Seventeen-Year-Old Female With History of Depression Presented With Mania and Enuresis

A 17-year-old girl with a history of major depressive disorder presented to the emergency department (ED) with increasingly erratic behavior for 2 weeks. Her depression had been in remission after a course of cognitive behavioral therapy without pharmacotherapy, and she was no longer in treatment. She had been engaging in unusual behaviors, including baking in excessive quantities, making candles, dying her hair with coffee, and swimming alone while wearing clothes. She had also been involved in unsafe behaviors, including mixing chemicals, lighting matches in her room, leaving pots in the oven or on the burner, picking up broken glass with her bare hands, and leaving her house with an uncharged phone, resulting in getting lost. These behaviors made her parents concerned about her safety. She had been sleeping only 2 to 4 hours a night but felt energized in the morning. A few days before presentation, in an unsuccessful attempt to treat her insomnia, she took 10 tablets of melatonin, 1 sleep aide, and 5 tablets of ibuprofen. She refused to wear feminine pads because “they were uncomfortable” and subsequently caused blood-soaked sheets. She had episodes of overeating to the point that she had emesis but at other times had decreased appetite and skipped meals. She was seen by her psychologist a few days before her presentation, and her psychologist expressed concerns for hypomania and scheduled a follow-up appointment with a psychiatrist in one week for possible medication initiation.

The day before presenting to the ED, she had 3 episodes of urinating on herself, which prompted her initial ED visit. When asked, she initially said she did not know why she had urinated. On further discussion, she reported she knew she needed to urinate but did not want to go to the bathroom, so she urinated in her bed.

In the ED, she denied any suicidal or homicidal ideation. She reported that she was attempting to pick up new hobbies because she was “bored” owing to social distancing throughout the coronavirus disease 2019 (COVID-19) pandemic. She did not believe that she was being unsafe. She felt her depression had improved. She was using oral contraceptive pills for acne for a few months but stopped taking them a few weeks ago because of heavier menstrual periods, worsening acne, and headaches.

She denied any other past medical or surgical history. No allergies or medications were reported. She was up to date on her vaccinations. She was living with her parents and younger brother. She was attending 11th grade and achieving high grades in advanced classes. In a confidential interview, she denied ever using alcohol or recreational drugs, smoking cigarettes, or being sexually active. Her vital signs were normal, and her physical examination result was unremarkable. She was alert, conversant, and well appearing. Specifically, for her neurologic examination, she was oriented to time, place, and person. Cranial nerves II to XII were intact. Her motor strength was 5 of 5 in upper and lower extremities bilaterally, with normal reflexes and no abnormal movements or tone. Light touch sensation was intact on buttocks and legs. No ataxia or hyperkinetic movements were observed. She had a normal gait and heel to toe examination and was able to balance on each leg independently.

Dr Yoshida, what was your initial assessment of this patient? What differential diagnosis did you consider? What initial workup did you do?

The patient was well appearing and conversant throughout her ED stay. Given her recent uncharacteristic behaviors, decreased sleep along with increased energy, and evaluation by her primary psychologist, we were concerned for manic behavior. With her history of depression and new manic-type behaviors, a psychiatric etiology, such as bipolar disorder, was high on the differential, although this is not a diagnosis we can typically make in the ED setting. Ingestion or intoxication was also on the differential given reports of taking medications to help her sleep. Neurologic deficits, underlying metabolic derangements, urinary tract infection, diabetes mellitus, and diabetes insipidus were also considered given her new episodes of enuresis. We initiated a broad workup, which included a complete blood cell count and differential, complete metabolic panel, and urinalysis. To evaluate for possible ingestion, a urine toxicology screen, measurement of acetaminophen and salicylate levels, and an electrocardiogram were done. Laboratory study results were overall reassuring and unrevealing. Results of rapid COVID-19 polymerase chain reaction and serum β human chorionic gonadotropin testing were negative. She remained hemodynamically stable and calm but had an episode of urinary incontinence in the ED. She continued to have a normal neurologic examination result, without saddle anesthesia or focal neurologic deficits. Given her unusual behaviors and concerns for her safety at home, we asked our mental health team to evaluate her further.

Per routine ED process, after being medically cleared with a reassuring physical examination and laboratory workup, the patient went through a mental health evaluation. Ms McElearney, what was your assessment of this patient from the mental health standpoint?

