“Hopping Mad” 4-year-old: frog hallucinations or encephalitis?

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Tyler Beauchamp This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8291199/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 12 You are reading this latest preprint version Abstract Background : While most children presenting with undifferentiated nightmare-like symptoms may commonly suffer from conditions like parasomnias or neurodevelopmental disorders (NDDs), clinicians must not forget to consider exclusionary diagnoses like seronegative autoimmune encephalitis (SAE). Case Presentation : This case presents a 4-year-old girl with acute visual hallucinations, an episode of unresponsiveness with shuffling movements, and a month-long history of increased falls and intermittent slurred speech. Although having no presenting deficits, her history of hallucinations and abnormal movements prompted further neurologic evaluation. During her hospital course, she developed a multitude of new concerning features including hallucinations, slurred speech, and new ataxia, along with a vEEG revealing left parietal slowing with interictal epileptiform discharges. Conclusions : While MRI and CSF studies—including autoimmune panels—were normal, she was treated empirically with IV steroids and IVIG for suspected seronegative autoimmune encephalitis. Prior to discharge, autoimmune serum testing revealed elevated IL-2 receptor and IL-6 levels, supporting an inflammatory process despite seronegativity. Following treatment, her hallucinations resolved and gait deficits steadily improved with therapy. This case demonstrates the diagnostic complexity of SAE in young children with nonspecific neuropsychiatric symptoms as well as the vitality of maintaining broad differential approaches in an emergency setting. Seronegative autoimmune encephalitis parasomnias night terrors encephalopathy pediatric emergencies Background When a four-year-old girl comes into the emergency department after waking up terrified, night terrors are not always the culprit. NREM parasomnias, or night terrors, are a common occurrence in childhood, peaking around age two and declining by ages five to thirteen [1-2] . While they commonly obfuscate other diagnoses such as nocturnal seizures or true nightmares, they are rarely misdiagnosed in young ages in lieu of more detrimental etiologies, one namely being autoimmune encephalitis [3] . This is partially due to typical semiologies of encephalitis involving a multitude of other abnormal neurologic features (focal neurologic deficits, seizures, movement disorders, slurred speech) that are not seen in simply night terrors, but also in that encephalopathies are more commonly seen in older populations. In a majority of current studies, the mean age of onset for pediatric autoimmune encephalitis occurs between ages four and seven, with the incidence under age of five being a minority [3-5] . Remarkably, while being a diagnosis of exclusion, seronegative autoimmune encephalitis (SAE) makes up the majority of pediatric encephalitic cases (approximately 67%) [6] . Of these seronegative cases, research has suggested there tends to be a higher rate of comorbid neurodevelopmental disorders, such as epilepsy or autism [7] . While studies are limited on the true extent of this correlation, families involving multiple siblings with one or more NDDs may warrant genetic evaluation and close neurologic following given the similarities between microglial activation in NDDs compared to acute encephalopathy [8-9] . All this to be said, even knowing the rarity of SAE occurring in children under five compared to the commonality of night terrors and other parasomnias, clinicians must be sure to keep their minds open in hopes of separating the two. Case Presentation Emergency Room : In this case, a previously healthy 4-year-old female presented to the emergency department with parental concerns for acute visual hallucinations and one episode of abnormal movements. She arrived to the emergency department with her parents, who reported that the night prior she had awoken screaming, claiming to be covered by “cockroaches and frogs.” The patient was consolable by parents until she awoke again later that night with similar symptoms, this time continually reporting symptoms even when parents turned on the lights and pointed to empty areas. She was eventually consoled back to sleep. Later that day, her mother was contacted over FaceTime via siblings reporting the patient was “acting strangely,” in which mother witnessed daughter “standing with a blank gaze, shuffling in place, not responding to us.” Prior to this episode, the patient had been playing with siblings with normal behavior. The episode lasted roughly 5 minutes, following by hysterical screaming that “the cockroaches and frogs are back.” Mother contacted her pediatrician who recommended bringing the patient to the emergency department (ED) at this time. On arrival to the ED, the patient was still reporting visual hallucinations up until she was roomed. By the time the ED team evaluated her, the hallucinations were gone and she was back to baseline behavior, neurologically typical, in no acute distress. Upon obtaining further history, her mother reported that the patient’s school had concerns she was “tripping and falling more than normal over the last month.” Her mother denies witnessing increased falls at home, however does report one home episode in the last month in which she “was walking around like a drunk