Abstract

Background: Neurosurgical procedures are essential for treating various brain and spinal conditions, but they also carry the risk of infections, including viral infections. These infections can disrupt brain homeostasis, leading to cognitive impairments. During surgery, protective barriers like the blood-brain barrier (BBB) can be compromised, and cerebrospinal fluid may be exposed to pathogens. This makes the brain more susceptible to viral infections, which can trigger inflammation. Over time, this inflammation can have lasting effects on cognitive function, impacting the brain’s ability to maintain neural integrity.

Methods: A review of the literature was performed using PubMed, Google Scholar, Scopus, and Web of Science from inception to January 2025. We focus on the impact of viral infections after neurosurgical procedures and how these infections lead to neuroinflammation.

Results: Viral infections after neurosurgery activate neuroinflammatory responses, with microglia and astrocytes playing a key role. The release of cytokines such as tumor necrosis factor-alpha and interleukin-1 causes significant neuronal damage, impairing synaptic function and connectivity. This inflammatory process, combined with BBB disruption, leads to cognitive dysfunction both in the immediate postoperative period and in the long-term. Understanding these processes is essential for addressing cognitive decline in patients who have undergone neurosurgery.

Conclusion: Viral infections following neurosurgery are a significant risk factor for cognitive decline. Neuroinflammation, especially when coupled with BBB disruption, contributes to both short-term and long-term cognitive impairments. This review highlights the need for targeted interventions to control inflammation and protect the BBB in the perioperative period. Future research focused on neuroprotective therapies, including anti-inflammatory agents and strategies to preserve BBB integrity, is critical for improving cognitive outcomes in neurosurgical patients.

Keywords: Brain homeostasis, Cognitive decline, Neuroinflammation, Neurological surgery, Viral infection

INTRODUCTION

Neurosurgical interventions employed to address neurological disorders and urgent situations often encompass the creation of a burr hole, performing a craniotomy to gain access to the brain, doing a laminectomy to access the spinal cord, and implanting a cerebral shunt.[ 42 , 66 ] These procedures have the possibility of postoperative infections, which can substantially impact patient outcomes. The average occurrence of cerebral infection is about 6% following surgery, and it is a notable complication that occurs after craniotomies, especially in oncological patients who are already immunocompromised due to the disease and treatment. Postoperative cerebral infections are influenced by various risk factors, such as the length of the surgery, the form of incision, cerebrospinal fluid leaks, and secondary surgeries.[ 111 ] The risk exists even with minimally invasive neurosurgical procedures, including deep brain stimulation, laser interstitial thermal therapy, and stereotactic electroencephalography. Moreover, factors such as usage of bevacizumab, cirrhosis, foreign body implantation, previous radiotherapy, and previous surgeries increase the likelihood of surgical site infections (SSIs) following craniotomy for neuro-oncologic disorders.[ 52 ] Severe intraoperative hyperglycemia is linked to an increased likelihood of postoperative infections in patients who are having elective brain neurosurgical procedures.[ 34 , 47 ] These infections can result in inflammation of the nervous system, disruption of the blood-brain barrier (BBB), and disturbances in homeostasis, highlighting the significance of taking preventive measures and closely monitoring patients to achieve improved results after surgery.[ 88 , 101 ]

The central nervous system (CNS) is characterized as an immune privilege, which results in a usually severe condition when infected. Factors leading to the danger of the host defense play a significant role in establishing neurosurgical infections. CNS infections possess unique features that differentiate them from infections impacting other organs.[ 29 ] First, CNS has a BBB that selectively allows certain drugs, such as antibiotics, to pass through. Second, the subarachnoid space within the CNS is uniform, enabling infections to spread continuously through the cerebrospinal fluid. Third, circulatory disturbances in the CNS can elevate intracranial pressure, resulting in reduced blood flow and potential damage to brain tissue due to venous and arterial infarctions. Last, cerebral edema caused by infection can increase intracranial pressure, leading to brain damage as the limited space within the skull cannot accommodate the increased volume.[ 111 ]

A CNS infection can pose a significant risk to individuals with compromised immune systems, potentially leading to life-threatening consequences. For instance, CNS infections in cancer patients result in prolonged administration of antibiotics, supplementary surgical interventions, increased treatment expenses, and inferior treatment results. Moreover, the treatment of the primary ailment may be prolonged or postponed due to the continuous infection.[ 111 ] Herein, we comprehensively review post-neurosurgical viral infections and their effect on brain homeostasis and cognitive function.

VIRAL CNS INFECTION

The etiologies of CNS infections include bacteria, viruses, parasites, and fungi. Viral CNS infections are rare and typically lead to mild, self-limiting illness. However, these infections are highly significant due to their capacity to cause fatalities and neurological harm. Neural tissues are highly susceptible to disruptions in metabolic processes, often with incomplete recovery.[ 29 ] Viruses can move from the original infection site to the CNS through the bloodstream (viremia) or the peripheral nervous system. Viruses can move through the bloodstream by attaching themselves to cells, such as monocytes, T cells, and B cells, or by existing freely in plasma.[ 7 , 56 , 86 ]

For CNS protection, the innate immune system uses pattern recognition receptors (PRRs), located either in the cytosol or on the surface of different cells, and induces intracellular pathways. The induction of these signaling pathways mediates an antiviral response mainly regulated by type I interferon (IFN).[ 43 , 106 , 123 ] Toll-like receptors (TLRs), retinoic acid-inducible gene I (RIG-1), NOD-like receptors (NLRs), and various cytokines, including interleukin (IL)-10 and transforming growth factor-beta (TGF-b), are also involved in CNS antiviral responses.[ 35 , 48 , 86 , 115 ]

Viruses can spread from the bloodstream to the CNS via infected T cells or monocytes, infection, and replication in the brain’s capillary endothelial cells, transcytosis without replication, increased BBB permeability, or cerebrospinal fluid (CSF). Viruses in the peripheral nervous system infect nerve fiber dendrites and axons, reproducing in neuron cytoplasm or nuclei. They spread through synapses, and the strong immune responses from microglia and astrocytes in the CNS are crucial for limiting infection and minimizing tissue damage.[ 40 , 43 , 56 , 75 , 86 ] Early detection and intervention are crucial for improved outcomes. Gaining a better understanding of CNS viral infections and the immune system’s role will aid in developing effective treatments, particularly for chronic infections.[ 40 , 106 ]

POST-SURGICAL CNS INFECTIONS

Viral infection due to surgical procedure

One major contributing cause to the development of postoperative cognitive decline (POCD) is the body’s inflammatory reaction, which can be triggered by a surgical procedure. Of course, it might be challenging to determine the source and the result of the interaction between inflammation and injury to brain tissue. Any tissue damage is usually followed by an inflammatory response, which aids in healing but can cause harm if excessively activated. Experimental research in the rat brain revealed that following subarachnoid hemorrhage[ 20 ] and experimental ischemia in the anterior region of the brain,[ 18 ] there was also an elevation of cell pathways linked to inflammation, including those embodied by the nuclear transcription factor kB (NF-kB).

