Anti-N-methyl-D-aspartate receptor type autoimmune encephalitis with severe pneumonia: a case report

Autoimmune encephalitis (AE) is a type of encephalitis caused by autoimmune disease. AE was included on a list of the first batch of 121 rare diseases published by the Chinese National Health Commission on 11^th May 2018. Currently, patients with AE account for 10%–20% of encephalitis cases, with 54%–80% of those cases classified as the anti-N-methyl-D-aspartate receptor (NMDAR) type, which is the most common type.[1] In 2010, China reported the first case of a patient with anti-NMDAR type AE. Although new neural autoantibody biomarkers and awareness among doctors have increased in recent years, reports of patients with AE are rare.[2] There are also many other differential diagnoses, such as toxic/metabolic encephalopathy, neoplasm, epilepsy, and functional neurological disorders, that might be misdiagnosed. Hear, we report a patient whose diagnosis of anti-NMDAR type AE with severe pneumonia was initially misdiagnosed.

CASE

A 75-year-old male was admitted to the emergency department with the chief complaint of abnormal behavior and drowsiness that had persisted for a week on 8^th October 2022. The patient’s wife reported that he was talking nonsensically and had lost the ability to communicate normally with others; he then developed drowsiness within one week. He had a history of hypertension and regularly took amlodipine to control his blood pressure. His wife denied a history of other chronic diseases, such as coronary heart disease, diabetes, and cerebral infarction. The patient also had no history of infectious diseases, allergies, tobacco use, or alcohol intake. He had no family history of mental disease, and his wife denied that he had recently experienced any psychological stress. On physical examination, his vital signs were an ear temperature of 36.7 °C, a heart rate of 85 beats per minute, blood pressure of 125/65 mmHg (1 mmHg=0.133 kPa), respiratory rate of 16 breaths per minute, and oxygen saturation (SpO₂) of 99% on room air. The patient had an obstacle in orientation. He could not remember his name and age and lost the ability to figure out his surroundings. The patient was also unable to distinguish between day and night. The patient showed no signs of meningeal irritation or pathological reflexes. His muscle tone and muscle strength were both normal, and he had no signs of heart, lung, or abdominal pain. His laboratory tests were as follows: white blood cell count of 8,430 cells/μL, percentage of neutrophils of 76.6%, serum potassium concentration of 3.13 mmol/L, serum sodium concentration of 132.29 mmol/L (Table 1). Other laboratory tests, such as liver function, renal function, myocardial enzyme spectrum, and coagulation function were all normal. Cranial computed tomography (CT) displayed multiple lacunar infarctions in the pontine, bilateral basal ganglia, and central oval regions (Supplementary Figure 1). Based on these tests, the emergency neurologist considered that the patient might have hypoxic ischemic encephalopathy and prescribed aspirin, atorvastatin, and citicoline to improve these symptoms. An appointment was made for the patient to undergo magnetic resonance imaging (MRI) of the brain for further examination.

Table 1.

Timeline of laboratory examination results after admission

On 10^th October 2022, the patient was sent to the hospital again because of a fever of 37.9°C. His wife reported that the patient’s symptoms persisted despite taking the abovementioned medication, and his lower limb muscle strength decreased to Class V. The laboratory tests were shown in Table 1. Ceftriaxone was administered to the patient for anti-infection, and troxerutin was administered to improve circulation. However, the patient’s symptoms worsened the following day. The patient still had a low fever along with the appearance of new symptoms, such as aphasia and incontinence of the feces and urine. On 12^th October 2022, MRI of the brain revealed ischemic lesions in the pontine brain and bilateral lateral ventricles (Figure 1). The patient was hospitalized in the emergency internal medicine ward.

Figure 1.

Patient’s cranial magnetic resonance imaging (MRI) results showed small patchy abnormal signal lesions at pontine brain and bilateral lateral ventricle. The lesions appear as low signal on T1 weighted imaging (A) and high signal on T2 weighted imaging (B) as well as on fluid attenuated inversion recovery (C).

Regular physical examination revealed no positive neurological signs, such as meningeal irritation or pathological signs. The patient had the same prior obstacle to the orientation. Repeated laboratory results and routine blood gas analysis results were shown in Table 1. CT of the chest revealed scattered inflammation in the lungs and a hydrothorax (Supplementary Figure 2). Magnetic resonance angiography of the brain revealed no abnormalities. An electroencephalogram (EEG) displayed a large amount of irregular θ waves of 5–6 Hz and a few δ waves in the frontotemporal region (Supplementary Figure 3). The primary diagnosis was intracranial infection, pneumonia, and hypertension. Therefore, the patient received anti-infection, antiplatelet, lipid-lowering therapies, and nutritional support.

