Clinical Features and Outcomes of Anti-N-Methyl-d-Aspartate Receptor Encephalitis in Infants and Toddlers.

OBJECTIVE: We describe the clinical features and outcomes of anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis in infants and toddlers. METHODS: This was a single-center retrospective study. Infants and toddlers who met the diagnostic criteria for anti-NMDAR encephalitis were recruited for the study. Data on clinical features, treatment, and long-term outcomes were collected retrospectively. RESULTS: A total of 41 patients (age range: six to 34 months; median age: 23 months; female: 19) were enrolled in this study. Nineteen (46%) patients exhibited classical anti-NMDAR encephalitis, whereas 22 (54%) patients exhibited anti-NMDAR encephalitis after viral encephalitis. There was a high presentation of movement disorders (100%), developmental regression (90%), abnormal behaviors (90%). All patients were administered first-line therapy, with only 17% of them being administered second-line immunotherapy. Two patients succumbed to the disease, whereas none of them relapsed. At the long-term follow-up (more than one year), 20 of 35 (57%) exhibited satisfactory outcomes (modified Rankin Scale ≤2). Compared with patients with classical anti-NMDAR encephalitis (n = 18), patients after viral encephalitis (n = 17) were more likely to have worse clinical outcomes. They exhibited a higher modified Rankin Scale/Pediatric Cerebral Performance Category score and more frequent seizures. A predictor of poor outcome was presentation after viral encephalitis (odds ratio 35.7, 95% confidence interval 4.64 to 275.03, P = 0.001). CONCLUSION: Anti-NMDAR encephalitis in infants and toddlers clinically presents with movement disorders, developmental regression, and abnormal behaviors. Interestingly, this group had a higher proportion of patients after viral encephalitis, which is regarded as the only risk factor for poor outcomes.

Clinical significance of Epstein-Barr virus in the cerebrospinal fluid of immunocompetent patients.

INTRODUCTION: Polymerase chain reaction (PCR)-based testing of cerebrospinal fluid (CSF) samples has greatly facilitated the diagnosis of central nervous system (CNS) infections. However, the clinical significance of Epstein-Barr virus (EBV) DNA in CSF of individuals with suspected CNS infection remains unclear. We wanted to gain a better understanding of EBV as an infectious agent in immunocompetent patients with CNS disorders. METHODS: We identified cases of EBV-associated CNS infections and reviewed their clinical and laboratory characteristics. The study population was drawn from patients with EBV PCR positivity in CSF who visited Pusan National University Hospital between 2010 and 2019. RESULTS: Of the 780 CSF samples examined during the 10-year study period, 42 (5.4 %) were positive for EBV DNA; 9 of the patients (21.4 %) were diagnosed with non-CNS infectious diseases, such as optic neuritis, Guillain-Barré syndrome, and idiopathic intracranial hypotension, and the other 33 cases were classified as CNS infections (22 as encephalitis and 11 as meningitis). Intensive care unit admission (13/33 patients, 39.3 %) and presence of severe neurological sequelae at discharge (8/33 patients, 24.2 %) were relatively frequent. In 10 patients (30.3 %), the following pathogens were detected in CSF in addition to EBV: varicella-zoster virus (n = 3), cytomegalovirus (n = 2), herpes simplex virus 1 (n = 1), herpes simplex virus 2 (n = 1), Streptococcus pneumomiae (n = 2), and Enterococcus faecalis (n = 1). The EBV-only group (n = 23) and the co-infection group (n = 10) did not differ in age, gender, laboratory data, results of brain imaging studies, clinical manifestations, or prognosis; however, the co-infected patients had higher CSF protein levels. CONCLUSION: EBV DNA in CSF is occasionally found in the immunocompetent population; the virus was commonly associated with encephalitis and poor prognosis, and frequently found together with other microbes in CSF.

SARS-CoV-2-mediated encephalitis: Role of AT2R receptors in the blood-brain barrier.

