Severe Psychotic Symptoms in Youth with PANS/PANDAS: Case-Series

Abstract

Objectives:

To report a case series of children presenting with episodes of abrupt onset psychotic symptoms presumably linked to pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) and pediatric acute-onset neuropsychiatric syndrome (PANS).

Methods:

Children/adolescents were selected among the group of individuals affected by clinical diagnosis of PANDAS/PANS. One group was selected by affected individuals coming from the Center UMDNJ—New Jersey Medical School, New Jersey, USA and the other from the Department of Pediatrics Catania University, Italy. Child health Questionnaire Parent form 50 was given to parents to describe children's quality of life.

Results:

Among the group of individuals with PANDAS/PANS disorders, eight children/adolescents were selected, six coming from the UMDNJ—New Jersey and two from Catania, University centers showing among the other typical manifestations severe episodes of abrupt onset of psychotic symptoms.

Conclusions:

Severe psychotic symptoms may be considered one among the other neuropsychiatric clinical manifestations presenting in individuals with PANDAS/PANS syndromes.

Introduction

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) were first reported by Swedo et al. (1998) in 1998 in a group of 50 patients. The original authors described a group of previously healthy children manifesting acute-onset obsessive-compulsive symptoms and/or tics and neurologic abnormalities, including hyperactivity and choreiform movements with a remitting-relapsing course. The symptoms were related to a recent group—A beta-hemolytic streptococcal infection (GABHS) and constituted the basis for the main clinical criteria for the diagnosis of PANDAS (Swedo et al. 2012; Gilbert et al. 2018). The clinical phenotypes of PANDAS have been broadened to provide new insights and boundaries to the disorder: Pediatric acute-onset neuropsychiatric syndrome (PANS) is characterized by abrupt, dramatic (overnight) onset of obsessive compulsive disorder or severely restricted food intake in association with severe neuropsychiatric symptoms (Zibordi et al. 2018; Silverman et al. 2019). PANDAS are now considered to be a subgroup of PANS, and the acronyms PANS/PANDAS have been correlated and used in association with each other because many features are shared between the two disorders. The clinical symptoms presented by subjects affected by PANS/PANDAS may vary from light to severe. Individuals with PANS/PANDAS manifest various neuropsychiatric symptoms, including complex and sonic tics, anxiety, emotional lability, irritability, aggressivity, oppositional behaviors, developmental regression, and psychotic symptoms including hallucinations and delusions (Muller and Roberts 2005; Wilbur et al. 2019).

Here, we describe eight youth affected by PANS/PANDAS and presenting with a particularly severe clinical type of psychotic behavior. The psychotic symptoms have had a dramatic and sudden onset with severe movement disorders and a mutation in the tone of the voice. Laboratory analysis performed during the psychotic attacks displayed positivity for group A streptococci (GAS) infection, which may be etiologically related to the observed symptoms. The clinical features, treatment, and course are reported (Table 1).

Table 1.

PANS/PANDAS Clinical Feature, Treatment, and Course of the Individuals Here Reported