Cerebral inflammation and localized inflammatory responses can lead to localized ischemia. Pre-existing brain diseases or surgical interventions can trigger systemic inflammatory reactions in the nervous system. Such inflammation can damage brain tissue and impair cognitive performance. This can result in a variety of clinical events, such as septic encephalopathy and delirium, with symptoms ranging from mild cognitive impairment to coma due to the suppression of electroencephalogram activity.[ 123 ] Histological analysis of septic mice showed secondary neuronal degeneration, perivascular edema, and significant BBB disruption.[ 20 ]

Endothelial swelling is the first response to acute hypoxia in endothelial cells, which may occur in neurosurgical procedures and anesthesia. Reperfusion and reoxygenation lead to the generation of active metabolites that mobilize neutrophils, causing them to aggregate with endothelial cells. This process results in microthrombi formation and the release of potent pressor chemicals, leading to capillary blockage and blood flow obstruction, even when major vessels have recovered, known as the no-reflow phenomenon.[ 49 , 59 , 87 ] Neutrophils adhere to the capillary endothelium, causing tissue damage by releasing proteolytic enzymes, leukotrienes, cytokines, and free oxygen radicals. These substances activate or are cytotoxic to platelets, arterial walls, and polymorphonuclear cells. During the preoperative phase, these mechanisms contribute to general nervous system damage.[ 1 ] Long-term postoperative CNS dysfunction or delayed recovery can result from the CNS reacting to systemic inflammatory mediators. Even a mild response, like fever, may lead to diminished nervous system function and cognitive impairment.[ 74 ]

Ninety percent of healthy, non-inflammatory CSF cells are T cells, primarily consisting of helper CD4 cells, regulatory CD4 cells, and CD8 cytotoxic T cells.[ 44 ] T cells can enter the brain parenchyma in a pathogenic state. T cells have been implicated in viral and autoimmune neurological disorders, including herpes simplex encephalitis (HSVE) and multiple sclerosis.[ 57 ] HSVE often results from a recurrence of a previous infection rather than a new infection during surgery. This reactivation can occur in two ways: the virus may reactivate in the trigeminal ganglion and travel to the CNS, or it may reactivate directly within the CNS where it has remained latent. Viral DNA can be found in the brains of individuals without neurological diseases, which may explain some HSVE cases without a clear prior history.[ 21 , 33 ] T-cell functions in neurodegenerative illnesses, including Parkinson’s Disease, have drawn a lot of attention lately.[ 8 ] There is no concrete evidence linking T cells to the pathogenic phase of POCD. One study found that after surgery-induced cognitive impairment in mice, interleukin (IL)-17 was upregulated while IL-10 was downregulated in T helper cells and regulatory T cells, respectively.[ 107 ] An imbalance in T-cell subtypes may exacerbate POCD. More research is required to understand how T cells contribute to POCD.[ 60 ] Table 1 is a detailed about common post-neurosurgical viral infections.

Table 1:

Overview of common post-neurosurgical viral infections.

BBB breakdown

The glial membrane, which comprised capillary endothelial cells, capillary basement membrane, and the terminal foot of astrocytes, generally comprised most of the BBB.[ 84 ] Due to this tight structure, only gases, water, and tiny fat-soluble molecules could passively spread across the BBB. Proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-a) and IL-1, however, can increase cyclooxygenase-2 in neurovascular endothelial cells, enhancing local prostaglandin synthesis and increasing BBB permeability.[ 24 ] In addition, TNF-a increased matrix metalloproteinase (MMP) transcription, particularly MMP-9, further breaking down the BBB and extracellular matrix proteins.[ 84 ] In response to surgical trauma, MMP-9 deletion mice exhibited better cognitive performance under fear-related conditions than wild-type mice. In these mice, Monocyte chemoattractant protein-1 (MCP-1) attracted brain monocyte-derived macrophages (BMDMs) to the CNS during inflammation and BBB disruption. On CNS entry, BMDMs increased NF-kB transcription, releasing proinflammatory cytokines[ 91 ] and triggering microglia cells to intensify the neuroinflammatory response. Preoperative BMDM depletion decreased the incidence of POCD in mice models.[ 22 ] The migration of BMDM may significantly contribute to POCD. Once the BBB is compromised, cytokines can more easily enter the CNS, promoting BMDM transport into neural tissues and triggering immune dysregulation. This connection between the peripheral and CNS’s immune systems can worsen neuroinflammation, harm brain tissue, and lead to POCD.[ 105 ]

The meningitis

It is well established that HSV-2 is the primary cause of aseptic meningitis, while HSV-1 is associated with encephalitis. Notably, over 15% of individuals with HSV-2 infections in the CNS present with encephalitis instead of meningitis due to a significant overlap between the two conditions.[ 70 ] The potential for aseptic inflammatory meningitis to arise from surgery can complicate the interpretation of CSF results in a postoperative setting. Although brain biopsy was previously considered the most effective method for definitively diagnosing HSVE, testing for HSV-1 or HSV-2 using polymerase chain reaction (PCR) on CSF is now recognized as more effective, boasting a sensitivity of over 95% and a specificity of more than 99%.[ 108 ]

Brain and subdural abscesses

Brain abscesses are regarded as infections that could be fatal. In the 1980s, reports stated that the death rate from brain abscesses might reach 40%. The death rate for patients with brain abscesses has decreased as a result of improvements in radiographic scanning, the creation of innovative surgical procedures, and the accessibility of more recent antibiotics.[ 11 ]

The signs and symptoms of a growing infection can be challenging to identify, particularly in the case of postoperative brain abscesses due to the neurologic changes brought on by the underlying disease and the rehabilitation process following brain surgery. Headaches, seizures, cranial nerve palsies, and behavioral abnormalities are the most common clinical signs of brain abscesses (primary and postoperative). Less frequently, fever and altered consciousness occur.[ 51 ]

IMMUNE RESPONSE IN THE CNS

Mechanisms of viral entry and neuroinvasion

Viruses use several methods to enter brain tissue. One such method is passive diffusion and endothelial cell infection, which enables viruses to breach the BBB by disrupting endothelial impermeability and releasing viral proteins into the bloodstream, as seen in flaviviruses.[ 4 ] The other way of virus neuroinvasion is virus transcytosis, through which viral particles are absorbed by endothelial cells and transported to the tissue side of the brain.[ 4 ] It is reported that the virus transcytosis method is seen in dengue virus infection.[ 13 ] The last entry mechanism of viruses into the brain tissue is cell-associated virus transport. In this method, viruses are carried by blood cells and undergo blood-to-tissue transmigration by endothelial cells. This means of neuroinvasion is shown to be used by the Visna virus, bacteria, and even parasites.[ 16 , 68 , 78 , 89 ]

Innate immune response and neuroinflammation

The innate immune system is considered the first line of defense against microorganisms and foreign bodies.[ 103 ] This part of the immune system consists of several components, including epithelium cells acting as a physical barrier, TLRs, antimicrobial enzymes, and particular defending cells in each tissue.[ 71 ] In the CNS, microglia and astrocytes are the essential parts of the innate immune system unique to this tissue. Microglia cells, which originate from the myeloid progenitors, monitor the brain tissue when they are in their resting state.[ 73 ] These cells can be activated following neuroinflammation through TLR activation and then release different cytokines, especially TNF-a, which exacerbates microglia activity within the CNS.[ 112 ] In addition, astrocytes are the other unique group of innate immune cells in the CNS, which various cytokines can stimulate from reactive microglia.[ 99 ] Furthermore, it is shown that reactive astrogliosis can release different cytokines, such as TNF and IL-6, exaggerating neuroinflammation in the brain tissue.[ 58 , 109 ] The innate immune system plays a significant role in restricting invading pathogens and activating the adaptive immune system. However, its function is highly dependent on the secretion of cytokines and chemokines.

Cytokine and chemokine release

Cytokines and chemokines can improve and trigger the function of microglia and astrocytes.[ 96 ] TNF-a is released by activated microglia, exacerbating the activity of innate immune cells within the brain tissue. Other cytokines released following neuroinflammation include IL-1 and IL-6, which promote the inflammatory process within the CNS.[ 96 ] On the other hand, microglia also produce cytokines such as IL-10 and TGF-b to modulate the immune response, preventing excessive tissue damage.[ 19 , 61 , 114 ] In addition, astrocytes also secrete particular chemokines and cytokines, including IL-1, IL-6, and IFN-gamma.[ 59 , 109 ] It is reported that following the surgery trauma, astrocytes release a particular chemokine named CCL2, which plays a key role in the stimulation of microglia cells.[ 117 ] Therefore, particular cells in the innate immune system release different cytokines and chemokines in response to virus invasion through which they can enhance the function of the innate system itself and provoke the adaptive immune system.