At the end of 2019, there was an outbreak of a new Coronavirus 2019 (COVID-19 disease). Studies suggest that SARS-CoV-2 can cause infection in the central nervous system (CNS) and trigger neurological symptoms that include headache, nausea and vomiting, mental confusion and loss of smell or taste. These findings reveal that Coronaviruses have neurological tropism and neuroinvasive capacity. The spread of SARS-CoV-2 in the brain tissue possibly occurs through the systemic circulation as reported in patients affected by SARS-CoV. Evidence highlights similarity between the SARS-CoV genome and SARS-CoV-2 and that both interact with the angiotensin-converting enzyme type 2 (ACE2) located in the brain tissue of infected patients. Hence, the presence of ACE2 is likely in the CNS to mediate the entry of the SARS-CoV-2 virus into neural tissue. Our hypothesis suggests that SARS-CoV-2 can cause encephalitis through the production of inflammatory mediators and activation of immune system cells resulting from the interaction of the ACE2 receptor with the viral Spike protein that causes an increase in angiotensin II. This mechanism has the ability to activate immune system cells by exacerbating stimuli at the angiotensin 2 receptor (AT2R). Thus, it leads to a status of brain injury preceded by vascular damage and destruction of the blood-brain barrier, making it responsible for the installation of acute inflammation.

Cross-Talk Between Key Players in Patients with COVID-19 and Ischemic Stroke: A Review on Neurobiological Insight of the Pandemic.

The global pandemic of novel coronavirus disease 2019 (COVID-19) has taken the entire human race by surprise and led to an unprecedented number of mortalities worldwide so far. Current clinical studies have interpreted that angiotensin-converting enzyme 2 (ACE2) is the host receptor for severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). In addition, ACE2 is the major component of the renin-angiotensin system. ACE2 deteriorates angiotensin II, a peptide that is responsible for the promotion of stroke. The downregulation of ACE2 further activates an immunological cascade. Thus, researchers need to explore and examine the possible links between COVID-19 and ischemic stroke (IS). Human ACE2 expression level and pattern in various tissues might be decisive for the vulnerability, symptoms, and treatment outcomes of the SARS-CoV-2 infection. The swift increase in the knowledge of SARS-CoV-2 has given creditable evidence that SARS-CoV-2 infected patients also encounter neurological deficits. As the SARS-CoV-2 binds to ACE2, it will hamper the activity of ACE2 in providing neuroprotection, especially in the case of stroke patients. Due to the downregulation of ACE2, the inflammatory response is activated in the ischemic penumbra. The COVID-19 pandemic has affected people with various pre-existing diseases, including IS, in such a way that these patients need special care and attention for their survival. Several clinical trials are currently ongoing worldwide as well as many other projects are in different stages of conceptualization and planning to facilitate the effective management of stroke patients with COVID-19 infection.

Neuropathogenic human coronaviruses: A review.

Human Coronaviruses (HCoVs) have long been known as respiratory viruses. However, there are reports of neurological findings in HCoV infections, particularly in patients infected with the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) amid Coronavirus disease 2019 (COVID-19) pandemic. Therefore, it is essential to interpret the interaction of HCoVs and the nervous system and apply this understanding to the COVID-19 pandemic. This review of the literature analyses how HCoVs, in general, and SARS-CoV-2, in particular, affect the nervous system, highlights the various underlying mechanisms, addresses the associated neurological and psychiatric manifestations, and identifies the neurological risk factors involved. This review of literature shows the magnitude of neurological conditions associated with HCoV infections, including SARS-CoV-2. This review emphasises, that, during HCoV outbreaks, such as COVID-19, a focus on early detection of neurotropism, alertness for the resulting neurological complications, and the recognition of neurological risk factors are crucial to reduce the workload on hospitals, particularly intensive-care units and neurological departments.

Impaired Autophagy Flux is Associated with Proinflammatory Microglia Activation Following Japanese Encephalitis Virus Infection.

Role of autophagy in Japanese encephalitis viral (JEV) infection is not well known. In the present study, we reported the role of autophagy flux in microglia activation, neurobehavioral function and neuronal death using a mouse model of JEV. Markers for autophagy (LC3-II/I, SQSTM1/P62, phos-Akt, phos-AMPK), and neuronal death (cleaved caspase 12, H2Ax, polyubiquitin) were investigated by western blot at 1, 3 and 7 days post inoculation. Cathepsin D was measured in cerebral cotex of JEV infected mice spectrophotometrically. Microglia activation and pro-inflammatory cytokines (IL1ß, TNF-α, IFNγ, IL6) were measured by immunohistochemistry, western blot and qPCR analysis. In order to determine the neuroinflammatory changes and autophagy mediated neuronal cell death, BV2-microglia and N2a-neuronal cells were used. Autophagy activation marker LC3-II/I and its substrate SQSTM1/P62 were significantly increased while cathepsin D activity was decreased on day 7 post inoculation in cerebral cortex. Microglia in cortex were activated and showed higher expression of proinflammatory mRNA of IL1ß, TNF-α, IFNγ and IL6, with increased DNA damage (H2AX) and neuronal cell death pathways in hippocampus and neurobehavioral dysfunction. Similar observations on JEV infection mediated autophagy flux inhibition and neuronal cell death was found in N2a neuronal cell. Collectively, our study provides evidence on the role of autophagy regulation, microglial activation and neurodegeneration following JEV infection.