Case no.	Gender/age of symptoms (years)	Signs and symptoms	Laboratory exams	Imaging exam	First-line treatment	Second-line treatment	Follow-up (month)
1	M/14.1	Severe ballistic tics of the extremities, severe OCDs, and falsetto voice as infantile, mild lingual dyskinesia.	ASLO: 381 IU/mL anti-DNAse B: 401 U/mL. ABGA: 1:200	CCTV exam: no significant alterations, MRI: a Basal Ganglia swelling	Antibiotics azithromycin, clindamycin, neuroleptics, corticosteroids	IVIG	6 (Mild OCDs)
2	M/13.2	Severe ballistic tics of the extremities and severe lingual dyskinesia, falsetto voice as infantile.	ASLO values: 549 IU/mL; anti-DNAase B 332 UI/mL; ABGA 1:100.	CCTV/EEG and MRI were normal	Antibiotics azithromycin, neuroleptics. corticosteroids	IVIG	38
3	M/7.5	Severe tics, moderate lingual dyskinesia, and infantile falsetto voice	ASLO = 406 IU/mL, anti-DNAase B = 528 IU/mL, ABGA: 1:100	No data about CCTV/EEG exam	Azithromycin neuroleptics	Corticosteroids	85
3	M/7.5		ASLO = 406 IU/mL, anti-DNAase B = 528 IU/mL, ABGA: 1:100	MRI normal,	Azithromycin neuroleptics	Corticosteroids	85
4	F/10.3	OCDs from mild to severe, outbreak of gruff falsetto voice, and severe lingual dyskinesia, mild ballistic tics of extremities	ASLO of 659 IU/mL; anti-DNAase B 321 IU/mL; ABGA: 1:80.	CCTV/EEG and MRI both normal	Azithromycin	IVIG	84 (mild OCD)
5	Twin F/8.6	Gruff voice and moderate lingual dyskinesia, together with mild ballistic tics	ASLO values of 631 IU/mL anti-DNAase B were of 271 IU/mL. ABGA 1:120	MRI normal CCTV/EEG normal	Azithromycin corticosteroid No IVIG		11 (moderate OCD)
6	Twin F/8.6	Gruff voice and moderate lingual dyskinesia, and ballistic tics.	ASLO values 558 IU/mL anti-DNAase B were 388 IU/mL. ABGA 1:116	MRI normal CCTV/EEG normal	Azithromycin corticosteroid. No IVIG.		11 (moderate OCD)
7	F/12.2	Severe ballistic tics, gruff falsetto voice, and severe OCDs. Lingual dyskinesia was mild.	ASLO 375 IU/mL, Anti-DNAase B = 654 IU/mL ABGA 1:200	CCTV/EEG: fronto-temporal polispike-wave complexes, without any sure relation with the symptoms. MRI: aspecific alterations of the white matter.	Neuroleptics. corticosteroids	IVIG	6
8	M/8.7	Suicide thoughts and psycho-motor impairment.	ASLO 341 IU/mL; anti-DNAase B 412 IU/mL. ABGA was not available	CCTV/EEG showed unspecific alterations with slow polispike-wave complex in centro-temporal region bilaterally; MRI showed lateral and peri-ventricular white matter abnormalities	Antibiotics neuroleptics corticosteroids IVIG		18 (OCD were present and the child needed recovery in a mental institute)

ABGA, anti-basal ganglia antibodies; ASLO, anti-streptolysine O Titer (normal values <250 IU/mL); anti-DNAse B, antibodies against deoxyribonuclease B of the GAS (normal values 0-200 IU/mL); GAS, group A streptococci; IVIG, intravenous immunoglobulins; MRI, magnetic resonance imaging; OCD, obsessive compulsive disorder.

Methods

The study was conducted in accordance with the World Medical Association Declaration of Helsinki and approved by the ethics Committee of the University of Catania, Italy (Ethical Committee, Catania 1 Clinical registration n. 95/2018 [PO]). Written informed consent was obtained from the parents.

We selected subjects diagnosed with PANS/PANDAS from November 2008 to November 2018; eight cases showed severe psychotic symptoms. Of these patients, six came from the Department of Neurology, UMDNJ-New Jersey Medical School (Newark, New Jersey, USA), and two were from the Department of Pediatrics, University-Hospital of Catania (Italy). Laboratory analyses included a complete blood count, sedimentation rate, C-reactive protein, standard tests of thyroid function, blood chemistries, and an immunologic panel plus ABGA titer. Each child also had a throat culture for GABHS, antistreptolysin O (ASO) titers, and antistreptococcal DNAase B titers. The EEG and magnetic resonance imaging (MRI) were performed in some cases. A Child Health Questionnaire Parent form 50 was given to the parents to describe their children's quality of life.

Case Reports

There were eight patients (Case #1 to #8). None of these had severe clinical anomalies before the onset of this disorder. Cases 5 and 6 are monozygotic twins, and they will be described together.

