Clinical manifestations

Presentation and course

	• Neuroinflammation, whether as a cause or effect, is a feature of several CNS diseases, including neurodegenerative disorders, CNS trauma, stroke, and epilepsy.
	• Neuroinflammation influences the clinical manifestations and prognosis of a disease.

The 4 cardinal signs of inflammation—redness, heat, swelling, and pain—are observed only in superficial parts of the human body. Swelling of the brain (cerebral edema) may occur in acute inflammation and manifests as raised intracranial pressure. Peripheral inflammation has been linked to neuroinflammation. Central neuropathic pain may be a manifestation of lesions of the CNS that have neuroinflammation, such as those due to trauma, stroke, multiple sclerosis, and Parkinson disease. Diseases in which neuroinflammation has a role in pathogenesis are listed below and further discussed in the Biological basis section.

	• Alzheimer disease
	• Parkinson disease
	• Huntington disease
	• Multiple sclerosis
	• Epilepsy
	• Cerebrovascular disease
	• Traumatic brain injury
	• Spinal cord injury
	• Viral encephalopathies, eg, neuroCOVID
	• Hepatic encephalopathy
	• Psychiatric disorders, eg, major depressive disorder and schizophrenia
	• Drug-induced encephalopathies
	• Central neuropathic pain

Prognosis and complications

Neuroinflammation is a pathological process and can be counteracted to some extent by anti-inflammatory agents. Other factors are also involved in the pathogenesis of various diseases, and prognosis takes these into consideration. Prognosis also depends on the balance between the harmful effects of chronic neuroinflammation and benefits of the transient acute inflammatory process.

Biological basis

Etiology and pathogenesis

	• Neuroinflammation is involved in the pathogenesis of several neurologic disorders.
	• Microglia play an important role in neuroinflammation.
	• There are several causes of inflammation, such as infections, trauma, etc.

Role of microglia in neuroinflammation. Microglia are the resident immune cells of the CNS, and their primary function is homeostasis. They also have other functions, including surveillance of the brain for perturbations, pruning synapses, and modulating neural systems and circuits. Microglia are the primary cells involved in neuroinflammation, which can induce neuronal damage if it becomes chronic.

Role of other players in neuroinflammation. Under some pathological conditions, peripheral circulating lymphocytes, neutrophils, and monocytes can infiltrate the CNS and exacerbate the neuroinflammatory response when activated by producing cytokines, which are key molecular players in inflammation. One common feature of most cytokines is a dual function. The same cytokine can trigger an inflammatory cascade that can have detrimental or protective functions in disease progression depending on timing, area of action, or cellular source (04). For example, tumor necrosis factor can produce both neurotoxic and neuroprotective effects in stroke. Tumor necrosis factor can contribute to endothelial cell necrosis and vascular leakage, which aggravate ischemic brain injury (10).

In some situations, communication between the brain and immune system involves neuroinflammatory processes that are beneficial and adaptive. A distinction between variations of neuroinflammation should be made in a context-specific manner and detail both positive and negative aspects of neuroinflammatory processes (14).

Causes. Various causes of neuroinflammation include the following:

	• Infections, eg, viruses, bacteria, and fungi
	• Neurodegenerative disorders
	• Trauma to the CNS
	• Epileptic seizures
	• Neurotoxicity due to the effect of chemical agents
	• Psychiatric disorders, eg, depression and schizophrenia

Infections. Viruses, bacteria, fungi, and parasites can cause encephalitis (inflammation of the brain) or meningitis (inflammation of the meninges). Each cause of an infection activates a slightly different pathway, leading to neuroinflammation.

Exposure to mild infection may cause only transient neuroinflammation, with activation of microglia and release of cytokines. This is a physiological response and is beneficial for the host. There is no tissue damage, cell death, or breach of the blood-brain barrier. Transient activation of the immune system prior to infection, euflammation, is associated with reduced inflammatory profiles and increased neuroprotection (46).