Individual interviews were conducted with the patient, her parents, and her psychologist, who had known her for years. The parents were understandably concerned about the personality change and lack of insight into the dangerous consequences of her behaviors. The patient occasionally expressed a “sense of euphoria” and feeling energetic despite poor sleep but also seemed unusually flat and withdrawn at times. Her psychologist indicated that the patient was not a risk taker and this behavior was unusual for her. Her depression had been stable, and appointments had been on an as needed basis over the past year. Given her relatively rapid decline in function and significant impairments with activities of daily living, combined with parental concerns for her safety at home, the team recommended admission for acute inpatient psychiatric evaluation and management.

Drs Kim and Kodish, what was your initial inpatient evaluation for this patient? What treatments were initiated?

The patient had been working with a psychologist for treatment of depression for the past 3 years and reportedly was in remission for 5 months. She presented with a recent increase in goal-directed activities (such as making candles and cupcakes and participating in social protests), erratic behavior, decreased sleep, and poor judgement over the past 2 weeks. The patient denied having perceptual disturbances or grandiose or paranoid delusions yet did endorse anxiety around natural disasters. She corroborated having felt hyperactive recently, with racing thoughts, increased energy, and reduced amount of sleep in the past week. This was most suggestive of acute mania with a working diagnosis of bipolar 1 disorder. The patient reported her mood was “back to normal” soon after admission and denied feeling depressed or elated. However, she continued to have urinary incontinence and persisting alterations in social and emotional functioning.

We initially elected to monitor the patient without prescribing medication. Individual therapy was focused on diagnostic formulation, psychoeducation, the development and reinforcement of emotion regulation, and distress tolerance skills.

On the second day of the admission, we discussed starting a mood stabilizer with the patient and parents, and aripiprazole was started at 4 mg/day. Her overall functioning remained variable but significantly impaired compared with baseline. She was noted to have polydipsia and polyuria, with continued episodes of urinating on herself and the floor and having “water-like” urine. Because of these physiologic concerns and a sense that her constellation of impairments was not entirely consistent with mania, further medical workup was pursued. Brain MRI was ordered to assess for intracranial pathologies. Infectious disease was consulted over the phone. Infectious encephalitis or meningitis and intracranial abscess were considered but were considered less likely because of her overall well appearance, supple neck, nonfocal neurologic examination results, and lack of elevated inflammatory markers. Neural larva migrans (Baylisascaris roundworm) was also considered, but this was felt to be unlikely because of low prevalence and lack of eosinophilia.

On the third day of admission, brain MRI revealed “multiple hyperintensities with adjacent enhancement involving right frontal cortex and subcortical lesions along the right lateral ventricle involving the white matter in the medial temporal lobe” (Fig 1). With this new finding, pediatric neurology was consulted, and the patient was transferred to the pediatric neurology inpatient service on day 4 of her hospitalization.

Dr Novotny, what was on your list of differential diagnoses? What next steps were taken for diagnosis and management?

Typical first steps in evaluation of neurologic disease as a cause of psychiatric symptoms may include multiple assessments such as serial neurologic examinations, clinical neurophysiologic testing, including EEG, or functional imaging, such as fluorodeoxyglucose-positron emission tomography or single-photon emission computed tomography, in addition to structural imaging (MRI) and laboratory assessments (testing of serum, urine, and cerebrospinal fluid [CSF] for metabolic, toxic, infectious, and immunologic causes).

In her case, the brain MRI scan revealed T2 hyperintensities in the right frontal cortex and subcortical lesions in the temporal lobe as well as the limbic system. Our initial differential included autoimmune encephalitis, paraneoplastic disease, infectious encephalitis, and demyelinating disease. The neurologic examination result at the time of consultation was nonfocal. The initial laboratory workup revealed a slightly elevated erythrocyte sedimentation rate, a normal C-reactive protein level, and positive antinuclear antibody levels. A lumbar puncture revealed normal opening pressure, a normal CSF cell count, and normal glucose and protein levels. Oligoclonal band cells were positive, which was suggestive of an inflammatory process.

Because autoimmune encephalitis can be paraneoplastic, a pelvic ultrasound was obtained to evaluate for the presence of an ovarian teratoma. This study result was normal. CSF and serum panels for antineuronal antibodies were sent to look for antibodies associated with autoimmune encephalitis. EEG was recorded for 33 minutes, including during sleep and while the patient was awake, and was normal. Although a definite diagnosis had not been confirmed, she was started on a 5-day course of high-dose steroids for probable autoimmune encephalitis. Corticosteroids were specifically selected because high-dose steroid is the first choice of treatment of suspected autoimmune encephalitis.¹  Aripiprazole was stopped. Her symptoms started to improve with intravenous steroids, and she was discharged on the sixth day of admission with 2 additional days of high-dose oral steroids followed by a steroid taper and close outpatient monitoring. Intravenous immunoglobulin (IVIG) treatment was considered but deferred on the basis of her symptomatic improvement. Four days after discharge, her antibody panels resulted positive for N-methyl-D-aspartate receptor (NMDAR) antibody both in the serum and CSF, and she was diagnosed with anti-NMDAR encephalitis (Table 1). On the basis of the demyelination seen on MRI, she was given the diagnosis of anti-NMDAR encephalitis with acute demyelination, which is a known overlapping condition.² 

