Clinical and imaging characteristics of 16 patients with autoimmune neuronal synaptic encephalitis
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.166532
Source of Support: None, Conflict of Interest: None
Objectives: Autoimmune neuronal synaptic encephalitis (AIE) encompasses a heterogeneous group of disorders characterized by immune-mediated neuronal cell destruction. In this study, we aim to study the clinical features, imaging profile and treatment outcome of patients with AIE.
Keywords: Autoimmune encephalitis; autoimmune neuronal synaptic encephalitis; glutamic acid decarboxylase; Hashimoto's encephalopathy; leucine-rich glioma inactivated 1; limbic encephalitis; N-methyl-D-aspartate; voltage-gated potassium channels
Autoimmune neuronal synaptic encephalitis (AIE) are a group of autoantibody-mediated inflammatory disorders being increasingly recognized in clinical practice. The term encompasses a group of clinical syndromes, which are immune-mediated and respond well to immunotherapy. The clinical presentation is diverse and includes memory loss, confusion, personality changes, and seizures. Some of them may have an underlying neoplasm. Magnetic resonance imaging (MRI) may show high-intensity signals in the medial temporal lobes in a few conditions. Early recognition is important as: (i) Few of them may be associated with underlying malignancy, and (ii) most of them improve with immunotherapy and carry a good prognosis.
Here we describe the clinical features, imaging profile, and treatment outcome of patients with AIE presenting to National Institute of Mental Health and Neurosciences, Bengaluru, which is a tertiary care neurology center in South India.
This study included patients who were referred to us between 2011 and 2015 (3½ years). All these patients were admitted and a detailed history, including their demographic profile, was obtained. They underwent MRI brain, electroencephalogram (EEG), and cerebrospinal fluid (CSF) examination. In addition, tests for other autoimmune disorders were carried out, such as assessment for the presence of antinuclear antibody as well as autoantibody, and evaluation of their vasculitic profile. These patients were screened for malignancy using computed tomography (CT) scan of the thorax, abdomen, and in few patients, whole body positron emission tomography (PET)-CT. All patients received immunotherapy either as the sole treatment or as a part of combination therapy.
There were 22 patients with suspected AIE over a period of 3½ years and 16 patients had positive autoimmune antibodies with encephalitis confirming the diagnosis of AIE [Table 1]. The remaining patients are not included in the current report as antibody markers were either not available or encephalitis was absent [Table 2]. Women were more common (F: M: 13:3); the mean age at onset of illness was 28.05 ± 19.7 years and the duration of illness was 1.7 ± 3.3 years.
Cognitive impairment and seizures were the predominant symptoms present in nearly all (100%) patients followed by psychiatric disturbances (87.5%), mutism (62.5%), movement disorders (62.5%), myoclonic jerks (37.5%), and visual hallucinations (18.75%). The clinical findings in each subgroup of AIE are described below. Antecedent illness (fever and upper respiratory infection) was present in 37.5% (4: anti-N-methyl-D-aspartate [NMDA]; 2: anti- thyroid peroxidase [TPO] antibody positivity) patients.
Hematological and biochemical parameters were within normal limits in all patients. EEG was available in all of them and was abnormal in 81.25% patients [Table 3] and [Figure 1]. Diffuse slowing of the background activity was the predominant EEG change. Epileptiform discharges were seen in 3 (18.75%) patients with anti-NMDA encephalitis and two of them showed evidence of extreme delta brush [Figure 1]a. CSF examination was available in 14 patients and was normal in 10 (71.4%) patients. One patient with anti-NMDA encephalitis had lymphocytic pleocytosis with normal protein and sugar. Three patients in each of the three subtypes of AIE had mildly elevated protein with normal cell count and sugar.
