplant Kaposi's Sarcoma (KS), with encephalitis. The patient was diagnosed with KS before developing neurological symptoms and received a prompt clinical response through intravenous foscarnet and ganciclovir treatment for 14 days. It is important to note that HHV-8 is a rare cause of encephalitis, and diagnosis requires a high index of suspicion in the appropriate clinical context, allowing for the use of antiviral therapy. This case also underscores the importance of considering the possibility of HHV-8-related diseases in SOT recipients, as they are at risk of developing such infections.

Solid organ transplant-related central nervous system infections.

PURPOSE OF REVIEW: Central nervous system (CNS) infections in solid organ transplant (SOT) recipients may present atypical or nonspecific symptoms. Due to a wider range of infectious agents compared with immunocompetent hosts, diagnosis is challenging. This review categorizes CNS infections in SOT recipients by cause. RECENT FINDINGS: New studies have reported new data on the epidemiology and the risk factors associated with each specific pathogen described in this review. Additionally, we included the treatment recommendations. SUMMARY: The latest findings give us an insight into the different pathogens causing infectious neurologic complications in SOT recipients.

Long-term evaluation of clinical success and safety of omadacycline in nontuberculous mycobacteria infections: a retrospective, multicenter cohort of real-world health outcomes.

Infections due to nontuberculous mycobacteria (NTM) continue to increase in prevalence, leading to problematic clinical outcomes. Omadacycline (OMC) is an aminomethylcycline antibiotic with FDA orphan drug and fast-track designations for pulmonary NTM infections, including Mycobacteroides abscessus (MAB). This multicenter retrospective study across 16 U.S. medical institutions from January 2020 to March 2023 examined the long-term clinical success, safety, and tolerability of OMC for NTM infections. The cohort included patients aged ≥18 yr, who were clinically evaluable, and` had been treated with OMC for ≥3 mo without a previous diagnosis of cystic fibrosis. The primary outcome was 3 mo clinical success, with secondary outcomes including clinical improvement and mortality at 6- and 12 mo, persistence or reemergence of infection, adverse effects, and reasons for OMC utilization. Seventy-five patients were included in this analysis. Most patients were female (48/75, 64.0%) or Caucasian (58/75, 77.3%), with a median (IQR) age of 59 yr (49-67). Most had NTM pulmonary disease (33/75, 44.0%), skin and soft tissue disease (19/75, 25.3%), or osteomyelitis (10/75, 13.3%), and Mycobacterium abscessus (60/75, 80%) was the most commonly isolated NTM pathogen. The median (IQR) treatment duration was 6 mo (4 - 14), and the most commonly co-administered antibiotic was azithromycin (33/70, 47.1%). Three-month clinical success was observed in 80.0% (60/75) of patients, and AEs attributable to OMC occurred in 32.0% (24/75) of patients, leading to drug discontinuation in 9.3% (7/75).

Seroprevalence of Measles, Mumps, Rubella, and Varicella-Zoster Virus and Seroresponse to the Vaccinations in Adult Solid Organ Transplant Candidates.

BACKGROUND: Updating live vaccines such as measles, mumps, rubella, and varicella (MMRV) is an important step in preparing patients for solid organ transplant (SOT) to prevent morbidity from these preventable diseases. However, data for this approach are scarce. Thus, we aimed to describe the seroprevalence of MMRV and the efficacy of the vaccines in our transplant center. METHODS: Pre-SOT candidates >18 y of age were retrospectively retrieved from SOT database in Memorial Hermann Hospital Texas Medical Center. MMRV serologies are routinely screened at the time of pretransplant evaluation. We divided patients into 2 groups: MMRV-positive group versus MMRV-negative group, patients with positive all MMRV serologies and with negative immunity to at least 1 dose of MMRV, respectively. RESULTS: A total of 1213 patients were identified. Three hundred ninety-four patients (32.4%) did not have immunity to at least 1 dose of MMRV. Multivariate analysis was conducted. Older age (odds ratio [OR]: 1.04) and liver transplant candidates (OR: 1.71) were associated with seropositivity. Previous history of SOT (OR: 0.54) and pancreas/kidney transplant candidates (OR: 0.24) were associated with seronegativity. Among 394 MMRV seronegative patients, 60 patients received 1 dose of MMR vaccine and 14 patients received 1 dose of varicella-zoster virus vaccine without severe adverse events. A total of 35% (13/37) of patients who had follow-up serologies did not have a serological response. CONCLUSIONS: A significant number of pre-SOT candidates were not immune to at least 1 dose of MMRV. This highlights the importance of MMRV screening and vaccinations pre-SOT. Postvaccination serological confirmation should be performed to evaluate the necessity for a second dose.

