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A Previously Healthy Adolescent With Acute Psychosis and Severe Tatiana Rosenblatt, BA,a Katherine Ort, MD,a,b Richard Shaw, MD,a,b Rebecca J. Levy, MD,a,c Chen Chen, MD,a,d Angela Niemi, MD,a Kim Hoang, MDa,d

A previously healthy 15-year-old boy presented with 3 months of progressive abstract psychosis, insomnia, back and groin , and hyperhidrosis. On examination, the patient was disheveled, agitated, and soaked with sweat, with systolic blood pressure in the 160s and heart rate in the 130s. Aside from occasional aStanford University School of Medicine and bDivision of auditory and visual hallucinations, his neurologic examination was normal. Child and Adolescent , Department of Psychiatry The patient was admitted for an extensive workup, including MRI of the brain and Behavioral Sciences, cDivision of Child Neurology, and spine and lumbar puncture, which were normal. Through collaboration Department of Neurology and Neurological Sciences, and dDivision of Pediatric Hospital Medicine, Department of with various pediatric specialists, including psychiatry and neurology, a rare , Stanford University, Stanford, California diagnosis was ultimately unveiled. Ms Rosenblatt contributed to the concept and design of the case report, outlined the manuscript, contributed to the abstract, case history, and conclusion sections of the text, created the figures, CASE HISTORY imaging modalities including chest and helped edit the final manuscript; Drs Ort, Shaw, radiograph, renal ultrasound, computed Levy, Chen, and Niemi contributed to the clinical and Tatiana Rosenblatt (Medical Student) subspecialty-related text portions of the case report; and Dr Angela Niemi (Pediatric Intern tomography scan of the abdomen Dr Hoang assisted with the concept and design of on General Pediatrics Inpatient Team) and pelvis, and MRI of the lumbar the case report, contributed to the clinical text spine, abdomen, and pelvis were portions, and helped edit the final manuscript; and A previously healthy 15-year-old boy unremarkable, with the exception all authors approved the final manuscript as submitted and agree to be accountable for all initially began to experience symptoms of some bone marrow edema and of knee and back pain and aspects of the work. sacralization of the L5-S1 transverse 5 months before admission. His DOI: https://doi.org/10.1542/peds.2019-3786 process, a common congenital primary care physician initiated abnormality of no clinical significance Accepted for publication Jan 15, 2020 a workup that resulted in normal knee in which L5 fuses fully or partially to Address correspondence to Tatiana Rosenblatt, BA, and lumbar spine radiographs and fi the sacrum. Rheumatologic disorders School of Medicine, Stanford University, c/o Of ce of a negative human leukocyte antigen Medical Student Affairs, 1265 Welch Rd, Suite 100, including , irritable bowel B27 result. Two months later, the Stanford, CA 94305. E-mail: [email protected] disease, tuberculosis, occult fracture, patient was admitted to an outside PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, spondyloarthropathy, oncologic hospital for worsening back and groin 1098-4275). process, and were ruled pain with notable weight loss of 17 lb. Copyright © 2020 by the American Academy of out on the basis of these results. The His pain was difficult to control and Pediatrics sacralization found on spine imaging required opiates, ketamine, and FINANCIAL DISCLOSURE: The authors have indicated was deemed unlikely to be causing his fi a lidocaine infusion. they have no nancial relationships relevant to this severe pain. The only significant article to disclose. Extensive workup was initiated at the abnormal results were a urinalysis FUNDING: No external funding. 1 outside hospital, with laboratory notable for 3 proteinuria and POTENTIAL CONFLICT OF INTEREST: The authors have results including a normal a kidney biopsy that revealed early indicated they have no potential conflicts of interest complete cell blood count, C-reactive membranous glomerulonephropathy to disclose. protein, complement component 3 and with a negative phospholipase A2 4, and calprotectin, with negative receptor stain suggestive of secondary To cite: Rosenblatt T, Ort K, Shaw R, et al. A antinuclear antibody, double-stranded causes.1 The patient was discharged Previously Healthy Adolescent With Acute Psychosis DNA, HIV, coccidiosis antibodies, and from the hospital with pain medications and Severe Hyperhidrosis. Pediatrics. 2020;145(6): e20193786 tuberculosis QuantiFERON. Multiple and close follow-up.