Surgical treatment in children with intractable epilepsy after viral encephalitis.

PURPOSE: To investigate the surgical outcome in children with epilepsy after viral encephalitis (VE), we studied the prognostic factors for surgery and summarized the surgical strategies of children with epilepsy secondary to VE. METHODS: We retrospectively analyzed 23 surgically treated children with VE. The subjects were divided into two groups according to their surgical outcome. All presurgical evaluation data were collected and analyzed. RESULTS: Among the 23 operated children, the mean age at surgery was 6.1 years. Surgeries were hemispherotomy (n = 12), temporal-parietal-occipital disconnection (n = 4), whole corpus callosotomy (n = 3), lobectomy (n = 3), and vagus nerve stimulation (n = 1). The mean patient follow-up time was 37.2 months, and 13 children had a good outcome (ILAE classification 1-3). Univariate analyses revealed that the latency from infection to the first unprovoked seizure, MRI laterality, concordance of PET and MRI abnormalities, and acute postoperative seizure (APOS) were prognostic factors of seizure outcomes (P < 0.05). No correlation was found between generalized seizures and poor outcome (P = 0.229). CONCLUSIONS: We concluded that the children who achieve favorable surgical outcomes are those with longer latency, unilateral abnormalities on MRI, consistency of PET and MRI abnormalities, and no APOS. Without invasive studies, epilepsy surgery may be successful for selected children with epilepsy after VE, despite diffuse interictal epileptiform discharges on scalp EEG. In addition, children with generalized seizures were not an absolute contraindication for surgery.

Coronavirus Disease 2019 and Stroke: Clinical Manifestations and Pathophysiological Insights.

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global health threat. Some COVID-19 patients have exhibited widespread neurological manifestations including stroke. Acute ischemic stroke, intracerebral hemorrhage, and cerebral venous sinus thrombosis have been reported in patients with COVID-19. COVID-19-associated coagulopathy is increasingly recognized as a result of acute infection and is likely caused by inflammation, including inflammatory cytokine storm. Recent studies suggest that axonal transport of SARS-CoV-2 to the brain can occur via the cribriform plate adjacent to the olfactory bulb that may lead to symptomatic anosmia. The internalization of SARS-CoV-2 is mediated by the binding of the spike glycoprotein of the virus to the angiotensin-converting enzyme 2 (ACE2) on cellular membranes. ACE2 is expressed in several tissues including lung alveolar cells, gastrointestinal tissue, and brain. The aim of this review is to provide insights into the clinical manifestations and pathophysiological mechanisms of stroke in COVID-19 patients. SARS-CoV-2 can down-regulate ACE2 and, in turn, overactivate the classical renin-angiotensin system (RAS) axis and decrease the activation of the alternative RAS pathway in the brain. The consequent imbalance in vasodilation, neuroinflammation, oxidative stress, and thrombotic response may contribute to the pathophysiology of stroke during SARS-CoV-2 infection.

Nervous system involvement after infection with COVID-19 and other coronaviruses.

Viral infections have detrimental impacts on neurological functions, and even to cause severe neurological damage. Very recently, coronaviruses (CoV), especially severe acute respiratory syndrome CoV 2 (SARS-CoV-2), exhibit neurotropic properties and may also cause neurological diseases. It is reported that CoV can be found in the brain or cerebrospinal fluid. The pathobiology of these neuroinvasive viruses is still incompletely known, and it is therefore important to explore the impact of CoV infections on the nervous system. Here, we review the research into neurological complications in CoV infections and the possible mechanisms of damage to the nervous system.