BBB disruption

Beyond the activation of the innate immune system following surgery trauma, released cytokines and chemokines can cause disruption in BBB to help macrophages enter the CNS.[ 64 ] It is reported that interruption of BBB can be directly due to anesthesia and surgery trauma weakening the junction of BBB endothelial cells.[ 120 ] In addition, some studies demonstrated increased amounts of mast cells within the brain tissue after surgery, resulting in decreased BBB integrity through reducing tight junction proteins such as claudin-5.[ 126 ] Disrupted BBB can also exacerbate neuroinflammation by losing integrity and admitting pathogens and inflammatory molecules to enter the brain tissue. BBB is the primary defense part of the brain, which is damaged by the neuroinflammation process triggered by the function of the innate immune system in response to neuroinvasion, posing the brain tissue to diverse pathogens and immune cells and proteins.[ 104 ]

Adaptive immune response

T-cell activation and function

The activation of the innate immune system may lead to the induction of the adaptive immune system through antigen presentation by dendritic cells, macrophages, and B cells to the naïve T cells, the main initiators of the adaptive system reaction.[ 12 , 27 ] In addition, all cells infected by viruses carry major histocompatibility complex (MHC) class I molecules, particularly molecules on their membranes, which trigger naïve T cells.[ 12 ] Presenting of antigens to T cells within the CNS is carried out by microglia cells, which are the major antigen-presenting cells in the brain tissue.[ 79 , 100 ] Within the CNS, CD4+ T cells act as helper cells to enhance adaptive immune reactions, and CD8+ cytotoxic T cells function as the central part of the adaptive immune cells against pathogens within the brain tissue, targeting cells expressing MHC class I, including astrocytes, microglia, and infected neurons.[ 41 , 90 , 100 ] CD8+ cytotoxic T cells utilize various methods to inhibit virus function within the CNS. These cells destroy infected neurons through apoptosis and eliminate infected microglia and astrocytes through the cytolysis process.[ 51 , 67 , 76 ] T cells have the most important role in defending the CNS against viruses, whereas the collaboration of B cells and humoral immunity can increase the strength of the whole CNS immune system in destroying these pathogens.

Antibody production and humoral immunity

B cells play a major role in humoral immunity by secreting antibodies and recognizing antigens.[ 23 ] B cells have particular B-cell receptors, which bind to their specific antigens, resulting in the differentiation of B-cells into plasma cells and memory B-cells. Plasma cells are the main cells producing antibodies, including immunoglobulin (Ig)G, IgM, IgA, IgD, and IgE.[ 94 ] In healthy conditions, B cells of CNS are found in the meninges, especially within the dura mater adjacent to its venous sinuses.[ 92 ] In addition, it is reported that IgA+ plasma cells, which play a crucial role in CNS humoral immunity, can be found in dural venous sinuses.[ 26 ] Once a pathogen enters the CNS, most of the antibody-secreting cells (ASCs) in early phases of humoral immunity activity are IgM+, and after a while, IgG⁺ secreting cells become the major part of the ASCs.[ 69 ] Secreted antibodies can neutralize various kinds of pathogens entering the brain tissue in two ways, including the stimulation of the proteins of the complement system and opsonization, the process through which antibodies coat the pathogen and induce the macrophages to eliminate it.[ 85 ] Thus, interaction of the B cells and T cells as the humoral and adaptive immune system alongside the function of the innate immune system consisting of microglia, astrocytes, cytokines, and chemokines plays a core role in destroying viruses invade the CNS following a neurosurgical intervention.

POSTOPERATIVE VIRAL INFECTION AND COGNITION

Mechanisms of neuroinflammation, neuronal damage, and cognitive impairments brought on by viruses

Surgery-induced systemic inflammation is found to raise plasma levels of TNF-a, IL-1, IL-6, and other inflammatory markers,[ 80 ] which trigger the CNS inflammatory response through various pathways. Due to relative permeability and the absence of a continuous BBB, inflammatory substances enter the CNS through diffusion in the periventricular region. Some transporters may also actively carry inflammatory substances into the CNS within the intact BBB. In addition, in pathological circumstances, the BBB’s permeability is altered. The production of TNF-a during the perioperative systemic inflammatory response increases BBB permeability.[ 127 ] Animal studies show that surgical trauma triggers peripheral TNF-a release, compromising the BBB. This leads to an influx of inflammatory cells, mainly macrophages, and factors into the CNS, provoking further inflammatory responses.[ 15 , 36 ] In addition, it was discovered that TNF-a antagonist therapy after inflammatory stimulation enhances cognitive function compared to the control group.[ 6 , 119 ] Peripheral inflammatory reactions involve the infiltration of inflammatory factors into the CNS, activating its immune response. Specifically, peripheral factors like IL-1 bind to receptors on BBB endothelial cells, prompting these cells to produce immunoreactive molecules that activate microglia and astrocytes in the CNS.[ 6 ] When activated by external inflammatory stimuli, vagal afferent nerves quickly initiate central inflammatory pathways, leading to responses in the CNS. This activation triggers local gastrointestinal and cardiovascular reflexes, enhancing the body’s defense mechanisms. Immune cells respond to inflammation by releasing mediators that activate primary afferent neurons in the vagal sensory ganglion. These mediators bind to receptors on vagal afferent fibers, stimulating an immunological response in the CNS. Vagal sensory neurons can also express messenger RNAs for IL-1 and prostaglandin receptors.[ 31 ] The term “gut-brain axis” refers to the relationship between gut microorganisms and the brain.[ 98 ] The intestinal flora comprises many bacteria, viruses, other microbes, and the gut microbiota. Surprisingly, disruption of the gut microbiota led to the release of inflammatory markers, including TNF-a and IL-6, and the advancement of neurodegenerative disorders.[ 121 ] An increasing amount of animal research has demonstrated in recent years that anesthesia and surgery can cause an imbalance in the gut microbiota, which can subsequently impact brain function through specific processes.[ 125 ]

An increase in useful bacteria in the gut, such as Lactobacillus, Bifidobacterium, and Galactose oligosaccharide, may help to mitigate these pathogenic mechanisms.[ 121 ] In addition, current studies have demonstrated that appropriate exercise reduced gut dysbiosis and elevated valeric acid, improving postoperative neuroplasticity and cognitive function.[ 50 ] It is still unknown how the brain’s neurons and gut microbiota interacted with one another and how this influenced cognitive performance in the normal brain.[ 14 ] It should be mentioned that the blood-cerebrospinal fluid and BBB, which separate the brain from the rest of the immune system and prevent it from being impacted by it, are essential to the CNS. However, Iliff et al.[ 39 ] recently identified glymphatic pathways in the CNS. Louveau et al.[ 62 ] demonstrated that meningeal lymphatic channels in the CNS interacted with the peripheral immune system. These results contributed to debunking the theory that the brain is an immune-privileged organ. Figure 1 depicts a summary of post-neurosurgical viral infection and following homeostasis disruption and cognitive decline.

Figure 1:

Viral immunological complications in neurological surgery. Procedures such as craniotomy and laminectomy increase the risk of CNS infections, allowing viral pathogens to infiltrate through CSF or BBB disruptions. This triggers microglial and astrocytic activation, releasing pro-inflammatory cytokines (TNF-α, IL-1), leading to potential POCD, memory loss, and neuronal damage. CNS: Central nervous system, CSF: cerebrospinal fluid, BBB: Blood-brain barrier, TNF-α: Tumor necrosis factor-alpha, IL-1: Interleukin 1, POCD: Postoperative cognitive dysfunction.