NeuroCOVID. It is now well recognized that severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection can cause significant neurologic disease in humans. Alterations in smell and taste are features of COVID-19 in humans. CNS inflammation may be associated with neurologic symptoms, such as encephalopathy and seizures, as the initial presentation of COVID-19 (17). Intranasal infection of K18-hACE2 mice with SARS-CoV-2 produced hallmarks of encephalitis characterized by the production of cytokines and chemokines, leukocyte infiltration, hemorrhage, and neuronal cell death (25). SARS-CoV-2 entered the brain by olfactory route after intranasal infection. Direct infection of CNS cells, together with the induced inflammatory response in the brain, resulted in the severe disease observed in SARS-CoV-2-infected K18-hACE2 mice and 100% mortality.

Primary CNS involvement in COVID-19 is due to direct neuroinvasion as well as secondary CNS sequelae of systemic hyper-inflammation provoked by maladaptive innate immunity, which may impair neurovascular endothelial function, disrupt the blood-brain barrier, activate CNS innate immune signaling pathways, and induce parainfectious autoimmunity, potentially contributing to the CNS complications associated with SARS-CoV-2 infection (35).

Adeno-associated virus (AAV) vector for gene therapy. Despite advances in the design and application of AAV-based therapies, preclinical studies in large animal models continue to show biomarkers of neuroinflammation following direct delivery to the CNS. Reported manifestations of AAV-associated neuroinflammation in preclinical studies include dorsal root ganglion and spinal cord pathology with mononuclear cell infiltration. However, neuroinflammation was not seen in all animal studies. With approved gene therapy for spinal muscular atrophy, possible neuroinflammation remains a concern.

Hepatic encephalopathy. In animal models of toxic liver injury, microglial activation and concomitantly increased expression of genes coding for proinflammatory cytokines in the brain occur early in the progression of hepatic encephalopathy, indicating that it is a neuroinflammatory disorder (05). Further studies provide robust evidence for the role of neuroinflammation in acute liver failure with the cardinal features of neuroinflammation, including activation of microglial cells and increased production of in situ proinflammatory cytokines, such as TNF-alpha and interleukins IL-1 beta and IL-6 (Butterworth 2016). Other factors that contribute to neuroinflammation are entry of acute liver failure-derived toxins into the brain due to altered permeability of the blood-brain barrier. Synergistic mechanisms involving ammonia and cytokines have been proposed. Experimental studies demonstrate that deletion of genes coding for TNF-alpha or IL-1 leads to attenuation of the CNS consequences of acute liver failure, and administration of the TNF-alpha receptor antagonist etanercept has comparable beneficial effects in experimental acute liver failure. Together, these findings confirm a major role for neuroinflammatory mechanisms, particularly those involving TNF-alpha, in the pathogenesis of hepatic encephalopathy.

Raised serum IL-6 levels, an indicator of inflammation, are associated with the presence of minimal hepatic encephalopathy in patients with liver cirrhosis and are a biomarker of the development of overt hepatic encephalopathy (26). The beneficial effect of anti-inflammatory agents in mild hepatic encephalopathy supports the role of neuroinflammation in the pathogenesis.

Neurodegeneration. Neuroinflammation is linked to neurodegeneration in diseases such as Alzheimer disease, Parkinson disease, Huntington disease, and multiple sclerosis.

Alzheimer disease. The brains of patients with Alzheimer disease are marked by conspicuous and chronic neuroinflammatory responses, which are manifested by reactive microgliosis, astrogliosis, and elevated levels of proinflammatory cytokines (20). There is an abundance of activated microglia that cannot phagocytose amyloid beta, which may lead or contribute to neurofibrillary tangles of hyperphosphorylated tau protein in the brain. Activated microglia and reactive astrocytes are the main indicators of Alzheimer disease progression. They are found close to amyloid beta plaques in the brains of Alzheimer disease patients as well as in rodent models of Alzheimer disease-like pathology.

Type I interferon (IFN), a cytokine that inhibits viral infection and malignancy, is a key element within the neuroinflammatory network of Alzheimer disease and critically contributes to neuropathogenic processes as shown in Alzheimer disease models and postmortem brains of patients with Alzheimer disease (42). Gene expression studies have revealed that the IFN pathway is grossly upregulated in patients with Alzheimer disease and significantly correlates with disease severity.