Next, a lumbar puncture was performed to identify the possibility of intracranial infection and potential pathogen in the lesion. The cerebrospinal fluid (CSF) was colorless and clear, the initial pressure of the CSF was approximately 12 cmH₂O (1 cmH₂O=0.098 kPa), and the terminal pressure was approximately 8 cmH₂O. The laboratory testing results for the CSF were as follows: a karyocyte count of 24 cells/μL (80% neutrophils and 20% lymphocytes). Next-generation sequencing (NGS) of the CSF showed infection with human herpesvirus type 5 (HHV-5), and the anti-NMDAR type antibody level in the CSF was 1:3.2 (Supplementary Figure 4).

The patient was diagnosed with anti-NMDAR type AE. Methylprednisolone (1,000 mg/d) was administered intravenously for 3 d and subsequently reduced to 500, 250, 120, 80, and 40 mg every three days, with a 20 g intravenous injection of human immunoglobulin for 5 d. During the treatment process, the patient’s pneumonia worsened, and respiratory failure occurred. Tracheal intubation was performed, and sputum culture showed infection with Staphylococcus aureus, Acinetobacter baumannii, and Acinetobacter pittii. The anti-infection treatment plan was adjusted to include vancomycin (1,000 mg/12 h for 16 d) and colistin sulfate (500,000 units/8 h for 10 d), which was based on the antibiotic susceptibility patterns.

On 27^th October 2022, the patient recovered consciousness and could perform actions according to instructions. Spontaneous breathing was smooth and tracheal intubation was removed. Laboratory results concerning infection and major organ function were improved, and the patient was transferred to a rehabilitation hospital for further recovery treatment on 7^th November. The patient was prescribed 45 mg/d prednisone, which was reduced to 5 mg every 1 or 2 weeks. We conducted a telephone follow-up five months later. The patient’s wife said he could use simple words to express his needs and recognize the family members. However, his muscle strength remained poor, and he is still undergoing rehabilitation treatment. The course of disease is summarized in Table 2.

Table 2.

Disease course of this patient

DISCUSSION

Anti-NMDAR type AE was first reported by Dalmau et al in 2007.[3] This type of encephalitis can cause relatively reversible neuronal dysfunction through humoral immune mechanisms.

There are a series of prodromal symptoms of anti-NMDAR type AE, such as fever and headache.[4] The patient sometimes has a prodromal viral infection of the central nervous system, often caused by herpes simplex virus (HSV). In this case, the patient had fever ahead of the other symptoms, and NGS revealed a prodromal viral infection with HHV-5.

Patients with anti-NMDAR type AE have a rapid onset of symptoms that generally peak within 2 weeks. The main clinical symptoms include mental and behavioral abnormalities, memory decay, speech disorders, dyskinesia, epileptic seizures, and autonomic nerve dysfunction, which mainly manifest as sinus tachycardia, bradycardia, increased salivary secretion, hypoventilation, hypotension, and central fever. In the present case, the patient was admitted because of behavioral abnormalities and reticence, and developed dyskinesia and hypoventilation subsequently.

The clinical manifestations of many other nervous system diseases are similar to the symptoms of anti-NMDAR AE, including viral encephalitis, metabolic encephalopathy, Hashimoto’s encephalopathy, central nervous system tumors, dementia with Lewy bodies, and other genetic diseases, such as mitochondrial encephalopathy and methylmalonic acidemia. A differential diagnosis is necessary for these diseases.

The currently recognized gold standard to detect anti-NMDAR antibodies is a cell-based assay.[5] Normal or elevated CSF pressure can be observed during lumbar puncture. Cytological examination of the CSF often shows lymphocytic inflammation and elevated protein levels in the CSF. MRI of the brain often shows no obvious abnormalities, and a higher signal on FLAIR sequences in the cerebral cortex. Positron emission tomography of the brain shows decreased metabolism in both occipital lobes and increased metabolism in the frontal lobes and basal ganglia.[6] EEG examination often shows diffuse or multifocal slow waves, and abnormal δ waves highly suggest anti-NMDAR type AE. In our case, the patient exhibited typical EEG manifestations and was positive for anti-NMDAR antibodies in the CSF.

