Approach to New-Onset Psychosis in Pediatrics: A Review of Current Practice and an Interdisciplinary Consensus-Driven Clinical Pathway at a Single-Center Institution

Abstract

New-onset psychosis in the pediatric population poses many diagnostic challenges. Given the diversity of underlying causes, which fall under the purview of multiple medical specialties, a timely, targeted, yet thorough workup requires a systematic and coordinated approach. A committee of expert pediatric physicians from the divisions of emergency medicine, psychiatry, neurology, hospitalist medicine, and radiology convened to create and implement a novel clinical pathway and approach to the pediatric patient presenting with new-onset psychosis. Here we provide background and review the evidence supporting the investigations recommended in our pathway to screen for a comprehensive range of etiologies of pediatric psychosis.

Keywords

autoimmune electroencephalography encephalitis neuroimaging neuroimmunology

New-onset psychosis in the pediatric population poses many diagnostic challenges. Given the diversity of underlying causes which fall under the purview of multiple medical specialties, a timely, targeted, yet thorough workup requires a systematic and coordinated approach. A committee of expert pediatric physicians from the divisions of emergency medicine, psychiatry, neurology, hospitalist medicine, and radiology convened to create and implement a novel clinical pathway and approach to the pediatric patient presenting with new-onset psychosis. Here we provide background and justification for the investigations recommended to screen for a comprehensive range of etiologies of pediatric psychosis. Our guidelines draw from a comprehensive review of limited published evidence specific to the pediatric population, as well as multidisciplinary expert consensus based on current clinical practice guidelines (Figure 1).

Background

The National Alliance on Mental Illness defines psychosis as “disruptions to a person's thoughts and perceptions that make it difficult for them to recognize what is real and what isn’t. These disruptions are often experienced as seeing, hearing and believing things that aren’t real or having strange, persistent thoughts, behaviors and emotions.”¹ Clinically significant psychotic disorders are rare in childhood. The recent best prevalence estimate for schizophrenia below age 15 years was 0.05%,² and only 2% of adult cases have an estimated age at onset below 13 years.³ Early-onset schizophrenia (<18 years old) and childhood-onset schizophrenia (<13 years old) are thought to be more severe than adult-onset disease in terms of premorbid impairment and treatment refractoriness, all forms existing along a neurobiological continuum.⁴ However, psychotic symptoms may exist on a continuum ranging from psychotic disorders to nonimpairing psychotic experiences, which are far more common. In one review, as many as 17% of 9- to 12-year-olds and 7.5% of 13- to 18-year-olds reported such experiences.⁵ Although close to 80% of these psychotic experiences are self-limited, they are associated with an increased risk of subsequent diagnosis of mental disorders.⁶

When pathologic, psychosis may be the sole initial presenting symptom of a range of potentially treatable medical conditions, which can mimic primary psychotic disorders. Consultants, including neurologists, are thus often asked the question of whether cognitive, emotional, and behavioral symptoms may reflect an underlying medical or neurologic disease process. A comprehensive review of medical etiologies to be considered is beyond the scope of this article, but some of these overall rare pathologies may present without distinctive phenotypic features, dysmorphism, cognitive impairment, or prominent neurologic signs that would otherwise trigger neurodiagnostic testing.^7,8 Selected categories of important readily diagnosed or treatable conditions include drug/toxin-related, electrolyte/substrate abnormality (hypocalcemia, hypoglycemia, hypoxia, ischemia), structural injury/brain tumor, seizure/postictal psychosis, infectious/autoimmune/paraneoplastic encephalitides (N-methyl-d-aspartate [NMDA], Hashimoto, subacute sclerosing panencephalitis, cerebral malaria, progressive multifocal leukoencephalopathy), rheumatologic disease (Wilson disease, lupus, and sarcoidosis), and other genetic/metabolic/endocrinologic causes (porphyrias, leukodystrophies, uremic/hepatic encephalopathy, thyroid storm).^7,9,10 No consensus algorithm in the approach to medical workup for new-onset psychosis exists.⁹ There is limited available evidence for both the diagnostic yield of a broad medical workup, and the predictive value of individual tests in this clinical context.