Alzheimer disease is a multifactorial disease, and one hypothesis is that herpes viruses play a causal role in Alzheimer disease. In particular, HSV-1 can establish latent infections in brain neurons that are punctuated by episodes of reactivation, especially in older persons. Studies on human and rat neurons show that infection with HSV-1 increases the formation of amyloid beta along the amyloidogenic pathway as well as the phosphorylation of tau proteins, another essential biomarker of Alzheimer disease. Thus, chronic infections and defense mechanisms, including inflammatory responses, are important factors in the pathogenesis Alzheimer disease (16),

Parkinson disease. Neuroinflammation is a major component of Parkinson disease as the inflammatory response in the gut may be linked with inflammation of the brain, particularly of the substantia nigra, thereby disrupting the production of dopamine.

Huntington disease. In Huntington disease, microglia are activated by stimulating molecules through the nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) signaling and kynurenine pathway, where tryptophan is metabolized to the neurotoxic quinolinic acid and 3-hydroxykynurenine by the enzyme kynurenine 3-monooxygenase (37). Quinolinic acid plays a role in neurotoxicity as it is a selective agonist of N-methyl-D-aspartic acid receptor. These processes result in chronic neuroinflammation, which can induce molecular processes leading to neuronal death. Atrophy of the striatum (caudate nucleus, putamen, and globus pallidus) is the neuropathological hallmark of Huntington disease.

There is an imbalance in the neuroprotective and neurotoxic roles of reactive astrocytes in Huntington disease that favor neurotoxicity. The mutant form of the Huntington disease gene, mHTT, interacts with astrocytes and microglia to perpetuate neuroinflammation and subsequent cell death.

Amyotrophic lateral sclerosis. Neuroinflammation is an important mediator of disease progression in patients with amyotrophic lateral sclerosis and is characterized by reactive CNS microglia and astroglia as well as infiltrating peripheral monocytes and lymphocytes. The number of regulatory T lymphocytes, a subpopulation of immunosuppressive T lymphocytes, declines, and they become dysfunctional as amyotrophic lateral sclerosis progresses, with the degree of dysfunction correlating with the extent and rapidity of the disease (47).

Multiple sclerosis. Neuroinflammation plays a major role in the initiation and progression of multiple sclerosis as the blood-brain barrier becomes disrupted by the presence of inflammatory cytokines, which allows for B cells and plasma cells to enter the CNS and damage the myelin sheaths of the neurons. Demyelination is a major feature of the disease.

CNS trauma. The role of neuroinflammation in the pathomechanism of brain and spinal cord injuries will be described separately.

Traumatic brain injury. Injury initiates degenerative reparative mechanisms, and the triggering of these pathways alerts the immune system and calls on it to generate an inflammatory response. The immune system begins sending out proinflammatory cytokines, such as IL-1 beta, which can worsen the damage caused by the impact, leading to cell death and DNA fragmentation. The proinflammatory microenvironment inhibits tissue repair and regeneration, which impairs the ability of the CNS to recover from diseases and injuries. The additional release of TNF-alpha along with the proinflammatory cytokines can sometimes lead to a compromise of the blood-brain barrier, reducing its ability to function as a gateway to the brain, thereby protecting it from toxins.

Spinal cord injury. This is somewhat different from traumatic brain injury as compression or transection of the spinal cord triggers factors such as sodium and calcium ion imbalances, excitotoxicity of glutamates, and damage from free radicals.

The initiation of apoptosis following injury, along with demyelination of neuronal cells, leads to inflammation at the location of the injury. This triggers the second phase, which activates reactive gliosis, edema, and cavitation of spinal parenchyma and can lead to an irrecoverable loss of spinal cord function.

An inflammatory response triggered by a spinal cord injury is linked with the secretion of proinflammatory cytokines, such as IL-1 beta, IL-6, IL-23, IFN-gamma, TNF-alpha, and inducible nitric oxide synthase. The recreation of these cytokines triggers the activation of local microglia and draws in bone marrow-derived macrophages, resulting in a pathogenesis related to spinal cord injury.

Epilepsy. Neuroinflammation has an important role in the pathogenesis of acquired epilepsy. Acute seizures and status epilepticus cause neuroinflammation by activating microglia, astrocytes, and induction and enhancement of inflammatory cytokines such as IL-1 beta, IL-6, and TNF-alpha in key brain regions such as the hippocampus (41). Prolonged seizures can lead to significant cell necrosis, neuroinflammation, and neurodegeneration.