Akinetic mutism and status epilepticus due to Epstein Barr virus encephalitis.

Neurological complications of Epstein Barr virus (EBV) infection are infrequent and may include occasionally encephalitis, usually with a benign evolution. We here report on an aggressive case of EBV encephalitis in a 14-year-old boy with extensive basal ganglia involvement, and to a lesser degree of brain cortex who presented atypically with akinetic mutism and non-convulsive status epilepticus, requiring intensive care but showed a favorable outcome. EBV encephalitis is uncommon and its best management is unclear. Its pathophysiology is not well understood but could include autoimmunity. Onconeuronal and synaptic antibodies were negative in serum and cerebrospinal fluid, including the dopamine D2 receptor. To the best of our knowledge, this is the first report to evaluate antibodies to D2 receptors in EBV encephalitis. Corticosteroid therapy is usually recommended but the use of acyclovir is controversial. Intensive care is required in severe cases to assure a favorable outcome.

Cerebrospinal Fluid Neopterin in Children With Enterovirus-Related Brainstem Encephalitis.

BACKGROUND: Enterovirus-A71 causes outbreaks of brainstem encephalitis, ranging from self-limited disease to acute flaccid paralysis. The aim of this study was to assess the role of cerebrospinal fluid (CSF) neopterin as a biomarker of disease severity in children with enterovirus-related brainstem encephalitis. METHODS: A descriptive, prospective cohort study was conducted from April 2016 to March 2017 in a tertiary hospital. Pediatric patients with a diagnosis of brainstem encephalitis with or without myelitis due to enterovirus infection were enrolled. The final study group comprised a convenience sample including all patients with sufficient CSF volume for neopterin determination. The major variables considered in estimating the severity were the diagnosis of encephalomyelitis, the presence of lesions and extensive lesions on brain and spinal magnetic resonance imaging (MRI), hospital stay length greater than seven days, and sequelae at day 30. RESULTS: Of 60 patients, CSF neopterin could be measured in 36. Median age was 26 months (interquartile range: 19 to 32). Thirty-three were diagnosed with brainstem encephalitis and three with encephalomyelitis. Enterovirus-A71 was the only identified genotype (25 of 25). CSF neopterin levels were elevated (>61 nmol/L) in 33 of 36 (92%), with a median of 347 nmol/L (interquartile range: 204 to 525). CSF neopterin was useful to distinguish patients with lesions on MRI (area under the receiver operating characteristic curve = 0.76; P = 0.02) and extensive lesions (area under the receiver operating characteristic curve = 0.76; P = 0.04). CONCLUSIONS: This study suggests an association between CSF neopterin levels and the presence of inflammatory lesions on MRI.

Long-term outcome in neuroZika: When biological diagnosis matters.

OBJECTIVE: To characterize the full spectrum, relative frequency, and prognosis of the neurologic manifestations in Zika virus (ZIKV) postnatal infection. METHODS: We conducted an observational study in consecutive ZIKV-infected patients presenting with neurologic manifestations during the French West Indies 2016 outbreak. RESULTS: Eighty-seven patients, including 6 children, were enrolled. Ninety-five percent of all cases required hospitalization. Guillain-Barré syndrome was the most frequent manifestation (46.0%) followed by encephalitis or encephalomyelitis (20.7%), isolated single or multiple cranial nerve palsies (9.2%), other peripheral manifestations (6.9%), and stroke (1.1%). Fourteen patients (16.1%), including one child, developed a mixed disorder involving both the central and peripheral nervous system. Mechanical ventilation was required in 21 cases, all of whom had ZIKV RNA in at least one biological fluid. Two adult patients died due to neuroZika. Clinical follow-up (median 14 months; interquartile range, 13-17 months) was available for 76 patients. Residual disability (modified Rankin Scale score ≥2) was identified in 19 (25.0%) patients; in 6 cases (7.9%), disability was severe (modified Rankin Scale score ≥4). Among patients with ZIKV RNA detected in one biological fluid, the risk of residual disability or death was higher (odds ratio 9.19; confidence interval 1.12-75.22; p = 0.039). CONCLUSIONS: NeuroZika spectrum represents a heterogeneous group of clinical neurologic manifestations. During an outbreak, clinicians should consider neuroZika in patients presenting with cranial nerve palsies and a mixed neurologic disorder. Long-term sequelae are frequent in NeuroZika. ZIKV reverse-transcription PCR status at admission can inform prognosis and should therefore be taken into consideration in the management of hospitalized patients.

