Clinical presentation of LGI1 encephalitis with teratoma
The patient was a 48-year-old woman with past medical history of nodular goiter and suspected teratoma. She began to suffer from anxiety six months prior to diagnosis, and have been treated with anxiolytics with no effect and with gradual deteriorization. In the two months prior to admission, she had been hyperglycemic, and for the prior month had suffered from short term memory dysfunction and drowsiness.
She was admitted to the endocrinology department and once glucose control was established, she was transferred to the neurology department because of ongoing cognitive impairment. The patient frequently forgot whether she had taken her medication, where her bed was located in the hospital, and who had visited her. MMSE was 13 (details in Table 1) and she could not complete the MoCA because of irritability. Laboratory data after admission confirmed slightly decreased sodium level of 135.4 mmol/L (normal range 136–145 mmol/L) and potassium 2.87 mmol/L (normal range 3.5–5.1 mmol/L), increased glucose 12.48 ( normal range 3.9–6.1 mmol/L ), but normal complete blood counts, urinalysis, liver and renal function, myocardial infarction markers and coagulation functions. On day 6 after admission, lumbar puncture was performed with normal routine and biochemical testing results, except for elevated glucose level of 4.74 mmol/L (normal range 2.22–3.89 mmol/L), normal immunology. Autoimmune encephalitis antibody panel (including NMDA, LGI1, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid 1 (AMPA1), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid 2 (AMPA2), gamma-aminobutyric acid-B receptor (GABAB) and Casper-2) of serum and CSF was also performed. On day 7, she developed visual hallucinations, and routine EEG was performed showing diffuse slow waves. Brain MRI showed bilateral hippocampal hyperintensity on T2 and T2-FLAIR sequences. Methylprednisolone (200 mg/d, I.V.) and 2.5 mg olanzapine were given immediately with the diagnosis of possible AE.
Table 1
Neuropsychological assessment in LGI1 encephalitis case with teratoma
Scale | Time since admission |
Day 6 | Day 32 | Month 3 | Month 4 | Month 5 |
MMSE Total | | | | | |
13 | 19 | 26 | 24 | 27 |
Orientation | 5 | 7 | 10 | 9 | 9 |
Registration | 2 | 3 | 3 | 3 | 3 |
Attention and Calculation | 2 | 1 | 1 | 1 | 5 |
Recall | 0 | 0 | 3 | 2 | 1 |
Language | 4 | 8 | 9 | 9 | 9 |
MoCA | | | | | |
Total | N/A | 20 | 24 | 28 | 29 |
Visuospatial and Executive function | N/A | 4 | 5 | 5 | 5 |
Animal naming | N/A | 3 | 3 | 3 | 3 |
Attention | N/A | 4 | 4 | 4 | 6 |
Language | N/A | 3 | 3 | 3 | 3 |
Abstraction | N/A | 2 | 1 | 2 | 2 |
Delayed recall | N/A | 0 | 2 | 5 | 4 |
Orientation | N/A | 4 | 6 | 6 | 6 |
HAMA | | | 8 | 2 | 4 |
HAMD | | | 12 | 0 | 3 |
N/A, MoCA was not performed because the patient was too irratated. |
MMSE, Mini-Mental State Examination; MoCA, Montreal cognitive assessment; HAMA, Hamilton Anxiety Scale; HAMD, Hamilton Depression Scale; BI, Barthel Index; ADAS-Cog, Alzheimer’s Disease Assessment Scale-Cognitive section. |
On day 8, she was transferred to intensive care unit (ICU) because of convulsive status epilepticus (SE) for 20 minutes unresponsive to diazepam (10 mg I.V.) twice and phenobarbital (200 mg I.M.) begun given 5 minutes after seizure onset. In the ICU, endotracheal intubation was followed by antibiotic therapy because blood oxygen saturation dropped to 70% and symptoms and signs of pneumonia were evident. Meanwhile, she was treated with midazolam, fentanyl and levetiracetam (LEV) initially followed by LEV monotherapy once she had been seizure-free for 24 hours. The diagnosis of LGI1 encephalitis was confirmed by the detection of LGI1 antibody both in blood (1:32) and CSF (1:3.2), whereas other autoimmune antibodies were all negative. Considering her hyperglycemia and that seizures were controlled, methylprednisolone pulse therapy (MPT) was deferred; instead the dose was maintained at 200 mg/d with combined immunoglobulin ((0.4 mg/kg/d), I.V. 5 days) therapy. She was extubated on day thirteen at which point her vital signs were continuously stable.