and slurring her speech,” which self-resolved without repeat occurrences. Additionally, the patient had experienced two weeks of recurrent epistaxis, and mom recalls “finding a tick on her face one day. I pulled it off and there was no bite.” Otherwise, review of systems was negative. The patient was previously healthy, developmentally appropriate, without recent illnesses or fevers, took no medications, and up to date on vaccinations. Her family history was positive for two older brothers with autism, one of whom with epilepsy soon to undergo neurosurgical ablation. Otherwise, no other family history of neurologic disease, seizures, autoimmune conditions, bleeding/hematologic disorders, or psychiatric illness. On exam, the patient was at baseline behavior per mother, playing with a coloring book, communicating appropriately without active hallucinations. Other than multiple small healing crusted lesions on her shins which mother reported were prior bug bites, no pertinent positive findings found on exam. Neurologically, no focal deficits appreciated, full sensation and strength of all extremities with normal gait and deep tendon reflexes diffusely. Blood pressure was elevated on arrival 114/103, otherwise stable vitals. She had an elevated WBC of 11.9 with normal differential. Initial chemistries and urine toxicology returned normal. Given the patient’s stable appearance, return to baseline behavior, and lack of repeat episodes witnessed with observation, night terrors were high on the initial differential given the known onset from sleep. However, with the history of recurrent falls, multiple episodes of visual hallucinations, and the single episode of absence/stiff behavior, pediatric neurology was consulted for workup recommendations to assess for potential seizures vs. epilepsy vs. encephalitis. Neurology concurred that the history was concerning enough to warrant further workup for seizures vs. encephalitis and recommended admission for video electroencephalogram (vEEG) monitoring and sedated MRI brain with lumbar puncture (LP) studies. Floor: Upon admission later that evening, the patient began to exhibit changes from her initial neurologic exam with new ataxic gait. Given the small bruising noted on shins and history of recent recurrent nosebleeds, the floor evaluated for potential underling bleeding etiologies. Platelets, coagulation panels, and repeat chemistries all returned within normal limits, along with normal urinalysis studies. Given the elevated white blood cell count (WBC) in the ED, a respiratory pathogen panel (RPP) was obtained which returned positive for COVID-19, Rhinovirus, and Enterovirus. Her initial video EEG showed left parietal focal slowing with spikes in wakefulness/sleep as well as interictal epileptiform discharges indicative of underlying seizures (unable to determine if new or pre-existing). Paired with her subacute neuropsychiatric symptoms, autoimmune encephalitis could not be ruled out. However, while undergoing sedation for her MRI and LP, the patient aspirated, was intubated, and emergently transferred to the pediatric intensive care unit (PICU) for stabilization. PICU: While intubated and sedated in PICU, the patient completed her lumbar puncture LP. While awaiting results, she was empirically started on 5-day course of IV solumedrol and 2-day course of IVIG for autoimmune encephalitis. She was extubated to high-flow nasal cannula oxygen (HFNC) and weaned off sedatives in preparation for transfer back to the floor. When weaned off sedation, the patient began to experience new abnormal neurologic symptoms including “screaming, crying, visual hallucinations, headaches, eye blinking and lip-smacking.” The following morning, her speech was slightly off from baseline but improved as the day went on. Working with PT, she continued to demonstrate unsteady gait and diffuse weakness, but without focal findings. Her MRI brain with/without contrast returned normal. The patient was kept on EEG to capture repeat events as well as determine if seizures could be contributing to symptom course. Her CSF studies returned grossly normal glucose, protein, and lymphocyte counts, with clear colorless fluid, as well as a full negative autoimmune CSF panel. CRP and ESR were mildly elevated at 15 and 28 respectively. Per neurology, it was unclear if she had neurologic involvement of her concurrent viral illness without clear neurologic infection or inflammation. A comprehensive serum autoimmune panel was obtained prior to transfer to the floor. While awaiting study results, the leading consideration for the patient’s symptoms was potential viral vs. autoimmune trigger of acute mental status changes, complicated by iatrogenic deconditioning. Floor to Discharge: The patient was transferred back to floor on room air with improvement in speech to baseline, however still exhibiting intermittent diffuse extremity weakness. Her extensive autoimmune panels returned notable for elevated IL-2 receptor level of 2315.8 (paired with IL-2 level <2) and elevated IL-6 of 53. Otherwise, all other autoimmune studies returned negative/within normal, including ANA, anti-SM, anti-SSA/B, bartonella panel, NDMA/AMPA rec antibodies, Lyme studies, as well as all other interleukin studies. The leading diagnosis was autoimmune encephalitis with potential concurrent hospital delirium. After completing her courses of solumedrol and IVIG, the patient ceased to have continued hallucination episodes, however her headaches and gait concerns persisted. With PT and neurology