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 145, number 6, June 2020:e20193786 DIAGNOSTIC DILEMMAS After discharge, the patient continued -type symptoms were symptoms and membranous to have worsening back and groin also remarkable, including nephropathy, neurosyphilis and heavy pain, along with increased weight hypertension, tachycardia, and metal toxicity were included in our loss. He developed new-onset hyperhidrosis, which appeared to be initial differential. increased agitation, erectile associated with his neuropsychiatric dysfunction, hyperhidrosis (requiring changes and were present throughout Ms Rosenblatt and Dr Niemi 12 showers daily), insomnia (sleeping his hospital course (see Supplemental Given the patient’s acute psychiatric – fi only 1 2 hours per night), and acute Fig 1). These objective ndings made symptoms, agitation, and severe psychosis with auditory and visual us broaden our initial differential to insomnia, the pediatric psychiatry hallucinations. Within 3 months, his include organic etiologies. We were and neurology teams were consulted symptoms had worsened such that he concerned for a central nervous to help with the evaluation and was no longer able to attend school system (CNS) abnormality such management of his symptoms. and had isolated himself entirely from as autoimmune , his peers. His worsening presentation paraneoplastic encephalitis, Dr Shaw and Dr Ort, as the child prompted an admission to our and pediatric acute-onset psychiatrists consulted to help care hospital for further evaluation and neuropsychiatric syndrome (PANS). for the patient, how did you approach management. CNS such as meningitis and the management of the patient’s encephalitis were also considered, psychiatric symptoms? What was On initial examination at our hospital, although he had no or included in your differential diagnosis the patient was extremely disheveled. before presentation, for his behavioral symptoms? His clothing and bedding were making these less likely. The patient completely soaked through with had never had brain imaging before Drs Richard Shaw (Child sweat. He was agitated, difficult to this admission, so our team decided Psychiatrist) and Katherine Ort calm down, and would intermittently on an MRI of the brain, lumbar (Child Psychiatry Fellow) cry out in pain. He would also puncture (LP), and EEG as part of the Psychiatry first consulted on the periodically mutter something in initial screen. Other medical patient in the emergency department response to one of his auditory or conditions shown to be associated when he presented with no previous visual hallucinations, for example, with acute mental status changes psychiatric history but with new- claiming that he saw chickens in the and/or autonomic changes that we onset mental status changes including examination room. He was afebrile, considered on our differential symptoms of significant and hypertensive (systolic blood pressure included metabolic diseases such as , insomnia, paranoia, and up to 160 mm Hg), and tachycardic acute intermittent porphyria and derogatory auditory hallucinations (heart rate up to 130 beats per Wilson disease, endocrine and agitation, along with distressing minute). Otherwise, the rest of his involvement such as objective medical symptoms. examination was normal, including and thyroiditis, Substance-induced psychosis was a neurologic examination without any rheumatologic processes such as entertained, although a urine focal deficits. systemic , toxicology screen was positive only Dr Hoang, as the pediatric hospitalist malignancy such as tumor, for tetrahydrocannabinol, which he caring for this patient on the general and heavy metal toxicity. An extensive was known to be using for his pediatric service, what was your laboratory workup was sent to insomnia, and his onset of psychotic initial differential diagnosis? How did evaluate for these possible etiologies behavior was reported before his you decide what initial workup to do? (Table 1). His newly diagnosed tetrahydrocannabinol use. The membranous glomerulonephropathy psychiatric differential included Dr Kim Hoang (General Pediatric was also noteworthy. The renal a primary psychotic or mood Hospitalist) biopsy staining was negative for disorder, although the presence of When the patient initially presented phospholipase A2 receptor, which vital sign changes and hyperhidrosis to our hospital, our team was most indicated that the nephropathy was suggested a likely organic