Pediatric Inflammatory Brain Disease

Introduction

Pediatric inflammatory brain diseases (PIBDs) vary widely in clinical presentation across neuropsychiatric domains. Emergence of psychiatric symptoms may be initial manifestations of PIBDs. Child psychiatrists who are alert for symptoms of PIBDs can hasten their diagnosis, and prompt referral to immunologic treatment can improve outcomes and lead to symptom resolution. In fact, psychiatric symptoms can fully resolve once the underlying inflammatory disease is controlled—if treatment is started early enough. For example, in cases of autoimmune N -methyl- d -aspartate receptor (NMDAR) encephalitis, 40% of which occur in the pediatric population, 80% of patients recover. Delay or failure in diagnosing PIBDs, on the other hand, can lead to permanent disability.

The child psychiatrist plays an important role in identification and ongoing care of PIBD patients. After PIBD is diagnosed, the child psychiatrist becomes part of the treatment team, providing ongoing psychiatric, behavioral, and supportive care during the PIBD evaluation, illness treatments, and continues later in addressing residual symptoms. His or her knowledge about PIBDs prevents administration of interventions which, while supported by evidence for particular psychiatric symptoms seen in other contexts, could be ineffective and sometimes harmful in PIBD patients. The child psychiatrist’s close monitoring and reporting of psychiatric symptoms is essential to direct medical treatment as psychiatric symptoms fluctuate with changes in the patient’s inflammatory state. Inflammation of the patient may be retriggered and may recrudesce when immunomodulation is weaned. Thus, close monitoring and reporting symptom changes to the medical team is necessary. The authors hope that this chapter will increase the reader’s interest in and knowledge about PIBDs so that the reader will consider PIBDs in their differential diagnosis of patients who present with new emotional, behavioral, cognitive, neurologic and other physical symptoms.

Brain Immunology

Local neuroinflammation is apparent in almost all pathologic central nervous system (CNS) conditions, including sterile injuries, chronic neurodegenerative diseases, neurodevelopmental diseases, and even depression. Until recently, the CNS was thought to be protected from the immune system as an evolutionary adaptation to guard it from the harmful and potentially permanent ramifications of local immune activation and infiltration of circulating immune cells. This idea was supported by the anatomical protection of the CNS by the cerebrospinal fluid (CSF), the meninges, and the blood-brain barrier (BBB) and the belief that the CNS lacked both lymphatic drainage and professional antigen-presenting cells.

However, it is becoming increasingly clear that the cross-talk between the brain and the immune system is complex, as important roles in maintaining homeostasis and healing are discovered for microglia and other monocyte-derived macrophages, as well as T cells. Moreover, discovery of a “glymphatic system” and meningeal lymphatic vasculature—which drain cellular and soluble substances from the CSF into the deep cervical lymph nodes—further demonstrates that CNS substances can be presented in the periphery. Thus, neuroimmune cross-talk is highly complex, and CNS immune privilege is being redefined, as we understand the mechanisms that the CNS utilizes to safely benefit from the immune system while minimizing immune and autoimmune disease. It is now believed that it is the dysregulation of these protection mechanisms—caused by pathogens, inflammation, aging, or trauma—that may lead to immune-mediated CNS pathogenesis.

The BBB is a selectively permeable physical interface between the vascular and nervous systems that restricts the entry of factors from the blood such as ions, pathogens, and circulating immune cells into the CNS. The BBB is formed by tight junctions between brain endothelial cells, the basal lamina of these cells, and astrocyte end-feet processes. The BBB protection can be compromised when blood-borne factors such as peripheral cytokines or cellular inflammation alter its permeability, thereby allowing entry of peripheral immune cells and antibodies into the CNS. Additionally, it is still believed that the brain parenchyma is immune-privileged to some extent, and that infiltration of lymphocytes into it indicates a potentially harmful activation.

Different types of pathologic neuroimmune interactions are thought to cause psychiatric symptoms in patients with PIBD ( Table 14.1 ). For instance, anti-NMDAR encephalitis is characterized by the presence of antibodies against the GluN1 subunit of the NMDAR causing internalization of the receptors and consequent reduction in synaptic signaling, leading to psychiatric symptoms.