following, her ataxia appeared more consistent with deconditioning than progressive neurologic disease. With normal MRI and CSF studies, paired with no clear direct trigger on her autoimmune workup, her leading diagnosis upon discharge became seronegative autoimmune encephalitis with concurrent deconditioning ailments. With patient’s neurologic status back to baseline, absence of hallucination episodes for over 48 hours, and improvement in ataxia/weakness with PT treatment, the patient was discharged without initiation of antiepileptic drugs (AEDs) or continued steroid management, but rather close follow up with neurology and PT/OT. She was continually evaluated by neurology until she exhibited return to baseline behavior, and she continues to work with PT/OT to date. Discussion There are several aspects to this case that made it uniquely challenging to workup, the first of which being her initial presentation without focal deficits, abnormal behavior, or concerning initial lab findings. With parasomnias being exceedingly more common than autoimmune encephalitis in this age [2,4] , neurologic evaluation was only initiated given her reported abnormal movement episode concerning for seizure-like activity, history of falls, and family history of epilepsy. Additionally, the combination of an abnormal EEG paired with multiple concurrent viruses presented difficulty in delineating neurologic vs. infectious etiologies. While viral encephalitis was considered, the majority of pediatric viral encephalopathies present with one or more prodromal symptoms such as fever, respiratory symptoms, gastrointestinal concerns [10] , all of which were absent in this patient. As far as her neurologic course including multiple repeat episodes of hallucination, slurred speech, and weakness/ataxia, it is difficult to determine how many of these symptoms were potentially present prior to her hospitalization (given the reported concerns from her school and episodes at home). With her hospital course being complicated by deconditioning secondary to required intubation and sedation, it is likely a combination of encephalitis and physical deconditioning contributed to her unique symptom course. A diagnosis of exclusion, seronegative autoimmune encephalitis required rapid progression of altered mental status or psychiatric symptoms, a minimum of one additional neurologic abnormality (new seizures, movement disorder, focal deficits), at least one test demonstrating CNS inflammation, while excluding seropositive etiologies [11-12] . While the epileptogenic potential from patient’s EEG was unable to be differentiated from new-onset vs. pre-existing, its presence demonstrated signs of inflammation. Additionally, all serum/CSF specific antibodies tested did not demonstrate a clear trigger. Her discrepancy between her elevated IL-2 receptor and normal IL-2 levels suggested underlying immune activation in spite or seronegativity, further supporting SAE [3,13] . Conclusion The true start date of the patient’s symptoms remains unclear, however the resolution in her neuropsychiatric symptoms following steroids and IVIG was reassuring. In those adequately treated with steroids and IVIG, studies have found over 90% of patients demonstrate clinical improvement and absence of relapse events after one year [14] . Given her significant symptom improvement and continued close neurologic/PT follow up, it is likely her symptoms will continue to improve with time in the absence of continued steroid treatment or AED initiation. That being said, given the high rates of comorbid neurodevelopmental disorders with SAE [7-9], and given her strong family history of autism, the family was contacted following discharge to inform them of this potential connection, along with the recommendations for their pediatrician and neurologist to consider genetic evaluation of not just this patient, but her siblings as well. Abbreviations NDDs - neurodevelopmental disorders SAE - seronegative autoimmune encephalitis ED - emergency department vEEG - video electroencephalogram WBC - white blood cell count RPP - respiratory pathogen panel LP - lumbar puncture PICU - pediatric intensive care unit HFNC - high-flow nasal cannula oxygen AEDs - antiepileptic drugs Declarations Ethics Approval and Consent to Participate: Not Applicable Consent for Publication : Verbal and written informed consent was obtained from the patient and their parents for any and all aspects of her hospital course and follow ups to be used in the development of this report. Availability of Data and Materials : The data and lab results incorporated in this report are from the patient’s hospital stay at UNC Children’s Hospital and therefore are not publicly available. Further investigation or interest in these results may be pursued via UNC Children’s Hospital upon reasonable request. Please reach out to the corresponding author for any and all data request needs. Competing Interests : The author declares that they have no competing interests. Funding : No funding was used in the production of this report. Authors’ Contributions : Tyler Beauchamp (TB) was the sole author and contributor to this case report. No other authors were used or aided in the development of this report. Acknowledgments : Not applicable. References Petit, Dominique, et al. “Childhood sleepwalking and sleep terrors: a longitudinal study of prevalence and familial aggregation.” JAMA Pediatrics , vol. 169, no. 7, 1 July 2015, p. 653, https://doi.org/10.1001/jamapediatrics.2015.127. Maski, Kiran, and