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|Year : 2021 | Volume
| Issue : 1 | Page : 149-152
A Rare Case of Wobbly, Psychotic Patient with Frozen Eyes - Anti-AMPA Receptor Encephalitis
VR Ashok1, D Nagabushana1, G Yashwanth2, A Mahadevan1, M Netravathi1
1 Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka, India
2 Department of Neuropathology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka, India
|Date of Submission||30-Mar-2020|
|Date of Decision||26-Apr-2020|
|Date of Acceptance||10-Jul-2020|
|Date of Web Publication||24-Feb-2021|
Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore - 560 029, Karnataka
Source of Support: None, Conflict of Interest: None
Background: Anti α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) encephalitis is a rare autoimmune encephalitis. They present with memory, confusion or behavioral changes.
Objective: The aim of this study was to describe unusual clinical features in a patient with AMPAR-associated encephalitis.
Case: A 42-year-old female presented to us with bulbar and gait disturbances of three weeks duration and behavioral changes for ten days. She was found to have memory impairment along with psychosis. She had left eye ptosis, restricted eye movements, sluggish deep tendon reflexes, and bilateral cerebellar signs. Her serum and CSF (cerebrospinal fluid) AMPAR2 antibodies were strongly positive; CT (computed tomography) chest showed evidence of Thymoma. She was treated with steroids with significant improvement initially but expired within 3 months of diagnosis.
Conclusion: This is the first report of AMPAR associated encephalitis from India presenting with unique clinical features affecting both the CNS (central nervous system)––(psychosis, ataxia, cognition) and PNS––peripheral nervous system involvement (ptosis, restricted eye movements, bulbar disturbances).
Keywords: AMPA encephalitis, ataxia, autoimmune encephalitis, brainstem syndrome, encephalopathy, thymoma
Key Message: AMPAR encephalitis is rare and can have varied presentations. Thymoma is the most common reported malignancy with AMPAR which can also have associated neuromuscular junction defect and thus have symptoms of CNS and PNS involvement.
|How to cite this article:|
Ashok V R, Nagabushana D, Yashwanth G, Mahadevan A, Netravathi M. A Rare Case of Wobbly, Psychotic Patient with Frozen Eyes - Anti-AMPA Receptor Encephalitis. Neurol India 2021;69:149-52
|How to cite this URL:|
Ashok V R, Nagabushana D, Yashwanth G, Mahadevan A, Netravathi M. A Rare Case of Wobbly, Psychotic Patient with Frozen Eyes - Anti-AMPA Receptor Encephalitis. Neurol India [serial online] 2021 [cited 2021 Apr 23];69:149-52. Available from: https://www.neurologyindia.com/text.asp?2021/69/1/149/310087
Autoimmune encephalitis (AIE) consists of antibody-mediated inflammatory disorders with varied presentations depending on the type of antibody. Patients typically present with triad of memory, behavioral changes, and seizures. Many of the AIE have a propensity to affect at varying ages and result in few classical clinical features. For example, NMDAR (N-methyl-D-aspartate receptor) encephalitis is most commonly observed in young female children and adolescents. LGI-1 (leucine-rich glioma-inactivated-1) associated encephalitis affects elderly people and causes hyponatremia. Similarly, Anti α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR2) has been described in elderly patients predominantly female resulting in confusion, amnesia, and behavioral changes. AMPA receptor is associated with fast neuronal synaptic transmission in the central nervous system (CNS) and is important for synaptic plasticity, memory, and learning. Anti α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR2) was first described in 2009. Patients present with varied features such as confusion, amnesia, seizure, encephalopathy, psychosis. We hereby describe the first case of AMPAR-related autoimmune encephalitis from India with unique clinical features.
| » Case Report|| |
A 42-year-old female presented to us with subacute onset of dysarthria, dysphagia, gait disturbances of three weeks duration and behavioral changes for ten days. Behavioral changes were in the form of excessive talkativeness, irritability, inappropriate laughter, suicidal thoughts, decreased sleep. She also developed mild memory impairment especially to recent events and gradually stopped indicating needs. She developed drooping of left eyelid, swallowing difficulty for both solids and liquids. There were no seizures, vomiting, headache. There was no significant history of any infections prior to the onset of illness. On examination, her vitals were stable, systemic examination was within normal limits.