Evaluation of cholinergic functions in patients with Japanese encephalitis and Herpes simplex encephalitis.

Cognitive and memory impairment are related to cholinergic dysfunction and are important complications of viral encephalitis, In view of paucity of studies on cholinergic dysfunction in encephalitis, this study has been undertaken. We report acetyl choline esterase (AChE) and muscurinic 2 (M2) receptor levels in herpes simplex encephalitis (HSE) and Japanese encephalitis (JE) patients, and correlate these with cognitive functions and MRI findings. Patients with JE and HSE were evaluated for consciousness, neurological and MRI findings, plasma AChE and M2 receptor levels on admission and after one year. Twenty-nine patients with JE and 23 with HSE were included. Admission AChE levels in JE (48.32 ±â€¯5.36 nmol/min/ml) and HSE (41.92 ±â€¯5.12 nmol/min/ml) were significantly lower compared with controls (70.50 ±â€¯8.30 nmol/min/ml). M2 receptor levels were also low in JE (4.52 ±â€¯0.56 ng/ml) and HSE (4.35 ±â€¯0.57 ng/ml) compared with controls (7.95 ±â€¯0.41 ng/ml). In JE, AChE activity (r = 0.43, p = 0.02) and M2 receptor levels (r = 0.43, p = 0.02) correlated with caudate involvement, and AChE activity (r = 0.76, p = 0.03) with Mini Mental State Examination ( MMSE) score. In HSE, M2 receptor levels (r = 0.53, p = 0.03) correlated with MMSE. The levels of AChE and M2 receptors increased at one year compared to the baseline, which was greater in JE than in HSE. Both AChE and M2 receptors were reduced in JE and HSE and correlated with cognition at one year. Recovery of these biomarkers was more in JE than HSE.

Flaviviruses and the Central Nervous System: Revisiting Neuropathological Concepts.

Flaviviruses are major emerging human pathogens on a global scale. Some flaviviruses can infect the central nervous system of the host and therefore are regarded as neurotropic. The most clinically relevant classical neurotropic flaviviruses include Japanese encephalitis virus, West Nile virus, and tick-borne encephalitis virus. In this review, we focus on these flaviviruses and revisit the concepts of flaviviral neurotropism, neuropathogenicity, neuroinvasion, and resultant neuropathogenesis. We attempt to synthesize the current knowledge about interactions between the central nervous system and flaviviruses from the neuroanatomical and neuropathological perspectives and address some misconceptions and controversies. We hope that revisiting these neuropathological concepts will improve the understanding of flaviviral neuroinfections. This, in turn, may provide further guiding foundations for relevant studies of other emerging or geographically expanding flaviviruses with neuropathogenic potential, such as Zika virus and dengue virus, and pave the way for intelligent therapeutic strategies harnessing potentially beneficial, protective host responses to interfere with disease progression and outcome.

Viral encephalitis in quantitative EEG.

OBJECTIVE: Our aim was to study the character of quantitative EEG of viral encephalitis. METHOD: Collect the EEG data of hospitalized children with viral encephalitis diagnosed by pediatricians from January 2013 to September 2016, and EEG data of normal cases at the same age were control group. Using quantitative EEG analysis technologies to obtain power spectrum value, power spectrum value, 1 power spectrum value, 12 power spectrum value, 21 power spectrum value, and 12 power spectrum value. Relative power spectrum values of 2 and were obtained by calculation. All the cases were divided into 5 groups according to the EEG character: age 3 group, age 4 group, age 5-6 group, age 7-9-year group, and age 10-14-year group. Viral encephalitis group and normal cases group were statistically compared to obtain characters of quantitative EEG with viral encephalitis. RESULTS: Power spectrum values and power spectrum values of 3-14-year-old cases with encephalitis increased. 1 power spectrum values existed in age 3 group with viral encephalitis and declined at the post-head lead, while 11 and 12 power spectrum values existed in age 4-14 group with viral encephalitis declined at the post-head lead. The value of 2 Power spectrum values of age 3-9 group was limited in diagnosing viral encephalitis. 1 and 12 power spectrum values decrease in age 10-14 group with viral encephalitis. Relative power spectrum values of 2 and increased in age 3-14 group with viral encephalitis; Relative power spectrum values of decreased in age 3-14 group with viral encephalitis, most lead of relative power spectrum decreased in age 3-14 group with viral encephalitis. CONCLUSION: The character of quantitative EEG of cases with viral encephalitis is similar to EEG, but more detailed, more precise, more intuitive and can be used for clinical diagnose of viral encephalitis.