Judith A Owens. “Insomnia, Parasomnias, and narcolepsy in children: Clinical features, diagnosis, and Management.” The Lancet Neurology , vol. 15, no. 11, Oct. 2016, pp. 1170–1181, https://doi.org/10.1016/s1474-4422(16)30204-6. Olivé-Cirera, Gemma, et al. “Differential diagnosis and comparison of diagnostic algorithms in children and adolescents with autoimmune encephalitis in Spain: A prospective cohort study and retrospective analysis.” The Lancet Neurology , vol. 24, no. 1, Jan. 2025, pp. 54–64, https://doi.org/10.1016/s1474-4422(24)00443-5. Brisca, Giacomo, et al. “Acute pediatric encephalitis: Etiology, course, and outcome of a 12-year single-center immunocompetent cohort.” Journal of Neurology , vol. 270, no. 10, 3 July 2023, pp. 5034–5047, https://doi.org/10.1007/s00415-023-11847-3. Madani, Jihan, et al. “Clinical features and outcomes in children with seronegative autoimmune encephalitis.” Developmental Medicine & Child Neurology , vol. 66, no. 10, 15 Mar. 2024, pp. 1310–1318, https://doi.org/10.1111/dmcn.15896. Dou, Qingyang, et al. “Clinical characteristics and prognosis of antibody-negative autoimmune encephalitis in children: A single-center retrospective study.” Pediatric Neurology , vol. 133, Aug. 2022, pp. 9–14, https://doi.org/10.1016/j.pediatrneurol.2022.05.007. Panzer, Kira, et al. “Retrospective comparison of patients evaluated for pediatric autoimmune encephalitis with typical and atypical premorbid neuropsychiatric development.” Journal of Autism and Developmental Disorders , vol. 55, no. 6, 26 July 2023, pp. 2059–2066, https://doi.org/10.1007/s10803-023-06065-9. Kern, Janet K., et al. “Relevance of neuroinflammation and encephalitis in autism.” Frontiers in Cellular Neuroscience , vol. 9, 19 Jan. 2016, https://doi.org/10.3389/fncel.2015.00519. Whiteley, Paul, et al. “Autoimmune encephalitis and autism spectrum disorder.” Frontiers in Psychiatry , vol. 12, 17 Dec. 2021, https://doi.org/10.3389/fpsyt.2021.775017. Pata, Davide, et al. “Diagnosis and therapy of infectious encephalitis in children: A ten-years retrospective study.” Pediatric Infectious Disease Journal , vol. 40, no. 6, 10 May 2021, pp. 513–517, https://doi.org/10.1097/inf.0000000000003070. “Pediatric acute-onset neuropsychiatric syndrome (PANS): Clinical report.” Pediatrics , vol. 155, no. 3, 24 Feb. 2025, https://doi.org/10.1542/peds.2024-070334. Cellucci, Tania, et al. “Clinical approach to the diagnosis of autoimmune encephalitis in the pediatric patient.” Neurology Neuroimmunology & Neuroinflammation , vol. 7, no. 2, Mar. 2020, https://doi.org/10.1212/nxi.0000000000000663. Zhang, Yiwei, et al. “Interleukin-2 and its receptors: Implications and therapeutic prospects in immune-mediated disorders of central nervous system.” Pharmacological Research , vol. 213, Mar. 2025, p. 107658, https://doi.org/10.1016/j.phrs.2025.107658. Kim, Hye J, et al. “Clinical features and outcomes of paediatric probable antibody‐negative autoimmune encephalitis.” Developmental Medicine & Child Neurology , vol. 67, no. 10, 19 Aug. 2025, https://doi.org/10.1111/dmcn.16491. Additional Declarations No competing interests reported. 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NREM parasomnias, or night terrors, are a common occurrence in childhood, peaking around age two and declining by ages five to thirteen\u003csup\u003e\u0026nbsp;[1-2]\u003c/sup\u003e. While they commonly obfuscate other diagnoses such as nocturnal seizures or true nightmares, they are rarely misdiagnosed in young ages in lieu of more detrimental etiologies, one namely being autoimmune encephalitis \u003csup\u003e[3]\u003c/sup\u003e. This is partially due to typical semiologies of encephalitis involving a multitude of other abnormal neurologic features (focal neurologic deficits, seizures, movement disorders, slurred speech) that are not seen in simply night terrors, but also in that encephalopathies are more commonly seen in older populations. In a majority of current studies, the mean age of onset for pediatric autoimmune encephalitis occurs between ages four and seven, with the incidence under age of five being a minority \u003csup\u003e[3-5]\u003c/sup\u003e. Remarkably, while being a diagnosis of exclusion, seronegative autoimmune encephalitis (SAE) makes up the majority of pediatric encephalitic cases (approximately 67%) \u003csup\u003e[6]\u003c/sup\u003e. Of these seronegative cases, research has suggested there tends to be a higher rate of comorbid neurodevelopmental disorders, such as epilepsy or autism \u003csup\u003e[7]\u003c/sup\u003e. While studies are limited on the true extent of this correlation, families involving multiple siblings with one or more NDDs may warrant genetic evaluation and close neurologic following given the similarities between microglial activation in NDDs compared to acute encephalopathy \u003csup\u003e[8-9]\u003c/sup\u003e. All this to be said, even knowing the rarity of SAE occurring in children under five compared to the commonality of night terrors and other parasomnias, clinicians must be sure to keep their minds open in hopes of separating the two. \u0026nbsp;\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003e\u003cstrong\u003eEmergency Room\u003c/strong\u003e: In this case, a previously healthy 4-year-old female presented to the emergency department with parental concerns for acute visual hallucinations and one episode of abnormal movements. She arrived to the emergency department with her parents, who reported that the night prior she had awoken screaming, claiming to be covered by “cockroaches and frogs.” The patient was consolable by parents until she awoke again later that night with similar symptoms, this time continually reporting symptoms even when parents turned on the lights and pointed to empty areas. She was eventually consoled back to sleep. Later that day, her mother was contacted over FaceTime via siblings reporting the patient was “acting strangely,” in which mother witnessed daughter “standing with a blank gaze, shuffling in place, not responding to us.” Prior to this episode, the patient had been playing with siblings with normal behavior. The episode lasted roughly 5 minutes, following by hysterical screaming that “the cockroaches and frogs are back.” Mother contacted her pediatrician who recommended bringing the patient to the emergency department (ED) at this time.