etiology. struck by his new onset of psychosis. likely due to secondary causes and The patient was admitted for Although he did not have any was not a primary nephropathy.1 It a medical workup, including a rule previous psychiatric history and had was unclear whether this renal out for infectious or inflammatory no family history of psychiatric involvement was linked to the causes that could provide a unifying illnesses, our team considered patient’s neuropsychiatric and diagnosis that explained both the whether this was a new diagnosis of autonomic changes and what the medical and psychiatric symptoms, a primary psychiatric disorder or possible secondary causes were. such as autoimmune encephalitis. substance-induced psychosis. His Given the presentation of neurologic Initial management of the patient’s

Downloaded from www.aappublications.org/news by guest on September 28, 2021 2 ROSENBLATT et al TABLE 1 Laboratory Tests Obtained Before Discharge olanzapine was added and uptitrated Test Value Reference Range to a maximum of 5 mg in the morning Rheumatoid factora ,10.0 IU/mL 0–13.9 IU/mL and 7.5 mg nightly. Olanzapine was HLA-B27a Negative Negative chosen for both sedating properties Celiac panela Negative Negative as well as antipruritic action2 given C-reactive proteina ,0.3 mg/L 0–4.9 mg/L the patient was complaining of a Tuberculosis QuantiFERON Negative Negative pruritis of the lower back and Antinuclear antibodya Negative Negative Lipase 32 U/L 13–60 U/L buttocks. Quetiapine was later added Ethanol 1 mg/dL ,11 mg/dL at a maximum dose of 250 mg nightly White blood cell count 10.4 K/mL 4.0–11.0 K/mL for insomnia. Hemoglobin 15.8 g/dL 13.5–17.7 g/dL Hematocrit 48.3% 40.0%–52.0% Ms Rosenblatt and Dr Niemi Platelet count 345 K/mL 150–400 K/mL Potassium 3.2 mmol/L 3.5–5.5 mmol/L Dr Levy and Dr Van Haren, from Aspartate aminotransferase 50 U/L ,44 U/L a child neurologist perspective, what g-glutamyl transferase 82 U/L ,60 U/L is included in your differential b Albumin 2.7 g/dL 3.2–4.5 g/dL diagnosis for a patient with acute -stimulating hormone 1.79 lU/mL 0.27–4.20 lU/mL m m onset of psychosis? Erythrocyte sedimentation rate 17 mm/hb 0–15 mm/h D-dimer 1.48 mg/mLb ,0.50 mg/mL vWF antigen 476%b 56%–123% Drs Rebecca Levy (Child Neurology vWF activity .390%b 54%–137% Resident) and Keith Van Haren (Child Factor VIII assay 363.9%b 42.8%–154.6% Neurologist) – Complement component 3 163 mg/dL 86 184 mg/dL Child neurologists work closely with Complement component 4 40.9 mg/dL 20.0–50.9 mg/dL Immunoglobulin A 118 mg/dL 69–309 mg/dL our psychiatry colleagues when Immunoglobulin G 311 mg/dLb 613–1295 mg/dL evaluating a child with acute onset of Immunoglobulin M 81.2 mg/dL 53–334 mg/dL psychosis. When thinking through our Ceruloplasmin 28.8 mg/dL 18–36 mg/dL differential diagnosis, we consider , , Antistreptolysin O 13 IU/mL 400 IU/mL a number of key etiologies: toxic Lyme antibody ,0.90 ,0.90 Lead level ,2 mg/dL ,5 mg/dL (recreational drugs, medication side ANCA panel Negative Negative effects), metabolic (liver and/or renal Protein, urine 31b Negative failure of toxin excretion, inborn Total protein, urine .600.0 mg/dLb 0–20 mg/dL errors of metabolism), infectious – 24-h creatinine, urine 508 mg/d 500 2300 mg/d (herpes simplex and other Toxin screen, urine 1tetrahydrocannabinol Negative Porphobilinogen, urine ,3 mmol/L 0.0–8.8 mmol/L infectious encephalitis), epilepsy Coproporphyrin III, urinec 19 mmol/mol 0–14 mmol/mol (particularly temporal lobe), primary Normetanephrine, urinec 518 mg/24 h 91–456 mg/24 h psychiatric, paraneoplastic (more Norepinephrine, urinec 111 mg/24 h 15–80 mg/24 h common in adults), genetic diseases # 5-HIAA, urine 4.6 mg/24 h 8.0 mg/24 h (Wilson disease, 22q11 deletion VDRL, CSF Negative Negative Meningitis and/or encephalitis PCR, CSF Negative Negative syndrome), neurodegenerative Glucose, CSF 77 mg/dL .40 mg/dL diseases (juvenile Huntington Protein, CSF 16 mg/dL 15–45 mg/dL disease), and autoimmune or White blood cell count, CSF 1 0–5/mL inflammatory conditions. The – Red blood cell count, CSF 8 0 5/mL differential of autoimmune Strep throat culture Negative Negative Stool gastrointestinal PCR Negative Negative psychosis includes vasculitis, acute Nasal influenza swab Negative Negative disseminated encephalomyelitis, Nasal RSV swab Negative Negative lupus cerebritis, Grave’s 5-HIAA, 5- hydroxyindoleacetic acid; ANCA, antineutrophilic cytoplasmic autoantibody; HLA-B27, human leukocyte antigen thyrotoxicosis, autoimmune