Spectrum of noncerebrovascular rapidly progressive cognitive deterioration: a 2-year retrospective study.

PURPOSE: The number of cognitive deterioration patients has been steadily increasing as the population ages in China. Patients with cognitive deterioration demonstrated diverse patterns, often making the diagnosis difficult, especially in rapidly progressive cognitive deterioration (RPCD) patients. The purpose of this study was to exhibit the disease spectrum and frequency of noncerebrovascular RPCD in patients from a medical college hospital of southeastern China. MATERIALS AND METHODS: We performed a 2-year retrospective cohort study including 310 RPCD patients who had been admitted to the Department of Neurology, Second Affiliated Hospital, Zhejiang University School of Medicine, from January 1, 2015 to December 31, 2016. RPCD patients' information on epidemiologic data and clinical aspects were collected. All the data were analyzed using SPSS. RESULTS: Of a total of 310 patients hospitalized for RPCD diagnosis, mean age of onset was 55.92±18.89 years. The most common cause of RPCD was viral encephalitis, accounting for 21.9% (68) of the cases, followed by Alzheimer's disease and autoimmune encephalitis, accounting for 14.5% (45) and 9.0% (28) of the cases, respectively. Creutzfeldt-Jakob disease accounted for 7.1% (22) of the cases. Patients in the secondary RPCD group tended to be younger than those in the primary RPCD group and experienced a more rapid progression course. CONCLUSION: Our study suggests that the most common causes of RPCD are secondary neurological diseases and most of them are potentially reversible under appropriate treatment of the underlying disease. The spectrum and frequency of RPCD in our cohort is comparable with a previous study performed in the European population.

Valnoctamide Inhibits Cytomegalovirus Infection in Developing Brain and Attenuates Neurobehavioral Dysfunctions and Brain Abnormalities.

Cytomegalovirus (CMV) is the most common infectious cause of brain defects and neurological dysfunction in developing human babies. Due to the teratogenicity and toxicity of available CMV antiviral agents, treatment options during early development are markedly limited. Valnoctamide (VCD), a neuroactive mood stabilizer with no known teratogenic activity, was recently demonstrated to have anti-CMV potential. However, it is not known whether this can be translated into an efficacious therapeutic effect to improve CMV-induced adverse neurological outcomes. Using multiple models of CMV infection in the developing mouse brain, we show that subcutaneous low-dose VCD suppresses CMV by reducing the level of virus available for entry into the brain and by acting directly within the brain to block virus replication and dispersal. VCD during the first 3 weeks of life restored timely acquisition of neurological milestones in neonatal male and female mice and rescued long-term motor and behavioral outcomes in juvenile male mice. CMV-mediated brain defects, including decreased brain size, cerebellar hypoplasia, and neuronal loss, were substantially attenuated by VCD. No adverse side effects on neurodevelopment of uninfected control mice receiving VCD were detected. Treatment of CMV-infected human fetal astrocytes with VCD reduced both viral infectivity and replication by blocking viral particle attachment to the cell, a mechanism that differs from available anti-CMV drugs. These data suggest that VCD during critical periods of neurodevelopment can effectively suppress CMV replication in the brain and safely improve both immediate and long-term neurological outcomes.SIGNIFICANCE STATEMENT Cytomegalovirus (CMV) can irreversibly damage the developing brain. No anti-CMV drugs are available for use during fetal development, and treatment during the neonatal period has substantial limitations. We studied the anti-CMV actions of valnoctamide (VCD), a psychiatric sedative that appears to lack teratogenicity and toxicity, in the newborn mouse brain, a developmental period that parallels that of an early second-trimester human fetus. In infected mice, subcutaneous VCD reaches the brain and suppresses viral replication within the CNS, rescuing the animals from CMV-induced brain defects and neurological problems. Treatment of uninfected control animals exerts no detectable adverse effects. VCD also blocks CMV replication in human fetal brain cells.