Steroids for the treatment of viral encephalitis: a systematic literature review and meta-analysis.

BACKGROUND: Specific antiviral treatment is only available for a small subset of viral encephalitis (VE). Adjunctive steroids are used, but there is scant evidence evaluating its utility. We present a systematic review and meta-analysis on the outcome of steroid use in VE. METHODS: We conducted a systematic literature review and reported it according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. Two observational studies from unpublished or partially published data were added. For the meta-analysis, we employed the metaphor package of the statistical software R-4.3.1. RESULTS: We screened 378 studies and included 50. 155 patients were added from the Houston and Linz cohorts. Individual data were available for 281 persons, 120 (43%) of whom received steroids. The most common pathogens were herpes simplex virus 1, West Nile virus, and measles. Study designs and patient outcomes were heterogeneous. Only three of the trials report an advantage of steroid therapy. Steroid-induced side effects were scarce. Ten cohorts were included into the meta-analysis. For the pooled data, the null hypothesis could not be rejected (p = 0.245) using a random effects model, i.e., a benefit of steroid treatment on survival in VE could not be shown. CONCLUSIONS: Steroids as potent anti-inflammatory agents may act through a reduction of secondary inflammation-mediated damage. Our data do not support the use of steroids in VE. However, multiple shortcomings apply. Standardized controlled trials are needed to investigate optimal dosing and timing of steroid administration and to explore potential subgroups that could benefit.

Viral meningitis and encephalitis: an update.

PURPOSE OF REVIEW: The most common infectious etiologies of meningitis and encephalitis are viruses. In this review, we will discuss current epidemiology, prevention, diagnosis, and treatment of the most common causes of viral meningitis and encephalitis worldwide. RECENT FINDINGS: Viral meningitis and encephalitis are increasingly diagnosed as molecular diagnostic techniques and serologies have become more readily available worldwide but recent progress in novel antiviral therapies remains limited. Emerging and re-emerging viruses that have caused endemic or worldwide outbreaks or epidemics are arboviruses (e.g., West Nile virus, Japanese encephalitis, Tick borne encephalitis, Dengue, Zika, Toscana), enteroviruses (e.g., Enterovirus 71, Enterovirus D68), Parechoviruses, respiratory viruses [e.g., severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza, metapneumoviruses, measles, mumps], and herpes viruses [e.g., herpes simplex virus (HSV) type 1 (HSV-1), HSV-2, human herpes (HV) 6, varicella zoster virus (VZV)]. Future efforts should concentrate in increasing availability for those viruses with effective vaccination [e.g., Japanese encephalitis, Tick borne encephalitis, varicella zoster viruses, SARS-CoV-2, influenza], prompt initiation of those with encephalitis with treatable viruses (e.g., HSV-1, VZV), increasing the diagnostic yield by using novel techniques such as metagenomic sequencing and avoiding unnecessary antibiotics in those with viral meningitis or encephalitis. SUMMARY: We review the current epidemiology, clinical presentation, diagnosis, and treatment of the common causative agents of viral meningitis and encephalitis worldwide.

Encephalitis in HIV-infected adults in the antiretroviral therapy era.

INTRODUCTION: Encephalitis presents with high morbidity and mortality in both HIV-infected and HIV-negative patients. There are currently no studies comparing HIV-infected and HIV-negative patients admitted to the hospital with acute encephalitis. METHODS: We conducted a multicenter, retrospective study of adults admitted to the hospital with a diagnosis of encephalitis in Houston, Texas between 2005 and 2020. We describe the clinical manifestations, etiology, and outcomes of these patients with a focus on those infected with HIV. RESULTS: We identified 260 patients with encephalitis, 40 of whom were infected with HIV. Viral etiology was identified in 18 of the 40 HIV-infected patients (45.0%); bacterial in 9 (22.5%); parasitic in 5 (12.5%); fungal in 3 (7.5%); immune-mediated in 2 (5.0%). Eleven cases had unclear etiology (27.5%). More than one disease process was identified in 12 (30.0%) patients. HIV-infected persons were more likely to have neurosyphilis (8/40 vs. 1/220; OR 55; 95%CI 6.6-450), CMV encephalitis [5/18 vs. 1/30; OR 11.2 (1.18-105)], or VZV encephalitis (8/21 vs. 10/89; OR 4.82; 1.62-14.6) compared to the HIV-negative patients. Inpatient mortality was similar in the HIV-infected and HIV-negative patients, 15.0% vs 9.5% [p = 0.4, OR 1.67 (0.63-4.44)], but one-year mortality was higher for the HIV-infected patients, 31.3% vs 16.0% [p = 0.04, OR 2.40 (1.02-5.55)]. CONCLUSION: This large, multicenter study shows that HIV-infected patients with encephalitis have a distinct pattern of disease when compared with HIV-negative patients, and that this population has nearly twice the odds of mortality in the year following hospitalization.