B27; RSV, respiratory syncytial virus; VDRL, venereal disease research laboratory. thyroiditis, and autoimmune a Indicates laboratory tests obtained at an outside hospital before admission at our hospital. encephalitis. From a neurologic b Indicates pertinent abnormal results. c All other urine porphyrins, metanephrines, and catecholamines were within normal range, so these borderline-elevated perspective, we consider time course, results were deemed clinically insignificant. associated new general and neurologic symptoms, family history, psychiatric symptoms included of 2 mg. The use of antipsychotics and exposure history. Key neurologic behavioral management of his was initially deferred to avoid to consider agitation and a trial of intravenous clouding the diagnostic picture, but include mental status, memory and lorazepam, uptitrated to a maximum because his distress persisted, cognition, movement disorders

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 145, number 6, June 2020 3 (chorea, tics, dystonia), , Drs Levy and Van Haren Dr Hoang, on the basis of the fl autonomic symptoms ( uctuations in There is a recent consensus article on laboratory and imaging results at this blood pressure and heart rate, when to consider a clinical diagnosis point, did you have any leading constipation, urinary retention), of autoimmune encephalitis in diagnoses at the top of your , numbness, and vision. It pediatric patients when differential? Did you seek the was notable that this patient autoantibodies are pending, negative, involvement of any additional 3 specialists? presented with multiple systems or unable to be sent. A patient affected, including autonomic should meet all 3 of the following Dr Hoang nervous system symptoms and criteria: (1) subacute (in the span of The preliminary laboratory and hallucinations, and the acute onset of ,3 months) rapid progression of imaging results were unremarkable his neurologic symptoms was working or short-term memory and did not provide a clear unifying striking. These features raised deficits, altered mental status, or diagnosis. Our leading diagnoses concern for a systemic, likely psychiatric symptoms; (2) at least continued to be autoimmune and autoimmune, process affecting his one of the subcriteria: new focal CNS paraneoplastic encephalitis because nervous system and prompted findings, seizures, CSF pleocytosis of the patient’s associated further workup, including brain MRI, (.5 white blood cells), or suggestive dysautonomia symptoms, which LP, and EEG. MRI features; and (3) reasonable persisted even when he was not exclusion of alternative causes. Thus, agitated or hallucinating; however, a patient can still meet clinical criteria Ms Rosenblatt and Dr Niemi the MRI of the brain was normal with if the time course, cognitive and/or no CNS findings, and the LP did not To help control his dysautonomia psychiatric symptoms, and focal reveal any CSF pleocytosis. The symptoms, the patient was started on neurologic symptoms and/or new- rheumatology team determined that clonidine. Additional medications onset seizures are all present. the patient did not meet clinical included continuation of his home criteria for PANS because he did not dose of lisinopril for blood pressure A new international consortium is have hyperacute onset of obsessive- control and the dosages of currently drafting updated criteria in compulsive symptoms.4 Additionally, olanzapine, quetiapine, and which a patient must have at least most children with PANS have lorazepam recommended by the child one of the following: CSF pleocytosis, a relapsing-remitting course with the suggestive MRI findings, and/or psychiatry team. Additionally, the initial onset typically occurring before patient was given Tylenol and slowing or epileptiform activity on age 10, which further made PANS oxycodone as needed for his EEG. Our patient would not have met unlikely.4 We wondered whether the continued back and groin pain. these clinical criteria. In general, secondary membranous nephropathy autoimmune encephalitis criteria could be the source of his psychosis; Meanwhile, the patient’s preliminary were drafted primarily to address however, our nephrology colleagues laboratory results revealed only a few neuropsychiatric symptoms that lack did not find any documented cases in abnormalities, including elevated the multiorgan pattern that raises the literature with this type of erythrocyte sedimentation rate, clinical concern for an