Cerebrovascular disease. Inflammation occurs at each stage of stroke pathophysiology, from the first minute after vascular occlusion, and lasts until the late phase, including the recovery and regeneration processes. Although the mechanisms are not well understood, anti-inflammatory and immunomodulatory therapies have shown beneficial effects in some of the experimental models, but not in clinical trials in humans (27).

Psychiatric disorders. Chronic psychosocial stress can lead to chronic neuroinflammation and subsequent mood disorders, such as depression.

Major depressive disorder. Hypothalamic inflammation is recognized as having an important role in the causation of cardiovascular diseases, metabolic syndrome, and even cancer. Studies indicate that hypothalamic inflammation is associated with stress exposure and some psychiatric diseases, such as depressive disorder. Chronic stress exposure is associated with the synthesis of inflammatory molecules in the hypothalamus, alteration in hypothalamic-pituitary-adrenal axis activity, and development of glucocorticoid resistance, which may play a role in the etiology of psychiatric disorders. It has been proposed that hypothalamic inflammation represents an interconnection between somatic diseases and depressive disorder (08).

Schizophrenia. Patients with schizophrenia have changes in microglia as well as increases in proinflammatory cytokines, indicating that neuroinflammation has a role in the development of schizophrenia. Although dysregulation of the dopaminergic system underlies the development of psychosis in schizophrenia, there is also a loss of cortical synapses that may be mediated by activated microglia (21).

Neurotoxicity due to the effect of chemical agents. Psychostimulants are the most widely abused drugs known to induce long-term neurobehavioral deficits and synaptic disturbances. These are well documented with chronic use of methamphetamine, cocaine, and nicotine. The use of psychostimulants can disrupt blood-brain barrier integrity and function, leading to an increased risk of neuroinflammation and brain edema. Neurovascular complications of drug abuse are attributed to oxidative stress (43). Changes in tight junction protein and cytoskeleton induced by drug abuse promote glial activation, enzyme potentiation, and blood-brain barrier remodeling, which affect neuroinflammatory pathways (40).

Neuropathic pain. A study provides class II evidence that levels of magnetic resonance spectroscopy-identified metabolites of neuroinflammation are elevated in patients with spinal cord injury and neuroinflammation compared to those without neuroinflammation (39).

Predisposing factors. The following factors predispose to neuroinflammation.

Impairment of the immune system. In the mature CNS, microglia are apparently dormant (resting microglia) but are actively monitoring the environment, contributing to the maintenance of neurovascular integrity to prevent access of potentially damaging immune system elements and mitigating inflammation. Damage to the immune system can enhance inflammation (02).

Aging. Levels of proinflammatory cytokines are increased and levels of anti-inflammatory cytokines are reduced in the aging brain, indicating that age alone can be linked with chronic neuroinflammation. Aging brains also have an increased number of activated microglia, a sign of activated immune system response, demonstrating another link between the aging brain and neuroinflammation.

Signaling of prostaglandin E2 is mediated by interactions with 4 distinct G protein-coupled receptors: EP1, EP2, EP3, and EP4. These are differentially expressed on neuronal and glial cells throughout the CNS. Inflammatory responses in the brain are associated with an increased level of prostaglandin E2 that is inherent to the aging brain and renders the aged brain more vulnerable to the disruptive effects of both intrinsic and extrinsic factors such as inflammation, infection, toxicants, or stress (34).

Epidemiology

Epidemiology is relevant to diseases in which neuroinflammation plays a role. For more information, refer to MedLink articles on these specific diseases.

Prevention

• Prevention of neuroinflammation involves addressing the risk factors.

The focus should be on preventable risk factors:

	• Treating immune disorders and improving immune function.
	• Adequate control of seizures in epileptic patients.
	• Reduction of CNS trauma, eg, by measures against repeated concussions to prevent chronic traumatic encephalopathy.
	• Discontinuation of drugs that induce toxic encephalopathy.

Differential diagnosis

Diseases with neuroinflammation are discussed the Biological basis section.

Diagnostic workup

• Tests to assess neuroinflammation are based on biomarkers in the blood or CSF and brain imaging.

