|Year : 2014 | Volume
| Issue : 5 | Page : 44-50
Gagandeep Singh1, Birinder Singh Paul1, Rajinder K Bansal1, Gunchan Paul2
1 Department of Neurology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
2 Department of Critical Care Medicine, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
|Date of Web Publication||19-Dec-2014|
Birinder Singh Paul
Department of Neurology, Dayanand Medical College, Civil Lines, Tagore Nagar, Ludhiana - 141 001, Punjab
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Neurologists often encounter encephalitis caused by unknown agents. Autoantibody-induced encephalitis is a new and exciting group of disorders that must be considered in the differential diagnosis as they are reversible if treated early in the course of the disease, but fatal if unrecognized. We describe the first report from the Indian subcontinent of three rare cases of different autoantibody-induced disorders, which were successfully managed with immunosuppressive therapy resulting in a good clinical outcome. Case 1 was a young woman with anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, not associated with tumor, who showed significant improvement with Rituximab. NMDA receptor encephalitis occurs typically in young females with psychiatric features, followed by an altered level of consciousness, dysautonomia, hyperkinetic movement disorder, seizures, and hypoventilation. Rituximab, which aims to suppress antibody production is an effective treatment modality. Anti-voltage-gated potassium channel antibodies (anti-VGKC-Ab) cause hyperexcitability of the peripheral nerve and central nervous system. Case 2 was a patient of limbic encephalitis presenting with complex partial seizures responding dramatically to steroids. Anti-VGKC-Ab-associated limbic encephalopathy is considered to be an autoimmune, non-paraneoplastic, potentially treatable encephalitis. The clinical features of anti-VGKC-Ab-associated limbic encephalitis are: Subacute onset of episodic memory impairment, disorientation, and agitation. Case 3 presented with Morvan's fibrillary chorea. Peripheral nerve hyperexcitability is the chief manifestation of the Morvan syndrome or cramp-fascilulation syndrome. The Morvan syndrome is characterized by neuromyotonia with autonomic and central nervous syndrome (CNS) involvement. Both VGKC-Ab-associated limbic encephalitis and Morvan syndrome can be successfully treated. Therefore, when these diseases are suspected, it is important to measure the anti-VGKC-Ab level.
Keywords: Anti-NMDA receptor encephalitis, limbic encephalitis, Morvan′s fibrillary chorea, NMDAR encephalitis, rituximab, voltage-gated potassium channel antibodies
|How to cite this article:|
Singh G, Paul BS, Bansal RK, Paul G. Autoantibody-induced encephalitis. Int J Nutr Pharmacol Neurol Dis 2014;4, Suppl S1:44-50
|How to cite this URL:|
Singh G, Paul BS, Bansal RK, Paul G. Autoantibody-induced encephalitis. Int J Nutr Pharmacol Neurol Dis [serial online] 2014 [cited 2020 Jun 5];4, Suppl S1:44-50. Available from: http://www.ijnpnd.com/text.asp?2014/4/5/44/147466
| Introduction|| |
Autoimmune encephalitis is a group of disorders characterized by symptoms of limbic and extra-limbic dysfunction. This spectrum of neurological diseases is associated with antibodies against synaptic antigens and proteins localized on the neuronal cell surface. In the last decade there has been a significant development in the understanding and diagnosis of this rare central nervous system condition, and recently, auto-antibodies (auto Abs) targeting the extracellular domain of neuronal proteins have also been increasingly recognized. 
Various cell surface proteins against which the auto-Abs have been detected include the voltage gated potassium channel (VGKC) complex antigens – (leucine-rich glioma inactivated protein 1(LGI1), contactin-associated protein2 (CASPR2), and contactin 2), amino-3-hydrxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR), N-methyl-D-aspartate receptor (NMDAR), γ-aminobutyric acid-B (GABABR), and glutamic acid decarboxylase (GAD).  These antibodies are found in more than one disorder. These unusual disorders offer the opportunity of developing an insight into the autoimmune disorders.
In a recently published meta-analysis, the etiology of encephalitis could not be identified even after extensive investigations in more than 50% of the cases, across the 41 studies reviewed. This highlights the potential importance of an immune-mediated causation in encephalitis. With an annual incidence of encephalitis at 2-3/100,000 in northern Europe, about 40% of the cases are infectious, 40% are due to unknown causes, at least 20% are immune-mediated, with the largest groups being anti-NMDA-receptor encephalitis (4%), and VGKC-complex antibody positive encephalitis (3%).  However, in different reports from India the overall incidence of meningitis varies from 12.12 to 56%, while the incidence of autoimmune encephalitis has not been studied separately.  Autoimmune encephalitis affects patients of all ages, mainly children, although the association with tumors, benign or malignant, may not be apparent at the first investigation. The other hallmark feature is that the neurological symptoms may relapse or progress if the disorder is not recognized in time.