underlying, association. A primary psychiatric D-dimer, von Willebrand factor unifying autoimmune process illness therefore remained on the (vWF), and factor VIII. This raised the affecting the brain as well as the rest differential given all the other suspicion that the patient may have of the body. These criteria help guide negative findings. We continued to fl an underlying in ammatory process. decision-making when antibodies are work with our psychiatry, The MRI of the brain and spine, LP, unavailable or negative. When rheumatology, nephrology, and fi and EEG revealed no signi cant patients have positive antibodies but neurology teams to understand his fl abnormalities, and cerebrospinal uid do not meet clinical criteria, however, clinical presentation. Our medical (CSF) meningitis and encephalitis practitioners must consider the team decided that the next best step polymerase chain reaction (PCR) relevance of antibody testing. Low was to partner with the patient and results were negative. antibody titers, antibodies that are his family to determine what their positive on blood samples drawn hospital goals were and how we could after receiving intravenous achieve them and provide a safe Ms Rosenblatt and Dr Niemi immunoglobulin (IVIg), antibodies discharge plan. Dr Levy and Dr Van Haren, given that are rarely seen in pediatric cases, normal MRI and LP results, when or the presence of multiple positive Ms Rosenblatt and Dr Niemi should autoimmune encephalitis antibodies suggest a lack of clinical With minimal improvement in his remain on the differential? significance. symptoms and laboratory and

Downloaded from www.aappublications.org/news by guest on September 28, 2021 4 ROSENBLATT et al imaging results yet to reveal a strong metanephrines and catecholamines, methylprednisolone. It was important unifying diagnosis, the decision was with a resulting negative scan. to discuss both short-term and long- made to hold a care conference with term expectations during this second Two weeks after discharge, the the general pediatrics team, the admission. Initially, the family was patient’s serum paraneoplastic multiple subspecialty teams involved, relieved to finally have a diagnosis autoimmune panel resulted positive and the patient’s family.5 At the but then struggled with how to for serum anti–contactin-associated meeting, the family voiced 3 main disclose this to the patient given the protein 2 (CASPR2) antibodies, which goals that became our criteria for disease’s chronicity and in the setting of his constellation of discharge: improving patient safety unpredictable time course with symptoms involving the peripheral by addressing the patient’s continued potential for relapse and intermittent nervous system (neuropathic pain), auditory and visual hallucinations flares after treatment.8 Fortunately, autonomic nervous system and depressed mood; improving his the patient had a robust response (hyperhidrosis, sympathetic hyperhidrosis, which was incredibly within a week of treatment, with overactivity), and CNS distressing for the patient; and better resolution of his hallucinations, (hallucinations, insomnia), was controlling his pain. The patient’s hyperhidrosis, and erectile consistent with Morvan syndrome. medications were adjusted with the dysfunction, and significant goal of establishing a regimen that improvement in his insomnia, mood, could be replicated at home. Notably, DISCUSSION and lower body and pain. the patient was started on The patient was diagnosed with Given this excellent response, he mirtazapine to address his insomnia Morvan syndrome (anti-CASPR2 continued to receive monthly and to further address autoantibody syndrome). treatment with IVIg and steroids, his hypertension and tachycardia and with a plan to continue until try to improve his hyperhidrosis. Ms Rosenblatt and Dr Niemi 3 months after complete return to baseline. Morvan syndrome is a rare By the last week of admission, the autoimmune encephalitis involving patient was much less agitated and no Ms Rosenblatt and Dr Niemi antibodies against voltage-gated longer required a 1:1 sitter. He was Drs Shaw and Ort, what can we learn potassium channels (CASPR2) found conversant and eloquent despite from this case in terms of on neuronal membranes of the continued occasional outbursts distinguishing a primary psychiatric central and peripheral nervous triggered by pain or frustration. His disorder from an organic etiology? systems.7,8 It has been described pain was relatively