Bacterial meningitis in Africa.

Bacterial meningitis differs globally, and the incidence and case fatality rates vary by region, country, pathogen, and age group; being a life-threatening disease with a high case fatality rate and long-term complications in low-income countries. Africa has the most significant prevalence of bacterial meningitis illness, and the outbreaks typically vary with the season and the geographic location, with a high incidence in the meningitis belt of the sub-Saharan area from Senegal to Ethiopia. Streptococcus pneumoniae (pneumococcus) and Neisseria meningitidis (meningococcus) are the main etiological agents of bacterial meningitis in adults and children above the age of one. Streptococcus agalactiae (group B Streptococcus), Escherichia coli, and Staphylococcus aureus are neonatal meningitis's most common causal agents. Despite efforts to vaccinate against the most common causes of bacterial neuro-infections, bacterial meningitis remains a significant cause of mortality and morbidity in Africa, with children below 5 years bearing the heaviest disease burden. The factors attributed to this continued high disease burden include poor infrastructure, continued war, instability, and difficulty in diagnosis of bacterial neuro-infections leading to delay in treatment and hence high morbidity. Despite having the highest disease burden, there is a paucity of African data on bacterial meningitis. In this article, we discuss the common etiologies of bacterial neuroinfectious diseases, diagnosis and the interplay between microorganisms and the immune system, and the value of neuroimmune changes in diagnostics and therapeutics.

Undetectable JC virus CSF PCR in patients with JC virus-induced progressive multifocal leukoencephalopathy.

The diagnosis of progressive multifocal leukoencephalopathy (PML) is based on a combination of clinical, radiographic, and laboratory findings. However, negative JC polyomavirus (JCPyV) PCR in CSF does not always rule out JCPyV-related PML. In this narrative review, we sought to examine the characteristic of biopsy-proven PML in patients with undetectable JCPyV CSF PCR and provide alternative approaches in this scenario.

Preliminary Validity of a Telephone-Based Neuropsychological Battery in a Consecutive Series of Persons with HIV Disease Referred for Clinical Evaluation.

OBJECTIVE: The COVID-19 pandemic necessitated use of remote assessments by clinical neuropsychologists. Telehealth was particularly important for vulnerable groups, including persons living with HIV (PLWH); however, limited internet access can be a serious barrier to care. This study examined the preliminary validity of a telephone-based neuropsychological assessment in a clinical sample of PLWH. METHOD: A consecutive series of 59 PLWH were assessed via telephone at an HIV clinic in the southern U.S. between April 2020 and July 2022. The battery included auditory-verbal neuropsychological tests of memory, attention, and executive functions, and questionnaires assessing self-reported mood and activities of daily living (ADL). RESULTS: Study measures demonstrated acceptable internal consistency. PLWH demonstrated worse neuropsychological performance compared with expectations derived from the normal curve and an HIV-seronegative adult sample (N = 44). PLWH assessed via telephone demonstrated similar impairment rates to that of a consecutive series of PLWH (N = 41) assessed in-person immediately prior to the pandemic. Higher telephone-based global neuropsychological scores were related to younger age, more education, better fund of knowledge, White race/ethnicity, fewer medical conditions, and fewer depression symptoms. Global neuropsychological impairment was strongly and independently associated with greater dependence in ADL domains, particularly for instrumental activities. CONCLUSIONS: Although telephone-based approaches to neuropsychological assessment are not ideal, these data provide support for the feasibility, internal consistency, and preliminary validity of this method in a consecutive clinical series of PLWH. The direct comparability of telephone-based and in-person neuropsychological assessments remains to be determined by prospective, counterbalanced study designs examining both PLWH and seronegative individuals.