An MRI of the brain was done in 15 patients while 1 patient underwent only a CT scan [Table 3] and [Figure 2]. The MRI was abnormal in 53.3% patients. Abnormalities were seen in all patients with anti-voltage-gated potassium channels (VGKC); and, 60% of patients with anti-NMDA antibody positivity. Imaging was normal in 26.7% of the patients (3: anti-NMDA; 1: anti-thyroid peroxidase [TPO] positivity) and diffuse cerebral atrophy was noted in rest of the 20% (3: anti-TPO positivity) patients. PET-CT was done in 4 patients (2: anti-VGKC, 2: anti-NMDA positivity) and none of them had any evidence of internal malignancy. CT thorax and abdomen were done in 9 patients as they were unable to afford a PET scan due to financial constraints. One patient with Hashimoto's encephalopathy (HE) and Turner's syndrome had streak ovaries, while 1 patient with anti-NMDA encephalitis had an ovarian cyst.
Details of the treatment are given in [Figure 3], and the follow-up and outcome of patients are given in [Table 4]. Sub-group analysis of the different AIE is given below.
Anti-N-methyl-D-aspartate autoimmune encephalitis
There were 10 patients of anti-NMDA encephalitis and four of them were children (3 girls, 1 boy). The mean age at onset was 14.7 ± 6.6 years and the mean duration was between 1 and 3 weeks except in 3 patients whose duration ranged from 9 to 12 months. An antecedent febrile illness was present in 30% patients prior to the onset of neurological disturbances. The triad of cognitive impairment, seizures, and mutism was present in all patients in the series. The other clinical features were psychiatric disturbances (90%), movement disorders (80%), myoclonic jerks (20%), and visual hallucinations (10%).
The behavioral disturbances were characterized by irritability, failure to recognize relatives, poor comprehension, restlessness, and disorientation. Among them, 80% of the patients were evaluated as having psychosis or a dissociative disorder initially and later referred to a neurologist for evaluation. Eight (80%) patients had movement disorders, namely, stereotypical movements (50%), orofacial dyskinesias and dystonia (40%), and hemiballismus with chorea (10%).
Only 1 (10%) patient had normal EEG findings. Three (30%) patients had epileptiform discharges, while 6 (60%) patients had diffuse slowing of background activity. Two patients had evidence of delta brush [Table 2] and [Figure 1]. PET-CT done in 2 patients was normal. Excepting for 1 patient, all others underwent CT scan of the thorax and abdomen. One patient had an ovarian cyst while the scan in all the other patients was noncontributory. MRI of the brain was done in 9 patients, and 1 patient underwent CT scan of the brain. MRI was abnormal in 66.7% patients [Table 2] and [Figure 2]. T2 and fluid-attenuated inversion recovery (FLAIR) hyperintense signal changes were seen in bilateral medial temporal lobe, hippocampus, and insular cortex. Apart from these areas, a few patients had subcortical hyperintensities at various regions, as described in [Table 2]. Three (33.3%) patients had a normal imaging. The CT scan performed in the single patient was found to be normal.
All patients were initially treated with pulse methylprednisolone followed by other immunomodulatory therapies [Figure 3]. Rituximab was not given to any of the patients due to financial constraints. Two patients were continued on monthly intravenous immunoglobulin (IVIG); 5 patients received a combination of oral steroids with monthly pulse plasmapheresis and 2 patients received oral steroids. One patient was lost at follow-up; hence information regarding the clinical status at follow up was not available for this patient. Follow-up information [Table 4] of more than 6 months was available in 60% patients; all patients were periodically reassessed and a repeat MRI done in 1 patient at 1-year interval showed disappearance of the lesions with significant clinical improvement. All patients had significant improvement especially in terms of cognition, behavioral disturbances, seizures, and movement disorders.
Four patients were detected to be having HE. All of them presented with a triad of cognitive impairment, seizures and behavioral changes; two of them presented with myoclonic jerks, visual hallucinations, and 1 patient had perioral dyskinesias. Behavioral disturbances were variable which included suspiciousness, irritability, irrelevant talking, apathy, disorientation and reduced speech output. Case 7 was also a case of Turner's syndrome with hypothyroidism. MRI brain [Figure 2] was normal in 1 patient while three of them showed diffuse cerebral atrophy. None of them had any parenchymal changes. All of them received pulse methylprednisolone initially followed by other immunomodulators as mentioned in [Figure 3].