Case #1

This young male was 14.1 years old when the symptoms started. He had a brief history of motor tics before the sudden onset of clinical exacerbation. The symptoms consisted of severe ballistic tics of the extremities, severe OCD, and he spoke with a falsetto voice. He also presented a mild lingual dyskinesia. The laboratory exams showed an ASO of 381 IU/mL (normal values <250 IU/mL) and anti-DNAse B (antibodies against deoxyribonuclease B of the GAS) of 401 IU/mL (normal values 0–200 IU/mL); the ABGA was 1:200. At the CCTV exam, there were no significant alterations. The MRI showed a swollen basal ganglia. The patient had a strict 6-month follow-up and was treated with antibiotics; there was no response to therapy with azithromycin and only a transient response to clindamycin. Therapy with neuroleptics gave no good improvement of symptoms. Corticosteroids were not tolerated, and the patient underwent a through treatment with a high dose of intravenous immunoglobulins (IVIG) (2 g/kg) with a good yet transient response. Although the symptoms are less severe, the subject still presents with OCD.

Case #2

This was a 13.2 year-old-male. Before the syndrome, he had a history of mild episodes of motor tics. The symptoms had a sudden onset with severe ballistic tics of the extremities and severe lingual dyskinesia with no OCD. The voice was infantile. ASLO: 549 IU/mL; anti-DNAase B: 332 UI/mL; ABGA: 1:100. The CCTV/EEG and MRI were normal. The patient was not responsive to antibiotic treatment with azithromycin, but the symptoms responded to neuroleptics. Only transient remittance was reached with corticosteroid treatment, so cyclic IVIG treatment was required. The patient's response to IVIG treatment was good, and his status at a 38-month follow-up was normal.

Case #3

This was a male patient aged 7.5 years. He suffered from a short period of motor tics before the onset of the exacerbation of the symptoms that were sudden and abrupt. He presented severe motor tics, moderate lingual dyskinesia, and an infantile falsetto voice. No OCDs were found. The ASLO: 406 IU/mL; Anti-DNAase B: 528 IU/mL; and ABGA: 1:100. There were no data on CCTV/EEG exams; MRI was normal. The response was negative to azithromycin and to neuroleptics, but there was a 1-month full response to the first corticosteroid treatment. On this basis, no IVIG treatment was needed while corticosteroid therapy was repeated. The patient's status appears to be normal after an 85-month follow-up.

Case #4

This female patient was 10.3 years at the onset of symptoms, which were preceded by OCD. The onset developed over 2 days, with worsening OCDs from mild to severe and an outbreak of gruff falsetto voice and severe lingual dyskinesia associated with mild ballistic tics in the extremities. Laboratory investigations showed ASLO of 659 IU/mL; anti-DNAase B 321 IU/mL; and ABGA: 1:80. Both the CCTV/EEG and MRI were normal. A transient response to azithromycin was reported. Several cycles of IVIG were performed after this treatment, but OCD symptomatology persisted after an 84-month follow-up.

Cases 5 and 6

Two monozygotic twin sisters were 8.6 years-old when they came to our attention. Their outbreak was sudden and followed the same pattern in both children, demonstrating how genetic predisposition has an important role in determining both the onset and the clinical outcome of this pathology. Mild OCD was present in both children before the syndrome. The OCD became more severe at the onset. Gruff voice and moderate lingual dyskinesia were reported together with mild ballistic tics. Case 5: ASLO: 631 IU/mL; anti-DNAase B: 271 IU/mL; ABGA: 1:120. Case 6: ASLO: 558 IU/mL, anti-DNAse B: 388 IU/mL; ABGA: 1:116. The MRI and CCTV/EEG were normal in both sisters. Treatment with azithromycin gave no positive response. Response to corticosteroid was full but temporary. No IVIG was performed. After a follow-up of 11 months, these children had a regression of symptomatology including moderate OCD.