Development and Validation of a Risk Score to Differentiate Viral and Autoimmune Encephalitis in Adults.

BACKGROUND: Encephalitis represents a challenging condition to diagnose and treat. To assist physicians in considering autoimmune encephalitis (AE) sooner, we developed and validated a risk score. METHODS: The study was conducted as a retrospective cohort of patients with a diagnosis of definite viral encephalitis (VE) and AE from​​ February 2005 to December 2019. Clinically relevant and statistically significant features between cases of AE and VE were explored in a bivariate logistic regression model and results were used to identify variables for inclusion in the risk score. A multivariable logistic model was used to generate risk score values and predict risk for AE. Results were externally validated. RESULTS: A total of 1310 patients were screened. Of the 279 enrolled, 36 patients met criteria for definite AE and 88 criteria for definite VE. Patients with AE compared with VE were more likely to have a subacute to chronic presentation (odds ratio [OR] = 22.36; 95% confidence interval [CI], 2.05-243.7), Charlson comorbidity index <2 (OR = 6.62; 95% CI, 1.05-41.4), psychiatric and/or memory complaints (OR = 203.0; 95% CI, 7.57-5445), and absence of robust inflammation in the cerebrospinal fluid defined as <50 white blood cells/µL and protein <50 mg/dL (OR = 0.06; 95% CI, .005-0.50). Using these 4 variables, patients were classified into 3 risk categories for AE: low (0-1), intermediate (2-3), and high (4). Results were externally validated and the performance of the score achieved an area under the curve of 0.918 (95% CI, .871-.966). DISCUSSION: This risk score allows clinicians to estimate the probability of AE in patients presenting with encephalitis and may assist with earlier diagnosis and treatment.

A risk score for identifying patients at a low risk of bacterial meningitis amongst adults with cerebrospinal fluid leucocytosis and a negative gram stain result: a derivation and validation study.

OBJECTIVES: We aimed to derive and validate a risk score to differentiate patients with bacterial meningitis from those with viral meningitis or encephalitis amongst patients presenting with cerebrospinal fluid (CSF) leucocytosis and a negative Gram staining result. METHODS: We included adults with bacterial and viral meningitis or encephalitis presenting with CSF leukocyte counts of >10 per mm3 and a negative Gram staining result from cohorts in Houston, Texas (2004-2019), and the Netherlands (2012-2021). Derivation and the first validation were performed in the American patients and further validation in the Dutch patients. RESULTS: Derivation was performed in 109 American patients with bacterial meningitis (median age, 56 years; interquartile range [IQR], 46-66 years; 46% women) and 194 with viral meningitis or encephalitis (median age, 46 years; IQR, 33-60 years; 53% women). Serum leukocyte counts of >10.0 × 109/L, CSF leukocyte counts of >2000 per mm3, granulocyte counts of >1180 per mm3, protein levels of >2.2 g/L, glucose levels of <1.9 mmol/L and fever on admission were included in the risk score, which was dichotomized into 'low risk' (0 present) and 'high risk' (>0 present). The first validation showed a sensitivity of 100% (95% CI, 96.6-100) and specificity of 34.0% (95% CI, 27.4-41.2). Further validation in 262 Dutch patients with bacterial meningitis (median age, 57 years; IQR 44-70 years; 45% women) and 68 with viral meningitis (median age, 34 years; IQR, 28-45 years; 60% women) showed a sensitivity of 99.6% (95% CI, 97.9-100) and specificity of 41.2% (95% CI, 29.4-53.7). CONCLUSIONS: Our risk score may be able to rule out bacterial meningitis amongst patients presenting with CSF leucocytosis and a negative Gram staining result. However, it needs prospective testing prior to clinical implementation.

Idiopathic Hypertrophic Spinal Pachymeningitis.