The family contacted the pediatric neurology office ∼1 week after discharge. Although she initially improved after discharge, she had worsening insomnia and agitation. She also had a recurrent episode of urinary incontinence after being continent during her first admission. The patient was advised to return to the ED.

Dr Yoshida, how was the patient’s presentation to the ED the second time?

Her parents reported that her erratic behaviors had improved, but her other symptoms had worsened. She was having episodes of confusion, memory loss, and word finding difficulties. She was agitated after receiving steroid doses. She denied alcohol or recreational drug use. Her vital signs were normal. She was alert and oriented to time, place, and person. She was frequently confused about the events of the past week, repeatedly asking why they were back in the hospital and was upset and distressed by her memory loss and insomnia. The rest of her physical examination was normal. Her complete blood cell count and complete metabolic panel were unrevealing. The concern was that symptoms of underlying autoimmune encephalitis were being exacerbated by steroids, insomnia, and possible additional psychiatric components. She was admitted to the pediatric neurology service for her worsening impulsivity, agitation, and safety.

Drs Kochar and Otten, what were the next steps taken for the treatment?

Despite completing first-line treatment with high-dose steroid therapy before this admission, she continued to experience worsening symptoms. In postpubertal patients, anti-NMDAR encephalitis is commonly associated with malignancies, which are most often, but not limited to, ovarian teratomas.³  Computerized tomography findings of the chest, abdomen, and pelvis were negative for malignancy. In patients who fail to respond to treatment, ongoing tumor surveillance is appropriate, especially in postpubertal women in whom there is a high rate of associated ovarian teratoma.¹  She also had acute demyelination at the time of her first presentation; thus, brain MRI was repeated, which revealed improvement of the initial demyelinating lesions in her brain. Spine MRI was added to the workup, which revealed a T2 hyperintense thoracic cord lesion consistent with spinal cord demyelination. Patients with anti-NMDAR encephalitis are at high risk for seizures, and so an EEG was repeated, which revealed no epileptiform charges but now had a highly abnormal background with nearly continuous bifrontal slowing, diffuse δ activity, and rare δ brushes consistent with encephalopathy and specifically with anti-NMDAR encephalitis.⁴ 

She had clinical progression on steroids, so we escalated her immunotherapy. She was treated with IVIG at 2 g/kg over 48 hours. Despite this, she continued to demonstrate worsening sleep dysregulation, hallucinations, and increasing delusional thinking requiring one-to-one sitter observation during most of the admission. Two weeks after IVIG was started, she received second-line treatment with rituximab at 1000 mg for 2 doses, 2 weeks apart. Her memory loss, confusion, and insomnia gradually improved, and she was discharged after 29 days of admission. After discharge, she continued to receive monthly maintenance IVIG at 1 g/kg for 5 months. At her clinic visit 5 months later, she reported she was 95% back to her baseline. Both the patient and mother described the improvement as a “miracle.”

A 17-year-old girl with a history of depression presented to the ED with mania and enuresis and was ultimately diagnosed with anti-NMDAR encephalitis with overlapping cerebral demyelination.

Drs Tunc and Yoshida, as pediatric emergency medicine providers, what are some considerations to keep in mind when approaching patients with mental health concerns in the ED?

Pediatric ED visits for mental health concerns have been increasing over time.⁵  During the COVID-19 pandemic, the proportion of mental health visits increased among all pediatric ED visits.⁶  This patient’s previous history of psychiatric disease, along with a reassuring physical examination, perhaps led us to consider a psychiatric etiology highly in our differential initially. This case reminds us that we must carefully consider both psychiatric and organic etiologies for these patients. Symptoms often evolve over time, and a single ED visit may not be enough time to make a diagnosis. Thus, for patients presenting with mental health concerns, perhaps the most important part of the visit is to have a safe disposition. As ED providers, we feel more comfortable when a patient is admitted because this guarantees continued evaluation. In this patient’s case, urinary incontinence was an unusual symptom, which led to a urinalysis to rule out urinary tract infection and repeated clinical assessments in the ED. The inpatient psychiatric team also continued a medical workup in conjunction with providing psychiatric care. For patients who are discharged, it is imperative that families have a safe discharge plan and close follow-up with an outpatient provider. Quality handoffs should be done with outpatient providers regarding the interventions in the ED and recommended follow-up. It is essential to partner with subspecialists and outpatient providers to ensure continued care of the patient.