Biomarkers of neuroinflammation. Biomarkers can be used as indicators, not only of disease progression but of therapeutic efficacy as well, to monitor clinical trials. Biomarkers of neuroinflammation also provide targets for therapeutics. Biomarkers of inflammation in the blood include the following:

	• C-reactive protein
	• Proinflammatory cytokines, such as IL-6 and TNF-alpha

A workshop explored the role and mechanisms of neuroinflammation in a variety of CNS diseases (36). The following were some of the highlights:

	• Receptors such as translocator protein and triggering receptor expressed on myeloid cells 2 as well as other proteins, such as ionized calcium-binding adaptor molecule 1 expressed by microglia, are upregulated in diseases of the brain characterized by neuroinflammation.
	• Identifying the signals involved in synaptic pruning may unveil biomarkers and therapeutic targets for many neuroinflammatory CNS diseases.
	• Blood-brain barrier dysfunction is common in many neuroinflammatory diseases, including stroke, brain trauma, epilepsy, and multiple sclerosis, possibly through common genetic and molecular mechanisms that may be exploited for the identification of biomarkers and therapeutics.
	• Fibrinogen, a blood protein involved in coagulation, is also involved in activating neuroinflammation and neurodegeneration. It is important for communication between the peripheral immune system and the CNS.

The ideal biomarker should be measurable in a specimen of blood. However, some biomarkers require CSF examination. High-titer anti-SARS-CoV-2 antibodies have been detected in the CSF of comatose or encephalopathic patients demonstrating intrathecal IgG synthesis or blood-brain barrier disruption (01). A disrupted blood-brain barrier may facilitate the entry of cytokines and inflammatory mediators into the CNS, enhancing neuroinflammation and neurodegeneration.

Brain imaging. The following are various imaging modalities that can be used to detect biomarkers of neuroinflammation.

Magnetic resonance spectroscopic imaging (MRSI). MRSI can be used to detect the following biomarkers of neuroinflammation:

	• Myo-inositol: Higher values represent greater microglia proliferation or gliosis.
	• Lactate: Higher values represent more severe inflammatory activity.
	• Choline: Higher values indicate greater cell turnover (inflammation, gliosis, or demyelination).
	• N-acetylaspartate: Lower values represent neurodegeneration.
	• Temperature: Higher values represent greater neuroinflammation.

Magnetic resonance imaging (MRI). One technique uses ferumoxytol, a drug with minimal side effects that is FDA-approved for the treatment of iron deficiency anemia, as the contrast agent in MRI. It is being tested in a clinical trial on patients with epilepsy who are candidates for surgery, and the findings will be correlated with neuroinflammation detected in surgical specimens of excised brain tissue.

Positron emission tomography (PET). PET is well suited for in vivo quantification neuroinflammation and has the potential to discriminate components of the neuroimmune response. Although PET imaging of neuroinflammation does not have an established clinical application, ongoing investigations are exploring these possibilities (24).

Imaging findings of 18 kDa translocator protein (TSPO) and the development of radioligands for other inflammatory targets has brought PET imaging of neuroinflammation to a promising stage. New targets that can be measured in the brain include monoamine oxidase B, cyclooxygenase-1 and cyclooxygenase-2, colony-stimulating factor 1 receptor, and the purinergic P2X7 receptor. TSPO imaging results have shown a consistent increase in TSPO levels in major depressive disorder and reduced levels in schizophrenia and psychosis (33).

Management

	• Several approaches have been used in the management of disorders characterized by neuroinflammation.
	• The role of anti-inflammatory drugs is limited in some diseases because of the multiplicity of causes, including factors besides neuroinflammation.

Various methods to counteract neuroinflammation are shown in Table 1.

Table 1. Methods for the Management of Neuroinflammation

• Anti-inflammatory drugs
	-- Antioxidants and free radical scavengers, eg, ascorbic acid (vitamin C) and alpha-tocopherol (vitamin E)
	-- Cannabinoids
	-- Immunomodulators
	-- Minocycline
	-- Mycophenolate
	-- Nanoparticles for targeted delivery of anti-inflammatory drugs
	-- Nonsteroidal anti-inflammatory drugs, eg, diclofenac and ibuprofen
	-- Steroidal anti-inflammatory drugs, eg, prednisolone and fluticasone
• Treatment of neuroinflammation due to infections
	-- Antibiotics and antiviral drugs
	-- Management of neuroinflammation as a complication of AAV gene therapy
• Cell therapy
• RNA interference
• Nonpharmacological approaches
	-- Hyperbaric oxygen
	-- Hypothermia
	-- Neurosurgical, eg, deep brain stimulation and vagal nerve stimulation
	-- Management of stress, eg, meditation and relaxation techniques
• A combination of different approaches