Anti-voltage-gated potassium channels (leucine-rich glioma-inactivated 1) autoimmune encephalitis
Anti-VGKC (leucine-rich glioma inactivated 1 [LGI1]) AIE was seen in 2 patients. The mean age at onset of illness was 52.0 ± 13.8 years with the duration of illness ranging from 11 to 120 days. Both patients had episodic behavioral disturbances in the form of irrelevant talking, irritability, confusion, memory impairment, and faciobrachial-dystonic-seizures (FBDS). Both patients demonstrated positive anti-VGKC antibodies in sera with the antibodies directed against LGI antigen. Their EEG demonstrated a slow background activity of 6–7 Hz in both the cases and in addition, case 6 had a frequent spike and polyspike activity in the right temporal region. MRI brain revealed involvement of bilateral medial temporal region, hippocampus, anterior cingulate, and insular cortex with restricted diffusion in these areas [Figure 2]. One patient had a T1 hyperintense basal ganglia, which has been reported previously. Repeat imaging in 1 patient at the end of 1-year showed disappearance of the lesions with diffuse cerebral atrophy that was more pronounced in the temporal lobe. Both of them received pulse methylprednisolone as the initial therapy [Figure 3] followed by IVIG and/or plasmapheresis. Significant improvement was noted in cognition, myoclonic jerks, and abnormal limb movements during follow-up visits. Case 6 showed an almost complete improvement and returned back to normalcy over 3 months. Case 1 continues to have mild behavioral and memory disturbances.
Limbic encephalitis was first reported by Brierley et al., in 1960, and can result from infective, autoimmune or cryptogenic causes. Paraneoplastic onconeural antibodies are located in the intracellular cytoplasm or nucleus. Another set of antibodies present on the neuronal surface, termed as “synaptic”or “neuronal surface antibodies,”were first described by Dalmau and Rosenfeld in 2001., There has been a progressive increase in the understanding of autoantibody-mediated disease of the central nervous system during the recent years. The spectrum of the disease is evolving and identification of specific antibodies helps in the diagnosis., A higher occurrence in women was reported by Dalmau et al., in their series of 100 patients. Our results are similar, while a case series from North India reported a male predominance.
The California Encephalitis Project was initiated in 1998 to identify the etiology, clinical and epidemiological features of encephalitis in California. From 1998 to 2000, they had identified 334 patients with encephalitis where the infectious etiologies were seen in nearly 12.6% patients, and 3 (0.9%) patients were identified as having an autoimmune etiology. Of the latter group, 2 patients were identified as having HE and 1 patient had clinical manifestations of stiff person syndrome. However, the antibody was not identified in the patient with stiff person syndrome. The same group reported 10 (50%) patients with NMDA encephalitis among a suspected group of 20 patients in 2009. Between September 2007 and February 2011, anti-NMDA encephalitis was 4 times more frequent than an infectious etiology, comprising 53% of the cohort. This indicates that with increased awareness, the diagnosis and frequency of AIE is increasing. Hence, it is important for a clinician to be aware of this evolving disorder. In our series, anti-NMDA encephalitis was more commonly observed in children and women in the second decade, while the other AIE were identified between the third and fifth decade. The triad of amnesia or cognitive impairment, seizures, and behavioral disturbances was seen in all the three AIE.
Among the 16 patients in our group, NMDA encephalitis was most common (62.5%) manifestation as documented in larger series from the Western countries.,, It affects all age groups, but is more common in children and women with an incidence ranging from 22% to 40%., Four (80%) of the patients in our study were children and the other patients were in the 2nd decade. An antecedent illness has been commonly reported in 40–82% patients,,. It was present in 30% of our patients. The onset of prodromal symptoms may suggest a viral trigger as an early feature of immune activation.