Case #7

This female patient presented symptoms at age 12.2 years. The onset was explosively sudden with severe ballistic tics, gruff falsetto voice, and severe OCDs. Lingual dyskinesia was mild. ASLO: 375 IU/mL; anti-DNAase B: 654 IU/mL; ABGA: 1:200. The MRI showed no specific anomalies of the cerebral white matter. The EEG detected fronto-temporal polispike-wave complexes without any relation with the symptoms. Follow-up lasted 18 months. The response to antibiotic therapy with cefotaxime was negative. Neuroleptics were given but only worsened the symptoms. Corticosteroids had no effect, whereas an IVIG approach had only a partially good response. After 6 months, the patient still represented recurrent OCDs and behavioral disorders with facial and vocal tics becoming prominent.

Case #8

This was a male patient with an age of onset of 8.7 years. The onset was abrupt and dramatic, after a short history of OCD. He started having suicide thoughts and psycho-motor impairment. ASLO: 341 IU/mL; anti-DNAase B: 412 IU/mL; ABGA was not available. The CCTV/EEG showed unspecific anomalies with slow polispike-wave complex in the centro-temporal region bilaterally. The MRI showed no specific lateral and peri-ventricular white matter abnormalities. The treatment with antibiotics gave only a transient response. Neuroleptics were used but without benefits. Corticosteroids had no good effect, whereas IVIG treatment had a partial response. The motor tic and OCD were still present at 18 months, and the child was recovering in an inpatient clinic.

Discussion

This report includes eight cases selected for their particularly severe psychotic behavior. The clinical features were initially consistent with the tics and/or OCD seen in the prepubertal or near postpubertal age. However, the onset of symptoms was sudden and dramatic—even “explosive.” The children presented ballistic tics without prominent facial or vocal tics. There were dramatic and violent movements; lingual and facial dyskinesia; and a falsetto, gruff, or deceptive voice.

Clinical differences between PANDAS and PANS have been described by Gilbert et al. (2018), who identified three key differences between these two disorders: (1) neurologic abnormalities (tics, motor hyperactivity, choreiform movements) reported in PANDAS versus psychiatric symptoms as the only clinical signs in PANS; (2) onset of acute and episodic symptoms (relapsing and remitting) in PANDAS and solely on the initial presentation in PANS; and (3) specific etiologic factor (GAS) in PANDAS with no specific etiologic events in PANS. However, there are many overlapping symptoms, and the tendency is to associate these disorders with the single term PANS/PANDAS.

Behavioral dysfunction and psychotic signs are usually found in patients with PANS/PANDAS. Vocal changes are ego-dystonic and recognized by the patients to be foreign and disturbing. The symptoms are associated with consistent behavioral changes, including suicide, anxiety, and irritability. Most of these children have aggressive behavior and attempt to harm themselves and others; they tend to live in isolation and have severe sociality problems and sleep disturbances. The severe symptoms are caused by consistent changes in personality so that the parents can hardly accept the pathology and recognize their own children. Quality-of-life results are very poor; physical and mental development may be compromised. The disorder, thus, appears to be very frightening for the parents and challenging for the doctors who must deal with the parent's fears together with the clinical matters and compromised life and development. Moreover, there are prejudices regarding the syndrome, including superstitious and religious matters, the parents' fears and skepticism, and the difficulty in clinical diagnosis and pharmacological approach. These issues make this pathology very difficult to manage.

