CSF studies which ultimately led to the possible diagnosis of anti-NMDAR encephalitis

Abstract

A 17-year-old man with no significant medical history presented with new-onset seizure activity and altered mental status manifesting as bizarre behaviour, which included rapid pressured and tangential speech, psychomotor agitation, insomnia and delusions. He also had autonomic dysregulation, manifested in labile blood pressures. He had been recently discharged from his first psychiatric hospitalisation. Many studies were performed, including electroencephalogram (EEG), head CT, laboratory work, urine drug screen and lumbar puncture with cerebral spinal fluid studies, which ultimately led to the diagnosis of anti-N-methyl-D-aspartate receptor (NMDAR) autoimmune encephalitis. He was treated with five rounds of plasmapheresis with complete resolution of his altered mental status. This case highlights the importance of being familiar with the presentation of anti-NMDAR autoimmune encephalitis, especially in cases of new-onset mental status changes with psychotic like symptoms, seizure-like activity and autonomic dysregulation as early detection and treatment improves chances of good prognosis with return to baseline cognitive function.

Background

Anti-N-methyl-D-aspartate receptor (NMDAR) autoimmune encephalitis is a rare but potentially reversible autoimmune encephalitis syndrome that presents with a predominance of psychiatric symptoms, seizure-like activity and autonomic dysregulation. While it has been reported that anti-NMDAR encephalitis is the most common antibody-associated encephalitis, the exact incidence of the disorder is unknown.¹ One large series of anti-NMDAR encephalitis found 37% of patients were under 18 years of age and over 80% of cases were women.² In patients greater than 18 years of age, around 50% have an underlying tumour, most commonly ovarian teratoma. Only 5% of men greater than 18 years of age have an identifiable tumour.³ It is particularly important for primary care physicians, emergency room physicians and psychiatrists to be aware of the clinical manifestations of this entity as early recognition and treatment ensures good prognosis and return to baseline cognitive function.

Case presentation

A 17-year-old previously healthy man initially presented to the emergency department of an outside facility with his parents for evaluation of altered mental status. His parents noted the sudden onset 2 days previously of bizarre behaviour at home, including rapid pressured and tangential speech, psychomotor agitation, insomnia and delusions. Prior to presentation he had been in his usual state of health, specifically without fevers or recent illness and no recent psychological stress. He had an unremarkable work up, including normal labwork (consisting of a metabolic panel, thyroid studies, complete blood count, urinalysis, serum alcohol and acetominophen levels, and urine drug screening), cerebral spinal fluid (CSF) studies for infection, and CT of the head. He was transferred to a nearby adolescent psychiatric unit for new-onset psychosis. He had some minimal improvement, although refused any antipsychotic agents and after 4 days was discharged home against medical advice at his parents request on no medications. After 2 weeks, he gradually returned to near baseline, but was still a bit fatigued with reduced concentration.

Four weeks after discharge, he returned to the emergency department following seizure-like activity described as generalised jerking movements of all four extremities that lasted about 3 min with no associated bowel or bladder incontinence. His parents reported that 2 days prior to this, he had again become altered with tangential thinking and confused responsiveness and had been unable to sleep. Prior to symptom onset, he was a high-functioning, high-achieving child with no known drug use. He had no known family history of mental illness or seizure disorder.

On arrival to the emergency department, he was awake and alert, but uncooperative with questioning and examination and unable to follow simple commands. His mental status waxed and waned from a catatonic state to inappropriate laughing and unintelligible language. His vital signs were most notable for labile blood pressures with systolic blood pressures ranging from 80s to 160s. He was hypertonic with flexed extremities. Physical examination was otherwise unremarkable. He was admitted to a general medicine service for further evaluation of possible new-onset seizure disorder and psychiatric illness.

Investigations

A repeat CT and MRI of the head were negative for intracranial pathology. Three days of continuous electroencephalogram (EEG) on admission was abnormal and revealed posterior dominant rhythm and excessive admixed slowing, though a component of artefact could not be excluded.