well controlled predominantly in elderly men and with Tylenol. His hypertension, Drs Shaw and Ort rarely in the pediatric population. tachycardia, and hyperhidrosis were Accurately differentiating primary Treatment options include IVIg, controlled with lisinopril, psychiatric illness from an organic steroids, and plasmapheresis. It is propranolol, and clonidine.6 His etiology is essential to allow prompt often associated with thymoma,9 insomnia had also improved, with the medical intervention and reduce although our patient did not have patient sleeping up to 5 hours each morbidity. Delays in the diagnosis of evidence of this on imaging. night. The patient was discharged medical illness, for example, in the from the hospital without a concrete Dr Chen, as the pediatric hospitalist case of autoimmune encephalitis, may diagnosis but with a strong suspicion medicine fellow managing the lead to more significant illness and an for an underlying inflammatory patient’s readmission for treatment, increased risk of incomplete recovery. condition, and close follow-up was how did you approach the diagnosis In this case, the presence of clear-cut arranged knowing that a few in terms of managing next steps for medical symptoms such as diagnostic tests had yet to result, treatment? hyperhidrosis directed the team particularly a urine heavy metal panel toward investigating a medical and paraneoplastic autoimmune and Dr Chen Chen (General Pediatric etiology. Other factors that should immune complex panels, which were Hospitalist) raise suspicion for a medical illness sent out to the Mayo Clinic Once the laboratory resulted as include atypical presentation, Laboratories (Table 2). After positive for Morvan syndrome, we including age of onset or the absence discharge, the patient also had an worked closely with the neurology of any clear psychological stressors. outpatient positron emission team to discuss next steps and Psychiatric illness should, in these tomography MRI to rule out treatment options. Ultimately, a direct cases, always be a diagnosis of a pheochromocytoma and admission was scheduled, and the exclusion. Data from studies of paraneoplastic process given patient was admitted for IVIg and a patients with medically unexplained borderline-elevated urine 3-day course of intravenous symptoms reveal that up to 75% of

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 145, number 6, June 2020 5 TABLE 2 Laboratory Tests That Resulted After Patient’s Discharge From the Hospital required ongoing psychiatric Test Value Reference Range treatment with consideration of an Paraneoplastic autoimmune panel, serum antidepressant for ongoing anxiety ANNA-1 Negative Negative and depressive symptoms. ANNA-2 Negative Negative ANNA-3 Negative Negative Ms Rosenblatt and Dr Niemi AGNA-1 Negative Negative PCA-1 Negative Negative Drs Levy and Van Haren, as the child PCA-2 Negative Negative neurologist team managing the PCA-Tr Negative Negative patient’s treatment and outpatient Amphiphysin antibody Negative Negative CRMP-5–IgG Negative Negative follow-up, what is your predicted P/Q-type calcium channel antibody 0.00 nmol/L #0.02 nmol/L prognosis for him? What are the N-type calcium channel antibody 0.00 nmol/L #0.03 nmol/L unique aspects of his presentation of AChR ganglionic neuronal antibody 0.00 nmol/L #0.02 nmol/L Morvan syndrome? What can we # AChR binding antibody 0.00 nmol/L 0.02 nmol/L learn from this patient’s case to better Striational (striated muscle) antibody Negative Negative Neuronal (V-G) potassium 1 channel antibody 0.10 nmol/La #0.02 nmol/L diagnose this and manage patients LGI1-IgG CBA Negative Negative with this, and similar conditions, in CASPR2-IgG CBA Positivea Negative the future? Paraneoplastic autoimmune panel, CSF ANNA-1 Negative Negative ANNA-2 Negative Negative Drs Levy and Van Haren ANNA-3 Negative Negative Anti-CASPR2 autoantibody syndrome, AGNA-1 Negative Negative also known as Morvan syndrome, is PCA-1 Negative Negative PCA-2 Negative Negative rare in the pediatric population, PCA-Tr Negative Negative making this patient rather unusual in Amphiphysin antibody Negative Negative his diagnosis because of age of CRMP-5–IgG Negative Negative presentation. In a recent Immune complex panel, serum retrospective analysis of pediatric C1Q binding assay 2.1 mgE/mL 0.0–3.9 mgE/mL Raji cell immune complex assay ,12 mgE/mL #24 mgE/mL presumed autoimmune encephalitis Metanephrines, serum ,0.20 nmol/L ,0.50 nmol/L cases in all of Denmark, only 