TABLE 14.1

Mechanisms for Immunologic Causes for Abnormal Brain/Neuron Function

Mechanism	Examples
Antibody modulates neuronal receptor	Anti-NMDAR encephalitis Neuromyelitis optica
Cytokine modulates neuron	Interleukin-1 disinhibits GABAergic interneurons Febrile infection–related epilepsy syndrome
Abnormally activated microglial cells	Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections Pediatric acute-onset neuropsychiatric syndrome Obsessive-compulsive disorder Tourette syndrome Depression
Lymphocytes drive inflammation	Multiple sclerosis
Immune system cells or antibodies drive inflammation of blood vessels and BBB	CNS vasculitis Neuropsychiatric lupus
Complement deposition	Neuropsychiatric lupus

BBB , blood-brain barrier; CNS , central nervous system; NMDA , N -methyl- d -aspartate receptor.

Preclinical animal models have also shed light on immune involvement in psychiatric diseases. In one animal study, aimed at determining the ability of Group A Streptococcus pyogenes to prime development of autoimmune disease, repeated nasopharyngeal S. pyogenes infection led to an abnormal T cell activation, and these T cells ultimately caused disruption of the BBB and neurovascular injury. This scientific finding implicates a subtype of T cells as possible drivers of poststreptococcal basal ganglia autoimmune encephalopathies, including Sydenham chorea and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS).

Clinical Presentation of Inflammatory Brain Disease

Symptoms of inflammatory brain disease vary greatly depending on the underlying etiology, which part of the brain is affected, and duration of brain inflammation. Encephalopathies triggered by infection may be preceded by fever and positive indices of infection from laboratory tests. Limbic encephalitis can present as psychosis, movement disorder, altered mental status, and, eventually, seizures. PIBDs that affect the basal ganglia can present as movement disorders, prominent sleep disruption, and sudden onset of obsessions and compulsions. If the amygdala is involved, anxiety may be a prominent symptom. A child’s developmental stage can also affect the disease phenotypes or chronology of symptoms of PIBDs. Cognitive deficits, readily detectable in adults upon mental status examination (MSE), may be difficult to detect in children because of the dynamic nature of cognitive development and uncertainty regarding the premorbid state.

Diagnostic Evaluation

Given the heterogeneity in the signs and symptoms of the different forms of inflammatory brain disease, it is essential to perform a complete evaluation to ensure an accurate diagnosis. Determining if the primary disease is due to CNS vasculitis versus an autoimmune encephalopathy (AE) is a helpful starting point, as treatments for these conditions differ. No single test is sufficient for diagnosing an AE; rather the diagnosis is made when the history, physical examination, and abnormalities on laboratory and imaging studies are consistent with inflammatory brain disease. Autoimmune etiologies for an encephalopathy include both primary disease (without other systemic autoimmune disease) and secondary disease (associated systemic rheumatic/autoimmune disease). Identifying signs and symptoms of systemic disease aids in making the diagnosis and instituting appropriate intervention.

Physical Examination Findings

If PIBD is suspected, the clinical team must pursue a detailed examination ( Box 14.1 ). The hallmark of PIBD is the involvement of multiple domains , including neurologic, cognitive, and psychiatric findings. Though some exam findings are more common in certain types of inflammatory disease (strokes in patients with vasculitis, for example), there is no single diagnostic exam finding. The physical exam should include a general exam looking for infectious, metabolic, and systemic autoimmune etiologies in addition to autoimmune brain disease. As some of the findings in the General Exam ( Box 14.1 ) may be present before the onset of the psychiatric symptoms (i.e., scarlatiniform rash and palatal petechiae could be seen during active strep infection before presentation of Sydenham chorea or PANDAS), review of records is warranted.

BOX 14.1

Physical Exam

General Exam:

Systemic : general state, level of alertness, fever (inflammation vs. autonomic instability)
Cardiopulmonary : autonomic instability with hyper- or hypotension, tachycardia, bradycardia (including heart block), heart murmur (i.e., rheumatic fever), rub (pericarditis of lupus)
Rash : erythema marginatum ^a

a This is best assessed when patient core temperature is elevated (while in hot bath or heated blankets).