Breakdown of the neuronal network and malfunctioning of synapses

The density of synapses is reduced with age, although aging affects various brain parts differently.[ 105 ] The prefrontal cortex and hippocampus showed more noticeable alterations than other brain regions.[ 5 , 9 ] Neurodegenerative illnesses result from malfunctioning synapses due to a lack of neuronal activity or cell death.[ 9 ] Newly generated synapses underwent constant modification to meet their behavioral needs in a continuously changing environment.[ 32 ] These alterations may occur in the development of new synapses or in synaptic plasticity, which is the improvement of synaptic efficacy.[ 2 ] Inflammatory cytokines produced by surgical or anesthetic drugs cross the BBB, allowing them to enter the CNS and activate inflammatory cells. Damaged proteins, neurotoxins, and inflammatory cytokines are just a few pathological proteins that these inflammatory cells would eventually release. These proteins could interact with neurons and synapses, synaptic loss, causing neuronal death, and impaired cell signaling, ultimately resulting in POCD.[ 37 ] There are two potential mechanisms: first, aggregations of phosphorylated Tau protein and synaptic terminal Ab plaques cause damage to the signaling function and the structure of neighboring neurons and synapses[ 25 ] and second, intoxication may result from the production of TNF-a from glial cells and IL-16 from lymphocytes, which impede metabolism and cause an excessive build-up of glutamate.[ 38 , 97 ] Parvalbumin neurons, an important class of GABAergic inhibitory interneurons, were downregulated, leading to a reduction in inhibitory neurotransmission through GABA receptors. This change could disturb the balance between excitatory and inhibitory neurotransmission, resulting in lower neuronal excitability and decreased synaptic activity.[ 82 ] After surgery or anesthesia, mitochondria-derived reactive oxygen species (ROS) are generated. These ROS not only functioned as upstream NOD-like receptor protein 3 (NLRP3) activators but also took part in the formation of downstream inflammasomes.[ 113 ] Attacks by ROS were most likely to target mitochondria since they are the primary location of ROS production. Following oxidative damage, a vicious loop that ultimately resulted in nerve apoptosis was created when the mitochondrial respiratory chain was damaged.[ 72 ] In general, the most important causes of POCD were neuronal injury and a decrease in synaptic plasticity. Future research will, therefore, concentrate on ways to intervene to lessen the loss of neuronal and synaptic function.[ 105 ]

Affected cognitive domains: Executive function, memory, and attention

Brain damage brought on by neuronal apoptosis can lead patients to experience emotional disturbances, cognitive decline, memory loss, and reduced learning capacities. Age decreases the ability of adult brain neurons to mend themselves through a process called neuronal regeneration.[ 110 ] Sun et al. found that Alzheimer’s disease (AD) mice’s hippocampus neurons had a much higher apoptotic index than the wild-type control group.[ 102 ] Cognitive performance was improved, and hippocampus neuronal death was decreased in AD mice treated with dexmedetomidine.[ 102 ] In their POCD model, Yuan et al. stated that autophagy and neuronal death are caused by activation of the NF-kB pathway in neurons, which leads to cognitive impairment.[ 124 ] The experiment was conducted using elderly mice with the left extrahepatic lobe excised. Shao et al. used sevoflurane to create the POCD model. They found that through blocking the NLRP3/caspase-1 pathway, Chikusetsu saponin IVa (ChIV) has a neuroprotective effect against sevoflurane-induced neuroinflammation and cognitive impairment. According to Shao et al., this indicates that ChIV may be a viable clinical approach for treating older patients’ anesthesia-induced POCD.[ 95 ] Disruption of synaptic plasticity refers to the independent modification of the strength of connections between nerve cell synapses. These changes can result in temporary modifications, such as inhibition, facilitation, and enhancement, as well as lasting alterations, including long-term potentiation and long-term inhibition. These processes form the neural basis for memory and learning mechanisms.[ 65 ] The post-synaptic density protein 95, or PSD95, is essential for synaptic plasticity. Gao et al. found that insults from surgery and anesthesia decreased synaptophysin and PSD95 in the hippocampal regions of mice, which affected postoperative cognitive function.[ 28 ] It was found that expression levels of histone deacetylase 3 were elevated in the dorsal hippocampus of an aged mouse model of POCD following exploratory laparotomy performed under anesthesia. This increase was associated with a significant decrease in dendritic spine density and in proteins related to synaptic plasticity. However, the cognitive impairment observed after surgery was restored in the dorsal hippocampus by specifically inhibiting histone deacetylase 3, which led to the recovery of dendritic spine density and the levels of proteins associated with synaptic plasticity.[ 54 , 118 ]

It was discovered that surgery caused an increase in the activity of histone deacetylase 2 and a decrease in dendritic arborization and spine density in the hippocampus of mice with POCD. The medically induced alterations were counteracted by administering suberanilohydroxamic acid by intraperitoneal injection. This compound is a highly specific inhibitor of histone deacetylase 2.[ 63 ] Xiao et al. found that inhibiting prostaglandin E2-receptor 3 using a stereotaxic virus injection into the dorsal hippocampus restored plasticity-related proteins, including activity and cyclic adenosine monophosphate (cAMP) response element-binding protein-controlled cytoskeletal-associated protein.[ 116 ] This intervention reduced the cognitive decline caused by surgery.[ 116 ] Table 2 explains a summary of how viral infections can lead to cognitive impairment and homeostatic disturbances after neurological surgery.

Table 2:

Mechanisms of viral-induced cognitive impairment and homeostatic disturbances.

PREVENTION AND MANAGEMENT STRATEGY

Patient-related risk factors

Certain patient-related factors increase the likelihood of viral infections following neurosurgery. These include being immunocompromised, whether due to underlying conditions such as untreated HIV, hematological malignancies, or the use of immunosuppressive therapies. In addition, a history of recent travel, contact with infected individuals, and behaviors such as injection drug use or unprotected sexual activity further elevate the risk. Use of steroids, exposure to radiotherapy, physical trauma, geographic location, the time of year, and vaccination history also influence susceptibility to viral reactivation or new infections. Recognizing these factors is crucial for identifying patients who may be at greater risk of developing complications, including cognitive decline after surgery.[ 3 , 46 ]

Procedure-related risk factors

Dural tears, laminectomy, and operation time >3 h have been identified as independent risk factors for bacterial meningitis following spinal surgery. Emergency surgeries, operations classified as clean-contaminated or dirty, procedures lasting more than 4 h, and recent neurosurgical interventions have been identified as independent predictive factors for developing SSIs. Despite the extensive data on bacterial complications, there is a significant gap in the literature regarding viral infections following neurosurgery.[ 55 , 77 ]

Infection control protocols and antiviral prophylaxis

HSV is the leading cause of sporadic encephalitis, a severe and potentially fatal condition with a high risk of long-term disability in survivors.[ 83 ] The introduction of acyclovir treatment has significantly reduced mortality from around 70% to below 20%. Intravenous acyclovir is the preferred treatment for HSV encephalitis. The standard dose is 10 mg/kg every 8 h, typically for 14–21 days, with adjustments for kidney function as necessary. Studies indicate that delaying treatment beyond 48 h after admission increases the risk of long-term neurological complications. The choice between a 14-day and 21-day treatment duration depends on the severity of the condition. If the chance of HSV encephalitis is low and a CSF HSV PCR test performed over 72 h after symptom onset is negative, acyclovir can be discontinued. However, if there is a strong suspicion of HSV encephalitis, treatment should proceed despite a negative CSF HSV PCR, unless another diagnosis is established.[ 108 ]

Managing homeostatic disturbances and cognitive impairments

The inflammation caused by HSV-1 can compromise the BBB, this is largely driven by high levels of cytokines such as IL-1b and TNF-a, which bind to ICAM-1 glycoproteins on brain endothelial cells. Mitochondrial dysfunction in astrocytes exacerbates these effects, causing cell death and altering aquaporin 4 (AQP4), a protein involved in fluid regulation, which leads to brain edema. HSV-1 triggers ongoing microglial activation, which results in significant neuroinflammation and the release of numerous cytokines and chemokines. Microglia and astrocytes recognize viral particles, known as pathogen-associated molecular patterns (PAMPs), through PRRs like TLRs, leading to an intense antiviral response. This response includes the production of inflammatory molecules such as TNF, IL-1, IFN-alpha, and IL-6. Microglia also produce chemokines and antimicrobial proteins, such as chemokine ligand 5 (CCL5), C-X-C motif chemokine ligand 10 (CXCL10), nitric oxide, and inducible nitric oxide synthase, which are essential in directing immune responses and controlling inflammation.[ 10 , 17 , 30 ] HSV-1 infection disrupts normal neuronal activity, leading to increased excitability, calcium imbalance, and heightened production of amyloid precursor protein, amyloid plaques, and hyper phosphorylated tau–hallmarks of AD.[ 81 ] Markers of HSV-1 infection, such as anti-HSV-1 IgM antibodies, have been linked to a greater risk of developing AD.[ 53 ] Mitochondrial dysfunction and oxidative stress contribute to neuronal apoptosis, while pro-inflammatory cytokines exacerbate neurotoxicity. This cycle of neuroinflammation and cellular damage emphasizes the importance of managing homeostatic disturbances to prevent cognitive decline over the long-term.