After her seizures and pulmonary infection were well controlled, she returned from the ICU to the neurology ward with impaired cognitive function, visual hallucinations and irritability. We reduced the daily dose of methylprednisolone gradually with a transition to oral prednisone acetate, and continued drugs for control of seizures and psychosis. At day 25 after admission, the patient could answer simple questions and complained of stomachache (right lower quadrant). Considering her past history of suspected teratoma, ultrasound examination of uterus and appendages was performed and indicated a right adnexal mixed cystic-solid lesion. Further abdominal computed tomography (CT) indicated a possible teratoma in this region. Gynecologic oncologists recommended elective surgery after the LGI1 encephalitis was stable. One week later, neuropsychological assessment was performed with MMSE of 19 and MOCA of 20 (details in Table 1). She was discharged with continued oral prednisone acetate (10 mg/d), LEV (1500 mg/d) and olanzapine (1.66 mg/d).
At month 1 followup, the patient presented to the clinic with impaired short term memory and spatial disorientation, but no hallucinations. She was intermittently unaware of where she was and why she had come. Short term memory was impaired to the extent that she had to write down her daily plan and what she did every day in her notebook. She was partially reliant on a home caregiver. Repeated MRI (3 months after onset of memory dysfunction) showed reduced swelling of the bilateral hippocampus on T2 and T2-FLAIR sequence, slightly improved. Considering her improved LGI1 encephalitis, she was admitted to the gynecological oncology department for laparoscopic oophorocystectomy. Postoperative pathological examination confirmed the diagnosis of teratoma: part of the left ovarian tissue was filled with colloidal substance, most of which was goiter, and was consistent with mature teratoma. Positive staining for LGI1 was observed with the deepest staining in the thyrocytes.
At month 2 followup, her spatial disorientation was gone; she knew where she was and how to get back home when she went out, but she complained that she felt anxious when facing daily activities such as answering phone calls, and her short term memory was still bad. Neuropsychological assessment showed improved cognitive function with MMSE of 26, MOCA of 24 (details in Table 1) and a mild mood problem with HAMA of 8 and HAMD of 12. LGI1 antibody titer in blood was 1:32 at this time (one month after surgery).
At month 3 followup, her anxiety was greatly improved, but she still had short term memory impairment. EEG background had improved and showed focal, bilateral frontal slowing. Neuropsychological assessment showed very mild cognitive impairment and normal HAMA and HAMD scores (details in Table 1).
At month 4 followup, the patient's anxiety was totally relieved and she could live independently and return to work as her memory had gradually improved and she could recall what she had done without checking her notebook.
At month 5 followup, she complained once again of short term memory impairment during work, she frequently forgot where to find her working tools and documents. She was afraid of being alone and she preferred to stay at home with her family rather than having social contact. Neuropsychological assessment scores were 27 for MMSE, 29 for MOCA, 4 for HAMA, 3 for HAMD (details in Table 1), 8 for Alzheimer 's disease assessment scale (ADAS-Cog) (scored 5 for memory, 2 for word recognition and 1 for orientation) and 100 for BI. Repeated MRI including structural and functional sequences indicated improvement: hyperintensity on T2 and T2-FLAIR were now gone on the left hippocampus though still present on the right side without swelling; no progressive brain atrophy was observed; DWI and DTI were symmetric bilaterally and normal; ASL showed slightly decreased blood flow in her left temporal lobe.
Clinical manifestations in LGI1 encephalitis cases with and without teratoma
The clinical features of this case of teratoma-associated LGI1 encephalitis and of the nine other cases without teratoma are summarized in Table 2.