History Taking: Red Flag Features

Characteristics of the presenting symptoms may be helpful in considering an underlying medical cause. For example, auditory hallucinations with certain features (command, third-person commentary, derogatory, lack of insight) may favor a primary psychotic disorder.¹¹ Meanwhile, visual-predominant hallucinations may suggest a disorder due to another medical condition including inborn errors of metabolism.¹² Based on clinical experience, Bonnot and colleagues also include acute confusion, catatonia, progressive cognitive decline, acute or early onset, and treatment resistance among their list of readily recognizable “atypical features” that should raise suspicion of disorders due to medical causes other than primary psychiatric disease, with the caveat that the specificity of such features has not been validated,¹² particularly for the pediatric population. For example, if pediatric presentations of psychosis are taken to exist along a neurobiologic continuum with adult-onset psychotic disorders with earliness of onset associated with disease severity (see above), then given higher rates of treatment refractoriness regardless of etiology compared to adult presentations,¹³ treatment refractoriness in and of itself should not be taken as indicative of an undiagnosed underlying medical etiology. The American Psychiatric Association (APA) Practice Guideline for the Treatment of Patients with Schizophrenia Third Edition (2021) citing the 2016 Graus criteria suggest red flag features for autoimmune encephalitis that would suggest the need for imaging (see Neuroimaging section, below) would include rapid progression of working memory deficits over less than 3 months, decreased level of consciousness, lethargy, and personality change.¹⁴ Another consensus guideline for psychosis of autoimmune origin in adults by Pollak and colleagues cites the following red flag symptoms: infectious prodrome, rapid progression, recent diagnosis of tumor, adverse response to antipsychotics (raising concern for neuroleptic malignant syndrome), and specific neurologic symptoms such as severe headache, new seizures, alteration of consciousness, movement disorder (dyskinesia and catatonia), disproportionate cognitive dysfunction, speech disorder (aphasia, mutism, or dysarthria), and clinically significant autonomic dysfunction.¹⁵ The presence of these would favor pursuing targeted workup for autoimmune conditions.

Examination Findings

General examination findings that suggest secondary causes of psychosis include the presence of dysmorphism, birthmarks, jaundice, and organomegaly. Although genetic testing is not routinely recommended for the workup of acute psychosis in most international guidelines, the Canadian Schizophrenia Guidelines do recommend specific genetic testing in presence of certain clinical features such as low IQ, midline or cardiac anomalies, facial dysmorphism, and hearing impairment.⁹ These features could be suggestive of the presence of velocardiofacial syndrome, caused by 22q11 deletion detectable by fluorescence in situ hybridization.⁹

Focality on the neurologic examination would favor secondary causes of psychosis and prompt further neurodiagnostic testing. Most central nervous system disease processes, particularly if acute or subacute in presentation, would be expected to progress over time, involving multiple domains of neurologic functioning. For example, in one large sample of patients with autoimmune encephalitis with >1 month of symptoms, >3 of the following features were invariably present: psychiatric features, memory disturbance, speech disorder, seizures, dyskinesias, decreased level of consciousness, autonomic instability, or hypoventilation.¹⁶

Considerations for Further Workup

Some reviews have argued that broad application of an extensive medical workup is likely to be low yield. In one recent single-center retrospective chart review of 131 patients aged 7-21 years hospitalized over a 4-year period for new-onset psychotic symptoms, all but 2 ultimately received a primary psychiatric diagnosis, whereas 10.7% had medical findings that required intervention, even if they did not explain psychotic symptoms.¹⁷ The most commonly performed laboratory tests included basic metabolic panel (96.9%), liver function tests (96.1%), thyroid-stimulating hormone (95.4%), complete blood count (94.7%), and urine drug screen (91.6%). Other testing included brain magnetic resonance imaging (MRI; 74.8%), head computed tomography (CT; 26.7%), routine electroencephalography (EEG; 49.6%), prolonged EEG (15.3%), and lumbar puncture with cerebrospinal fluid testing (46.6%). None of the neuroimaging, EEG, or cerebrospinal fluid testing revealed clinically significant abnormalities. This report thus suggested that extensive medical testing had a low yield for detecting medical etiologies of new-onset psychosis. However, the value and importance of prompt exclusion/diagnosis/treatment of medical mimics of primary psychiatric disease relative to the cost of such a workup was not specifically analyzed.