\u003c/p\u003e\n\u003cp\u003eOn arrival to the ED, the patient was still reporting visual hallucinations up until she was roomed. By the time the ED team evaluated her, the hallucinations were gone and she was back to baseline behavior, neurologically typical, in no acute distress.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUpon obtaining further history, her mother reported that the patient’s school had concerns she was “tripping and falling more than normal over the last month.” Her mother denies witnessing increased falls at home, however does report one home episode in the last month in which she “was walking around like a drunk and slurring her speech,” which self-resolved without repeat occurrences. Additionally, the patient had experienced two weeks of recurrent epistaxis, and mom recalls “finding a tick on her face one day. I pulled it off and there was no bite.” Otherwise, review of systems was negative. The patient was previously healthy, developmentally appropriate, without recent illnesses or fevers, took no medications, and up to date on vaccinations. Her family history was positive for two older brothers with autism, one of whom with epilepsy soon to undergo neurosurgical ablation. Otherwise, no other family history of neurologic disease, seizures, autoimmune conditions, bleeding/hematologic disorders, or psychiatric illness. On exam, the patient was at baseline behavior per mother, playing with a coloring book, communicating appropriately without active hallucinations. Other than multiple small healing crusted lesions on her shins which mother reported were prior bug bites, no pertinent positive findings found on exam. Neurologically, no focal deficits appreciated, full sensation and strength of all extremities with normal gait and deep tendon reflexes diffusely. \u0026nbsp;Blood pressure was elevated on arrival 114/103, otherwise stable vitals. She had an elevated WBC of 11.9 with normal differential. Initial chemistries and urine toxicology returned normal.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGiven the patient’s stable appearance, return to baseline behavior, and lack of repeat episodes witnessed with observation, night terrors were high on the initial differential given the known onset from sleep. However, with the history of recurrent falls, multiple episodes of visual hallucinations, and the single episode of absence/stiff behavior, pediatric neurology was consulted for workup recommendations to assess for potential seizures vs. epilepsy vs. encephalitis. Neurology concurred that the history was concerning enough to warrant further workup for seizures vs. encephalitis and recommended admission for video electroencephalogram (vEEG) monitoring and sedated MRI brain with lumbar puncture (LP) studies.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFloor:\u0026nbsp;\u003c/strong\u003eUpon admission later that evening, the patient began to exhibit changes from her initial neurologic exam with new ataxic gait. Given the small bruising noted on shins and history of recent recurrent nosebleeds, the floor evaluated for potential underling bleeding etiologies. Platelets, coagulation panels, and repeat chemistries all returned within normal limits, along with normal urinalysis studies. Given the elevated white blood cell count (WBC) in the ED, a respiratory pathogen panel (RPP) was obtained which returned positive for COVID-19, Rhinovirus, and Enterovirus. Her initial video EEG showed left parietal focal slowing with spikes in wakefulness/sleep as well as interictal epileptiform discharges indicative of underlying seizures (unable to determine if new or pre-existing). Paired with her subacute neuropsychiatric symptoms, autoimmune encephalitis could not be ruled out. However, while undergoing sedation for her MRI and LP, the patient aspirated, was intubated, and emergently transferred to the pediatric intensive care unit (PICU) for stabilization.