Novel antiviral therapies and immunomodulatory agents

Among all strategies for controlling viral infections after neurosurgical procedures, there are novel therapies yet to be considered; monoclonal antibodies are engineered proteins designated to target specific antigens. They can affect the proteins that are essential for the replication of virus thereby reducing the overall viral load.[ 45 ] Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) is a revolutionary gene-editing technology that allows scientists to make precise changes to DNA. It is based on a naturally occurring defense mechanism found in bacteria and archaea, which use CRISPR to protect themselves from viruses and other foreign genetic elements. CRISPR-based antiviral therapies are currently in the early stages of clinical development. Ongoing research is focused on optimizing delivery methods, improving specificity, and evaluating the safety and efficacy of these therapies in humans. CRISPRCas9 can be programmed to target specific DNA sequences, including those found within viral genomes. By targeting essential viral genes, researchers can disrupt viral replication, assembly, or entry processes, effectively eliminating infected cells and preventing the spread of the virus.[ 122 ]

Long-term Follow-up Studies and Patient Outcomes

Even mild forms of viral meningoencephalitis can cause permanent long-term sequelae, and the severity of the disease during the acute phase has a significant impact on the long-term outcome. A significant proportion of survivors from acute encephalitis experience long-term effects, including memory problems, headaches, fatigue, and mood disorders. The severity of these challenges can vary widely, and some survivors may require ongoing support and resources to manage their symptoms and improve their quality of life.[ 93 ]

DISCUSSION

Viral infections that occur after neurosurgical procedures can significantly impact CNS homeostasis and cognitive function. After surgery, disruptions in the BBB and CSF pathways can facilitate viral infiltration. This infiltration triggers neuroinflammatory processes involving microglia and astrocytes. The release of cytokines, such as TNF-a and IL-1, promotes neuroinflammation, disrupts synaptic connections, and causes neuronal damage, all of which can lead to cognitive decline. While previous studies have highlighted the role of neuroinflammation in cognitive impairment, this review specifically examines these mechanisms within the context of neurosurgery, emphasizing the brain’s increased vulnerability to viral pathogens following invasive procedures.

Limitations

The existing literature often lacks comprehensive, surgery-specific data on viral infections and neuroinflammation. Variations in patient immune responses, surgical techniques, and post-operative care can lead to differing outcomes, making it challenging to generalize findings. Future research should aim to incorporate longitudinal data and standardized metrics for measuring neuroinflammation and cognitive function post-surgery. This approach would strengthen the interpretation of results and help establish causal links. A better understanding of neuroimmunology enhances our awareness of the risks associated with viral infections in neurosurgical settings. One important goal is to preserve brain homeostasis during and after neurosurgery, alongside the need for improved infection control measures.

Future direction

Future research should focus on developing neuroprotective interventions, such as anti-inflammatory agents or compounds that stabilize the BBB, to reduce the risk of CNS infections and neuroinflammation in the perioperative period. In addition, more studies are needed to investigate patient-specific factors, such as genetic predispositions or variations in immune response, which may influence susceptibility to POCD following neurosurgery. Finally, clinical trials that examine the effectiveness of preventive measures in diverse patient populations could provide crucial insights for tailored strategies to mitigate the cognitive impacts of viral infections in neurosurgical contexts.

CONCLUSION

Neurosurgical procedures can increase susceptibility to CNS viral infections, which may disrupt brain homeostasis and contribute to cognitive decline through neuroinflammatory mechanisms. Understanding these pathways and the associated risks offers new perspectives on post-surgical care and points to potential interventions for safeguarding cognitive health. Enhanced infection control, combined with future neuroprotective therapies, holds promise for minimizing the cognitive impacts of neurosurgery and improving long-term patient outcomes.

Authors’ Contributions:

MM, RZ, MJE, and HS prepared the first draft, revised the manuscript, and designed the table and figures. ASK conceptualized the title, edited and finalized the draft, critically revised the manuscript, and supervised the project. All the authors have read and approved the final draft of the manuscript.

Ethical approval:

The Institutional Review Board approval is not required.

Declaration of patient consent:

Patient’s consent was not required as there are no patients in this study.

Financial support and sponsorship:

Nil.

Conflicts of interest:

There are no conflicts of interest.

Use of artificial intelligence (AI)-assisted technology for manuscript preparation:

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

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References

1. Allan SM, Rothwell NJ. Cytokines and acute neurodegeneration. Nat Rev Neurosci. 2001. 2: 734-44

2. Apple DM, Solano-Fonseca R, Kokovay E. Neurogenesis in the aging brain. Biochem Pharmacol. 2017. 141: 77-85

3. Asensio VC, Campbell IL. Chemokines and viral diseases of the central nervous system. Adv Virus Res. 2001. 56: 127-73

4. Ayala-Nunez NV, Gaudin R. A viral journey to the brain: Current considerations and future developments. PLoS Pathog. 2020. 16: e1008434

5. Ball MJ. Neuronal loss, neurofibrillary tangles and granulovacuolar degeneration in the hippocampus with ageing and dementia. A quantitative study. Acta Neuropathol. 1977. 37: 111-8

6. Banks WA, Plotkin SR, Kastin AJ. Permeability of the blood-brain barrier to soluble cytokine receptors. Neuroimmunomodulation. 1995. 2: 161-5

7. Behzad F, Sefidgar E, Samadi A, Lin W, Pouladi I, Pi J. An overview of zinc oxide nanoparticles produced by plant extracts for anti-tuberculosis treatments. Curr Med Chem. 2022. 29: 86-98

8. Brochard V, Combadière B, Prigent A, Laouar Y, Perrin A, Beray-Berthat V. Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest. 2009. 119: 182-92

9. Burke SN, Barnes CA. Neural plasticity in the ageing brain. Nat Rev Neurosci. 2006. 7: 30-40

10. Campos EM, Rodrigues LD, Oliveira LF, Dos Santos JC. Dementia and cognitive impairment in adults as sequels of HSV-1-related encephalitis: A review. Dement Neuropsychol. 2021. 15: 164-72

11. Carpenter J, Stapleton S, Holliman R. Retrospective analysis of 49 cases of brain abscess and review of the literature. Eur J Clin Microbiol Infect Dis. 2007. 26: 1-11

12. Carson MJ, Doose JM, Melchior B, Schmid CD, Ploix CC. CNS immune privilege: Hiding in plain sight. Immunol Rev. 2006. 213: 48-65

13. Chanthick C, Suttitheptumrong A, Rawarak N, Pattanakitsakul SN. Transcytosis Involvement in transport system and endothelial permeability of vascular leakage during dengue virus infection. Viruses. 2018. 10: 69

14. Chen Y, Xu J, Chen Y. Regulation of neurotransmitters by the gut microbiota and effects on cognition in neurological disorders. Nutrients. 2021. 13: 2099