0.4% of Normetanephrines, serum 1.0 nmol/L ,0.9 nmol/L all pediatric patients who had NMDA receptor antibody, IgG ,1:10 ,1:10 antibody panels sent were positive Heavy metals panel, urine for anti-CASPR2 antibodies.12 There Arsenic 6 mg/L ,35 mg/L Cadmium ,0.5 mg/24 h ,0.6 mg/24 hb are only a few pediatric cases 13 Mercury 48 mg/24 h ,2 mg/24 hb, .50 mg/24 hc published with clinical descriptions. Lead ,1 mg/24 h ,1 mg/24 hb This patient has hallmark features of Protein and immunofixation electrophoresis, CSF neuroexcitability as seen in his , IgG 0.5 mg/dL 6.0 mg/dL insomnia, autonomic dysfunction, and Albumin 6.8 mg/dL ,30.0 mg/dL IgG/albumin index 0.41 ,0.70 psychosis, but he lacked Oligoclonal banding Negative Negative or other muscular AChR, acetylcholine receptor; AGNA, antiglial nuclear antibody; ANNA, antineuronal nuclear antibody; C1Q, complement and sensory hyperexcitability component 1q; CBA, cell binding assay; CRMP, collapsin response mediator protein; IgG, immunoglobulin G; LGI1, leucine- features. His case is a reminder that rich glioma inactivated 1; NMDA, N-methyl-D-aspartate; PCA, Purkinje cell cytoplasmic antibody; PCA-Tr, Purkinje cell clinical syndromes are often cytoplasmic antibody, type Tr; V-G, voltage-gated. a Indicates pertinent abnormal results. a spectrum of symptoms, which can b Indicates reference values for patients $18 y old because no reference exists for patients ,18 y old. make diagnosis challenging when c A urine mercury level .50 mg/24 h in patients $18 y old suggests toxic concentration, with 50 mg/24 h being the lowest only some features are initially concentration at which toxicity is usually apparent. present. On the basis of adult encephalitis literature, this is patients are subsequently diagnosed when an organic etiology is found, it a treatable but chronic and severe with a treatable medical condition.10 is important not to dismiss the neuropsychiatric syndrome that In addition, many patients in whom patient’s psychiatric symptoms affects multiple organ systems partly there are clear psychological factors because they themselves can cause because of peripheral nervous system at play, for example, patients with significant morbidity when not dysregulation. We advised the patient nonepileptic seizures, are found to properly addressed. In this case, the and his family that we are hopeful for have co-occurring medical and patient’s psychotic symptoms improvement and possibly resolution psychiatric illness.11 However, even resolved over time; however, he still of his symptoms with treatment but

Downloaded from www.aappublications.org/news by guest on September 28, 2021 6 ROSENBLATT et al that he may have future relapses or autoantibodies (and similar the treatment of pruritus. Psychosom require ongoing immunotherapy. mechanisms) that are also capable of Med. 2007;69(9):970–978 causing neuropsychiatric pathology. 3. Graus F, Titulaer MJ, Balu R, et al. A This patient could have been treated clinical approach to diagnosis of empirically with IVIg earlier in his As research continues on immune- mediated neuropsychiatric autoimmune encephalitis. Lancet hospital course while the autoimmune Neurol. 2016;15(4):391–404 encephalitis panel was still pending; phenomena, we are hopeful that there 4. Chang K, Frankovich J, Cooperstock M, however, IVIg has its own adverse will be new avenues of diagnosis and et al; PANS Collaborative Consortium. reactions and side effects that must be treatment of our patients. Practitioners should therefore keep Clinical evaluation of youth with weighed against potential therapeutic pediatric acute-onset neuropsychiatric fi a broad differential diagnosis for bene t. The decision to treat syndrome (PANS): recommendations pediatric patients with acute or empirically often depends on the from the 2013 PANS Consensus severity of the patient’ssymptoms subacute neuropsychiatric symptoms; Conference. J Child Adolesc fi after maximal medical management. If attempt a patient-speci c but broad Psychopharmacol. 2015;25(1):3–13 remaining symptoms are mild or workup that likely includes serum, CSF, and imaging studies; and 5. Fox D, Brittan M, Stille C. The pediatric moderate, many patients can await inpatient family care conference: engage a multidisciplinary team on laboratory results before empirical a proposed structure toward shared treatment. Moreover, treatment with treatment options that include decision-making. Hosp Pediatr. 