Drs Kim and Kodish, what are your recommendations to ED physicians, primary care providers, and pediatric hospitalists when evaluating mental health complaints?

Psychiatric presentations in youth are often complex and challenging because neurophysiologic abnormalities can contribute to a range of emotional and behavioral impairments. Comprehensive care requires extensive emergency health resources with broad attunement to the potential impact of impairments in pain, sleep, nutrition, and inflammation. The COVID-19 pandemic has dramatically amplified our ongoing mental health pandemic, imposing even more barriers to in-person engagement typically offered by schools and outpatient agencies, which has resulted in greater use of emergency care.⁷  Although the utility of screening laboratory tests for psychiatric presentation to pediatric ED settings is felt to be limited,⁸  uncommon neuropsychiatric symptoms and heterogeneous psychiatric profiles call for heightened vigilance to underlying medical and neurologic etiologies. For example, inborn errors of metabolism may present later in life with isolated neuropsychiatric symptoms, such as mood, anxiety, and learning and cognition problems, especially during times of stress or physiologic change. A time of onset for many inborn errors of metabolism associated with psychiatric symptoms is puberty.⁹ 

Although there is no distinct phenotype for psychiatric symptoms associated with anti-NMDAR encephalitis, the presentation often includes cognitive deficits in executive function, which compromise memory, language, attention, sleep, and mood regulation. Given the extent of impairments in cognitive processing, delusions and hallucinations are also common, particularly early in the course of illness.^10,11  Unsurprisingly, up to 77% of the patients with anti-NMDAR encephalitis are initially referred to psychiatry.¹²  Another study revealed that 40% of the patients were initially admitted to inpatient psychiatry settings, although the majority also showed neurologic symptoms at first evaluation.¹³  Definitive management is often hampered by delay in results of laboratory tests, and patients and families understandably struggle with the initial uncertainty around diagnosis to firmly guide treatment decisions and optimal care settings.

Pharmacologic management can be particularly challenging in anti- NMDAR encephalitis because antipsychotic agents can exacerbate symptoms and clinical improvement is felt to rely heavily on the overall recovery course of the inflammatory illness.¹⁴  Therefore, medication management is generally reserved for acute agitation, with the goal of restoring primary brain functions through sleep regulation and gradually advancing daytime behavioral activation in a highly predictable and structured setting.

This patient perseverated on the meaning of her diagnosis and attributed her impairments to having a “bad brain.” She then became preoccupied with her body parts not truly belonging to her and needed frequent reminders of her need to be in the hospital. As her agitation worsened to include inconsolable preoccupations and intermittent efforts to leave the room, quetiapine was started. Trazodone was also used for sleep impairments. Both medications were timed in an effort to gradually optimize daytime alertness.

Engaging patients through approachable schedules offered by psychosocial service clinicians that incorporate rehabilitative physical and occupational therapies, as was done for this patient, can be critical to help scaffold motor and cognitive capabilities. Encephalitis is thought to compromise pathways regulating communication and motor planning, so supporting these basic processes can help facilitate neuroplasticity and bolster the recovery of social and emotional functions underlying psychiatric health.¹⁵ 

Drs Kochar, Novotny, and Otten, what are the clinical characteristics and management of anti-NMDAR encephalitis?

Anti-NMDAR encephalitis is an antibody-mediated autoimmune encephalitis that has been increasingly recognized in the past decade. It may be the most common cause of autoimmune encephalitis in children. In the California Encephalitis Project, it was the most frequently identified cause of encephalitis, more common than any single virus.¹⁶  A significant proportion of the cases are paraneoplastic and are most often associated with teratomas.¹⁷  Herpes simplex encephalitis has been correlated with the development of NMDAR antibodies.¹⁸  Patients have been reported to develop anti-NMDAR encephalitis after viral encephalitis.¹⁹  Screening for associated malignancy is essential in all patients suspected with the disease, particularly postpubertal patients.^12,20  Onset may include subacute psychiatric symptoms in adolescents and adults, but in children <12 years old, it is more likely to include language regression and abnormal movements.^21,22  Symptoms can include psychosis, encephalopathy, hyperkinetic movement disorder, weakness, ataxia, status epilepticus, and focal seizures with alteration in awareness often with frontal and temporal lobe clinical semiology.⁴  Patients can rapidly develop autonomic dysfunction and severe encephalopathy, with a large portion requiring critical care.²³  Examination findings may reveal encephalopathy and hyperkinetic movement disorders. In particular, orofacial dyskinesias in anti-NMDAR encephalitis appear like exaggerated facial expressions.¹²  Urinary incontinence has also been described as part of autonomic dysfunction, along with hypersalivation, diaphoresis, pallor, or flushing.¹⁰  Patients can also experience blood pressure fluctuations (including hypotension or hypertension), hypoventilation, heart rate changes, or arrhythmias that require intensive care.²³  The initial symptom development can be subacute, which makes diagnosis challenging.¹¹ 