15. Cheon SY, Kim JM, Kam EH, Ho CC, Kim EJ, Chung S. Cell-penetrating interactomic inhibition of nuclear factor-kappa B in a mouse model of postoperative cognitive dysfunction. Sci Rep. 2017. 7: 13482

16. Choi MR, Stanton-Maxey KJ, Stanley JK, Levin CS, Bardhan R, Akin D. A cellular Trojan Horse for delivery of therapeutic nanoparticles into tumors. Nano Lett. 2007. 7: 3759-65

17. Chu H, Xiang J, Wu P, Su J, Ding H, Tang Y. The role of aquaporin 4 in apoptosis after intracerebral hemorrhage. J Neuroinflammation. 2014. 11: 184

18. Clemens JA, Stephenson DT, Smalstig EB, Dixon EP, Little SP. Global ischemia activates nuclear factor-kB in forebrain neurons of rats. Stroke. 1997. 28: 1073-81

19. Constam DB, Philipp J, Malipiero UV, Ten Dijke P, Schachner M, Fontana A. Differential expression of transforming growth factor-beta 1,-beta 2, and-beta 3 by glioblastoma cells, astrocytes, and microglia. J Immunol. 1992. 148: 1404-10

20. Davies D. Blood-brain barrier breakdown and oedema formation in systemic sepsis and human brain tumours. J Anat. 2002. 200: 528-29

21. De Tiège X, Rozenberg F, Des Portes V, Lobut JB, Lebon P, Ponsot G. Herpes simplex encephalitis relapses in children: Differentiation of two neurologic entities. Neurology. 2003. 61: 241-3

22. Degos V, Vacas S, Han Z, Van Rooijen N, Gressens P, Su H. Depletion of bone marrow-derived macrophages perturbs the innate immune response to surgery and reduces postoperative memory dysfunction. Anesthesiology. 2013. 118: 527-36

23. Dorrier CE, McGavern DB. Humoral immune defense of the central nervous system. Curr Opin Immunol. 2022. 76: 102179

24. Engblom D, Monica E, Saha S, Ericsson-Dahlstrand A, Jakobsson PJ, Blomqvist A. Prostaglandins as inflammatory messengers across the blood-brain barrier. J Mol Med (Berl). 2002. 80: 5-15

25. Fang EF, Hou Y, Palikaras K, Adriaanse BA, Kerr JS, Yang B. Mitophagy inhibits amyloid-b and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat Neurosci. 2019. 22: 401-12

26. Fitzpatrick Z, Frazer G, Ferro A, Clare S, Bouladoux N, Ferdinand J. Gut-educated IgA plasma cells defend the meningeal venous sinuses. Nature. 2020. 587: 472-6

27. Galea I, Bechmann I, Perry VH. What is immune privilege (not)?. Trends Immunol. 2007. 28: 12-8

28. Gao S, Zhang S, Zhou H, Tao X, Ni Y, Pei D. Role of mTOR-regulated autophagy in synaptic plasticity related proteins downregulation and the reference memory deficits induced by anesthesia/surgery in aged mice. Front Aging Neurosci. 2021. 13: 628541

29. Giovane RA, Lavender PD. Central nervous system infections. Prim Care. 2018. 45: 505-18

30. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010. 140: 918-34

31. Goehler LE, Gaykema RP, Opitz N, Reddaway R, Badr N, Lyte M. Activation in vagal afferents and central autonomic pathways: Early responses to intestinal infection with Campylobacter jejuni. Brain Behav Immun. 2005. 19: 334-44

32. Gomez AM, Traunmüller L, Scheiffele P. Neurexins: Molecular codes for shaping neuronal synapses. Nat Rev Neurosci. 2021. 22: 137-51

33. Gordon L, McQuaid S, Cosby SL. Detection of herpes simplex virus (types 1 and 2) and human herpesvirus 6 DNA in human brain tissue by polymerase chain reaction. Clin Diagn Virol. 1996. 6: 33-40

34. Gruenbaum SE, Toscani L, Fomberstein KM, Ruskin KJ, Dai F, Qeva E. Severe intraoperative hyperglycemia is independently associated with postoperative composite infection after craniotomy: An observational study. Anesth Analg. 2017. 125: 556-61

35. Hanamsagar R, Hanke ML, Kielian T. Toll-like receptor (TLR) and inflammasome actions in the central nervous system. Trends Immunol. 2012. 33: 333-42

36. He HJ, Wang Y, Le Y, Duan KM, Yan XB, Liao Q. Surgery upregulates high mobility group box-1 and disrupts the blood-brain barrier causing cognitive dysfunction in aged rats. CNS Neurosci Ther. 2012. 18: 994-1002

37. Hovens IB, Schoemaker RG, Van der Zee EA, Heineman E, Izaks GJ, Van Leeuwen BL. Thinking through postoperative cognitive dysfunction: How to bridge the gap between clinical and pre-clinical perspectives. Brain Behav Immun. 2012. 26: 1169-79

38. Hridi SU, Franssen AJ, Jiang HR, Bushell TJ. Interleukin-16 inhibits sodium channel function and GluA1 phosphorylation via CD4-and CD9-independent mechanisms to reduce hippocampal neuronal excitability and synaptic activity. Mol Cell Neurosci. 2019. 95: 71-8

39. Iliff JJ, Goldman SA, Nedergaard M. Implications of the discovery of brain lymphatic pathways. Lancet Neurol. 2015. 14: 977-9

40. Jorgačevski J, Potokar M. Immune functions of astrocytes in viral neuroinfections. Int J Mol Sci. 2023. 24: 3514

41. Kang SS, McGavern DB. Inflammation on the mind: Visualizing immunity in the central nervous system. Curr Top Microbiol Immunol. 2009. 334: 227-63

42. Kapoor R, Hussain I, Hussain I, Stieg P, editors. Basic neurosurgical procedures. Cham: Springer; 2015. p.

43. Kigerl KA, De Rivero Vaccari JP, Dietrich WD, Popovich PG, Keane RW. Pattern recognition receptors and central nervous system repair. Exp Neurol. 2014. 258: 5-16

44. Kivisäkk P, Mahad DJ, Callahan MK, Trebst C, Tucky B, Wei T. Human cerebrospinal fluid central memory CD4+ T cells: Evidence for trafficking through choroid plexus and meninges via P-selectin. Proc Natl Acad Sci U S A. 2003. 100: 8389-94

45. Krawczyk A, Arndt MA, Grosse-Hovest L, Weichert W, Giebel B, Dittmer U. Overcoming drug-resistant herpes simplex virus (HSV) infection by a humanized antibody. Proc Natl Acad Sci U S A. 2013. 110: 6760-5

46. Krett JD, Beckham JD, Tyler KL, Piquet AL, Chauhan L, Wallace CJ, et al. Neurology of acute viral infections. Neurohospitalist. 2022. 12: 632-46

47. Kulikov A, Krovko Y, Nikitin A, Shmigelsky A, Zagidullin T, Ershova O. Severe intraoperative hyperglycemia and infectious complications after elective brain neurosurgical procedures: Prospective observational study. Anesth Analg. 2022. 135: 1082-8

48. Kurtel H, Fujimoto K, Zimmerman BJ, Granger DN, Tso P. Ischemia-reperfusion-induced mucosal dysfunction: Role of neutrophils. Am J Physiol. 1991. 261: G490-6

49. Lai Z, Shan W, Li J, Min J, Zeng X, Zuo Z. Appropriate exercise level attenuates gut dysbiosis and valeric acid increase to improve neuroplasticity and cognitive function after surgery in mice. Mol Psychiatry. 2021. 26: 7167-87

50. Lane TE, Hardison JL, Walsh KB. Functional diversity of chemokines and chemokine receptors in response to viral infection of the central nervous system. Curr Top Microbiol Immunol. 2006. 303: 1-27

51. Lange N, Berndt M, Jörger AK, Wagner A, Lummel N, Ryang YM. Clinical characteristics and course of postoperative brain abscess. World Neurosurg. 2018. 120: 675-83