Hypertrophic pachymeningitis (HP) is a rare presentation with duramater thickening and fibrosis which can result in cranial or spinal compressive disease. Most cases of spinal HP require surgical management. We present an uncommon case of idiopathic hypertrophic spinal pachymeningitis (IHSP) in a 40-year-old male who showed complete improvement to steroids without any further relapses. The patient presented with bilateral upper limb weakness with magnetic resonance imaging (MRI) spine showing diffuse dural thickening of the entire spine with cervical cord compression. He had an extensive workup for underlying etiology and worsening symptoms until he was diagnosed with IHSP. Later, he was started on high-dose steroids with good response and no relapse after 2 years. A descriptive analysis of IHSP cases since 2009 including ours showed that it usually occurs after 50s with female preponderance. Weakness and sensory loss are the most common complaints with 50% patients showing clinical signs of myelopathy like hyperreflexia, clonus, Babinski sign and sensory level. Cerebrospinal fluid (CSF) and inflammatory markers like erythrocytic sedimentation rate (ESR) and C-reactive protein (CRP) can be used to assess disease progression and prognosis. Surgical removal of HP followed by steroids is the best line of management while steroids alone can be tried in cases where clinical signs of myelopathy are absent.

Progress and Challenges in Bacterial Meningitis: A Review.

Importance: Bacterial meningitis is a worldwide health problem, with incidence rates ranging from approximately 0.9 per 100 000 individuals per year in high-income countries to 80 per 100 000 individuals per year in low-income countries. In low-income countries, bacterial meningitis has a mortality rate of up to 54%. Up to 24% of those who survive develop chronic neurological sequelae, such as hearing loss or focal neurological deficits. Observations: Streptococcus pneumoniae causes about 72% and Neisseria meningitidis causes about 11% of cases of bacterial meningitis in people older than 16 years. Escherichia coli and Streptococcus agalactiae cause about 35% of cases of early-onset neonatal meningitis. In adults, risk factors for bacterial meningitis include older age and immunosuppressive conditions. The most common symptoms are headache (84%), fever (74%), stiff neck (74%), altered mental status (median [IQR] Glasgow Coma Scale score of 11 [9-14] on a scale ranging from 3-15), and nausea (62%). Brain imaging should be performed before lumbar puncture if patients present with altered mental status, focal neurological deficits, papilledema, or history of immunocompromising conditions or central nervous system disease. Bacterial meningitis should be suspected if any of the following are present on admission: serum leukocytes greater than 10.0 ×109/L, cerebrospinal fluid (CSF) leukocytes greater than 2000/µL, CSF granulocytes greater than 1180/µL, CSF protein greater than 2.2 g/L, CSF glucose less than 34.23 mg/dL, or fever. A positive Gram stain result for bacteria is diagnostic, but the sensitivity of a positive Gram stain result for bacterial meningitis ranges from 50% to 90%. In countries in which the prevalence of ceftriaxone-resistant Streptococcus pneumoniae exceeds 1%, vancomycin and ceftriaxone are the empirical antibiotics of choice, with the addition of ampicillin in neonates, older patients, and immunocompromised patients. Adjunctive dexamethasone should be used in patients with bacterial meningitis but stopped if Listeria monocytogenes is confirmed. Conclusions and Relevance: Bacterial meningitis affects approximately 0.9 per 100 000 individuals to 80 per 100 000 individuals per year and has a mortality rate as high as 54%. First-line therapy is prompt empirical intravenous antibiotic therapy and adjunctive dexamethasone.

The impact of Pleistocene glaciations and environmental gradients on the genetic structure of Embothrium coccineum.

The South American temperate forests were subjected to drastic topographic and climatic changes during the Pliocene-Pleistocene as a consequence of the Andean orogeny and glacial cycles. Such changes are common drivers of genetic structure and adaptation. Embothrium coccineum (Proteaceae) is an emblematic tree of the South American temperate forest (around 20°S of latitude) that has strongly been affected by topographic and climatic events. Previous studies have shown a marked genetic structure in this species, and distinct ecotypes have been described. Yet, little is known about their adaptive genetic responses. The main goal of this study was to investigate the effects of historical and contemporary landscape features affecting the genetic diversity and connectivity of E. coccineum throughout its current natural distribution. Using over 2000 single nucleotide polymorphisms (SNPs), we identified two genetic groups (a Northern and a Central-Southern group) that diverged around 2.8 million years ago. The level of genetic structure was higher among populations within the Northern genetic group than within the Central-Southern group. We propose that these differences in genetic structure may be due to differences in the assemblages of pollinators and in the evolutionary histories of the two genetic groups. Moreover, the data displayed a strong pattern of isolation by the environment in E. coccineum, suggesting that selection could have led to adaptive divergence among localities. We propose that in the Chilean temperate forest, the patterns of genetic variation in E. coccineum reflect both a Quaternary phylogenetic imprint and signatures of selection as a consequence of a strong environmental gradient.