(Sydenham chorea), erythema migrans (Lyme), scarlatiniform (streptococcal infection), livedo reticularis, malar, photosensitivity, petechial, urticarial, folliculitis (Behcet’s)
Head, ears, eyes, nose, throat : nasal or oral ulcers, palatal petechiae, pharyngitis, tonsillitis, sinus tenderness
Neck: lymphadenopathy, thyromegaly
Musculoskeletal : arthritis (joint swelling, tenderness, pain on range of motion, loss of range of motion), tenderness at entheseal sites

Ophthalmologic Exam:

Evaluate for uveitis (Behcet’s), retinal vasculitis (lupus, antiphospholipid antibody syndrome), optic nerve swelling (multiple sclerosis, neuromyelitis optica [NMO])

Neurologic Exam:

Motor : chorea, dyskinesia, dystonia, nystagmus/abnormal eye movements, ataxia, dysmetria, hypo- or hyperreflexia, hemiparesis, stiffness, tics
Speech : decreased production or loss of language, dysarthria, language regression (“baby talk”)
Seizures : partial or generalized, often multifocal

Mental Status Exam:

Behavior : aggression/rages, inappropriate sexual behaviors, panic attacks, compulsive behaviors, irritability, psychomotor retardation, stereotypies, catatonia
Mood/affect : anxiety, fear/terror, depression, emotional lability
Thought process and content : confusion (loss of orientation), non-logical, paranoia, hallucinations, obsessions, compulsions
Insight/judgment : poor judgment, impulsivity
Cognition : memory impairment (especially short term), cognitive impairment (loss of academic skills, activities of daily living), inattentiveness, slowed response time

Laboratory Studies

Given the inability to distinguish various forms of autoimmune brain disease from other causes of encephalopathy by history or physical exam findings alone, the initial laboratory workup must be quite broad. For children with suspected pediatric acute-onset neuropsychiatric syndrome (PANS)/PANDAS presenting with new-onset, mild-moderate psychiatric symptoms associated with infections, the work-up may be more limited and focused on infectious etiologies. However, for patients who present with severe psychiatric symptoms (psychosis/delirium and/or other psychiatric symptoms strongly impacting psychosocial function), encephalopathy, seizures, focal neurologic deficits, and severe movement disorder (other than tics), a thorough evaluation, including lumbar puncture (LP), for autoimmune brain disease is indicated.

Cerebrospinal fluid (CSF) studies should include the standard cell count, protein and glucose, as well as opening pressure, oligoclonal bands and immunoglobulin G (IgG) synthesis index (indicating CNS production of immunoglobulins), and relevant anti-neuronal antibodies. Anti-neuronal antibody testing should be sent on both the serum and CSF, as some relevant antibodies have higher positive rates in the CSF and others in the serum. For example, up to 20% of patients with NMDAR encephalitis have only CSF antibodies, and the diagnosis would be missed if only serum studies were sent. The presence of oligoclonal bands in the CSF may be the only abnormality seen in AE, providing valuable evidence of an autoimmune process. Although basic testing for infectious organisms, metabolic, hematologic, and oncologic diseases may be performed, the extent of testing will vary based on the clinical features and initial test results ( Table 14.2 ).

TABLE 14.2

Laboratory Evaluation

Systemic laboratories which may reflect generalized inflammation or metabolic disease	Complete cell count and differential Comprehensive metabolic panel Erythrocyte sedimentation rate, C-reactive protein, ferritin
Autoimmune disease	Autoimmune encephalopathy antibody panel (NMDA, GAD 65 [glutamate decarboxylase], GABA, AMPA [α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor: a non-NMDA-type ionotropic transmembrane receptor for glutamate], VGKC [voltage-gated potassium channels]) on serum and CSF Antinuclear antibodies (ANA) Specific ANA (e.g. anti-double-stranded DNA, extractable nuclear antigen antibodies [Smith, Ro, La]) Antiphospholipid antibodies (lupus anticoagulant, anti-cardiolipin, anti-beta-2-glycoprotein 1) Urinalysis and protein/creatinine ratio Thyroid-stimulating hormone, free thyroxine, thyroid autoantibodies (anti–thyroid peroxidase, anti-thyroglobulin, anti-thyroid-stimulating hormone receptor) Celiac panel (TTG [tissue transglutaminase antibody], IgA) Complement (C3, C4) Angiotensin converting enzyme (depending on clinical scenario) von Willebrand factor antigen Quantitative immunoglobulin levels ^a
Infectious disease	Serologic testing for Mycoplasma , Bartonella , Epstein-Barr virus Nasopharyngeal swab for respiratory viruses and Mycoplasma PCR Group A Streptococcus culture, ASO (antistreptolysin O), and anti-DNAse B (anti-deoxyribonuclease B) CSF PCR for enterovirus, herpes simplex virus (HSV), and varicella zoster virus Consider consult with Infectious Disease for regional (i.e., Lyme disease), seasonal, and travel-related infectious disease evaluation
Metabolic/toxic	Serum lactate level Vitamin B12 level, vitamin D level Testing for recreational drugs (e.g. marijuana, cocaine) Consider urine organic acids, serum amino acids depending on clinical scenario
Oncology	For children with concern for possible oncologic etiology (based on MRI or suspicion for paraneoplastic disease), consult Hematology/Oncology: Cytology/cytometry (blood and CSF) Chest/abdomen/pelvis MRI (teratoma) Pelvic or testicular ultrasound (teratoma)