Table 2
Clinical characteristics of LGI1 encephalitis cases with and without teratoma
Clinical characteristics | LGI1encephalitis without teratoma (N (%)) | LGI1 encephalitis with teratoma |
Total Number | 9 | 1 |
Female | 3/9 (33%) | Yes |
Age at onset (y, mean ± SD (range)) | 47.3 ± 15.6 (19–67) | 48 |
Disease onset Acute Sub-acute Chronic | 9 6 (67%) 3 (33%) 0 | Yes |
Clinical symptoms Symptoms at onset Behavioral disorders FBDS Cognitive impairment Behavioral disorders + Cognitive impairment RBD Dizziness Mood disorder Mood disorder + FBDS Symptoms through entire disease course Seizures Generalized convulsions FBDS Focal seizures Status epilepticus Cognitive impairment Hallucinations Sleep disorder Insomnia RBD Drowsiness | 9 9 2 (22%) 2 (22%) 1 (11%) 1 (11%) 1 (11%) 1 (11%) 0 1 (11%) 9 8 (89%) 4/8 (50%) 3/8 (38%) 1/8 (13%) 0 6 (67%) 3 (33%) 6 (67%) 3/6 (50%) 2/6 (33%) 1/6 (17%) | Yes Yes Yes Yes Yes Yes |
Ancillary test results Evidence of tumor Hyponatremia CSF Cell count < 8 cells/mL Protein < = 0.58 g/L Positive LGI1 antibody immunoassay Serum CSF Serum + CSF EEG Background slowing Background slowing + epileptic discharges Normal MRI Hippocampal lesion Bilateral Unilateral Normal | 9 0 7 (78%) 7 (78%) 7/7 (100%) 7/7 (100%) 9 (100%) 2/9 (22%) 2/9 (22%) 5/9 (56%) 6 (67%) 3/6 (50%) 1/6 (17%) 2/6 (33%) 9 (100%) 8 (89%) 4/8 (50%) 4/8 (50%) 1 (11%) | Yes Yes Yes Yes Yes Yes Yes |
Cognitive function evaluation results MMSE < = 24 MOCA < = 26 Normal | 6 (67%) 3/6 (50%) 1/6 (17%) 2/6 (33%) | Yes Yes |
Follow-up mRS evaluation <=2 > 2 Residual symptoms or death No symptom Short-term memory impairment FBDS Death* | 8 (89%) 8 (89%) 6/8 (75%) 2/8 (25%) 8 (89%) 3/8 (38%) 2/8 (25%) 1/8 (13%) 2/8 (25%) | Yes Yes |
Yes means the LGI1 encephalitis patient with teratoma had the symptom. |
LGI1, leucine-rich glioma-inactivated 1; FBDS, faciobrachial dystonic seizures; RBD: rapidly eye movement behavior disorder; CSF, cerebrospinal fluid; EEG, electroencephalography; MRI: magnetic resonance imaging; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment; mRS: modified Rankin Scale. |
* one patient died of pneumonia because of comorbid myasthenia gravis and one patient died of hepatic failure due to chronic schistosomiasis liver disease and hepatitis B, deteriorated after immunotherapy. |
Our case with teratoma shared many clinical features with those subjects without teratoma (NT group), including 1) age at onset of 48, near the average of 47.3 years in the NT group; 2) hyponatremia, as seen in 78% of the NT group; 3) normal CSF cell count and protein, as seen in 78% of the NT group; 4) positive LGI1 antibody, as seen in blood and/or CSF of all subjects; 5) hippocampal hyperintensity on MRI, as seen in 89% of the NT group; 6) slow waves on EEG, as seen in 33% of the NT group; 7) cognitive impairment and sleep disorder, seen in 67% of the NT group; 8) residual cognitive impairment > 1 year after admission, as seen in 67% of the NT group; and 9) only mild neurological disability during follow-up: the mRS score was 1 in the patient with teratoma, as compared to < = 2 in 67% of the NT group.
However, there are also four key points in which the patient with teratoma significantly differed from those without. First, she presented with chronic anxiety as a prominent symptom; only one patient in the NT group had anxiety as a symptom, and this was acute anxiety beginning simultaneously with FBDS. Second, her anxiety was persistent, lasting until her most recent follow up (13 months from onset); the NT patient with acute anxiety had resolution of this feature by two months follow up. Third, the patient with teratoma developed convulsive status epilepticus during her course, but never had FBDS, as was seen in several of the NT group in both the acute stage of their disease and during follow up.
We followed the patient with teratoma for five months; one patient in the NT group was lost to follow up after discharge, but the other eight were followed for an average of 26.1 ± 12.0 months. After immunotherapy and removal of the teratoma, the patient with teratoma recovered, becoming seizure-free and living independently. Similarly, intravenous immunoglobulin (IVIG) and/or methylprednisolone pulse therapy treatment was effective in 78% of the NT group; one patient died of pneumonia because of comorbid myasthenia gravis and one patient died of hepatic failure due to chronic schistosomiasis liver disease and hepatitis B, deteriorated after methylprednisolone pulse therapy followed by oral azathioprine. None of the NT patients relapsed within the follow-up period.