Serum Laboratory Testing

Most workup approaches discussed in the literature argue for the utility of basic blood tests including complete blood count, electrolytes (including calcium), tests of kidney function and liver function, and a urine drug screening.⁹ Some also recommend inclusion of inflammatory markers to screen for inflammatory/rheumatologic disorders (erythrocyte sedimentation rate and antinuclear antibody), and screening tests for other readily treatable conditions including thyroid disease (thyroid-stimulating hormone), Wilson disease (ceruloplasmin level, especially if there is an associated movement disorder), pernicious anemia (vitamin B₁₂), as well as neurosyphilis and HIV when indicated.^7,9 In regard to testing for autoimmune conditions from the serum, in patients with a suspicious clinical presentation, we often send serum myelin oligodendrocyte glycoprotein (MOG) and NMDA receptor antibody, with consideration of GAD65 and other commercially available serum panels such as the Mayo Encephalopathy (ENS2, https://www.mayocliniclabs.com/test-catalog/Overview/92116) and/or Paraneoplastic (PAVAL, https://www.mayocliniclabs.com/test-catalog/Overview/83380) panels in the appropriate clinical context. Of note, if the history is concerning for malignancy and Mayo Paraneoplastic panel is sent, there is no need to separately send NMDA receptor GAD65 as these are included in the panel. Additionally, in young adult males with presentations concerning for limbic encephalitis, we would consider adding anti-Ma and anti-Ta antibodies which can be seen in paraneoplastic limbic encephalitis associated with germ cell tumor¹⁸ and are not included in the Mayo Paraneoplastic panel. The presence of antibodies in the serum such as NMDA, particularly at low titers, should be interpreted with caution as a screening test with both less sensitivity and less specificity than if present in the cerebrospinal fluid.¹⁹ One large study (N = 2817) demonstrated a seropositivity rate for NMDA receptor antibodies around 10% in the general population, with a comparable distribution across multiple subgroups including those with neuropsychiatric illness and schizophrenia bringing into question its pathologic significance.²⁰ False positives can also be seen in other autoimmune conditions such as multiple sclerosis and neuromyelitis optica, though this is considered rare (<1%).²¹ One clinical trial in first episode psychosis found no difference between NMDA-seropositive and seronegative patients in response to antipsychotics or outcome and concluded that seropositivity may have limited disease relevance and alone was not an indication for immunotherapy.²² Another study concluded that in the absence of cognitive deficits, catatonia, speech disturbance, and antipsychotic sensitivity, NMDA-seropositive patients with isolated psychiatric symptoms and negative cerebrospinal fluid antibodies should be treated with traditional psychiatric care alone.²³ Thus, although interpretation of either a negative or positive result should be made with caution, positive serology would indicate a need for further investigation including confirmation with cerebrospinal fluid testing and possibly other neurodiagnostic testing. MOG is a notable exception to this rule as cerebrospinal fluid testing for MOG is at present of unclear clinical utility.