52. Lee KS, Borbas B, Chaudhry D, Kuri A, Best L, Gillespie CS. Surgical site infection after craniotomy in neurooncology (SINO): A protocol for an international prospective multicentre service evaluation across the United Kingdom and Ireland. PLoS One. 2025. 20: e0316237

53. Letenneur L, Pérès K, Fleury H, Garrigue I, Barberger-Gateau P, Helmer C. Seropositivity to herpes simplex virus antibodies and risk of Alzheimer’s disease: A population-based cohort study. PLoS One. 2008. 3: e3637

54. Li WX, Luo RY, Chen C, Li X, Ao JS, Liu Y. Effects of propofol, dexmedetomidine, and midazolam on postoperative cognitive dysfunction in elderly patients: A randomized controlled preliminary trial. Chin Med J (Engl). 2019. 132: 437-45

55. Liang S, Wang Z, Wu P, Chen Z, Yang X, Li Y. Risk factors and outcomes of central nervous system infection after spinal surgery: A retrospective cohort study. World Neurosurg. 2023. 170: e170-9

56. Libbey JE, Fujinami RS. Adaptive immune response to viral infections in the central nervous system. Handb Clin Neurol. 2014. 123: 225-47

57. Liblau RS, Gonzalez-Dunia D, Wiendl H, Zipp F. Neurons as targets for T cells in the nervous system. Trends Neurosci. 2013. 36: 315-24

58. Lieberman AP, Pitha PM, Shin HS, Shin ML. Production of tumor necrosis factor and other cytokines by astrocytes stimulated with lipopolysaccharide or a neurotropic virus. Proc Natl Acad Sci U S A. 1989. 86: 6348-52

59. Lin L, Wang X, Yu Z. Ischemia-reperfusion injury in the brain: Mechanisms and potential therapeutic strategies. Biochem Pharmacol (Los Angel). 2016. 5: 213

60. Liu Y, Yin Y. Emerging roles of immune cells in postoperative cognitive dysfunction. Mediators Inflamm. 2018. 2018: 6215350

61. Lodge PA, Sriram S. Regulation of microglial activation by TGF-beta, IL-10, and CSF-1. J Leukoc Biol. 1996. 60: 502-8

62. Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015. 523: 337-41

63. Luo F, Min J, Wu J, Zuo Z. Histone deacetylases may mediate surgery-induced impairment of learning, memory, and dendritic development. Mol Neurobiol. 2020. 57: 3702-11

64. Lv S, Song HL, Zhou Y, Li LX, Cui W, Wang W. Tumour necrosis factor-alpha affects blood-brain barrier permeability and tight junction-associated occludin in acute liver failure. Liver Int. 2010. 30: 1198-210

65. Magee JC, Grienberger C. Synaptic plasticity forms and functions. Annu Rev Neurosci. 2020. 43: 95-117

66. Manninen PH, Raman SK, Boyle K, El-Beheiry H. Early postoperative complications following neurosurgical procedures. Can J Anaesth. 1999. 46: 7-14

67. Medana IM, Gallimore A, Oxenius A, Martinic MM, Wekerle H, Neumann H. MHC class I-restricted killing of neurons by virus-specific CD8+ T lymphocytes is effected through the Fas/FasL, but not the perforin pathway. Eur J Immunol. 2000. 30: 3623-33

68. Mendez OA, Koshy AA. Toxoplasma gondii Entry, association, and physiological influence on the central nervous system. PLoS Pathog. 2017. 13: e1006351

69. Metcalf TU, Baxter VK, Nilaratanakul V, Griffin DE. Recruitment and retention of B cells in the central nervous system in response to alphavirus encephalomyelitis. J Virol. 2013. 87: 2420-9

70. Moon SM, Kim T, Lee EM, Kang JK, Lee SA, Choi SH. Comparison of clinical manifestations, outcomes and cerebrospinal fluid findings between herpes simplex type 1 and type 2 central nervous system infections in adults. J Med Virol. 2014. 86: 1766-71

71. Murphy K, Weaver C, editors. Innate immunity: The first lines of defense. Janeway’s immunobiology. United States: W.W. Norton and Company; 2017. p. 37-76

72. Netto MB, De Oliveira Junior AN, Goldim M, Mathias K, Fileti ME, Da Rosa N. Oxidative stress and mitochondrial dysfunction contributes to postoperative cognitive dysfunction in elderly rats. Brain Behav Immun. 2018. 73: 661-9

73. Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005. 308: 1314-8

74. Pappa M, Theodosiadis N, Tsounis A, Sarafis P. Pathogenesis and treatment of post-operative cognitive dysfunction. Electron Physician. 2017. 9: 3768-75

75. Pardridge WM. CSF, blood-brain barrier, and brain drug delivery. Expert Opin Drug Deliv. 2016. 13: 963-75

76. Parra B, Hinton DR, Marten NW, Bergmann CC, Lin MT, Yang CS. IFN-gamma is required for viral clearance from central nervous system oligodendroglia. J Immunol. 1999. 162: 1641-7

77. Patel S, Thompson D, Innocent S, Narbad V, Selway R, Barkas K. Risk factors for surgical site infections in neurosurgery. Ann R Coll Surg Engl. 2019. 101: 220-5

78. Pedemonte E, Mancardi G, Giunti D, Corcione A, Benvenuto F, Pistoia V. Mechanisms of the adaptive immune response inside the central nervous system during inflammatory and autoimmune diseases. Pharmacol Ther. 2006. 111: 555-66

79. Peluso R, Haase A, Stowring L, Edwards M, Ventura P. A Trojan Horse mechanism for the spread of visna virus in monocytes. Virology. 1985. 147: 231-6

80. Peng M, Wang YL, Wang CY, Chen C. Dexmedetomidine attenuates lipopolysaccharide-induced proinflammatory response in primary microglia. J Surg Res. 2013. 179: e219-25

81. Piacentini R, Civitelli L, Ripoli C, Marcocci ME, De Chiara G, Garaci E. HSV-1 promotes Ca2+-mediated APP phosphorylation and Ab accumulation in rat cortical neurons. Neurobiol Aging. 2011. 32: 2323.e13-26

82. Pribiag H, Stellwagen D. TNF-a downregulates inhibitory neurotransmission through protein phosphatase 1-dependent trafficking of GABAA receptors. J Neurosci. 2013. 33: 15879-93

83. Raschilas F, Wolff M, Delatour F, Chaffaut C, De Broucker T, Chevret S. Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: Results of a multicenter study. Clin Infect Dis. 2002. 35: 254-60

84. Rempe RG, Hartz AM, Bauer B. Matrix metalloproteinases in the brain and blood-brain barrier: Versatile breakers and makers. J Cereb Blood Flow Metab. 2016. 36: 1481-507

85. Rogers KJ, Vijay R, Butler NS. Anti-malarial humoral immunity: The long and short of it. Microbes Infect. 2021. 23: 104807

86. Rouse BT, Sehrawat S. Immunity and immunopathology to viruses: What decides the outcome?. Nat Rev Immunol. 2010. 10: 514-26

87. Salimi H, Klein R, editors. Disruption of the blood-brain barrier during neuroinflammatory and neuroinfectious diseases. Cham: Springer; 2019. p.