CSF , cerebrospinal fluid; GABA , γ-aminobutyric acid; MRI , magnetic resonance image; NMDA , N -methyl- d -aspartate; PCR , polymerase chain reaction.

a Low immunoglobulins may indicate immunodeficiency. Immunodeficiency syndromes predispose autoimmune disease. If immunoglobulins are low, intravenous immunoglobulin (IVIG) will need to be given +/− other immunomodulation.

While anti-neuronal antibody detection is important for the diagnosis of AE, the presence of an antibody alone does not make the diagnosis. Rather, the diagnosis of AE depends on the combination of a physical exam findings and clinical history consistent with AE, in addition to supporting laboratory, imaging, and electroencephalogram (EEG) findings that together give a diagnosis. Antibody testing should include not only anti-neuronal antibodies but also antibodies associated with systemic autoimmune conditions such as anti-nuclear antibodies, anti-phospholipid antibodies, extractable nuclear antigen antibodies (Ro, La, Smith), and thyroid antibodies (anti-microsomal and anti-thyroglobulin).

Infectious encephalopathies differ in their presenting histories and required initial evaluations. The spectrum of infectious organisms to consider is broad and the mechanism of disease varies; pathology may stem from a primary infection, a post-infectious process, or infections triggering the development of a subsequent autoimmune disease. The most common organisms associated with new-onset neuropsychiatric symptoms include Group A Streptococcus (Sydenham chorea PANDAS), Mycoplasma (basal ganglia encephalitis, possibly PANS), and influenza virus. A combination of culture or polymerase chain reaction (PCR) for early diagnosis, and serology for later diagnosis, has the highest diagnostic yield. It is important to recognize that initial infectious encephalitis can induce a secondary autoimmune encephalitis. This is best described with herpes simplex virus (HSV) encephalitis triggering anti-NMDAR encephalitis. In these situations, careful consideration of possible infectious agents and mechanisms is required for diagnosis and management.

Imaging

Children presenting with an encephalopathy should have a magnetic resonance image (MRI) with and without contrast to assess for inflammation, as well as diffusion weighted imaging to evaluate for ischemic changes. Finding a normal MRI greatly reduces the possibility of CNS vasculitis, but it does not exclude a diagnosis of AE. Of note, 50% or more of AE cases have a normal brain MRI. An MRI is essential for two reasons: (1) to support a possible autoimmune/inflammatory process and (2) to rule out important mimickers on the differential. The findings on MRI in autoimmune encephalitis vary greatly, from normal to hyperintensities on T2-weighted or fluid-attenuated inversion recovery sequences. Such changes may be focal, such as in the medial temporal lobes, or more diffuse. Some patients have enhancing lesions or abnormalities on diffusion weighted imaging. Computerized tomography (CT) scans do not detect the changes seen in inflammatory brain disease. While the role of positron-emission tomography (PET) scans is not well established, they may be useful in cases of suspected inflammatory disease when other studies are normal.

Electroencephalogram

EEG can provide further evidence of an encephalopathy with new onset multifocal epilepsy, temporal lobe epilepsy, or diffuse slowing. Extreme delta brush, though not a common finding, is more specific for anti-NMDAR encephalitis. A prolonged EEG should be performed, including overnight monitoring to capture awake and asleep periods. Abnormalities on EEG provide further evidence of encephalopathy and help to distinguish patients with inflammatory brain diseases from those with primary psychiatric disease.

Neuropsychiatric Testing

Neuropsychiatric testing provides an objective measure of cognition and memory, two domains impacted by inflammatory brain diseases. This testing quantifies the degree of deficits and can be followed over time to assess response to therapy.