These patients present with neuropsychiatric symptoms in the form of behavioral disturbances, seizures, cognitive impairment, and abnormal involuntary movements in the form of orofacial dyskinesias, stereotypes, and perseveration. This was noticed in 80% of our patients. Speech disturbance initially takes the form of slurring of speech, reduced speech output, unintelligible speech, and later progresses to mutism. Speech disturbance is more often found in children. Mutism was present in 100% of our patients and was not a feature in other encephalitis, thus helping in the clinical diagnosis of this entity.
The EEG abnormalities reported include background slowing and epileptiform discharges manifesting either as a generalized waveform or focally in the frontotemporal regions.,, In the present study, only 1 patient had a normal EEG; 3 patients had epileptiform discharges; while, the rest had background slowing. Two patients had the characteristic delta brush observed in anti-NMDA patients. MRI abnormalities were seen in 66.7% of our patients (as also reported in other series) with a predilection for the medial temporal lobes, insular cortex, and hippocampus.
Anti-voltage-gated potassium channel encephalitis (leucine-rich glioma-inactivated 1)
Anti-VGKC encephalitis along with LGI1 has been associated with limbic encephalitis, neuromyotonia, faciobrachial-dystonic seizure (FBDS), and Morvan's syndrome.,, FBDS is seen as an adult onset brief dystonic seizure involving the face and ipsilateral arm. Both of our patients with anti-VGKC encephalitis presented with behavioral problems, memory disturbances, and FBDS. In our series, only 1 patient had hyponatremia. Increased sweating and hypersecretion of anti-diuretic hormone have been postulated to result in hyponatremia., MRI brain shows signal changes in bilateral medial temporal lobes on T2 and FLAIR sequences., Patients with anti-VGKC AIE respond remarkably to immunotherapy,,, a phenomenon that was also observed in both of our patients.
It was first described by Brain et al., in 1966 and is also known as steroid-responsive encephalopathy associated with autoimmune thyroiditis., The exact etiology is not known; however, various mechanisms have been proposed which include autoimmune cerebral vasculitis, toxic effects, and neuronal reaction. Our patients presented predominantly with behavioral changes, memory disturbances, and seizures. In both of our patients, the MRI showed mild diffuse cerebral atrophy. In a case series from India, patients presented with acute to subacute-onset, rapidly progressive encephalopathy with psychiatric manifestations and the MRIs were normal or showed a mild cerebral atrophy.
None of the patients were treated with rituximab in view of financial constraints. As in other autoimmune disorders, these people were treated with different immunomodulators depending on their clinical features and affordability [Figure 4]. A combination of oral steroids and large volume plasmapheresis at monthly intervals was performed in 37.5% patients; monthly IVIG was also administered in 18.75% patients. The rest received either oral steroids or a combination of oral steroids, along with other immunomodulators. In ten of these patients, the follow-up information of more than 6 months was available. All these patients showed a significant improvement as depicted in [Table 4]. Hence, in developing countries with financial constraints, patients with AIE can be offered immunomodulators either in the form of oral steroids alone or in conjuction with monthly plasmapheresis.
Our study group contained lesser number of patients. However, they possessed a unique clinical semiology that may help in the clinical diagnosis of this entity. (i) NMDA receptor encephalitis is more common in children and young women. Mutism and speech abnormalities are distinctive clinical features that may help in the clinical diagnosis of anti-NMDA encephalitis; (ii) both anti-VGKC and Hashimoto's encephalitis presented with the classic triad of amnesia, seizures, and cognitive impairment as is seen in any limbic encephalitis; (iii) FBDS is almost exclusively seen in anti-VGKC associated encephalitis; and, (iv) a combination of oral steroids with monthly plasmapheresis or oral steroids alone may be helpful in the treatment of the disease. AIE is an evolving disorder and the spectrum of neurological features may vary among different ethnicity. A long-term follow-up and prompt evaluation and management is required for an adequate understanding of this disorder.
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Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]