In recent times, autoimmune encephalitis has been characterized into two broad categories – those associated with antibodies to intracellular neuronal antigen and those associated with antibodies to cell membrane antigens of the hippocampus or cerebellum neurons. VGKC-Abs were first identified in the Morvan's syndrome, later in limbic encephalitis, and recently in patients with faciobrachial dystonic seizures (FBDS). ,, NMDA autoantibodies (auto-Abs) are likely to directly contribute to the pathology of a severe and reversible form of encephalitis that was first described in 2007.  Here, we describe three rare cases of different autoantibody-induced encephalitis. All three cases have different clinical presentations and the learning points associated with each case, along with their response to immunosuppressive therapy, are discussed.
| Case Reports|| |
A 15-year-old girl presented with a headache and low-grade fever of two-weeks' duration followed by strange abnormalities in behavior such as wandering, grasping, and changes in personality. Psychiatrist consultation was taken and she was prescribed antipsychotics with the diagnosis of depression. However, her symptoms persisted, and about a week later she developed an episode of loss of consciousness for which she was referred to a tertiary care center. On examination the patient was confused. Neurological examination did not reveal any motor or sensory deficit and there were no meningeal signs. On the next day, she developed orofacial dyskinesia as shown in [Figure 1]a-d. Routine hematological and biochemical tests were unrevealing and cerebrospinal fluid (CSF) examination and brain magnetic resonance imaging (MRI) were normal. She was managed as a case of drug-induced movement disorder. However, during her stay, there were marked fluctuations in blood pressure and sensorium, with an increase in the severity of oral movements. A detailed neuropsychological assessment revealed frontal lobe dysfunction. On account of the constellation of personality change, autonomic instability, and orofacial dyskinesia, with generalized seizures, a repeat CSF examination was done and sent for a panel of autoimmune antibodies. In view of the worsening neurological status, the patient was started on methylprednisolone, but there was neither improvement in the cognitive status, nor in the severity of the oral movements. On the twenty-fourth hospital day, NMDA antibodies were reported to be positive, hence, confirming the diagnosis of anti-NMDA receptor encephalitis. As there was no response to steroids, the patient was started on Rituximab. Oral dyskinesia decreased after the second dose and the patient was discharged after completing the fourth dose of Rituximab. There was also a marked improvement in her cognitive functions with no residual deficit [Figure 1]e.
|Figure 1: The figure shows abnormal oro-lingual movements occurring in a patient with NMDA encephalitis. (a-d) are sequential static video images taken every 0.5 seconds. The involuntary abnormal movements were grimacing, chewing, and repetitive jaw opening and closing. (e) shows complete resolution of the abnormal orofacial movements after treatment, with no psychiatric features on the three-month follow up|
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A 35-year-old female presented to the Emergency Department with complaints of episodes of lapses of consciousness with oral automatisms and dystonic posturing of the right hand, occurring several times in a day, following a febrile episode. On admission she had similar episodes suggestive of faciobrachial dystonic seizures (FBDS). Her general physical examination was normal, but detailed neuropsychological testing revealed a global deterioration and impairment of verbal and visual memory with normal motor examination and localizing pathology to the temporal lobe. Routine hematological and biochemical investigations were normal. In spite of being on three antiepileptic drugs the frequency of episodes increased. In view of multiple uncontrolled seizures following a febrile episode with semiology, suggesting FBDS, and abnormal neuropsychological assessment, a differential diagnosis of autoimmune encephalitis was considered. Details of the CSF, electroencephalography (EEG), and MRI [Figure 2] findings are given in [Table 1]. As the patient did not respond to antiepileptics and acyclovir therapy, she was also worked up for other systemic disorders like thyroid disease, malignancy, and autoantibody-induced encephalitis. Results of all investigations were negative including tumor markers except for the VGKC antibodies in the CSF, confirming the diagnosis of limbic encephalitis. She was treated with a pulse of methylprednisolone (1 g) for five days followed by oral steroids. Marked improvement was noted in the seizure frequency within the first week of starting the treatment. Gradually, her memory function also improved and she was completely asymptomatic on follow up at three months. The corticosteroid had been gradually tapered.