Cerebrospinal Fluid Laboratory Testing

Lumbar puncture is an invasive procedure carrying risks including headache, bleeding, infection, and may be difficult to obtain without sedation in certain age groups, particularly during an acute presentation of psychosis. On one end of the spectrum, some groups argue for moving toward a universal screening approach for cerebrospinal fluid antibodies in all patients with subacute-onset psychoses,²⁴ based on a high positive rate reported in some research protocols—4 of a series of 113 patients (3.8%) with <3 months of symptoms tested positive for NMDA receptor antibodies.²⁵ In another series of clinically “atypical” presentations of NMDA encephalitis defined by lack of focal findings/seizure/movement disorder/hypoventilation, Yoshimura and colleagues found high response rates to immunotherapy (21 of 22 patients) and recommended all patients who had memory impairment, catatonia or abnormal MRI/EEG receive lumbar puncture given increased sensitivity of cerebrospinal fluid over serum antibody detection.²⁶ Others have also supported that cerebrospinal fluid antibodies are more reflective of disease activity, with high titer corresponding to worse prognosis and conversion from high to low titer correlated with good outcome and lower relapse rates.²⁷ Like other authors,⁹ we recommend lumbar puncture only for patients in which CNS infection/inflammation is clinically suspected and would otherwise be performed (eg, fever with persistent altered mentation, meningismus, cranial neuropathy, or other focal finding) or when an immune-mediated etiology is suspected on clinical grounds, but serum studies alone would be inadequate to establish the diagnosis; for instance, in a patient with concerning features without paraclinical evidence of neuroinflammation, but in whom a finding of pleiocytosis could favor initiation of empiric immunotherapy.²⁸ In terms of study selection, we recommend basic studies including cell count, glucose, protein, bacterial culture, meningoencephalitis panel, oligoclonal bands (compare with serum), IgG index, NMDA-R antibody, and GAD65 antibody and consider other studies or there are multiple commercially available panels that we considered on a case-by-case basis.

Electroencephalography

Some authors recommend EEG for all patients presenting with first episode psychosis,²⁹ whereas others note almost half of these patients will have incidental EEG abnormalities of unclear significance.³⁰ One neurologic mimic of a primary psychotic disorder is psychosis in the context of new-onset seizures, which can be subtle if arising from limbic structures in the setting of the autoimmune encephalitides. Although missing an underlying autoimmune diagnosis is appropriately feared as it leads to delaying immunotherapy and is associated with poorer outcomes,²⁸ few encephalitis patients manifest with isolated psychotic symptoms—in one series of confirmed NMDA-receptor encephalitis, only 4% presented with psychosis alone and only 4 of the 23 of these were at presentation (the rest included symptoms during relapses).³¹ In patients where there is concern for autoimmune encephalitis, EEG is a sensitive screening tool as a normal EEG is virtually incompatible with this diagnosis.^28,32 Seizure-related psychosis may also arise from symptomatic seizures related to neoplasms or an undiagnosed primary epilepsy, the diagnosis of which can be supported by EEG findings. Patients with epilepsy have an 8-fold increased risk of psychosis during their lifetime.³³ Psychosis generally can be seen in 5% to 9% of those with temporal lobe epilepsy, especially if longstanding, bitemporal, or in patients with a history of status epilepticus.³³ Postictal psychosis is defined as psychosis occurring within 1 week after full return to normal neurologic function following a seizure (often a cluster followed by a lucid interval and insomnia) and may represent 25% of psychosis seen in patients with epilepsy with an annual incidence around 6%.³⁴ However, known risk factors include clustered generalized seizures, longstanding epilepsy for more than 5-10 years,³⁴ making postictal psychosis unlikely to be the first presentation of seizure. Postictal psychosis usually will be distinguished from other medical causes of psychosis by its clinical course, more acute in onset, and generally short-lived following a cluster of generalized or secondarily generalized seizures.³⁴ On the other hand, postictal psychoses may progress to chronic interictal psychosis particularly if recurrent,³⁵ though psychoses in epilepsy tend to have a more benign course and are more responsive to antipsychotics.³⁶ In conclusion, considering the potential difficulties of obtaining reliable data without use of potentially confounding medications, we recommend EEG for cases in which recording would likely be tolerated and aspects of the history or examination suggest delirium,^37,38 paroxysmal episodes, or other findings specific for a presentation of autoimmune encephalitis. There is little evidence to date in regard to the sensitivity of brief vs prolonged continuous video EEG recording, which patients with prominent psychiatric manifestations are often unable to tolerate. Some authors reasonably suggest sensitivity could be increased from prolonged recording,³⁹ although there is limited evidence; however, from our clinical experience, even a very brief recording demonstrating a completely normal electrographic background is helpful to exclude autoimmune encephalitis, particularly several weeks after symptom onset.