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePICU:\u0026nbsp;\u003c/strong\u003eWhile intubated and sedated in PICU, the patient completed her lumbar puncture LP. While awaiting results, she was empirically started on 5-day course of IV solumedrol and 2-day course of IVIG for autoimmune encephalitis. She was extubated to high-flow nasal cannula oxygen (HFNC) and weaned off sedatives in preparation for transfer back to the floor. When weaned off sedation, the patient began to experience new abnormal neurologic symptoms including “screaming, crying, visual hallucinations, headaches, eye blinking and lip-smacking.” The following morning, her speech was slightly off from baseline but improved as the day went on. Working with PT, she continued to demonstrate unsteady gait and diffuse weakness, but without focal findings. Her MRI brain with/without contrast returned normal. The patient was kept on EEG to capture repeat events as well as determine if seizures could be contributing to symptom course. Her CSF studies returned grossly normal glucose, protein, and lymphocyte counts, with clear colorless fluid, as well as a full negative autoimmune CSF panel. CRP and ESR were mildly elevated at 15 and 28 respectively. Per neurology, it was unclear if she had neurologic involvement of her concurrent viral illness without clear neurologic infection or inflammation. A comprehensive serum autoimmune panel was obtained prior to transfer to the floor. While awaiting study results, the leading consideration for the patient’s symptoms was potential viral vs. autoimmune trigger of acute mental status changes, complicated by iatrogenic deconditioning. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFloor to Discharge:\u0026nbsp;\u003c/strong\u003eThe patient was transferred back to floor on room air with improvement in speech to baseline, however still exhibiting intermittent diffuse extremity weakness. Her extensive autoimmune panels returned notable for elevated IL-2 receptor level of 2315.8 (paired with IL-2 level \u0026lt;2) and elevated IL-6 of 53. Otherwise, all other autoimmune studies returned negative/within normal, including ANA, anti-SM, anti-SSA/B, bartonella panel, NDMA/AMPA rec antibodies, Lyme studies, as well as all other interleukin studies. The leading diagnosis was autoimmune encephalitis with potential concurrent hospital delirium. After completing her courses of solumedrol and IVIG, the patient ceased to have continued hallucination episodes, however her headaches and gait concerns persisted. With PT and neurology following, her ataxia appeared more consistent with deconditioning than progressive neurologic disease. With normal MRI and CSF studies, paired with no clear direct trigger on her autoimmune workup, her leading diagnosis upon discharge became seronegative autoimmune encephalitis with concurrent deconditioning ailments.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWith patient’s neurologic status back to baseline, absence of hallucination episodes for over 48 hours, and improvement in ataxia/weakness with PT treatment, the patient was discharged without initiation of antiepileptic drugs (AEDs) or continued steroid management, but rather close follow up with neurology and PT/OT. She was continually evaluated by neurology until she exhibited return to baseline behavior, and she continues to work with PT/OT to date.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThere are several aspects to this case that made it uniquely challenging to workup, the first of which being her initial presentation without focal deficits, abnormal behavior, or concerning initial lab findings. With parasomnias being exceedingly more common than autoimmune encephalitis in this age \u003csup\u003e[2,4]\u003c/sup\u003e, neurologic evaluation was only initiated given her reported abnormal movement episode concerning for seizure-like activity, history of falls, and family history of epilepsy. Additionally, the combination of an abnormal EEG paired with multiple concurrent viruses presented difficulty in delineating neurologic vs. infectious etiologies. While viral encephalitis was considered, the majority of pediatric viral encephalopathies present with one or more prodromal symptoms such as fever, respiratory symptoms, gastrointestinal concerns \u003csup\u003e[10]\u003c/sup\u003e, all of which were absent in this patient. As far as her neurologic course including multiple repeat episodes of hallucination, slurred speech, and weakness/ataxia, it is difficult to determine how many of these symptoms were potentially present prior to her hospitalization (given the reported concerns from her school and episodes at home). With her hospital course being complicated by deconditioning secondary to required intubation and sedation, it is likely a combination of encephalitis and physical deconditioning contributed to her unique symptom course. A diagnosis of exclusion, seronegative autoimmune encephalitis required rapid progression of altered mental status or psychiatric symptoms, a minimum of one additional neurologic abnormality (new seizures, movement disorder, focal deficits), at least one test demonstrating CNS inflammation, while excluding seropositive etiologies \u003csup\u003e[11-12]\u003c/sup\u003e. While the epileptogenic potential from patient’s EEG was unable to be differentiated from new-onset vs. pre-existing, its presence demonstrated signs of inflammation. Additionally, all serum/CSF specific antibodies tested did not demonstrate a clear trigger. Her discrepancy between her elevated IL-2 receptor and normal IL-2 levels suggested underlying immune activation in spite or seronegativity, further supporting SAE \u003csup\u003e[3,13]\u003c/sup\u003e. \u0026nbsp;\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe true start date of the patient’s symptoms remains unclear, however the resolution in her neuropsychiatric symptoms following steroids and IVIG was reassuring. In those adequately treated with steroids and IVIG, studies have found over 90% of patients demonstrate clinical improvement and absence of relapse events after one year \u003csup\u003e[14]\u003c/sup\u003e. Given her significant symptom improvement and continued close neurologic/PT follow up, it is likely her symptoms will continue to improve with time in the absence of continued steroid treatment or AED initiation. That being said, given the high rates of comorbid neurodevelopmental disorders with SAE [7-9], and given her strong family history of autism, the family was contacted following discharge to inform them of this potential connection, along with the recommendations for their pediatrician and neurologist to consider genetic evaluation of not just this patient, but her siblings as well.