Anti-inflammatory drugs. These are the most used drugs for inflammatory disorders, including those involving the nervous system. The efficacy varies according to the disease. One of the limitations of long-term therapy is that most of the anti-inflammatory drugs have undesirable side effects. The efficacy of the anti-inflammatory therapies is the result of a delicate balance between the potency of the drug and side effects on healthy organs. To prevent side effects, doses of these drugs are usually limited to values below the therapeutic dose, which often results in an insufficient amount of the active drug reaching the site of action. This limitation can be overcome by nanoformulations of drugs.

Nanoparticles for targeted delivery of anti-inflammatory drugs. Emerging nanotechnologies are providing promising methods of drug delivery to CNS tissues affected by neuroinflammation in a controlled manner (09). Design and development of several different anti-inflammatory nanomedicines are being achieved by associating these drugs with nanodelivery systems, which enable control of the liberation, absorption, distribution, metabolism, excretion (LADME) biological pathway and can improve the bioavailability of anti-inflammatory drugs. The technical characteristics of these nanomedicines enable the following effects (44):

	• Improvement of unfavorable physicochemical properties, such as poor water solubility and protection against inactivation—chemical, enzymatic, or immunological processes—from the site of administration to the site of action
	• Targeted and controlled drug delivery
	• Facilitation of passage across different biological barriers, eg, blood-brain barrier
	• Accumulation of higher doses in the inflamed area and a decrease of undesirable side effects on the normal tissues
	• Reduction of interactions with the mononuclear phagocyte system to prolong circulation in the bloodstream
	• Overcoming drug-resistance mechanisms

A few anti-inflammatory nanomedicines have been approved for other conditions, such as inflammation of the eyes and joints. A product that is relevant to neurology is Nanocort, a polyethylene glycol-liposomal prednisolone sodium phosphate in an intravenous formulation. Nanocort was tested in clinical trials for the treatment of atherosclerosis and acute exacerbation of relapsing-remitting multiple sclerosis; the trial was terminated. An implantable drug delivery system consisting of ultrathin nanomaterials, sugar polymers, and neural proteins to release methylprednisolone has been shown to create an anti-inflammatory microenvironment that is favorable for promoting tissue repair and recovery after CNS injury (49).

There is some concern about the neurotoxicity of nanoparticles, but some have antioxidant, anti-inflammatory, and neuroprotective effects on the brain and are potential therapeutics (22).

	• Polyethylene glycol-functionalized hydrophilic carbon cluster carbon nanoparticles show antioxidant activity that reduces neuroinflammation.
	• Ceria nanoparticles protect neurons from free radical-mediated damage.
	• A fullerene derivative, ABS-75, attached to an NMDA receptor antagonist combines antioxidant and anti-excitotoxic properties and can block axonal damage.
	• Gold nanoparticles have immunosuppressive effects that control damage from neuroinflammation as a secondary effect of traumatic brain injury.
	• Redox polymer nanoparticles ameliorate cerebral edema and oxidative damage.
	• Yttrium oxide nanoparticles are more effective free radical scavengers than ceria nanoparticles.

Cannabinoids. A major physiological function of the cannabinoid signaling system is to modulate neuroinflammation. Results of investigations of the anti-inflammatory, antioxidant, and antiapoptotic properties of 2 nonpsychoactive phytocannabinoids, cannabigerol and cannabidiol, provide preliminary support for further preclinical studies on the potential therapeutic applications of a cannabigerol-cannabidiol combination for neurodegenerative disorders (30). However, clinical trials of cannabinoids in Huntington disease showed no improvement.

Links have been identified between epilepsy, neuroinflammation, and the endocannabinoid system, forming the basis of using cannabinoids as potential alternatives to conventional anticonvulsant therapies (11). Further research is needed to better characterize these pathways and improve the application and regulation of medicinal cannabis.