Neuroimaging

Current American Psychiatric Association practice guidelines recommend brain imaging for select patients with first episode psychosis, only if indicated on the basis of neurologic examination or history, with MRI preferred to CT.¹⁴ Advantages of MRI over CT include superior differentiation of parenchymal lesions (ie, white matter, temporal lobe abnormalities, and brain tumors), a lack of exposure to ionizing radiation and generally superior prognostication. The addition of contrast enhanced sequences is preferred in patients without a contraindication to gadolinium such as allergy or renal impairment for superior discrimination of inflammatory, infectious, or neoplastic lesions including those of encephalitis, sarcoidosis, and primary brain tumors. MRI can be useful in detecting etiologies ranging from limbic encephalitis (eg, temporal lobe fluid-attenuated inversion recovery signal abnormalities), Wilson disease (eg, basal ganglia mineral deposition), sarcoidosis (eg, leptomeningeal involvement, nodular lesions), genetic syndromes such as leukodystrophies (eg, abnormal myelination pattern). The sensitivity of MRI for autoimmune encephalitis is estimated at 50% to 70% depending on antibody/syndrome,⁴⁰ possibly higher if repeated later in the disease course.⁴¹ Although utility of MRI is primarily to rule out a disorder due to a medical condition other than primary psychosis, which could require an alternative approach to management, structural imaging in research contexts have demonstrated progressive gray matter volume loss and cortical thinning in childhood-onset schizophrenia compared to healthy controls.⁴² Additional considerations include that structural brain imaging revealing no explanatory pathology can be reassuring to patients and their families,⁹ and even help with the process of accepting a primarily psychiatric diagnosis.⁴³ However, in patients without suggestive indications on history or examination, abnormalities that would influence treatment or require follow-up (including potentially serious incidental findings) were found in <1% of imaging studies.^44,48 Therefore, we recommend consideration of MRI brain with and without contrast in patients with high clinical suspicion or potential to benefit in keeping with current APA practice guidelines.

Considerations for the Future

Given the subspecialization of medicine, knowledge gaps across disciplines and the broad range of etiologies of new-onset psychosis, clinical reviews and guidelines can be difficult to implement in clinical practice. Additionally there are limited resources nationally in access to pediatric subspecialists and variation institutionally and internationally in approaching assessment of psychosis in children. Some reviews offer theoretically comprehensive but impractically broad workups for a nonspecific symptom, whereas others focus on defining criteria for specific disease entities rather than a symptom-based approach. For example, Cellucci et al³⁹ recently proposed best practice guidelines for the diagnosis of autoimmune encephalitis in children adapted from evidence in the adult literature although there is also an international comparison of assessment and treatment pathways⁴⁹ based on resource availability and different diagnosis premises around psychiatric syndromes. Specifically, the Cellucci algorithm turns away from syndrome-based criteria (eg, limbic encephalitis) patterns of presentation pediatric patients are less likely to follow. A holistic, symptom-based approach encompassing a broad range of etiologies may represent a more practical strategy in clinical practice.

Future directions will include monitoring changes to the quality of care at our center subsequent to the implementation of our pathway, including the times to diagnosis, treatment, disposition outside of acute care, and recovery. The value of specific clinical predictors and the sensitivity and specificity of individual tests in different subgroups need further study to develop an evidence-based, risk-stratified approach to invasive testing in order to minimize harm, prevent delays in care, and optimize medical resource utilization. We hope that our proposed guidelines will inspire comparison of practice standards across institutions and lead to further collaboration in optimizing care for patients presenting with this challenging presentation.

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article

Author Contributions

AJ drafted and prepared the manuscript which was revised and approved by all other authors. DF designed the figure. All authors made a substantial contribution to the conception and design of the pathway.

ORCID iD

Alexander Jonokuchi

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