|Figure 2: Fluid-attenuated inversion recovery MRI of Case 2 shows hyperintense signals in the medial temporal lobe. Brain MRIs were obtained on the third day after admission|
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A 68-year-old male presented with a burning sensation in his feet and hands for six to eight months. Apart from positive sensory symptoms he also noticed a spontaneous twitching and rippling movement over his calf and forearm muscles on both sides. There was a history of insomnia, visual hallucinations, and he had two short episodes of confusional behavior lasting for a few minutes. On examination higher mental functions and cranial nerves were normal. Motor system examination, on inspection, revealed diffuse fasciculation's over the bilateral upper and lower limb muscles with normal muscle strength and sensory examination [Figure 3]. An electrophysiological examination revealed neuromyotonia (spontaneous rippling of the muscles). The patient was worked up for a paraneoplastic autoantibody disorder. Although the tumor maker and contrast-enhanced computed tomography (CECT) of the chest and abdomen were negative, the serum was positive for VGKC antibodies. In view of the signs and symptoms of involvement of the peripheral and central nervous system, with associated autonomic disturbances, the diagnosis of Morvan's fibrillary chorea was considered, although before admission, he had received multiple forms of treatment with no relief. The patient was started on intravenous immunoglobulin (IVIG), after which he experienced reduction in his sensory symptoms and fasciculations. Following IVIG, immunosuppression was continued with oral steroids, although the fasciculations and cramps persisted.
|Figure 3: (a) Continous muscle activity noticed in the deltoid muscle in Case 3. (b-e) The panel demonstrates the electromyography records performed on day 2. It revealed triplets, multiplets, and continous neuromyotonic discharges of frequency 150 - 200 Hz, with abrupt onset in the proximal and distal muscles of the upper and lower limbs, without evidence of denervation|
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| Discussion|| |
The purpose of this case series is to highlight the importance of having a low threshold for diagnosing primary autoimmune disorders, including autoimmune encephalitis. The identification of specific autoantibodies was the initial step, which revealed the pathogenesis of this new category of neurological disorders, and recently, there has been lot of development and understanding in the immune modulating treatment of this spectrum of CNS diseases that are probably autoantibody mediated.
Our first case highlights an important feature that in spite of normal MR imaging, there are specific symptoms and signs that can lead to the suspicion of NMDA encephalitis in young females. Literature suggests that in most of these patients the clinical course progresses through characteristic phases of a prodromal viral-like illness followed by psychobehavioral symptoms. In this stage, emotional disturbances, cognitive decline, and prominent schizophrenia-like symptoms develop. It has been postulated that N-Methyl-D-aspartate receptor (NMDAR) antagonists have been attributed to the functional blocking of NMDAR in presynaptic-γ-aminobutyric acid (GABAergic)-mediated interneurons of the thalamus and frontal cortex, causing a decrease in the release of GABA. This results in glutamate and dopamine dysregulation, which may be responsible for the neuropsychiatric symptoms.  Our patient went through these stages for over two weeks. The next phase is characterized by the akinetic state to severe mutism, which is reported in 82% of the patients.  Our patient also had marked fluctuations in her sensorium. This phase is followed by hyperkinetic activity including orolingual dyskinesia and athetoid dystonic posturing due to subsequent involvement of the basal ganglia.
Definitive diagnosis was by the detection of anti-NMDA Abs in the blood or CSF, as was confirmed in Case 1. There was evidence that this autoimmune encephalitis was associated with ovarian teratoma in young females (95%), although in this case CECT abdomen and chest were normal.  The trigger for the production of antibodies in the absence of a tumor could be a prodromal viral illness that had been reported in almost 86 - 100% of the cases in previous reports.  The other highlighting feature of the case was an excellent response to Rituximab, a monoclonal anti-CD 20 antibody, which caused a decrease in B cells, prevented their maturation into plasma cells, and also depleted memory B cells. , As the symptoms in the above reported case were refractory to steroids, Rituximab was started. The poor response to steroid could be due to the delay in the initiation of treatment, as diagnosis was established later, during her hospital stay. The dyskinesia and neuropsychiatric features showed a dramatic response to Rituximab, with complete recovery over seven weeks. About 75% of the cases showed complete recovery with treatment; however, few may have had a prolonged course, and mortality of about 7% was also reported with this encephalitis. ,
The second case teaches us that in a clinical situation of specific seizure semiology, with rapid progression to intractability, the differential of autoimmune encephalitis, especially limbic encephalitis must be considered. Till recent years limbic encephalitis was regarded as a paraneoplastic manifestation of underlying malignancy, with poor prognosis, but with the identification of voltage-gated potassium channel (VGKC) autoantibodies, a new insight has opened in the pathogenesis of limbic encephalitis.  Voltage-gated potassium channel antibodies (VGKC-Ab) cause hyperexcitability of the peripheral and central nervous system. It has been identified that the antibodies themselves are not directed against the VGK channel, but target various components of the channel complexes present in mammalian brain extracts. The main VGKC-complex proteins that have been identified so far are LGI1  and CASPR2.  The detection of anti-VGKC is almost confirmatory for the diagnosis. The most common manifestation is acute or subacute onset of cognitive and behavioral changes, presenting as inattention, confusion, and short-term memory disturbances. The other hallmark feature is the presence of FBDS.  Our patient had a subacute onset of cognitive impairment and refractory seizures. The diagnosis of anti-VGKC encephalitis could easily be overlooked in patients presenting with the above-mentioned symptoms and it could be treated as herpes simplex encephalitis. The clue to the diagnosis was the identification of persistent hyponatremia, with no apparent cause identified. It was hypothesised that hyponatremia could be secondary to inappropriate anti-diuretic hormone release. FBDS seizures and MR showed a hyperintense signal involving the bilateral medial temporal lobes that also helped to clinch the diagnosis.