Cognitive function declines in a portion of new-onset primary psychosis patients, but a profound drop in intelligence quotient (IQ) may suggest the presence of a diffuse encephalopathy. Obtaining timely testing and the difficulty of the child participating in testing are challenging, but neurocognitive testing may provide key information for diagnosing an encephalopathy in patients with severe cognitive decline who lack classic imaging or CSF changes.

Diagnosis

Currently, pediatric-specific diagnostic criteria have not been developed for many forms of inflammatory brain disease. This is problematic because, in the absence of definitive markers, making the diagnosis of any specific inflammatory brain disease depends on meeting clinical criteria. While these diseases differ in children from adults in certain aspects, the recently developed diagnostic criteria for adult AE provide a useful framework, including those for anti-neuronal antibody–associated encephalitis (anti-NMDAR encephalitis, limbic encephalitis), as well as antibody-negative AE and Hashimoto’s/Steroid Responsive Encephalopathy. Many feel that thyroiditis is not required to meet criteria for pediatric Hashimoto’s encephalopathy, as most affected children have normal thyroid function. Pediatric and adult presentations for antibody-negative AE differ, as in children, new-onset seizures, especially refractory epilepsy, are important manifestations. Existing pediatric diagnostic criteria for primary CNS vasculitis, acute disseminated encephalomyelitis (ADEM), PANDAS, and PANS are included in Box 14.2 , as these inflammatory brain diagnoses are frequently in the differential diagnosis of encephalopathy or new-onset neuropsychiatric symptoms ( Box 14.2 ).

BOX 14.2

Current Diagnostic Criteria for Pediatric Encephalopathies and New-Onset Neuropsychiatric Symptoms

CNS, central nervous system; CSF, cerebrospinal fluid; EEG, electroencephalogram; GABA, γ-aminobutyric acid; IgG, immunoglobulin G; MRI, magnetic resonance image; NMDAR, N-methyl-d-aspartate receptor.

Diagnostic Criteria for Anti-NMDAR Encephalitis

Requires all three of the following criteria

1.
Rapid onset (less than 3 months) of at least four of the six following major groups of symptoms:
- Abnormal (psychiatric) behavior or cognitive dysfunction
- Speech dysfunction (pressured speech, verbal reduction, mutism)
- Seizures
- Movement disorder, dyskinesias, or rigidity/abnormal postures
- Decreased level of consciousness
- Autonomic dysfunction or central hypoventilation
2.
At least one of the following laboratory study results:
- Abnormal EEG (focal or diffuse slow or disorganized activity, epileptic activity, or extreme delta brush)
- CSF with pleocytosis or oligoclonal bands
3.
Reasonable exclusion of other disorders
4.
Definite NMDAR encephalitis diagnosis if one or more of the six major groups of symptoms and presence of IgG anti-GluN1 antibodies, after reasonable exclusion of other disorders

The presence of three of the above groups of symptoms accompanied by a teratoma

Diagnostic Criteria for Autoimmune Limbic Encephalitis

Requires all four of the following criteria:

1.
Subacute onset (rapid progression of less than 3 months) of working memory deficits, seizures, or psychiatric symptoms suggesting involvement of the limbic system
2.
Bilateral brain abnormalities on T2-weighted fluid-attenuated inversion recovery MRI highly restricted to the medial temporal lobes ^†

† Not required for diagnosis of limbic encephalitis in pediatric population
3.
At least one of the following:
- CSF pleocytosis (white blood cell count of more than five cells per cubic millimeter)
- EEG with epileptic or slow-wave activity involving the temporal lobes
4.
Reasonable exclusion of alternative causes

Diagnostic Criteria for Hashimoto’s Encephalopathy (Modified ^∗

∗ Not required for diagnosis of Hashimoto’s encephalopathy in pediatric population

)

Requires all six of the following criteria:

1.
Encephalopathy with seizures, myoclonus, hallucinations, or stroke-like episodes
2.
Subclinical or mild overt thyroid disease∗ (most often normal in children)
3.
Brain MRI normal or with non-specific abnormalities
4.
Presence of serum thyroid (thyroid peroxidase, thyroglobulin) antibodies
5.
Absence of well-characterized neuronal antibodies in serum and CSF
6.
Reasonable exclusion of alternative causes

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