Neurological examination revealed; a conscious lady with irrelevant talk, occasionally not obeying commands, not amenable for detailed higher mental status evaluation. She had left eye ptosis with normal reactive pupils, restricted eye movements in both horizontal and vertical directions. Facial weakness was present bilaterally with absent gag reflex. Tone and power in the limbs were normal, deep tendon reflexes were sluggish. She had bilateral (left more than right) cerebellar signs, ataxic gait and required one-person support to walk. In view of the eye movement abnormalities, ataxia, encephalon involvement possibilities considered were miller fisher variant of GBS (Guillain barre syndrome) with encephalon involvement, Bickerstaff encephalitis or autoimmune encephalitis and was investigated.
Her hematological and biochemical parameters were within normal limits. MRI brain showed bilateral medial temporal and insular hyperintensities [Figure 1]. CT thorax showed an enhancing lesion in the anterior mediastinum suggestive of thymoma. EEG (electroencephalography) showed slowing of background activity without any epileptiform discharges suggestive of diffuse encephalopathy [Figure 2]. CSF (cerebrospinal fluid) examination was normal with 7 cells; all lymphocytes with protein: 44 mg/dL and glucose: 64 mg/dL. Nerve conduction studies revealed absent right common peroneal nerve conductions with rest of the motor and sensory conductions being normal. Ganglioside antibodies were negative, Anti-Nuclear Antibody (ANA) profile showed anti-histone positivity (1+), serum and CSF AMPAR2 antibodies were strongly positive [Figure 3]. Diagnosis of AMPAR2 associated encephalitis was made and she was treated with intravenous methyl prednisolone and five cycles of large volume plasma exchange. Evaluation for neuromuscular junction defect was not ascertained in the initial stages. AchR (acetylcholine receptor)-antibodies could not be done in view of the financial constraints. She made significant improvement within two days with the disappearance of the ptosis, bulbar, and eye changes. Behavioral disturbances persisted which gradually decreased with immunomodulation and Olanzapine. At discharge she made significant improvement in memory, recall, and MMSE (mini-mental status examination) was 16. Follow up after one month showed significant improvement in MMSE of 26 and significant improvement in functional status. She was independent of few activities and able to eat and walk with minimal support. Patient was referred to oncologist for further management of the thymoma. During Oncological evaluation within 1 month her CT thorax had shown worsening with lesions in right lower lobe and right parotid gland. Three months after discharge she developed respiratory distress and expired before the nature of the mass lesion could be ascertained.
|Figure 1: (a) T1 Axial MRI- Normal study, (b) T2 Axial image shows bilateral mesial temporal hyper intensities. (c) T2 FLAIR shows bilateral mesial temporal hyperintensities (red arrow), (d) T1 post Gadolinium contrast -Normal, (e) Axial image of Computed Tomography of thorax showing calcified anterior mediastinal lesion, (f) Contrast image of thorax shows no enhancement|
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|Figure 2: EEG shows background slowing suggestive of diffuse encephalopathy|
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|Figure 3: Strong cytoplasmic fluorescence for CASPR2 antibodies using cell-based immunofluorescence assay|
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Our patient presented with a combination of neuromuscular junction defect (ptosis, restricted eye movements, bulbar disturbances) and central nervous system (psychosis, cognition and ataxia) involvement. The peripheral nervous system involvement was initially suspected to be of miller fisher variant of GBS (Guillain barre syndrome) and investigated. Neuromuscular junction defect was not considered during the patient admission. Following the MRI (magnetic resonance imaging), she was started on plasmapheresis and steroids and there was a dramatic improvement of her symptoms. Hence, the clinical symptomatology could be due to the complex autoimmunity of the thymoma due to possible multiple antibodies – AMPAR and possibly? AchR.
| » Discussion|| |
Our patient was a 42-year-old lady who presented with subacute onset of central and peripheral nervous system involvement. On evaluation, found to have anterior mediastinal mass probably thymoma, with AMPAR2 antibodies. Following treatment with steroids and plasma exchange, she made significant recovery in memory and ataxia and became functionally independent in one month. But subsequently, she had worsening of the lung parenchymal lesions and died within three months. To our knowledge, this is the first case report presenting with both central and peripheral nervous system involvement in literature and first report of AMPAR2 encephalitis from India.