Specific EEG findings, including the δ brush pattern, as seen in this patient, support the diagnosis.⁴  Her initial EEG was reviewed after the diagnosis and was a limited <40-minute study with the patient awake during the majority of the recording. The lack of the EEG finding in the initial EEG may have been due to sampling error. It is not known how this finding is related to the course of the disease, state of the patient (awake, drowsy, and depth of sleep), and influence of medications. This is an aspect of the disorder that requires further investigation. In this particular case, there were changes in medications (initiation of steroid treatment) that may have influenced this finding. δ brushes are a normal EEG finding in premature infants. There are reports that these extreme δ brushes may represent ictal (seizure) patterns. There are ongoing studies and reports that this feature may be an important biomarker for disease progression and severity.²⁴  MRI findings can include nonspecific inflammation but are often absent or, less commonly, may include demyelination, as in this patient.²  Treatment often must be started before a definitive diagnosis can be made with detection of anti-NMDAR antibodies in the CSF. Early recognition and treatment are important for better outcomes.³  Collaboration between psychiatry and neurology is often essential to help patients receive rapid medical evaluation when their psychiatric symptoms are not consistent with a primary psychiatric disease.

First-line treatment with high-dose IV steroids is commonly followed by a long oral steroid taper. Therapeutic plasma exchange can be added to acutely remove antibodies. Alternatively, IVIG could be used as an adjunctive first-line therapy, especially if access to therapeutic plasma exchange is not available. Escalation to second-line treatments is undertaken rapidly if improvement is not seen, and these may include rituximab (B cell–depleting agent) or cyclophosphamide. In a large observational study, 57% of patients received second-line immunotherapy after first-line therapy with either steroids, IVIG, or plasma exchange given alone or in combination.³  If still refractory, tocilizumab may be used.¹  If a tumor is present, urgent tumor resection is indicated.³  Immunosuppression may be needed for months to years depending on the response to treatment.¹ 

Supportive care is essential, including behavioral management for agitation, pharmacologic treatment including benzodiazepines or antiepileptics for hyperkinetic movements, and antipsychotic agents for psychosis and agitation.²⁵  ICU management is often needed for those with status epilepticus, refractory hyperkinetic movements, or severe autonomic dysfunction, such as hypoventilation or cardiac arrhythmia.²³  During recovery, multidisciplinary care is important and can include psychiatry, pediatric neurology, occupational therapy, physical therapy, speech and language therapy, and rehabilitation medicine.²⁶  Coordination with school, including appropriate accommodations, is important, as well as support from neuropsychology for ongoing cognitive symptoms.²⁷ 

The prognosis includes a wide range of outcomes after acute hospitalization and treatment. In severe cases, intensive care and prolonged rehabilitation require longer hospital stays. In rare cases, patients may not survive the disease.²⁸  When symptoms improve, it is often after weeks to months of treatment, and it is reported that 15% of patents will relapse.^1,3,26  Patients can be left with residual cognitive symptoms but may also have epilepsy, mood disorders, weakness or spasticity, or incomplete recovery with ongoing movement disorder and encephalopathy despite treatment.¹¹  In general, early recognition with rapid treatment, including tumor resection if indicated, is associated with better outcomes.³ 

We reported a case of a patient who presented to the ED with unusual behavioral impairments and enuresis and was eventually diagnosed with anti-NMDAR encephalitis as her symptoms evolved. It is important to keep a broad differential and to consider anti-NMDAR encephalitis when evaluating patients with atypical mental health complaints and behavioral changes. Treatment involves immunotherapy and managing behavioral symptoms. A multidisciplinary team including neurology, psychiatry, neuropsychology, occupational therapy, physical therapy, and speech and language therapy plays a critical role in achieving better outcomes.

We thank Sandra Lynn McElearney, LICSW, for her outstanding care of this patient.

COVID-19

coronavirus disease 2019

CSF

cerebrospinal fluid

ED

emergency department

IVIG

intravenous immunoglobulin

NMDAR

N-methyl-D-aspartate receptor