Definitive diagnosis can be confirmed by the detection of autoantibodies to the VGKCs in the CSF or serum.  Immunosuppressive therapy with either high-dose intravenous methylprednisolone, intravenous immunoglobulin or plasmapheresis, alone or in combination, are the treatment modalities that can prevent neurological damage and lead to clinical improvement.  The other learning point is that if these patients are diagnosed early and started on early immunosuppressive treatment, the response will be good with minimal neurological sequelae. This patient responded to high-dose intravenous steroids and resulted in complete clinical recovery.
The third case highlights that if signs and symptoms suggest involvement of both peripheral and central nervous systems in a patient in the older age group, paraneoplastic autoantibody disorder must be a differential diagnosis, otherwise it can be missed. The phenotypic presentation depends on the type of antibody detected to be positive. Hence, the spectrum of disorders varies. On one hand the presentation may be in the form of limbic encephalitis with predominant central nervous system involvement, while Morvan's syndrome presents with characteristic involvement of the peripheral nervous system.
Morvan first coined the term 'La choree fibrillaire' to describe patients with myokymia (visible spontaneous rippling and twitching of the muscles), dysautonomia, and CNS dysfunction in the form of encephalopathy.  The patient described above was suspected to be with Morvan's chorea, because of the characteristic clinical manifestations of peripheral nervous system in the form of neuromyotonia (repetitive motor unit potentials firing in rhythmic bursts), which were confirmed by electromyography (EMG) and central nervous system involvement in the form of encephalopathy, severe insomnia, and visual hallucinations. The accompanying feature was anorexia with significant weight loss of 8 kg over three months. As highlighted, it can be misdiagnosed as a psychiatric disorder till muscle involvement is recognized on clinical examination. VGKC Abs helps in definitive diagnosis and the antibody-mediated immune response to various target antigens explains the neurological components of the disease. Most common neoplastic disorders associated with Morvan's Chorea are thymoma and myasthenia.  Although the symptoms remit spontaneously, Morvan's fibrillary chorea is a potentially fatal disorder, which underscores the importance of early diagnosis and treatment as well as an aggressive search for the underlying neoplasm.
| C0 ONCLUSION|| |
This case series, first and foremost, have enforced the awareness of highly under-recognized syndromes that have an autoimmune basis. Each of these syndromes have autoantibodies with specific characteristic clinical presentation as well as neurological signs that help in reaching a diagnosis even before the antibody reports are available. However, the diagnosis is confirmed on the detection of specific antibodies directed against the central nervous system targets. Second, these disorders show a rapid and effective response to immunosuppressant therapy, hence, minimizing the chances of neurological sequelae. Thus, they must be considered in the differential of all patients presenting with features of encephalitis, with complex psychiatric symptoms, with uncontrolled seizures (complex) or movement disorders involving the face and upper limbs.
Lessons learnt from this clinical experience
• The study of encephalitis associated with antibodies to cell surface antigens provides a link between the immunological processes and neuronal events involved in memory, cognition, seizures, and neuronal degeneration
• They affect patients of all ages, including children
• The associated tumors may be benign or malignant; may not be apparent on the first investigation. Hence, a long-term follow up is required
• The associated neurological syndromes are more responsive to immunotherapy than the paraneoplastic syndromes related with antibodies to intracellular antigens
• The neurological symptoms may relapse or progress if the disorder is not recognized.
| Acknowledgment|| |
The authors are deeply grateful to Joseph Dalmau MD, Professor at the Division of Neuro-Oncology, Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA, for helping in the detection of antibodies.
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[Figure 1], [Figure 2], [Figure 3]