Autoimmune limbic encephalitis in 39 patients: immunophenotypes and outcomes. J Neurol Neurosurg Psychiatry. Dalmau J, Bataller L Clinical analysis of anti-Ma2-associated encephalitis. Dalmau J, Rosenfeld MR Paraneoplastic syndromes of the CNS.
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This article has been cited by other articles in PMC. Abstract Limbic encephalitis is a rare disorder affecting the medial temporal lobe of the brain, sometimes also involving hippocampus atrophy. It was initially considered to be only of paraneoplastic origin but now auto-immune non-paraneoplastic cases have also been reported.
Most common non paraneoplastic antibodies associated with limbic encephalitis are Voltage gated potassium channel antibodies, NMDA receptor antibodies and GAD receptor antibodies.
We present a case of limbic encephalitis which presented with sudden onset seizures which was preceded by confusion, disorientation and other psychiatric symptoms for a period of 5 weeks. No tumor was found on imaging and the classic paraneoplastic panel was negative. CSF and serum examination showed high titers GAD65 antibody guiding towards a diagnosis of non paraneoplastic limbic encephalitis.
Her symptoms and GAD 65 antibody titers showed significant improvement following immunomodulatory therapy. The case presented here is unique and scientifically relevant, as it intends to raise awareness of Auto-immune Limbic Encephalitis, a potentially reversible cause of a medical emergency.
Few of the challenges are related to the diagnosis of the underlying condition, others pertaining to restricted therapeutic options. Limbic encephalitis LE as a pathology poses both these challenges. Myriad of clinical presentation and lack of symptom specificity including seizure, memory problems, irritability, depression, confusion and dementia leads to a wide differential diagnosis [ 1 ].
Limbic encephalitis is a rare disorder affecting the medial temporal lobe of the brain, sometimes also involving hippocampus atrophy. It was first described by Breirly et al in s when they reported 3 cases of sub-acute encephalitis involving the limbic area [ 2 ]. Many neuronal antibodies have been associated with LE.
The former category is related to cancer paraneoplastic limbic encephalitis , showing limited response to immunomodulatory therapy whereas the latter category is less frequently associated with tumors and responds significantly better to immunomodulatory therapy.
It has also been recognized that some patients presenting with limbic encephalitis with negative antibody screen in serum and CSF show full recovery after treatment with steroids or immunomodulatory therapy indicating an autoimmune etiology [ 6 , 7 ]. We present a case of a patient with rapidly deteriorating cognitive function and recurrent seizures. She was diagnosed with autoimmune limbic encephalitis associated with GAD65 antibodies. Her symptoms showed dramatic improvement following immunomodulatory therapy.
Case Report A year-old right handed woman without any significant past medical history presented with episodes of sudden onset seizures, inability to recognize immediate family members and familiar places, apathy, bizarre behaviors, and brief episodes of disorientation for 5 weeks.
Cranial nerve, language, sensory, motor and cerebellar function test were within normal limits. MRI showed bilateral signal hyper intensity in temporal lobes.
Lumbar puncture was performed and CSF analysis showed no pleocystosis and CSF protein and glucose were within normal limit. Seizure episodes were documented on video-EEG monitoring. Psychiatry expert were also consulted which ruled out any psychiatric disorder for patient symptoms.
A diagnostic search for cancer including imaging and serological studies for various tumor markers was negative. Suspecting an autoimmune etiology immunomodulatory treatment with intravenous immunoglobulin and intravenous methyl-prednisone was initiated, which subsequently resulted in marked improvement in symptoms. Discussion Limbic encephalitic syndrome presents as a diagnostic challenge. Classic presentation includes the rapid development of irritability, short-term memory loss, depression, sleep disturbances, hallucinations and seizures.
Confusion, repetition of same questions over and over, staring episodes and involvement of temporal lobe is hallmark of LE patients.
Autobiographical memory is characteristically preserved in this disorder. LE usually has a sub-acute development, in days or weeks, presenting initially as short-term memory deficits, but this deficit is surprisingly overlooked in some patients [ 1 ]. Initial investigation in these patient commonly include CT of the brain with contrast, LP with cell count, protein, glucose and serum glucose , viral screen especially HSV, HHV-6 , acid-alcohol fast bacilli AAFB smear, bacterial and mycobacterium culture.
CSF and serum examination for anti-neuronal antibodies, paraneoplastic proteins and antibodies against neuronal cell membrane antigen is also essential. These abnormalities are often asymmetric, and sometimes seem to be unilateral [ 6 , 8 ].
Contrast enhancement is infrequent, but can occur with all clinical-immunologic variants of limbic encephalitis [ 9 ]. Sometimes clinically classic limbic encephalitis may also have a normal MRI, hence manifesting as a diagnostic challenge.