2014; IVIg before workup is completed may immunomodulation, psychiatric 4(5):305–310 medications, and behavioral therapy. lead to false-positives on future 6. Axelrod FB. : antibody testing. a review of the current ACKNOWLEDGMENTS pharmacological treatments. Expert – We acknowledge Dr Keith Van Haren, Opin Pharmacother. 2005;6(4):561 567 CONCLUSIONS Stanford Division of Child Neurology, 7. Lancaster E, Huijbers MGM, Bar V, et al. This patient highlights the difficulties and Dr Jennifer Frankovich, Stanford Investigations of caspr2, an autoantigen we as providers face in trying to Division of Allergy, Immunology, and of encephalitis and neuromyotonia. Ann recognize and diagnose autoimmune Rheumatology in the Department of Neurol. 2011;69(2):303–311 encephalitis. Although there are several Pediatrics, for their contributions to 8. van Sonderen A, Ariño H, Petit-Pedrol M, well-described syndromes within the case and this article. et al. The clinical spectrum of autoimmune encephalitis, such as anti- Caspr2 antibody-associated disease. CASPR2, anti–N-methyl-D-aspartate Neurology. 2016;87(5):521–528 receptor encephalitis, limbic ABBREVIATIONS 9. Vale TC, Pedroso JL, Dutra LA, et al. encephalitis, Bickerstaff brainstem CASPR2: contactin-associated Morvan syndrome as a paraneoplastic encephalitis, acute disseminated protein 2 disorder of thymoma with anti-CASPR2 encephalomyelitis, anti–myelin antibodies. Lancet. 2017;389(10076): CNS: central nervous system oligodendrocyte glycoprotein 1367–1368 CSF: cerebrospinal fluid encephalitis, accurate diagnosis is not IVIg: intravenous immunoglobulin 10. Smith RC, Dwamena FC. Classification always simple. Some patients are LP: lumbar puncture and diagnosis of patients with antibody positive but do not fit PANS: pediatric acute-onset medically unexplained symptoms. J Gen into a defined syndrome for easy Intern Med. 2007;22(5):685–691 neuropsychiatric syndrome clinical recognition. In other, still PCR: polymerase chain reaction 11. Bodde NMG, Brooks JL, Baker GA, Boon rare, cases, individuals may have vWF: von Willebrand factor PAJM, Hendriksen JGM, Aldenkamp AP. aneuropsychiatricsyndromethatis Psychogenic non-epileptic seizures-- due to an autoantibody that has not yet diagnostic issues: a critical review. Clin been discovered and thus cannot yet be Neurol Neurosurg. 2009;111(1):1–9 detected by using currently available REFERENCES 12. Boesen MS, Born AP, Lydolph MC, assays. The current (adult) criteria 1. Larsen CP, Messias NC, Silva FG, Blaabjerg M, Børresen ML. Pediatric 3 from Graus et al allow for this Messias E, Walker PD. Determination of autoimmune encephalitis in Denmark possibility when patients meet specific primary versus secondary during 2011-17: a nationwide multicenter clinical and laboratory criteria. membranous glomerulopathy utilizing population-based cohort study. Eur However, for most patients with phospholipase A2 receptor staining in J Paediatr Neurol. 2019;23(4):639–652 anegativeorborderlineautoantibody renal biopsies. Mod Pathol. 2013;26(5): 13. López-Chiriboga AS, Klein C, Zekeridou – result, nonimmunologic diagnoses are 709 715 A, et al. LGI1 and CASPR2 neurological more likely. In the future, we are likely 2. Shaw RJ, Dayal S, Good J, Bruckner AL, autoimmunity in children. Ann Neurol. to discover more pathogenic Joshi SV. Psychiatric medications for 2018;84(3):473–480

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 145, number 6, June 2020 7 A Previously Healthy Adolescent With Acute Psychosis and Severe Hyperhidrosis Tatiana Rosenblatt, Katherine Ort, Richard Shaw, Rebecca J. Levy, Chen Chen, Angela Niemi and Kim Hoang Pediatrics originally published online May 22, 2020;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2020/05/21/peds.2 019-3786 References This article cites 13 articles, 2 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2020/05/21/peds.2 019-3786#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Hospital Medicine http://www.aappublications.org/cgi/collection/hospital_medicine_su b Neurology http://www.aappublications.org/cgi/collection/neurology_sub Neurologic Disorders http://www.aappublications.org/cgi/collection/neurologic_disorders_ sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 28, 2021 A Previously Healthy Adolescent With Acute Psychosis and Severe Hyperhidrosis Tatiana Rosenblatt, Katherine Ort, Richard Shaw, Rebecca J. Levy, Chen Chen, Angela Niemi and Kim Hoang Pediatrics originally published online May 22, 2020;

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