Extensive laboratory workup was notable for positive antinuclear antibody (ANA) 1:80 speckled, elevated von Willebrand factor antigen and activity and elevated serum acetylcholinesterase antibodies (ACE) 54 U/L (8–53) with normal CSF ACE. Serum NMDAR Antibody (Ab) testing using cell-based assay was positive, suggestive of anti-NMDAR encephalitis. Other laboratory findings included C reactive protein (CRP) of 1.2 mg/dL and erythrocyte sedimentation rate (ESR) of 5 mm/hour, which were normal. Serum testing for thyroperoxidase Ab, extractable nuclear antigen (ENA) screen, double stranded DNA, rheumatoid factor (RF), thyroid stimulating hormone (TSH), ceruloplasmin, C3/C4, porphyrins profile, gamma-aminobutyric acid antibodies, bath salts and synthetic cannabinoids, serum copper, zinc, B₁₂, ferritin, vitamin E and methylmalonic acid were all negative. CSF IgG, albumin, paraneoplastic panel and oligoclonal bands were all normal. Urine organic acids and toxicology screen were all normal. Infectious workup, including serum hepatitis B and C serologies, HIV, human T-cell leukemia virus (HTLV), mycoplasma, Bartonella and enterovirus were normal. CSF infectious testing of arbovirus, enterovirus, human herpesvirus 6 (HHV6) PCR, herpes simplex virus 1 and 2 (HSV-1 and HSV-2), and cultures were negative. CSF NMDAR Ab using cell-based assay was negative.

For evaluation of his labile blood pressures, he had an echocardiogram, serum vanillylmandelic acid level and homovanillic acid level, which were all normal. After the diagnosis of anti-NMDAR encephalitis was made, he had a positron emission tomography (PET) scan to evaluate for an underlying tumour as the source of anti-NMDAR antibodies, which did not reveal an underlying tumour and there were no brain abnormalities.

Differential diagnosis

Initially, our differential diagnosis of his bizarre behaviour was primary psychiatric disease, including depression, bipolar disorder, childhood-onset schizophrenia or brief reactive psychosis. His age of 17 was consistent with the common age onset of psychotic disorders rarely occurring before age 14, but showing a marked increase in prevalence between ages 15 and 17 years.⁴ Drug exposure was also considered, but this was less likely as his urine drug screen was negative as well as more specific testing for bath salts or synthetic cannabinoids. In addition, he continued to display symptoms in a controlled hospitalised environment, where repeat ingestion was unlikely.

We were able to exclude other medical causes of altered mental status and seizure-like activity such as epilepsy, metabolic causes, infection, mass lesion, head trauma and hypertensive emergencies, such as posterior reversible encephalopathy syndrome, given negative head imaging and CSF cultures with non-specific EEG findings of slowing. In addition, his laboratory results testing for toxic metals, vitamins, infectious sources and porphyrins all returned negative.

We initially suspected agitation as the cause of his labile blood pressures, given his presentation with psychosis and altered mental status. We also considered secondary hypertension, as the patient was young and thin, and had an acute rise in blood pressure above a previously stable baseline, but the patient had a normal cardiovascular physical examination, basic metabolic panel, echocardiogram, serum vanillylmandelic acid level and homovanillic acid level. The lability of his blood pressure that persisted despite waxing and waning agitation led to us consider autonomic dysregulation, which is common in anti-NMDAR encephalitis. A psychiatric cause was less likely, as there was no prodromal period of deteriorating functioning prior to the onset of psychotic symptoms; he had no previous psychiatric history and no family history of mental illness. The sudden onset of altered mental status, bizarre behaviour, seizures and autonomic dysregulation led us to consider anti-NMDAR encephalitis in the differential.

Clinical manifestations of the late phase of illness, including autonomic dysregulation and catatonia, can be confused with neuroleptic malignant syndrome, as this condition also presents with autonomic dysregulation and catatonia following the administration of antipsychotics.^{5 6} Patients with anti-NMDAR encephalitis have often received typical antipsychotics in attempt to stabilise psychiatric symptoms making it important to differentiate between these diagnoses as treatments are different.

Treatment

Paediatric neurology and psychiatry were consulted early in his admission for assistance with diagnosis and recommendations for treatment. Olanzapine and other atypical antipsychotics are preferred medications for stabilisation of psychiatric symptoms in anti-NMDAR encephalitis, as they have a lower risk of extrapyramidal symptoms.⁷ He was treated initially with intramuscular olanzapine 2 mg as needed, which was changed to oral olanzapine 2.5 mg two times per day. He became calmer and more cooperative, but remained confused with mumbling and unintelligible speech.