Minocycline. Minocycline is a second-generation tetracycline with anti-inflammatory and antiapoptotic properties. It reduces the proliferation and activation of resting microglial cells, subsequently decreasing the release of cytokines, chemokines, lipid mediators of inflammation, and nitric oxide. It also inhibits transmigration of T lymphocytes. It crosses the blood-brain barrier and has a neuroprotective effect. In animal experimental studies, minocycline has shown a beneficial effect by ameliorating neuroinflammation. Some examples include the following:

	• Attenuates the extent of neuroinflammation in encephalomyelitis and demyelination in experimental autoimmune encephalopathy.
	• Reduces the severity of encephalitis and decreases the expression of CNS inflammatory biomarkers in HIV encephalitis.
	• Delays progression of disease and extends lifespan in animal models of Huntington disease, but no benefit has been demonstrated in human clinical trials.
	• Decreases the size of infarcts in ischemic stroke.
	• Minocycline plus N-acetylcysteine induces remyelination, protects oligodendrocytes, and modifies neuroinflammation in a rat model of mild traumatic brain injury (18).
	• Various studies in animals and humans have shown some beneficial effects and demonstrated the safety of minocycline, but controlled clinical trials have failed to confirm the neuroprotective effect of minocycline in Parkinson disease (07).

Treatment of AAV vector-mediated neuroinflammation. Strategies for the management of neuroinflammatory responses after CNS-targeted delivery of AAV-mediated gene therapy include the following (38):

	• Vector design and strategies to prepare the immune system for AAV exposure should be carried out prior to the administration of gene therapy.
	• The route of administration is selected to target disease-relevant tissues to minimize toxicities from transgene expression in nontarget tissues.
	• Post-dosing immune management strategies protect transgene expression and neural tissue and decrease neuroinflammation.
	• Biomarkers of neuroinflammation should be used to monitor the whole procedure.

Cell therapy for neuroinflammation. Bone marrow-derived mesenchymal stem cells (BM-MSCs) are being investigated for therapeutic effects in inflammatory diseases. Targeting neuroinflammation via BM-MSC transplantation is a novel approach for treating stroke and traumatic brain injury. Clinical trials of BM-MSC transplants for stroke and traumatic brain injury support their promising protective and regenerative properties (03). Future research is needed to allow for better comparison among trials and to elaborate on the emerging area of cell-based combination treatments.

Hyperbaric oxygen. Oxygen under greater than normal atmospheric pressure has a beneficial effect on recovery from ischemic stroke and CNS injuries due to other causes (23). Apart from counteracting hypoxia, it reduces neuroinflammation as well. Hyperbaric oxygen can be used as a preconditioning measure for oxidative stress, a cause of neuroinflammation, and has a neuroprotective effect in ischemic stroke (12).

Hypothermia. Induced hypothermia is used as a neuroprotective measure for brain injuries, and mechanisms of this action include reductions in excitatory neurotransmitters, apoptotic cell death, and dysfunctional mitochondria as well as suppression of protein synthesis. Hypothermia also inhibits microglia and neuroinflammation, which may be the underlying mechanism of its neuroprotective effect. An experimental study showed that delayed hypothermia initiated after the inflammatory stimulation of the microglia in culture could attenuate the production of inflammatory mediators, indicating that post-injury or post-ischemic hypothermia has therapeutic potential to reduce neuroinflammation and secondary brain injury (45). Clinical guidelines based on clinical and preclinical evidence recommend that therapeutic hypothermia for infants with moderate to severe hypoxic-ischemic encephalopathy should be started within 6 hours of birth and continued for a period of 72 hours, with a target brain temperature of 33.5 ± 0.5°C (13). The rate of rewarming is not stated in the guidelines. In adult rats with traumatic brain injury, rapid rewarming over 15 minutes after an hour of hypothermia is associated with increased axonal injury and impaired cerebrovascular responsiveness to vasoactive agents and injury expansion, whereas rewarming over 90 minutes is associated with improved axonal recovery.

Deep brain stimulation. There is considerable evidence to support a disease‐modifying role of deep brain stimulation in preclinical models of Alzheimer disease, Parkinson disease, and epilepsy. Deep brain stimulation may have a wide range of neuroprotective effects, including stimulation of neurotrophic factor release, synaptic remodeling, inhibition of apoptosis, dampening of neuroinflammation, reduction in glutamate excitotoxicity, and enhanced clearance of toxic misfolded proteins (32). A 5-year follow-up of a phase III, multicenter, randomized double‐blind, placebo-controlled trial has shown that deep brain stimulation implanted in early-stage Parkinson disease decreases the risk of disease progression and polypharmacy compared to optimal medical therapy alone (19).