According to the Graus and Dalmau standards published in 2016, the diagnosis of anti-NMDAR type AE requires at least one of the following symptoms:[5] mental and behavioral abnormalities, cognitive impairment, speech disorders, epileptic seizures, dyskinesia, involuntary movements, decreased levels of consciousness, and autonomic nerve dysfunction. Laboratory tests for CSF are also necessary, especially for the presence of anti-NMDAR antibodies in the cell-based assay method. If CSF cannot be obtained, serum samples can be used for test. Serum samples were tested using the tissue-based assay for final confirmation. However, when the serum titer was < 1:10, the results showed no diagnostic significance.

Treatment of anti-NMDAR type AE includes immunotherapy, supportive therapy, and rehabilitation therapy. Patients with coexisting tumors require comprehensive antitumor treatment. Therefore, imaging examinations are required for all patients, especially female patients who diagnosed with anti-NMDAR type AE. If a tumor is detected, surgical treatment, chemotherapy, or radiotherapy should be administered as early as possible.[7] During the period of antitumor treatment, patients should undergo immunotherapy at the same time. Patients without tumors, especially female patients under 12 years old, should undergo pelvic ultrasound examinations every 6–12 months for 4 years.[8]

First-line immunotherapy includes glucocorticoids (GCs), immunoglobulins (IG), and plasma exchange (PE), with GCs being the first choice of treatment.[9] The combined use of GCs and IG was effective in patients diagnosed with severe anti-NMDAR type AE.[10] PE is typically performed on patients with severe anti-NMDAR type AE.[11] If a patient require both IG and PE, IG therapy ought to be administered after PE.

Patients with low first-line immunotherapy efficacy, particularly those who have had two or more treatments without a discernible improvement in symptoms, may benefit from second-line immunotherapy, which consists of cyclophosphamide and rituximab.[12] Cluster of differentiation 19 (CD19) lymphocytes are used to evaluate the efficacy.[13] If the patient achieves good results with second-line immunotherapy, they can continue to receive long-term immunotherapy which normally lasts at least 12 months. Mycophenolate mofetil and azathioprine are commonly used in long-term immunotherapy. Regular follow-up of the peripheral lymphocyte subgroup and immunoglobulin G can facilitate personalized dosage.[14]

Upgraded immunotherapy can be used in patients who show no improvement after one or two months of second-line immunotherapy. Tocilizumab is the most commonly used drug for immunotherapy.[15]

For severely refractory patients, additional immunotherapies can also be considered, including methotrexate and bortezomib.[16,17] During methotrexate treatment, some complications, such as acute chemical arachnoiditis and myeloradiculopathy can occur.

For patients with epilepsy, drugs such as benzodiazepines, sodium valproate, and levetiracetam can be used to control symptoms.[18] Patients with mental symptoms can be treated with drugs such as olanzapine, clonazepam, and quetiapine.

The overall prognosis of patients with anti-NMDAR type AE is generally favorable. Severe patients are usually treated in the intensive care unit for 1 to 2 months on average, with a mortality rate of 2.3%–9.5%. Some patients require more than 2 years to achieve complete recovery.[19,20]

Our patient did not have the usual prodromal symptoms of AE, but presented with behavioral abnormalities, lethargy, and other neurological manifestations. Anti-NMDAR type AE patients often have a history of at least 2 weeks when they develop symptoms, as described in our patient. Therefore, the patient visited the emergency department when the disease was at its worst. Our patient was first considered to have ischemic hypoxic encephalopathy, but his condition worsened with fever, limited limb movement, and respiratory failure after the treatment. Fortunately, lumbar puncture was performed in a timely manner. HHV-5 and anti-NMDAR antibodies in the CSF were positive, which cleared the diagnosis. The patient was administered GCs combined with IG therapy. Considering that the patient had severe pneumonia and that large doses of GCs may inhibit the anti-inflammatory mechanisms, we reduced the dose of GCs. After the adjustment of the immunotherapy strategy, the patient’s subsequent prognosis was good.

CONCLUSION

Anti-NMDAR type AE is a rare disease that is easily misdiagnosed and missed at emergency setting. Therefore, if a patient presents with relevant clinical symptoms, a CSF examination is necessary. Immunotherapy should be administered as soon as possible. And imaging examinations are required to exclude tumors. Patients with anti-NMDAR type AE and epilepsy or psychiatric symptoms might be administrated drugs to manage their condition.