The first description of limbic encephalitis (LE) as a result of antibodies against GluR1/2 (glutamate receptors-1/2) subunits of the AMPAR was described in ten patients in 2009 by Lai et al. Nine patients had presented with symptoms suggestive of LE and one with rapidly progressive dementia. Seven of them had malignancy of the lung, thymus, or breast. Predominant subjects were female (9) and all of them showed good response to immunotherapy but had frequent relapses. The study found that the clinical parameters such as neurological outcome, relapse, disease severity were not dependent on the presence of tumor. But there was adverse outcome if there were overlapping immune responses when other autoimmune antibodies were coexistent such as GAD (Glutamic acid decarboxylase), CRMP5 (Collapsin response mediator protein 5).
The largest cases series till date by Hofberger et al. reported clinical features and treatment profile of 22 subjects. They described four different clinical syndromes: Limbic encephalitis (55%), limbic dysfunction with diffuse encephalopathy (36%), motor deficits at onset (4.5%), and psychosis with bipolar disorder (4.5%). Thirteen patients had associated tumor and seven had additional autoimmune antibodies (onconeuronal-3, tumor-related-1, cell surface-2, tumor-related, and cell surface-1). They found that patients with anti-AMPAR encephalitis present with symptoms of multifocal encephalitis, LE, or pure psychosis. Patients need to be extensively screened for malignancy and investigated for other autoimmune antibodies. They require prompt therapy with either tumor removal or immunotherapy as they are reversible conditions. They found that patients with or without tumor did not show any difference in the clinical outcome but those patients with tumor and associated autoimmune antibodies had poor prognosis. Hence screening for tumor and onconeural antibodies depicted the neurological outcome.
A systematic literature review of all the published 55 cases till 2019 was done. Psychiatric symptoms were found to be more common in younger individuals. Confusion, amnesia, psychiatric complaints resulted in delayed diagnosis. Other neurological signs were ataxia (10), apraxia (10), movement disorders (6), pyramidal signs (6), aphasia (6), focal weakness (5), autonomic dysfunction (2), sensory symptoms (2). None of them were found to have eye movement abnormalities, bulbar symptoms as seen in our patient. Brain MRI was abnormal in 86% with frequent abnormality affecting bilateral temporal lobes. Young age, presence of confusion at onset was associated with better prognosis while psychiatric symptoms at onset had poor prognosis.
The clinical spectrum of AMPAR encephalitis has been found to be very variable and having varied presentation and outcome. However, as there are very few patients described; the characteristics and prognosis need to be established. Joubert et al. described four patterns of encephalitis in AMPAR encephalitis patients: (i) Confusion, (ii) Isolated epilepsy, (iii) Isolated amnestic syndrome and (iv) Severe fulminant encephalitis. Till date, five cases of AMPAR and CRMP5 antibodies have been reported. When these two antibodies occur simultaneously in LE patients, they have been found to have poor prognosis probably due to synergistic action of both antibodies, but CRMP5 was absent in our patient.
There is a single case report of AMPAR encephalitis presented initially with LE and later as myasthenia gravis due to the underlying thymoma. Li et al. described a lady who presented with behavioral changes and found to have AMPAR encephalitis along with thymoma. She was treated with thymectomy and steroids following that showed almost complete improvement. Nine months later she presented with ptosis, bulbar disturbances, and fatiguability. During which she was detected to have positive neostigmine test with RNS (repetitive nerve stimulation) showing decremental response and positive AchR-antibodies and titin-antibodies.
In conclusion, AMPAR encephalitis affects usually elderly females with confusion, psychosis, cognitive disturbances. MRI Brain shows characteristic bilateral temporal lobe signal changes. They respond well to tumor removal and immunotherapy, but relapses are frequent requiring long-term immunomodulation. They need to be extensively investigated for other autoimmune antibodies as detection of other antibodies may warrant periodic evaluation of malignancy or other autoimmune disorders and may have poor prognosis. When AMPAR encephalitis occurs as a result of thymoma, they may have symptoms of neuromuscular junction defect. Recognition of this is important for management and prognostication purposes.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]