Vagal nerve stimulation. Invasive vagal nerve stimulation applies electrical stimulation to the left cervical branch of the vagus nerve, and afferent impulses initiate brainstem activity in the nucleus of the solitary tract and provoke typical brainstem and cerebral activation patterns that have anticonvulsive action. Vagal nerve stimulation is approved for the treatment of drug-resistant epilepsy, a disorder in which neuroinflammation is one of the pathological features.

A combination of different approaches. An integrated approach combining pharmacotherapy with nonpharmacologic interventions, such as meditation and yoga, can increase success in reducing neuroinflammation (28).

Innovative methods for targeting neuroinflammation in various diseases. Some examples are as follows:

Huntington disease. Currently, the development of antisense oligonucleotides to mHTT is providing a promising future therapy for Huntington disease. mHTT interacts with astrocytes and microglia to perpetuate neuroinflammation and subsequent cell death. Therefore, the clearance of mHTT using antisense oligonucleotides could possibly lead to the reduction of neuroinflammation. Furthermore, using these RNAi therapeutics in conjunction with anti-inflammatory therapies might lead to more effective treatment of Huntington disease.

Pharmacoresistant epilepsy. Inflammatory mediators in the blood and molecular imaging of neuroinflammation could provide diagnostic, prognostic, and predictive biomarkers for epilepsy, which will be instrumental for patient stratification in future clinical studies. IL-1 receptor—Toll-like receptor 4 axis, the arachidonic acid-prostaglandin cascade, oxidative stress, and transforming growth factor-beta signaling associated with blood-brain barrier dysfunction, are pathways that are activated in pharmacoresistant epilepsy in humans and can be modulated in animal models to produce therapeutic effects on seizures (48).

Transcutaneous vagal nerve stimulation of the auricular branch of the vagus nerve is an alternative method without invasiveness. Cerebral activation patterns triggered by invasive vagal nerve stimulation and transcutaneous vagal nerve stimulation resemble each other in appearance. Clinical trials in patients address the safety and performance of transcutaneous vagal nerve stimulation and provide evidence for its application in drug-resistant epilepsy (15).

Stroke. Chemokine (C-X-C motif) ligand 8 (CXCL8) is involved in acute neuroinflammation through the phosphoinositide-3-kinase/protein kinase B/nuclear factor-κB (PI3K/Akt/NF-κB) signaling pathway. A study in mouse ischemic stroke models has shown that functional suppression of CXCL8 by RNA interference promotes neuroglial activation and inhibits neuroinflammation by regulating the PI3K/Akt/NF-κB signaling pathway, which might provide a new approach for ischemic stroke treatment (29).

Clinical trials for neuroinflammation. As of February 15, 2021, 107 clinical trials involving neuroinflammation were listed on the U.S. Government website for clinical trials.

The trials use diagnostic biomarkers to characterize diseases suspected to have neuroinflammation as well as the effects of various treatment strategies.

Personalized management of neuroinflammation. The failure of many clinical trials indicates that the effects of anti-inflammatory treatments, eg, NSAIDs, global immunosuppression, and corticosteroids, are probably too broad and do not consider the heterogeneity in microglia and astrocyte phenotypes (31). A better understanding of the characteristics and function of these cells in healthy and in different disease states, eg, trauma, infection, development, and aging, is necessary for an individualized treatment strategy. Removal of neuroinflammation may not stop the neurodegenerative process. A neuroimmunology approach should instead study the individual situations and specific context in which neuroinflammation is occurring before selecting a management strategy.

Outcomes

The outcome depends on the disease and the method(s) used.

Special considerations

Pregnancy

Information on the effect of pregnancy on the course of a disease characterized by neuroinflammation can be found in MedLink articles on the individual diseases.

Information on the effects of many of the therapeutic agents used in the management of neuroinflammation can be found in MedLink articles on the individual drugs or methods of treatment.

Anesthesia

Any adverse effects of anesthesia or special precautions required in patients suffering from neurologic disorders characterized by neuroinflammation are described in MedLink articles on the individual diseases.