First-line therapies include corticosteroids, intravenous immunoglobulin and plasma exchange (PLEX) therapy.⁸ While studies have not demonstrated a preferred regimen, first-line treatments are often used in conjunction. The options were presented to the patient’s family, who decided to move forward with plasmapheresis. He underwent five rounds of plasmapheresis over the course of 10 days. He tolerated the procedure well with complete resolution of psychosis and return to baseline mental status. After PLEX therapy, he had a repeat EEG, which showed no slowing, indicating response to PLEX therapy. Olanzapine was slowly tapered prior to discharge without return of psychosis. He had no further seizures, so he was not started on antiepileptic drugs.

Outcome and follow-up

The patient completed five rounds of plasmapheresis, with immediate resolution of psychosis after his third round. He had no further seizure like episodes and at discharge was back to his cognitive baseline. He continued outpatient follow-up with neurology and primary care every 2 months and had occasional headaches, fatigue, and some mental slowing with trouble with memory, attention, and concentration. Despite this, he was able to function well in school and socially.

He continued to have labile blood pressures up to 8 months after his plasmapheresis when they normalised. His anti-NMDAR antibodies remained positive at 2 months after discharge, but when repeated 20 months after discharge were negative.

He successfully graduated from high school and then college. At the time of contact in writing this article, our patient has graduated from college and reports he has had no recurrences of anti-NMDAR encephalitis and his issues with memory, concentration and attention have completely resolved.

Discussion

Antibody-mediated or autoimmune encephalitis refers to a group of inflammatory brain diseases characterised by prominent neuropsychiatric symptoms in the setting of autoantibodies against the central nervous system.⁹ Some reports suggest that anti-NMDAR encephalitis incidence may be higher than any individual viral encephalitis.^{1 10}

In anti-NMDAR encephalitis, IgG autoantibodies develop against the GluN1 subunit of the NMDAR.^{9 11} The aetiology that leads to the formation of these autoantibodies is not well understood. The confirmatory diagnostic test for autoimmune encephalitis is through detection of autoantibodies in serum and CSF, with the gold standard being detection in CSF. Gresa-Arribas et al found at the time of diagnosis that the sensitivity of anti-NMDAR Ab in CSF is 100%, which is higher than the 85.6% sensitivity for serum (95% CI 9.6% to 18.0%); both titres have a specificity of 100%.¹² In addition, this study found through testing serum and CSF titres at 3–4 months after diagnosis and again at final follow-up (there was a variable time range among their subjects with a median of 12.5 months, and IQR of 8.8–20.1 months) an early decrease of CSF antibody titres during the first months of the disease correlated with good outcome.¹² In our patient, CSF and laboratory findings were obtained after 6 weeks of symptom onset and anti-NMDAR antibodies were negative in his CSF but positive in his serum, thus leading one to believe that it is possible that antibody levels in our patient’s CSF had declined as CSF anti-NMDAR antibodies were not obtained until almost 2 months after symptom onset. It is also possible that the serum anti-NMDAR Ab was a false positive, although the patient met criteria for probable anti-NMDAR encephalitis (see below) responded to treatment with plasmaphereisis, and after 5 years has completed college with no further episodes of psychosis. In addition, Gresa-Arribas et al found that CSF and serum titres were higher in patients with poor outcomes and with teratomas, which may also explain why our patient had undetectable anti-NMDAR CSF antibody titres, as he had an excellent outcome with no evidence of associated malignancy. It is possible that serum antibodies have the ability to persist, as also documented in a case report that demonstrated a patient whose serum antibodies remained positive after 4 years, despite clinical improvement and normal brain imaging. This author proposed serum antibodies may remain positive given B cell clones, which remain positive in peripheral lymphoid tissue to remain capable of triggering an immune response.¹³ We performed an extensive literature review to look for cases of positive anti-NMDAR Ab in serum with negative anti-NMDAR Ab in CSF fluid and found one other recent case report in a 22-year-old woman who presented with psychotic symptoms and was found to have anti-NMDAR Ab in her serum but not in her CSF. She made a full recovery after receiving steroids. The authors hypothesise that the brain may act as an immunoprecipitator of serum Ab preventing drainage of them into the CSF.¹⁴