Electro-encephalography shows epileptiform activity in either one or both temporal lobes. It may also show focal or generalized slowing in the temporal areas [ 8 ]. There are two sets of diagnostic criteria utilized for diagnosis of paraneoplastic limbic encephalitis. First criterion was proposed by Gultekin et al in Table 1 , which was later revised by Graus et al in Table 2 [ 10 , 11 ]. Therefore 2 broad categories of autoimmune limbic encephalitis were formulated: 1 one associated with antibodies to intracellular neuronal antigens, which include all previously known paraneoplastic antigens, and 2 one associated with antibodies to cell membrane antigens, including the VGKc, NMDA receptor, GAD [ 12 ].
The above case describes a young lady with anti-GAD positive limbic encephalitis who responded well to immune-modulatory therapy and the GAD antibody level decreased after the therapy. Decrease of GAD antibody titers with therapy along with improvement of symptoms, points toward the possible causal relationship of GAD65 antibody with limbic dysfunction. These antibodies have been associated with some other neurological disorders as well such as stiff-person syndrome, cerebellar ataxia and palatal myclonus.
They are also seen in patients with anti GABA B receptor encephalitis which is frequently associated with Small cell lung cancer or neuroendocrine tumor of lung [ 14 ].
Exposure of these intracellular antigens during exocytosis could lead to formation of these pathologic antibodies [ 15 , 16 ]. A study conducted by Malter et al showed Anti GAD antibody positive limbic encephalitis cases presented at a younger age compared to VGKc antibody encephalitis.
These cases are more commonly found in females than males. Common initial presentation is seizure, which remains resistant to anticonvulsive therapy [ 18 ]. Other studies have shown patients with GAD antibody LE presenting initially with short term memory loss [ 19 ]. Corticosteroids, intravenous immunoglobulin and plasma exchange are most frequently used as therapeutic options. Other immune-suppressive agents like cyclophosphamide and rituximab can also be utilized as a therapeutic option [ 7 , 20 ].
But these patients have responded well to intravenous immunoglobulin and plasma exchange [ 13 , 21 ]. A study conducted by Saidha et al also shows promising results with decrease in seizure frequency and improvement in Behavior memory testing in these patients with use of mycophenolate mofetil [ 22 ].
Development of these therapeutic options highlights the need for early detection and aggressive management for patients with autoimmune limbic encephalitis.
If this disease process is considered early, diagnosed promptly and treated appropriately, it can be reversed and the patient restored to their premorbid state. Conclusion Limbic encephalitis, when initially discovered in s was believed to be exclusively of paraneoplastic origin, but there have been an increasing frequency of cases in adults and pediatric population without evidence of a tumor at presentation.
Anti-GAD receptor antibody-positive limbic encephalitis is an emerging diagnosis amongst the adult population. It is important that we consider autoimmune limbic encephalitis in our differential diagnosis in adults with encephalopathy, particularly if psychiatric symptoms are seen. Therapeutic responsiveness of this condition reiterates the importance of diagnosing a reversible neurologic pathology. With timely intervention, clinicians may be able to avoid permanent cognitive and behavioral damage.
Conflict of Interest All authors declare no conflict of interest. Source of Funding None. References 1. Tuzun E, Dalmau J. Limbic encephalitis and variants: classification, diagnosis and treatment. Subacute encephalitis of later adult life. Mainly affecting the limbic areas. Limbic encephalitis - a review. J Clin Neurosci. Ann Neurol. Serial MRI of limbic encephalitis. Autoimmune limbic encephalitis in 39 patients: immunophenotypes and outcomes. J Neurol Neurosurg Psychiatry.
Clinical, magnetic resonance imaging, and electroencephalographic findings in paraneoplastic limbic encephalitis. Mayo Clin Proc. Focal paraneoplastic limbic encephalitis presenting as orgasmic epilepsy. J Neurooncol. Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients. Graus F, Saiz A. Limbic encephalitis: a cause of temporal lobe epilepsy with onset in adult life. Epilepsy Behav. Non-paraneoplastic limbic encephalitis associated with anti-glutamic acid decarboxylase antibodies.
J Neuroimmunol. Antibodies to the GABA B receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol. EMBO J. Membrane anchoring of the autoantigen GAD65 to microvesicles in pancreatic beta-cells by palmitoylation in the NH2-terminal domain. J Cell Biol. Glutamic acid decarboxylase autoantibodies and neurological disorders. Neurol Sci. Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis.
Limbic encephalitis associated with anti-GAD antibody and common variable immune deficiency. Dev Med Child Neurol.
La proteína LGI1 es la responsable de la encefalitis límbica autoinmune
Abstract The neurologic presentation of limbic encephalitis is variable and when it occurs due to a rare cause the diagnosis may be problematic. We present a case of autoimmune limbic encephalitis due to glutamic acid decarboxylase antibody and consider the magnetic resonance imaging and antineural antibody screening aspects in the diagnosis of this entity. Keywords: epilepsy, neuroimmunology, neuroradiology, seizures Introduction Limbic encephalitis LE is characterized by acute or subacute development of seizure, short-term memory loss, irritability, hallucinations, and psychiatric symptoms with a pathogenesis related to inflammation of the medial temporal lobes. Magnetic resonance imaging MRI and electroencephalogram EEG are abnormal in the majority of patients, yet seizures are not an absolute requirement for LE.
O que é Encefalite Autoimune e como tratar