88. Salimi H, Klein RS. Disruption of the blood-brain barrier during neuroinflammatory and neuroinfectious diseases. Neuroimmune Diseases. 2019. 1: 195-234

89. Santiago-Tirado FH, Onken MD, Cooper JA, Klein RS, Doering TL. Trojan Horse transit contributes to blood-brain barrier crossing of a eukaryotic pathogen. mBio. 2017. 8:

90. Savarin C, Bergmann CC. Neuroimmunology of central nervous system viral infections: The cells, molecules and mechanisms involved. Curr Opin Pharmacol. 2008. 8: 472-9

91. Saxena S, Maze M. Impact on the brain of the inflammatory response to surgery. Presse Méd. 2018. 47: e73-81

92. Schafflick D, Wolbert J, Heming M, Thomas C, Hartlehnert M, Börsch AL. Single-cell profiling of CNS border compartment leukocytes reveals that B cells and their progenitors reside in non-diseased meninges. Nat Neurosci. 2021. 24: 1225-34

93. Schwitter J, Branca M, Bicvic A, Abbuehl LS, Suter-Riniker F, Leib SL. Long-term sequelae after viral meningitis and meningoencephalitis are frequent, even in mildly affected patients, a prospective observational study. Front Neurol. 2024. 15: 1411860

94. Sebina I, Pepper M. Humoral immune responses to infection: Common mechanisms and unique strategies to combat pathogen immune evasion tactics. Curr Opin Immunol. 2018. 51: 46-54

95. Shao A, Fei J, Feng S, Weng J. Chikusetsu saponin IVa alleviated sevoflurane-induced neuroinflammation and cognitive impairment by blocking NLRP3/caspase-1 pathway. Pharmacol Rep. 2020. 72: 833-45

96. Shastri A, Bonifati DM, Kishore U. Innate immunity and neuroinflammation. Mediators Inflamm. 2013. 2013: 342931

97. Skvarc DR, Berk M, Byrne LK, Dean OM, Dodd S, Lewis M. Post-operative cognitive dysfunction: An exploration of the inflammatory hypothesis and novel therapies. Neurosci Biobehav Rev. 2018. 84: 116-33

98. Smith PA. The tantalizing links between gut microbes and the brain. Nature. 2015. 526: 312-4

99. Sofroniew MV. Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci. 2009. 32: 638-47

100. Steel CD, Hahto SM, Ciavarra RP. Peripheral dendritic cells are essential for both the innate and adaptive antiviral immune responses in the central nervous system. Virology. 2009. 387: 117-26

101. Sulhan S, Lyon KA, Shapiro LA, Huang JH. Neuroinflammation and blood-brain barrier disruption following traumatic brain injury: Pathophysiology and potential therapeutic targets. J Neurosci Res. 2020. 98: 19-28

102. Sun W, Zhao J, Li C. Dexmedetomidine provides protection against hippocampal neuron apoptosis and cognitive impairment in mice with Alzheimer’s disease by mediating the miR-129/YAP1/JAG1 axis. Mol Neurobiol. 2020. 57: 5044-55

103. Taguchi T, Mukai K. Innate immunity signalling and membrane trafficking. Curr Opin Cell Biol. 2019. 59: 1-7

104. Takata F, Nakagawa S, Matsumoto J, Dohgu S. Blood-brain barrier dysfunction amplifies the development of neuroinflammation: Understanding of cellular events in brain microvascular endothelial cells for prevention and treatment of BBB dysfunction. Front Cell Neurosci. 2021. 15: 661838

105. Tan XX, Qiu LL, Sun J. Research progress on the role of inflammatory mechanisms in the development of postoperative cognitive dysfunction. Biomed Res Int. 2021. 2021: 3883204

106. Telikani Z, Monson EA, Hofer MJ, Helbig KJ. Antiviral response within different cell types of the CNS. Front Immunol. 2022. 13: 1044721

107. Tian A, Ma H, Cao X, Zhang R, Wang X, Wu B. Vitamin D improves cognitive function and modulates Th17/T reg cell balance after hepatectomy in mice. Inflammation. 2015. 38: 500-9

108. Tunkel AR, Glaser CA, Bloch KC, Sejvar JJ, Marra CM, Roos KL. The management of encephalitis: Clinical practice guidelines by the infectious diseases society of America. Clin Infect Dis. 2008. 47: 303-27

109. Van Neerven S, Nemes A, Imholz P, Regen T, Denecke B, Johann S. Inflammatory cytokine release of astrocytes in vitro is reduced by all-trans retinoic acid. J Neuroimmunol. 2010. 229: 169-79

110. Vasic V, Barth K, Schmidt MH. Neurodegeneration and neuro-regeneration-Alzheimer’s disease and stem cell therapy. Int J Mol Sci. 2019. 20: 4272

111. Velnar T, Kocivnik N, Bosnjak R. Clinical infections in neurosurgical oncology: An overview. World J Clin Cases. 2023. 11: 3418-33

112. Von Zahn J, Möller T, Kettenmann H, Nolte C. Microglial phagocytosis is modulated by pro-and anti-inflammatory cytokines. Neuroreport. 1997. 8: 3851-6

113. Wei P, Yang F, Zheng Q, Tang W, Li J. The potential role of the NLRP3 inflammasome activation as a link between mitochondria ROS generation and neuroinflammation in postoperative cognitive dysfunction. Front Cell Neurosci. 2019. 13: 73

114. Williams K, Dooley N, Ulvestad E, Becher B, Antel JP. IL-10 production by adult human derived microglial cells. Neurochem Int. 1996. 29: 55-64

115. Woodroofe MN. Cytokine production in the central nervous system. Neurology. 1995. 45: S6-10

116. Xiao JY, Xiong BR, Zhang W, Zhou WC, Yang H, Gao F. PGE 2-EP 3 signaling exacerbates hippocampus-dependent cognitive impairment after laparotomy by reducing expression levels of hippocampal synaptic plasticity-related proteins in aged mice. CNS Neurosci Therapeut. 2018. 24: 917-29

117. Xu J, Dong H, Qian Q, Zhang X, Wang Y, Jin W. Astrocyte-derived CCL2 participates in surgery-induced cognitive dysfunction and neuroinflammation via evoking microglia activation. Behav Brain Res. 2017. 332: 145-53

118. Yang L, Hao JR, Gao Y, Yang X, Shen XR, Wang HY. HDAC3 of dorsal hippocampus induces postoperative cognitive dysfunction in aged mice. Behav Brain Res. 2022. 433: 114002

119. Yang N, Liang Y, Yang P, Wang W, Zhang X, Wang J. TNF-a receptor antagonist attenuates isoflurane-induced cognitive impairment in aged rats. Exp Ther Med. 2016. 12: 463-8

120. Yang S, Gu C, Mandeville ET, Dong Y, Esposito E, Zhang Y. Anesthesia and surgery impair blood-brain barrier and cognitive function in mice. Front Immunol. 2017. 8: 902

121. Yang XD, Wang LK, Wu HY, Jiao L. Effects of prebiotic galactooligosaccharide on postoperative cognitive dysfunction and neuroinflammation through targeting of the gut-brain axis. BMC Anesthesiol. 2018. 18: 177

122. Ying M, Wang H, Liu T, Han Z, Lin K, Shi Q. CLEAR strategy inhibited HSV proliferation using viral vectors delivered CRISPR-Cas9. Pathogens. 2023. 12: 814

123. Young GB, Bolton CF, Archibald YM, Austin TW, Wells GA. The electroencephalogram in sepsis-associated encephalopathy. J Clin Neurophysiol. 1992. 9: 145-52

124. Yuan N, Wang X, Zhang Y, Kong L, Yuan L, Ge Y. Intervention of NF-Kb signaling pathway and preventing post-operative cognitive dysfunction as well as neuronal apoptosis. Iran J Public Health. 2022. 51: 124-132

125. Zhan G, Hua D, Huang N, Wang Y, Li S, Zhou Z. Anesthesia and surgery induce cognitive dysfunction in elderly male mice: The role of gut microbiota. Aging (Albany NY). 2019. 11: 1778-90

126. Zhang S, Dong H, Zhang X, Li N, Sun J, Qian Y. Cerebral mast cells contribute to postoperative cognitive dysfunction by promoting blood brain barrier disruption. Behav Brain Res. 2016. 298: 158-66

127. Zhvania MG, Chilachava LR, Japaridze NJ, Gelazonia LK, Lordkipanidze TG. Immediate and persisting effect of toluene chronic exposure on hippocampal cell loss in adolescent and adult rats. Brain Res Bull. 2012. 87: 187-92