\u0026nbsp;\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eNDDs\u003c/strong\u003e - neurodevelopmental disorders\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSAE\u003c/strong\u003e - seronegative autoimmune encephalitis\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eED\u003c/strong\u003e - emergency department\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003evEEG\u003c/strong\u003e - video electroencephalogram\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWBC\u003c/strong\u003e - white blood cell count\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRPP\u0026nbsp;\u003c/strong\u003e- respiratory pathogen panel\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLP\u003c/strong\u003e - lumbar puncture\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePICU\u003c/strong\u003e - pediatric intensive care unit\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHFNC\u003c/strong\u003e - high-flow nasal cannula oxygen\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAEDs\u0026nbsp;\u003c/strong\u003e- antiepileptic drugs\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics Approval and Consent to Participate:\u0026nbsp;\u003c/strong\u003eNot Applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication\u003c/strong\u003e: Verbal and written informed consent was obtained from the patient and their parents for any and all aspects of her hospital course and follow ups to be used in the development of this report.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data and Materials\u003c/strong\u003e:\u0026nbsp;The data and lab results incorporated in this report are from the patient’s hospital stay at UNC Children’s Hospital and therefore are not publicly available. Further investigation or interest in these results may be pursued via UNC Children’s Hospital upon reasonable request. Please reach out to the corresponding author for any and all data request needs.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e: The author declares that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: No funding was used in the production of this report.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ Contributions\u003c/strong\u003e: Tyler Beauchamp (TB) was the sole author and contributor to this case report. No other authors were used or aided in the development of this report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e: Not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePetit, Dominique, et al. \u0026ldquo;Childhood sleepwalking and sleep terrors: a longitudinal study of prevalence and familial aggregation.\u0026rdquo; \u003cem\u003eJAMA Pediatrics\u003c/em\u003e, vol. 169, no. 7, 1 July 2015, p. 653, https://doi.org/10.1001/jamapediatrics.2015.127. \u003c/li\u003e\n\u003cli\u003eMaski, Kiran, and Judith A Owens. \u0026ldquo;Insomnia, Parasomnias, and narcolepsy in children: Clinical features, diagnosis, and Management.\u0026rdquo; \u003cem\u003eThe Lancet Neurology\u003c/em\u003e, vol. 15, no. 11, Oct. 2016, pp. 1170\u0026ndash;1181, https://doi.org/10.1016/s1474-4422(16)30204-6. \u003c/li\u003e\n\u003cli\u003eOliv\u0026eacute;-Cirera, Gemma, et al. \u0026ldquo;Differential diagnosis and comparison of diagnostic algorithms in children and adolescents with autoimmune encephalitis in Spain: A prospective cohort study and retrospective analysis.\u0026rdquo; \u003cem\u003eThe Lancet Neurology\u003c/em\u003e, vol. 24, no. 1, Jan. 2025, pp. 54\u0026ndash;64, https://doi.org/10.1016/s1474-4422(24)00443-5. \u003c/li\u003e\n\u003cli\u003eBrisca, Giacomo, et al. \u0026ldquo;Acute pediatric encephalitis: Etiology, course, and outcome of a 12-year single-center immunocompetent cohort.\u0026rdquo; \u003cem\u003eJournal of Neurology\u003c/em\u003e, vol. 270, no. 10, 3 July 2023, pp. 5034\u0026ndash;5047, https://doi.org/10.1007/s00415-023-11847-3. \u003c/li\u003e\n\u003cli\u003eMadani, Jihan, et al. \u0026ldquo;Clinical features and outcomes in children with seronegative autoimmune encephalitis.\u0026rdquo; \u003cem\u003eDevelopmental Medicine \u0026amp;amp; Child Neurology\u003c/em\u003e, vol. 66, no. 10, 15 Mar. 2024, pp. 1310\u0026ndash;1318, https://doi.org/10.1111/dmcn.15896. \u003c/li\u003e\n\u003cli\u003eDou, Qingyang, et al. \u0026ldquo;Clinical characteristics and prognosis of antibody-negative autoimmune encephalitis in children: A single-center retrospective study.\u0026rdquo; \u003cem\u003ePediatric Neurology\u003c/em\u003e, vol. 133, Aug. 2022, pp. 9\u0026ndash;14, https://doi.org/10.1016/j.pediatrneurol.2022.05.007. \u003c/li\u003e\n\u003cli\u003ePanzer, Kira, et al. \u0026ldquo;Retrospective comparison of patients evaluated for pediatric autoimmune encephalitis with typical and atypical premorbid neuropsychiatric development.\u0026rdquo; \u003cem\u003eJournal of Autism and Developmental Disorders\u003c/em\u003e, vol. 55, no. 6, 26 July 2023, pp. 2059\u0026ndash;2066, https://doi.org/10.1007/s10803-023-06065-9. \u003c/li\u003e\n\u003cli\u003eKern, Janet K., et al. \u0026ldquo;Relevance of neuroinflammation and encephalitis in autism.