A child's risk of developing PANS/PANDAS is related to GAS infections and other infectious events, genetic predisposition, and environmental factors. Stress is another trigger with a chronically activated immune system predisposing the onset of the symptoms (Murphy et al. 2004). Although the pathophysiology is not yet well defined, it is probable that autoantibodies raised against GABHS or other infective events cross-react with brain antigens, but the targets of these antibodies are unclear and may be heterogeneous (Pavone et al. 2014; Frick et al. 2018). Two neurotransmitters have been found to play a major role in the outcome of OCD symptoms: serotonin (5-HT) and dopamine (DA) and their associated neuronal systems (Fornaro et al. 2009; Marazziti et al. 2015). A chronically activated immune system seems to have a relevant role in the pathogenesis mediated by both innate and acquired immunity. This leads to the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), eotaxin-3, and interleukin (IL)-6; the chemokine CXCL8 is seen in many neurodegenerative disorders. In addition, a significant reduction in the expression of IL-8, interferon inducible protein-10, IL-17a, interferon-γ, IL-10, and IL-12 demonstrates a wide involvement of the immune mechanisms (Walls et al. 2015). TNF-α, IL-6, and IL-1β are mediators of the innate immunity response and are widely involved in the pathogenesis of PANS/PANDAS and other diseases (Gray and Bloch 2012). Patients with OCD showed increased plasma levels of sTNFR1, sTNFR2, and chemokines CXCL8 and CCL3. These have been related to specific symptom clusters, although data should be considered as simply mere suggestions (Lochner et al. 2008). IL-1β is produced by monocytes and tissue macrophages such as microglia. It is a proinflammatory cytokine through activation of macrophage and lymphocyte function and expression of other mediators such as inducible nitric oxide synthase, COX-2, IL-6, and IL-17. It stimulates Th-2 and Th-17 lymphocytes (Dustin et al. 2011).

Diagnostic laboratory analyses often fail in PANS/PANDAS subjects, including throat swab and hematologic exams. Pharyngeal swabs can be positive for GAS mixed with other pathogens. However, the temporal relation is often poorly defined. Further, the throat swab could be negative for any pathogen even if the symptoms have already occurred. Thus, none of the laboratory exams is sufficient to confirm the diagnosis. A recent study studied EEG and ECG alterations and RMN abnormalities—these were found to be variably related to symptom onset and not constantly associated to the syndrome (Elia et al. 2005). There are some scales and questionnaires to characterize the symptoms and evaluate psychiatric symptoms. The EEG, polysomnography, brain MRI, and brain computed tomography are objective tests that should be performed. Lumbar puncture may also be useful in the differential diagnosis with immune encephalitis.

There are still many doubts about the treatment of PANS/PANDAS due to a lack of evidence about the long-term results in these subjects. Moreover, there is a variability in the response of these subjects—perhaps due to individual immune system reactions. Many therapeutic attempts have been performed. Therapy for PANS/PANDAS and related symptoms consists of antibiotics, anti-inflammatory medications, corticosteroids, IVIG, therapeutic plasma exchange, plasmapheresis, psychotropic medications, psychotherapy, and complementary and alternative medicines (Chang et al. 2015).

Conclusion

The diagnosis of PANS/PANDAS is still difficult. It is hard to clearly distinguish this syndrome from other psychiatric conditions, including Tourette's syndrome. More work is needed to understand the link between molecular triggers and the syndrome.

Our clinical challenge in the future is to provide a sure diagnostic method and begin appropriate treatment as soon as possible. Long-term follow-up is needed to avoid relapses. Indeed, this disease typically presents a remitting-relapsing chronic course, and the response to treatments can often be only temporary. By monitoring patients' conditions, we can make the symptoms significantly better and improve quality of life for both patients and their parents.

Clinical Significance

PANS/PANDAS can manifest with heterogeneous neuropsychiatric expressions from mild to severe. Here, the individuals affected by PANS/PANDAS manifested severe psychotic symptoms. In the presence of such severe psychiatric disturbances, a suspicion of PANS/PANDAS disorders must be considered.

Footnotes

Acknowledgments

This document has been edited for proper English language, grammar, punctuation, typos error, and spelling by AME (American manuscript editors USA. Certificate Verification Key: 349-803-034-006-242:Project Number: 72814). The authors confirm that they have read the Journal's position on issues involved in ethical publication and affirm that this article is coherent with these guidelines. Plagiarism check has been done with Small seo tools.

Authors' Contributions

R.F., P.P., S.D.M., R.R.T., E.P., S.D.M., and C.B. reviewed the literature; critically discussed various aspects of epilepsy in pediatric patients; and read the article. C.B. wrote the article and prepared the table.

Disclosures

No competing financial interests exist.

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