Anti-NMDAR encephalitis was first reported as a paraneoplastic syndrome, as it was found to be associated with ovarian teratoma in reproductive age women.¹⁵ Thirty eight percent of patients have an underlying neoplasm with this finding being more common in female patients (46%) rather than male patients (6%). In addition, the presence of a tumour predominates in cases between 12 and 45 years.¹ Anti-NMDAR encephalitis may also occur as a post-viral autoimmune encephalitis and the connection between anti-NMDAR encephalitis following herpes simplex encephalitis has been well established.^{16 17} While prevalence has not been described, one retrospective study found that 13 of 44 patients with documented HSV encephalitis developed anti-NMDAR antibodies.¹⁸

The clinical presentation can be divided into three phases that have been well documented in the literature.5 9 11 19 First, a prodromal phase, which can be characterised by several days of fever, cold-like symptoms, nausea, vomiting and fatigue. This phase has only been reported in 50% of cases,²⁰ but further suggests the possibility of an inciting viral aetiology as previously referenced. Within 2 weeks of the prodromal phase, an early phase has been characterised by prominent psychiatric and neurologic symptoms, which may include behaviour changes, psychosis, delusions, insomnia, seizures and abnormal movements, including hyperkinesis or chorea. The late phase is characterised by catatonia, autonomic dysregulation, including blood pressure instability, hyperthermia, tachycardia, hypersalivation and in the most severe cases, loss of consciousness, cardiac arrhythmias and central hypoventilation, which can be fatal. Without treatment, patients will progress to the late phase within several weeks.^{9 11}

Autonomic instability is often seen in cases of autoimmune encephalitis. One case series described autonomic instability in 69% of patients (91% of patients were women with a median age of 23 years), the largest proportion of patients with cardiac dysrhythmia (37%), followed by dysthermia (36%) and then blood pressure instability (21%).²¹ The pathophysiology of autonomic instability is thought to be tied to the autoimmune destruction of NMDARs in the dopaminergic, noradrenergic and cholinergic systems. The decrease in receptors is directly correlated with the autoantibody titres, linking disease severity with titre levels.²²

Diagnostic criteria have been described for both probable and definite disease. In probable disease, patients must present with rapid onset (3 months or less) of at least four or six of the major symptom groups: abnormal psychiatric behaviour or cognitive dysfunction; speech dysfunction; seizures; movement disorder, dyskinesia, rigidity or abnormal posture; decreased level of consciousness and autonomic dysfunction or central hypoventilation. Additionally, they must have an abnormal EEG (focal or diffuse slowing, epileptic activity or extreme delta brush pattern) and/or CSF with pleocytosis or oligoclonal bands. Definite disease is defined by the presence of IgG anti-GluN1 antibodies (preferably in the CSF), in the presence of one or more of the six major groups of symptoms described above. In both probable and definite anti-NMDAR encephalitis, there must be reasonable exclusion of other disorders.²³ In our patient, he had developed five of the six major symptom groups over the course of a month, EEG showed diffuse slowing and serum was positive for autoantibodies making the diagnosis probable anti-NMDAR encephalitis.

First-line treatments include corticosteroids, intravenous immunoglobulin and PLEX and improve symptoms in 50% of the cases.⁸ Often, first-line treatments are started prior to confirmation of diagnosis. While most patients receive more than one agent for treatment, no preferred regimen has been identified. Plasmapheresis requires several exchange procedures and should be considered prior to intravenous immunoglobulin or second line therapies as plasmapheresis will remove other treatments from the circulating blood.²⁴

Learning points.

• Autoimmune encephalitis should be considered in the differential diagnosis of new-onset psychosis, particularly in the adolescent population.

• Autonomic dysregulation is not a typical finding in psychiatric conditions. Other diagnoses, such as autoimmune encephalitis, should be considered when this is present.

• While anti-N-methyl-D-aspartate receptor (NMDAR) antibodies are typically present in the cerebral spinal fluid (CSF) in this patient, the anti-R antibodies were negative in the CSF and positive in the serum.

• Early diagnosis and treatment is essential for improving chances of good prognosis with return to baseline cognitive function.