\u0026rdquo; \u003cem\u003eFrontiers in Cellular Neuroscience\u003c/em\u003e, vol. 9, 19 Jan. 2016, https://doi.org/10.3389/fncel.2015.00519. \u003c/li\u003e\n\u003cli\u003eWhiteley, Paul, et al. \u0026ldquo;Autoimmune encephalitis and autism spectrum disorder.\u0026rdquo; \u003cem\u003eFrontiers in Psychiatry\u003c/em\u003e, vol. 12, 17 Dec. 2021, https://doi.org/10.3389/fpsyt.2021.775017. \u003c/li\u003e\n\u003cli\u003ePata, Davide, et al. \u0026ldquo;Diagnosis and therapy of infectious encephalitis in children: A ten-years retrospective study.\u0026rdquo; \u003cem\u003ePediatric Infectious Disease Journal\u003c/em\u003e, vol. 40, no. 6, 10 May 2021, pp. 513\u0026ndash;517, https://doi.org/10.1097/inf.0000000000003070. \u003c/li\u003e\n\u003cli\u003e\u0026ldquo;Pediatric acute-onset neuropsychiatric syndrome (PANS): Clinical report.\u0026rdquo; \u003cem\u003ePediatrics\u003c/em\u003e, vol. 155, no. 3, 24 Feb. 2025, https://doi.org/10.1542/peds.2024-070334. \u003c/li\u003e\n\u003cli\u003eCellucci, Tania, et al. \u0026ldquo;Clinical approach to the diagnosis of autoimmune encephalitis in the pediatric patient.\u0026rdquo; \u003cem\u003eNeurology Neuroimmunology \u0026amp;amp; Neuroinflammation\u003c/em\u003e, vol. 7, no. 2, Mar. 2020, https://doi.org/10.1212/nxi.0000000000000663. \u003c/li\u003e\n\u003cli\u003eZhang, Yiwei, et al. \u0026ldquo;Interleukin-2 and its receptors: Implications and therapeutic prospects in immune-mediated disorders of central nervous system.\u0026rdquo; \u003cem\u003ePharmacological Research\u003c/em\u003e, vol. 213, Mar. 2025, p. 107658, https://doi.org/10.1016/j.phrs.2025.107658. \u003c/li\u003e\n\u003cli\u003eKim, Hye J, et al. \u0026ldquo;Clinical features and outcomes of paediatric probable antibody‐negative autoimmune encephalitis.\u0026rdquo; \u003cem\u003eDevelopmental Medicine \u0026amp;amp; Child Neurology\u003c/em\u003e, vol. 67, no. 10, 19 Aug. 2025, https://doi.org/10.1111/dmcn.16491. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Seronegative autoimmune encephalitis, parasomnias, night terrors, encephalopathy, pediatric emergencies","lastPublishedDoi":"10.21203/rs.3.rs-8291199/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8291199/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: While most children presenting with undifferentiated nightmare-like symptoms may commonly suffer from conditions like parasomnias or neurodevelopmental disorders (NDDs), clinicians must not forget to consider exclusionary diagnoses like seronegative autoimmune encephalitis (SAE).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase Presentation\u003c/strong\u003e: This case presents a 4-year-old girl with acute visual hallucinations, an episode of unresponsiveness with shuffling movements, and a month-long history of increased falls and intermittent slurred speech. Although having no presenting deficits, her history of hallucinations and abnormal movements prompted further neurologic evaluation. During her hospital course, she developed a multitude of new concerning features including hallucinations, slurred speech, and new ataxia, along with a vEEG revealing left parietal slowing with interictal epileptiform discharges.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: While MRI and CSF studies—including autoimmune panels—were normal, she was treated empirically with IV steroids and IVIG for suspected seronegative autoimmune encephalitis. Prior to discharge, autoimmune serum testing revealed elevated IL-2 receptor and IL-6 levels, supporting an inflammatory process despite seronegativity. Following treatment, her hallucinations resolved and gait deficits steadily improved with therapy. This case demonstrates the diagnostic complexity of SAE in young children with nonspecific neuropsychiatric symptoms as well as the vitality of maintaining broad differential approaches in an emergency setting.\u003c/p\u003e","manuscriptTitle":"“Hopping Mad” 4-year-old: frog hallucinations or encephalitis?","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-18 17:51:32","doi":"10.21203/rs.3.rs-8291199/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-01-30T13:08:32+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-25T03:13:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"82840282336214522116033643490618728976","date":"2026-01-25T02:01:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"164248925649547829039068625895246671394","date":"2026-01-21T14:20:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"222748133734612903010890123559546058952","date":"2026-01-19T11:18:22+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-17T15:21:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"182639801240668819971394513675051930227","date":"2026-01-17T15:12:18+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-14T10:26:20+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-13T03:23:16+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-17T06:18:29+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-16T19:31:35+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2025-12-16T16:42:01+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"45fc4d6d-4bb0-4cf1-b145-eb21738acdd6","owner":[],"postedDate":"January 18th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-01-18T17:51:32+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-18 17:51:32","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8291199","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8291199","identity":"rs-8291199","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}